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Pflug C, Müller F, Koseki JC, Petersen C, Nienstedt JC, Tribius S. Objective dysphagia is very common after radiotherapy in oropharyngeal cancer patients. Oral Surg Oral Med Oral Pathol Oral Radiol 2025; 140:54-63. [PMID: 40169338 DOI: 10.1016/j.oooo.2025.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/30/2024] [Accepted: 02/08/2025] [Indexed: 04/03/2025]
Abstract
OBJECTIVE Dysphagia is one of the most serious adverse events in the treatment of head and neck cancer. This cross-sectional study aimed to assess pharyngeal residue, and penetration/aspiration in oropharyngeal cancer patients (OPC) after radiotherapy using flexible endoscopic evaluation of swallowing (FEES). METHODS A total of 35 OPC patients who had received radio-(chemo) therapy (R(C)T), including 8 patients with primary R(C)T), were included and examined by FEES to determine the swallowing status and were asked to indicate their swallowing ability on a visual scale to reflect the problem perceived by the patient. During FEES the patients were given three standardized bolus consistencies and four test pills. Penetration, aspiration, and residue were evaluated and classified. RESULT Relevant dysphagia was present in 23/35 (66%) patients. Almost half of all patients (15/35) showed aspiration (53% (8/15) silent). Residue occurred in 91% but without correlation to aspiration. A significant association between dysphagia and impaired pill swallowing was found (P = .003) occurring in 20 of 35 patients. Even in patients with small tumors and without prior surgery severe dysphagia was found. CONCLUSIONS Severe dysphagia is frequent after R(C)T affecting more than half of the patients with OPC. The frequent impaired pill swallowing ability should be considered Therefore, regular dysphagia diagnostics in the follow-up setting are advisable to initiate appropriate treatment and raise patients' quality of life, prevent aspiration pneumonia, and improve overall outcomes after tumor therapy.
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Affiliation(s)
- Christina Pflug
- Department of Voice, Speech and Hearing Disorders, Center for Clinical Neurosciences, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Frank Müller
- Department of Voice, Speech and Hearing Disorders, Center for Clinical Neurosciences, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jana-Christiane Koseki
- Department of Voice, Speech and Hearing Disorders, Center for Clinical Neurosciences, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cordula Petersen
- Department of Radiotherapy and Radiation Oncology, Center for Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julie Cläre Nienstedt
- Department of Voice, Speech and Hearing Disorders, Center for Clinical Neurosciences, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Silke Tribius
- Department of Radiation Oncology, Asklepios Hospital St. Georg, Hamburg, Germany; Hermann-Holthusen Institute for Radiation Oncology, Asklepios Hospital St. Georg, Hamburg, Germany
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2
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Li J, Zhou K, Zhan X, Lu H, Hao D, Song K, Wang S, Feng Y, Xu H, He Z, Yang X, Shang W, Wang L. Prognostic analysis of inconsistent combinations of HPV and p16 in a Chinese/Asian oropharyngeal squamous cell carcinoma population. Infect Agent Cancer 2025; 20:35. [PMID: 40490828 DOI: 10.1186/s13027-025-00657-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 04/15/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND The aim of this study was to investigate the effect of inconsistent expression of p16 and HPV on the prognosis of patients with Oropharyngeal squamous cell carcinoma (OPSCC) in Chinese/Asian populations. METHODS The study included 130 patients. Inclusion criteria were primary OPSCC. The primary outcome was the proportion of cohort patients showing different combinations of p16 and HPV outcomes, as well as overall survival (OS) and progression-free survival (PFS). Patients with relapsed or metastatic disease or palliative care were excluded from the survival analysis. A multivariate analysis model was used to calculate the adjusted hazard ratio for overall survival for different p16 and HPV tests, adjusted for pre-specified confounders. RESULTS Among the 130 patients, 25 (19.2%) demonstrated inconsistency between HPV and p16 expressions. The inconsistency in HPV/p16 status was significantly associated with patient age, smoking history, and alcohol consumption, leading to significant differences in tumor site, TNM staging, and differentiation, thereby influencing treatment decisions. There were significant differences in OS (P = 0.04) and PFS (P = 0.011) among the three groups, with the inconsistent group falling between the HPV+/p16 + group and the HPV-/p16- group but closer to the latter. Out of 54 p16-positive patients, only 33 (61.1%) were HPV-positive, indicating a lower predictive value of p16 for HPV positivity in OPSCC than observed in Western populations. Moreover, the study suggested a potential positive correlation between p16 expression intensity and improved patient prognosis. CONCLUSION In the China/Asia region, where HPV infection rates are relatively low, the predictive power of p16 for HPV-related OPSCC is low. We recommend additional HPV testing in patients with p16 + OPSCC to improve diagnostic accuracy, thereby enabling the selection of the best de-escalation treatment strategy, increasing treatment response rates, and ultimately improving the overall prognosis in these patients.
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Affiliation(s)
- Jieying Li
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Kai Zhou
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Xiaohong Zhan
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
- Department of Pathology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Haijun Lu
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
- Cancer Radiotherapy Center, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Dapeng Hao
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
- Department of Radiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Kai Song
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Shuangyi Wang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Yuanyong Feng
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Haoyue Xu
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Zongxuan He
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Xiaochen Yang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China
| | - Wei Shang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China.
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China.
| | - Lin Wang
- Department of Oral & Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong Province, 266000, China.
- School of Stomatology, Qingdao University, Qingdao, Shandong Province, 266000, China.
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3
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Zupancic M, Kostopoulou ON, Marklund L, Dalianis T. Therapeutic options for human papillomavirus-positive tonsil and base of tongue cancer. J Intern Med 2025; 297:608-629. [PMID: 40246777 PMCID: PMC12087873 DOI: 10.1111/joim.20088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
Abstract
The incidences of human papillomavirus-positive (HPV+) tonsillar and base tongue squamous cell carcinomas (TSCC and BOTSCC) have increased in recent decades. Notably, HPV+ TSCC and BOTSCC have a significantly better prognosis than their HPV-negative counterparts when treated with current surgical options, radiotherapy, or intensified chemoradiotherapy. However, a cure is not achieved in 20% of patients with HPV+ TSCC/BOTSCC. Meanwhile, cured patients often present with severe chronic side effects. This necessitates novel tailored alternatives, such as targeted therapy, immune checkpoint inhibitors (ICIs), and treatment de-escalation, together with better follow-up. Current precision medicine therefore focuses on detecting predictive and driver cancer genes to better stratify patient treatment, provide those with poor prognostic markers targeted therapy, and select those with favorable markers for de-escalated therapy. Moreover, detecting cell-free HPV DNA (cfHPV DNA) in plasma before and after treatment has been attempted to improve follow-up. In this context, this perspective discusses the significance of optimally defining HPV+ status, which requires HPV DNA and p16INKa overexpression, using prognostic markers, such as high CD8+ T-cell counts and HPV E2 mRNA expression, tumor size, and following cfHPV DNA for patient selection for specific therapies. Clinical trials with ICI with/without chemotherapy, targeted therapy with specific inhibitors-such as phosphoinositide 3-kinase and fibroblast growth factor receptor inhibitors-or immune therapy with various HPV-based vaccines for treating recurrences have yielded promising results.
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Affiliation(s)
- Mark Zupancic
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
- Medical Unit Head, Neck, Lung, and Skin Cancer, Theme CancerKarolinska University HospitalStockholmSweden
| | | | - Linda Marklund
- Medical Unit Head, Neck, Lung, and Skin Cancer, Theme CancerKarolinska University HospitalStockholmSweden
- Department of Surgical SciencesSection of Otolaryngology and Head and Neck SurgeryUppsala UniversityUppsalaSweden
- Division of Ear Nose and Throat DiseasesDepartment of Clinical Sciences Intervention and TechnologyKarolinska InstitutetStockholmSweden
| | - Tina Dalianis
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
- Medical Unit Head, Neck, Lung, and Skin Cancer, Theme CancerKarolinska University HospitalStockholmSweden
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Yarlagadda S, Rohe RM, McNeill V, Nemec JR, Tohtz CP, Fellows ZW, McAllister N, Rzepczynski AE, McConnell KA, Kalman NS. Tubarial gland sparing for oropharyngeal cancer: Feasibility with intensity modulated proton therapy & intensity modulated radiation therapy. Radiother Oncol 2025; 207:110882. [PMID: 40194703 DOI: 10.1016/j.radonc.2025.110882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/31/2025] [Accepted: 04/01/2025] [Indexed: 04/09/2025]
Abstract
The feasibility of sparing tubarial glands in oropharyngeal radiotherapy was assessed using IMPT and IMRT. Tubarial gland absolute mean dose differences of up to 18 Gy were observed between clinical and re-optimized plans without compromising target coverage. IMPT plans met tubarial gland mean dose constraints more often than IMRT plans.
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Affiliation(s)
- Sreenija Yarlagadda
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Robert M Rohe
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Valeriane McNeill
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Joanna R Nemec
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Chelsea P Tohtz
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Zachary W Fellows
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Nicole McAllister
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Amy E Rzepczynski
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
| | - Kristen A McConnell
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA; Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Noah S Kalman
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA; Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA.
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5
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Beddok A, Popovtzer A, Calugaru V, Fontaine M, Shih HA, Thariat J. Proton therapy for primary and recurrent HPV-related oropharyngeal cancer. Oral Oncol 2025; 165:107309. [PMID: 40315804 DOI: 10.1016/j.oraloncology.2025.107309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 02/28/2025] [Accepted: 04/13/2025] [Indexed: 05/04/2025]
Abstract
The incidence of Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has risen over the past two decades, now accounting for 44-75 % of cases in Europe and the USA. This review synthesized data from PubMed, additional academic sources, and ongoing studies to summarize the potential role of proton therapy (PT) role in treating HPV-related OPSCC. In vitro studies support PT radiosensitization of HPV-positive cells and clinical experiences report high locoregional control (LRC) rates of 88.6-97 % with significantly reduced side effects such as xerostomia by 12.5 % and brain necrosis by 2.3 %, compared to intensity-modulated radiation therapy (IMRT). A randomized trial (NCT01893307) has also recently provided level 1 evidence showing that PT is non-inferior to IMRT for tumor control while reducing treatment-related toxicities, such as feeding tube dependence (28 % vs. 42 %, p = 0.019) and facilitating better work resumption outcomes (71 % vs. 52 % at 2 years). Despite the success of radiation de-escalation achieving LRC up to 95 %, recent trials indicate potential survival risks when standard treatments are modified. Failure pattern analysis showed that up to 70 % of locoregional recurrences occurred in-field, highlighting the potential role of PT in achieving LRC while minimizing toxicity. PT could also play a role in the reirradiation of recurrent OPSCC, with reported 1-year LRC rates of 71.8-80.8 %, 2-year LRC rates of 72.8-80.3 %, 1-year overall survival (OS) rates of 65.2-81.3 %, 2-year OS rates of 32.7-69 %, and late grade ≥2 toxicities of 11.9-36.3 %. Methodologies improving reRT approaches include dose/volume histogram comparisons, which recommended PT when it resulted in lower predicted toxicities.
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Affiliation(s)
- Arnaud Beddok
- Department of Radiation Oncology, Institut Godinot, Reims, France; Université de Reims Champagne-Ardenne, CRESTIC, Reims, France; PET Research Center, Yale School of Medicine, New Haven, CT, USA.
| | - Aron Popovtzer
- Department of Radiation Oncology, Sharett Institute of Oncology, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Valentin Calugaru
- Department of Radiation Oncology, Proton Therapy Centre, Institut Curie, Orsay, France
| | - Marine Fontaine
- Department of Radiation Oncology, Institut Godinot, Reims, France
| | - Helen A Shih
- Department of Radiation Oncology, Massachusetts General Hospital/Mass General Brigham, Proton Therapy Centre, Harvard Medical School, Boston, USA
| | - Juliette Thariat
- Centre François Baclesse, Department of Radiation Oncology, Caen, Unicaen, France; ARCHADE (Advanced Resource Center for Hadrontherapy in Europe), Caen, France; Laboratoire de physique corpusculaire IN2P3/ENSICAEN, UMR6534, Unicaen, France
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6
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Choulli M, Morey F, Tous S, Brenes J, Wang X, Quirós B, González-Tampán AR, Pavón MA, Gomà M, Taberna M, Alemany ME, Oliva M, Mena M, Arribas L, Mesia R. Exploring the role of human papillomavirus (HPV) status in body composition and nutritional features in patients with oropharyngeal cancer. Clin Nutr ESPEN 2025; 67:417-426. [PMID: 40118181 DOI: 10.1016/j.clnesp.2025.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 02/28/2025] [Accepted: 03/07/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND AND AIMS Patients with oropharyngeal squamous cell carcinoma (OPSCC) are highly prone to malnutrition and sarcopenia due to the tumor's location and treatment-related toxicity. Human papillomavirus (HPV)-related and HPV-unrelated OPSCC represent two distinct biological entities. This study aimed to assess nutritional characteristics and body composition differences at diagnosis, as well as 3- and 6-months post- (chemo) radiation treatment, stratified by HPV status in OPSCC patients. METHODS Retrospective data analysis of a prospective cohort of OPSCC patients diagnosed and treated with curative intent from 2016 to 2022 at our center. Sociodemographic, clinical, and nutritional data were retrieved from medical records from diagnosis to 6 months post-treatment. Body composition parameters were assessed by analyzing the cross-sectional area of the third lumbar vertebra (L3) using available positron emission tomography (PET) and computed tomography (CT) scans at baseline, 3- and 6-months post-treatment. RESULTS Seventy patients were included, 33 (47.1 %) of whom had HPV-related OPSCC. HPV-related patients had higher body mass index (27.3 vs 21.9 kg/m2; p < 0.001) and better baseline nutritional status (p = 0.023), but no differences in skeletal muscle index (SMI, p = 0.103) compared to HPV-unrelated patients. At 3- and 6-months post-treatment the two groups showed similar SMI and total adipose tissue index loss (p > 0.05 for both). HPV status was not independently associated with body composition changes over time (p = 0.624). CONCLUSIONS Although HPV-related patients were better nourished than HPV-unrelated patients at diagnosis, by the end of treatment, both groups exhibited similar nutritional deterioration.
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Affiliation(s)
- M Choulli
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; University of Barcelona, Campus Diagonal, Av. de Joan XXIII, 27-31, 08028, Barcelona, Spain; Clinical Nutrition Unit, Catalan Institute of Oncology (ICO), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
| | - F Morey
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
| | - S Tous
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - J Brenes
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; University of Barcelona, Campus Diagonal, Av. de Joan XXIII, 27-31, 08028, Barcelona, Spain; Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
| | - X Wang
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; University of Barcelona, Campus Diagonal, Av. de Joan XXIII, 27-31, 08028, Barcelona, Spain
| | - B Quirós
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - A R González-Tampán
- Clinical Nutrition Unit, Catalan Institute of Oncology (ICO), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
| | - M A Pavón
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; Infections and Cancer Laboratory (INCALAB), Catalan Institute of Oncology (ICO), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
| | - M Gomà
- Pathology Department, Bellvitge University Hospital, Carrer de la Feixa Llarga, s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
| | - M Taberna
- Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
| | - M E Alemany
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - M Oliva
- Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain
| | - M Mena
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain; Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - L Arribas
- Clinical Nutrition Unit, Catalan Institute of Oncology (ICO), Av. de la Granvia de l'Hospitalet, 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
| | - R Mesia
- Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona, B-ARGO group, IGTP, Carretera de Can Ruti, 21A, 08916, Badalona, Spain
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Fontana G, Pepa M, Camarda AM, Strikchani M, Meregaglia M, Vai A, Mirandola A, Vischioni B, Pella A, Baroni G, Jereczek-Fossa BA, Scorsetti M, Cianchetti M, D'Angelo E, Bonomo P, Krengli M, Orlandi E. Envisioning an Italian Head and Neck Proton Therapy Model-Based Selection: Challenge and Opportunity. Int J Part Ther 2025; 16:100745. [PMID: 40230401 PMCID: PMC11995119 DOI: 10.1016/j.ijpt.2025.100745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 03/13/2025] [Accepted: 03/17/2025] [Indexed: 04/16/2025] Open
Affiliation(s)
- Giulia Fontana
- Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
| | - Matteo Pepa
- Bioengineering Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
| | - Anna Maria Camarda
- Radiation Oncology Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
| | - Mimoza Strikchani
- Administrative Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
| | - Michela Meregaglia
- Center for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Milan, Italy
| | - Alessandro Vai
- Medical Physics Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
| | - Alfredo Mirandola
- Medical Physics Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
| | - Barbara Vischioni
- Radiation Oncology Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
| | - Andrea Pella
- Bioengineering Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
| | - Guido Baroni
- Bioengineering Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
- Department of Electronics, Information and Bioengineering, Politecnico di Milano (POLIMI), Milan, Italy
| | - Barbara Alicja Jereczek-Fossa
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Department of Radiation Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Marta Scorsetti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Department of Radiotherapy and Radiosurgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Marco Cianchetti
- Proton Therapy Unit, Azienda Provinciale per i Servizi Sanitari, Trento, Italy
| | - Elisa D'Angelo
- Radiation Oncology Department, Bellaria Hospital, AUSL of Bologna, Bologna, Italy
| | - Pierluigi Bonomo
- Department of Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy
| | - Marco Krengli
- Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padova, Padova, Italy
- Radiotherapy Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Ester Orlandi
- Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy
- Radiation Oncology Unit, Clinical Department, CNAO National Center for Oncological Hadrontherapy, Pavia, Italy
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8
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Citro S, Ghiani L, Doni M, Miccolo C, Tagliabue M, Ansarin M, Chiocca S. HPV-mediated PARP1 regulation and drug sensitization in head and neck cancer. Oral Oncol 2025; 165:107307. [PMID: 40306238 DOI: 10.1016/j.oraloncology.2025.107307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 02/27/2025] [Accepted: 04/13/2025] [Indexed: 05/02/2025]
Abstract
INTRODUCTION Human Papillomavirus (HPV)-positive Head and Neck (HNC) cancer responds better to radiotherapy and platinum-based chemotherapy than HPV-negative HNC, likely due to impaired DNA damage repair. Inhibiting PARP1 enhances the effects of radiation and chemotherapy in tumours with defective DNA repair, such as HPV-positive cancers. In this study we investigated the role of HPV in the upregulation of PARP1, determining HNC cell sensitivity to both olaparib and cisplatin. MATERIALS AND METHODS PARP1 expression was assessed in HPV-positive and HPV-negative HNC using TCGA data, HNC cell lines and frozen tumour tissue samples from HNC patients. HPV16 expression was modulated by E6/E7 transduction in Human Primary keratinocytes (HK). Sensitivity to the PARP inhibitor olaparib and cisplatin, alone and in combination, was assessed in HNC cell lines. RESULTS HPV-positive tumours and cell lines showed upregulated PARP1 expression and activity, mediated by HPV16 oncoproteins. HPV-positive cell lines were more sensitive to olaparib or cisplatin treatment than HPV-negative ones. Combining cisplatin with olaparib synergistically inhibited cell viability in all HNC cell lines tested, regardless of HPV status. CONCLUSION Our study demonstrates that PARP1 is upregulated in HPV-positive HN tumours and cell lines, compared to HPV-negative. Despite the higher sensitivity of HPV-positive HNC cell lines to olaparib and cisplatin compared to HPV-negative cells, the combination of cisplatin with olaparib synergistically inhibits cell viability across all HNC cell lines tested, regardless of HPV status. This combination may allow for reduced drug concentrations, potentially decreasing side effects and enhancing therapeutic efficacy in HN tumours.
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Affiliation(s)
- Simona Citro
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy.
| | - Lavinia Ghiani
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy
| | - Mirko Doni
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy
| | - Claudia Miccolo
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy
| | - Marta Tagliabue
- Division of Otolaryngology Head & Neck Surgery, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Mohssen Ansarin
- Division of Otolaryngology Head & Neck Surgery, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
| | - Susanna Chiocca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy.
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9
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Costantino A, Haughey BH, Alamoudi U, Magnuson JS. Prognostic significance of distant metastasis site at diagnosis in HPV-related oropharyngeal cancer. Oral Oncol 2025; 165:107361. [PMID: 40345020 DOI: 10.1016/j.oraloncology.2025.107361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 05/03/2025] [Accepted: 05/05/2025] [Indexed: 05/11/2025]
Abstract
INTRODUCTION This study aimed to determine whether different distant metastasis (DM) sites at the time of diagnosis exhibit distinct survival outcomes human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and to assess whether intensifying treatment with local surgery or radiotherapy (RT) offers particular advantages for specific subcategories of patients. METHODS A retrospective cohort study included patients with invasive OPSCC with single-site DM at diagnosis between 2010 and 2020 from the US National Cancer Database (NCDB). Hazard ratios (HR) for overall survival were estimated with the corresponding 95% confidence interval (95% CI). RESULTS A total of 780 patients were included. Patients with distant lymph node demonstrated better survival compared to lung (adjusted HR: 1.45; 95 % CI: 1.10 - 1.93; p = 0.009), liver (adjusted HR: 1.97; 95 % CI: 1.35 - 2.88; p < 0.001), and bone (adjusted HR: 1.90; 95 % CI: 1.39 - 2.59; p < 0.001) metastases. Locoregional RT showed survival benefit compared to no treatment (adjusted HR: 0.71; 95 % CI: 0.57 - 0.88; p = 0.002), particularly for patients with distant lymph node (adjusted HR: 0.64; 95 % CI: 0.41 - 1.00; p = 0.05) and lung (adjusted HR: 0.72; 95 % CI: 0.51 - 1.00; p = 0.05) metastases. CONCLUSIONS Patients diagnosed with isolated distant lymph node metastases in HPV-positive OPSCC demonstrate a more favorable prognosis compared to those with metastases at other sites. Our results suggest that RT may confer a survival advantage for patients with distant lymph node and lung metastases, potentially enhancing their long-term outcomes.
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Affiliation(s)
- Andrea Costantino
- Department of Otolaryngology - Head and Neck Surgery, AdventHealth Orlando, 410 Celebration Place, Celebration, FL 34747, United States
| | - Bruce H Haughey
- Department of Otolaryngology - Head and Neck Surgery, AdventHealth Orlando, 410 Celebration Place, Celebration, FL 34747, United States; Department of Otolaryngology - Head and Neck Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, United States; Department of Surgery, University of Auckland School of Medicine and Allied Health Sciences, Auckland, New Zealand.
| | - Uthman Alamoudi
- Department of Otolaryngology - Head and Neck Surgery, AdventHealth Orlando, 410 Celebration Place, Celebration, FL 34747, United States.
| | - J Scott Magnuson
- Department of Otolaryngology - Head and Neck Surgery, AdventHealth Orlando, 410 Celebration Place, Celebration, FL 34747, United States.
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10
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Lewis JS, Beadle B, Bishop JA, Chernock RD, Colasacco C, Kalicanin T, Krane JF, Lacchetti C, Moncur JT, Rocco JW, Schwartz MR, Seethala RR, Faquin WC. Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline Update. Arch Pathol Lab Med 2025; 149:e115-e150. [PMID: 40126379 DOI: 10.5858/arpa.2024-0388-cp] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 03/25/2025]
Abstract
CONTEXT.— In 2018, an evidence-based guideline was published by the College of American Pathologists to develop recommendations for the testing, application, interpretation, and reporting of high-risk human papillomavirus and surrogate marker tests in head and neck carcinomas. Substantial new evidence has prompted a review, including data on human papillomavirus (HPV) in nonoropharyngeal anatomic sites, HPV global rates, p16 immunohistochemistry, and HPV testing performance in cytology specimens, and performance of p16 immunohistochemistry as a surrogate marker. OBJECTIVE.— To assess research published since the release of the original 2018 guideline and to update evidence-based recommendations for HPV testing in head and neck carcinomas. DESIGN.— The College of American Pathologists convened a panel of experts to update the guideline following the standards established by the National Academy of Medicine for developing trustworthy clinical practice guidelines. The expert panel defined the key questions and performed a systematic review of the literature. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, recommendations were updated on the basis of available evidence, certainty of that evidence, and key judgments. RESULTS.— Seven strong recommendations, 4 conditional recommendations, and 5 good practice statements are offered in the guideline update. CONCLUSIONS.— The updated guideline statements provide direction on the nature of HPV testing in various head and neck specimens (including key updates based on new research on sinonasal squamous cell carcinoma) and expanded guidance on specific scenarios and practice settings. The goal is to improve and standardize, where possible, HPV testing across diverse pathology practice settings and different countries.
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Affiliation(s)
- James S Lewis
- From Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona (Lewis)
- the Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee (Lewis)
| | - Beth Beadle
- the Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (Beadle)
| | - Justin A Bishop
- the Department of Pathology, UT Southwestern Medical Center, Dallas, Texas (Bishop)
| | - Rebecca D Chernock
- the Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri (Chernock)
| | - Carol Colasacco
- Pathology and Laboratory Quality Center for Evidence-Based Guidelines, College of American Pathologists, Northfield, Illinois (Colasacco, Kalicanin)
| | - Tanja Kalicanin
- Pathology and Laboratory Quality Center for Evidence-Based Guidelines, College of American Pathologists, Northfield, Illinois (Colasacco, Kalicanin)
| | - Jeffrey F Krane
- Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California (Krane)
| | - Christina Lacchetti
- Policy and Advocacy, American Society of Clinical Oncology, Alexandria, Virginia (Lacchetti)
| | - Joel T Moncur
- Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Moncur)
| | - James W Rocco
- the Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus (Rocco)
| | - Mary R Schwartz
- the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Schwartz)
| | - Raja R Seethala
- the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Seethala)
| | - William C Faquin
- the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston (Faquin)
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11
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Ma B, Guo J, Dijk LVV, Langendijk JA, Ooijen PMAV, Both S, Sijtsema NM. PET and CT based DenseNet outperforms advanced deep learning models for outcome prediction of oropharyngeal cancer. Radiother Oncol 2025; 207:110852. [PMID: 40118186 DOI: 10.1016/j.radonc.2025.110852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 03/14/2025] [Accepted: 03/16/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND In the HECKTOR 2022 challenge set [1], several state-of-the-art (SOTA, achieving best performance) deep learning models were introduced for predicting recurrence-free period (RFP) in head and neck cancer patients using PET and CT images. PURPOSE This study investigates whether a conventional DenseNet architecture, with optimized numbers of layers and image-fusion strategies, could achieve comparable performance as SOTA models. METHODS The HECKTOR 2022 dataset comprises 489 oropharyngeal cancer (OPC) patients from seven distinct centers. It was randomly divided into a training set (n = 369) and an independent test set (n = 120). Furthermore, an additional dataset of 400 OPC patients, who underwent chemo(radiotherapy) at our center, was employed for external testing. Each patients' data included pre-treatment CT- and PET-scans, manually generated GTV (Gross tumour volume) contours for primary tumors and lymph nodes, and RFP information. The present study compared the performance of DenseNet against three SOTA models developed on the HECKTOR 2022 dataset. RESULTS When inputting CT, PET and GTV using the early fusion (considering them as different channels of input) approach, DenseNet81 (with 81 layers) obtained an internal test C-index of 0.69, a performance metric comparable with SOTA models. Notably, the removal of GTV from the input data yielded the same internal test C-index of 0.69 while improving the external test C-index from 0.59 to 0.63. Furthermore, compared to PET-only models, when utilizing the late fusion (concatenation of extracted features) with CT and PET, DenseNet81 demonstrated superior C-index values of 0.68 and 0.66 in both internal and external test sets, while using early fusion was better in only the internal test set. CONCLUSIONS The basic DenseNet architecture with 81 layers demonstrated a predictive performance on par with SOTA models featuring more intricate architectures in the internal test set, and better performance in the external test. The late fusion of CT and PET imaging data yielded superior performance in the external test.
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Affiliation(s)
- Baoqiang Ma
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
| | - Jiapan Guo
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Machine Learning Lab, Data Science Center in Health (DASH), Groningen, Netherlands; Bernoulli Institute for Mathematics, Computer Science and Artificial Intelligence, University of Groningen, Groningen, Netherlands
| | - Lisanne V van Dijk
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Johannes A Langendijk
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Peter M A van Ooijen
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands; Machine Learning Lab, Data Science Center in Health (DASH), Groningen, Netherlands
| | - Stefan Both
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Nanna M Sijtsema
- Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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12
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Seenivasagam RK, Singh A, Gowda VN, Poonia DR, Majumdar KS, Abhinav T, Kaul P, Panuganti A, Kailey VS, Kumar R, Chowdhury N. Clinico-Pathological Significance of Tumor Infiltrating Immune Cells in Oral Squamous Cell Carcinoma-Hope or Hype? Head Neck 2025; 47:1706-1716. [PMID: 39865357 PMCID: PMC12068536 DOI: 10.1002/hed.28083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/29/2024] [Accepted: 01/12/2025] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND To correlate between immunohistochemical expression of tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and natural killer (NK) cells with the AJCC 8th edition TNM staging system and other disease-modifying clinico-pathological variables. METHODS The representative histology sections of tumor invasive margin (IM) and tumor core (TC) were selected according to the International Immuno-Oncology Biomarker Working Group and were subjected to immunohistochemistry with antibodies for TILs (CD3, CD8, FOXP3), NK Cells (CD57), TAMs (CD68, CD163) and pan-leukocyte marker (CD45). Histo-immuno-density-intensity (HIDI) scoring was calculated as a product of the proportion and intensity of staining. Ordinal-ordinal and continuous-ordinal variables were correlated using Kendall's tau-b (τb), and binary-ordinal variables were correlated using Rank-Biserial (rrb) statistics. RESULTS A total of 111 patients were included in the study. None of the clinical and pathological parameters showed a strong correlation with any of the immune infiltrates including TNM staging. CONCLUSION We hypothesize an independent activity of tumor immunology in the disease prognosis. TRIAL REGISTRATION CTRI/2020/07/026335.
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Affiliation(s)
- Rajkumar K. Seenivasagam
- Department of Surgical OncologyPSG Institute of Medical Sciences & ResearchCoimbatoreIndia
- Department of Surgical OncologyAll India Institute of Medical SciencesRishikeshIndia
| | - Ashok Singh
- Department of PathologyAll India Institute of Medical SciencesRishikeshIndia
| | - Vinay N. Gowda
- Department of PathologyAll India Institute of Medical SciencesRishikeshIndia
- Department of Pathology and Laboratory MedicineAll India Institute of Medical SciencesJodhpurIndia
| | - Dharma R. Poonia
- Department of Surgical OncologyAll India Institute of Medical SciencesRishikeshIndia
- Department of Surgical OncologyAll India Institute of Medical SciencesJodhpurIndia
| | - Kinjal S. Majumdar
- Department of Surgical OncologyAll India Institute of Medical SciencesRishikeshIndia
- Department of Head & Neck SurgeryKasturba Medical CollegeManipalIndia
- Manipal Academy of Higher EducationManipalIndia
- Department of Otolaryngology―Head & Neck SurgeryAll India Institute of Medical SciencesRishikeshIndia
| | - Thaduri Abhinav
- Department of Surgical OncologyAll India Institute of Medical SciencesRishikeshIndia
- Department of Otolaryngology―Head & Neck SurgeryAll India Institute of Medical SciencesRishikeshIndia
- Department of ENTPrathima Relief Institute of Medical SciencesWarangalIndia
| | - Pallvi Kaul
- Department of Surgical OncologyAll India Institute of Medical SciencesRishikeshIndia
- Department of Otolaryngology―Head & Neck SurgeryAll India Institute of Medical SciencesRishikeshIndia
- Department of Surgical OncologyShri Guru Ram rai Institute of Medical and Health SciencesDehradunIndia
| | - Achyuth Panuganti
- Department of Surgical OncologyAll India Institute of Medical SciencesRishikeshIndia
- Department of Otolaryngology―Head & Neck SurgeryAll India Institute of Medical SciencesRishikeshIndia
- Department of ENTMediciti Institute of Medical SciencesMedchalIndia
| | - Vikramjit S. Kailey
- Department of Otolaryngology―Head & Neck SurgeryAll India Institute of Medical SciencesRishikeshIndia
- Mohandai Oswal HospitalLudhianaIndia
| | - Rahul Kumar
- Department of Surgical OncologyAll India Institute of Medical SciencesRishikeshIndia
| | - Nilotpal Chowdhury
- Department of PathologyAll India Institute of Medical SciencesRishikeshIndia
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13
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Zhang J, Sun Y, Yao JQ, Liu DM. Comment on "Prognostic significance of diagnosis-to-surgery interval in oral cavity squamous cell carcinoma: A nationwide study". Oral Oncol 2025; 165:107352. [PMID: 40339434 DOI: 10.1016/j.oraloncology.2025.107352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2025] [Accepted: 05/04/2025] [Indexed: 05/10/2025]
Abstract
This commentary addresses methodological limitations in the recent study by Kang et al. [1] on the prognostic role of diagnosis-to-surgery interval (DSI) in oral cavity squamous cell carcinoma (OSCC). While the study highlights the clinical importance of timely surgery, key concerns include potential immortal time bias due to its retrospective design, oversimplified DSI categorization (14/28 days) ignoring non-linear survival trends, and unaddressed competing risks in disease-specific survival analysis. Additionally, critical variables such as molecular markers such as TP53 mutations) and missing data handling were not adequately discussed. To enhance validity, we recommend employing advanced statistical approaches such as Fine-Gray models for competing risks, cubic splines for DSI effects and integrating molecular profiling. Addressing these issues may improve prognostic accuracy and guide optimal surgical timing in OSCC management.
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Affiliation(s)
- Jian Zhang
- Yulin City First Hospital, Second Affiliated Hospital of Yanan University, China
| | - Ying Sun
- Yulin City First Hospital, Second Affiliated Hospital of Yanan University, China
| | - Jian-Qiang Yao
- Yulin City First Hospital, Second Affiliated Hospital of Yanan University, China
| | - Dong-Mei Liu
- Yulin City First Hospital, Second Affiliated Hospital of Yanan University, China.
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14
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Chen AM, Tjoa T, Armstrong WB. Circulating Tumor HPV-DNA in the Management of HPV-Positive Oropharyngeal Carcinoma: A Systematic Review. Head Neck 2025; 47:1674-1679. [PMID: 39846227 PMCID: PMC12068533 DOI: 10.1002/hed.28057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/10/2024] [Accepted: 12/22/2024] [Indexed: 01/24/2025] Open
Abstract
PURPOSE Blood-borne, cell-free DNA has been proposed as a means of individualizing the management of human papillomavirus (HPV)-positive oropharyngeal carcinoma. METHODS AND MATERIALS This study was designed based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement. A comprehensive literature search of peer-reviewed publications from January 2013 to January 2024 was undertaken to identify prospective studies pertaining to the use of circulating HPV-DNA for oropharyngeal carcinoma. RESULTS A total of 11 prospective studies were identified and differed in their clinical design, methods, and endpoints. Five included patients treated by chemoradiation; 3 by surgery; 2 by both; and 1 not specified. The timing and frequency of HPV-DNA draws was highly variable. The sample size ranged from 16 to 262 (mean, 99 patients). CONCLUSIONS While interest is growing with integrating circulating HPV-DNA into clinical practice, the supporting evidence is limited by the heterogeneity of the evidence.
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Affiliation(s)
- Allen M. Chen
- Department of Radiation OncologyUniversity of California, Irvine, Chao Family Comprehensive Cancer CenterOrangeCaliforniaUSA
| | - Tjoson Tjoa
- Department of OtolaryngologyUniversity of California, Irvine, Chao Family Comprehensive Cancer CenterOrangeCaliforniaUSA
| | - William B. Armstrong
- Department of OtolaryngologyUniversity of California, Irvine, Chao Family Comprehensive Cancer CenterOrangeCaliforniaUSA
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15
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Zandberg DP, Vujanovic L, Clump DA, Isett BP, Wang H, Sica G, Bao R, Li H, Ohr J, Skinner HD, Seethala RR, Chiosea SI, Ferris RL, Bauman JE. Randomized Phase II Study of Concurrent Versus Sequential Pembrolizumab in Combination With Chemoradiation in Locally Advanced Head and Neck Cancer. J Clin Oncol 2025:JCO2401580. [PMID: 40424564 DOI: 10.1200/jco-24-01580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 01/16/2025] [Accepted: 03/28/2025] [Indexed: 05/29/2025] Open
Abstract
PURPOSE The optimal timing of pembrolizumab with chemoradiation (CRT) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) is unknown. PATIENTS AND METHODS Our phase II trial randomly assigned patients 1:1 to concurrent pembrolizumab (200 mg once every 3 weeks × 8) starting 1 week before CRT (cisplatin 40 mg/m2 once weekly + radiation 70 Gy) versus sequential pembrolizumab starting 2 weeks after CRT. Human papillomavirus (HPV)+ (>10 pack-years or T4 or N3) and HPV(-) LA HNSCC were included, stratified by HPV and N stage. In our pick-the-winner design, if both arms met the trivariate primary end point (1-year locoregional failure <60%, progression-free survival [PFS] ≥60%, and dose limiting toxicity rate ≤20%), the arm with numerically superior 1-year PFS would be selected. Survival end points were compared by a univariate Cox model. Pretreatment and on-treatment tumor biopsies (week 2 of CRT) were evaluated by multispectral imaging and compared using two-sided paired t-tests. RESULTS Treated patients (41 concurrent and 39 sequential) were 71% oropharynx (53% HPV+), 92.5% stage IV (46% T4, 76% N2), similar by arm. Both arms met the trivariate primary end point, with superior 1-year PFS in the sequential arm (84% v 71%) and favorable 4-year outcomes: locoregional control (96% v 64%; hazard ratio [HR], 0.11 [95% CI, 0.01 to 0.89]; P = .012), PFS (69% v 49%; HR, 0.55 [95% CI, 0.25 to 1.22]; P = .132), and overall survival (83% v 71%; HR, 0.51 [95% CI, 0.19 to 1.37]; P = .17). There was a significant increase in macrophages, PD-L1+ macrophages, and PD-L1+ tumor cells with treatment in the concurrent but not the sequential arm. CONCLUSION CRT with sequential pembrolizumab met criteria for further study. Immunosuppressive changes in the TME differed between arms, reflecting the impact of one dose of pembrolizumab in the concurrent arm.
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Affiliation(s)
- Dan P Zandberg
- UPMC Hillman Cancer Center, Pittsburgh, PA
- Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA
| | - Lazar Vujanovic
- UPMC Hillman Cancer Center, Pittsburgh, PA
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA
| | - David A Clump
- Department of Radiation Oncology, West Virginia University, Morgantown, WV
| | - Brian P Isett
- UPMC Hillman Cancer Center, Pittsburgh, PA
- UPMC Hillman Cancer Center Bioinformatics Core, Pittsburgh, PA
| | - Hong Wang
- UPMC Hillman Cancer Center, Pittsburgh, PA
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA
| | - Gabriel Sica
- UPMC Hillman Cancer Center, Pittsburgh, PA
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| | - Riyue Bao
- UPMC Hillman Cancer Center, Pittsburgh, PA
- UPMC Hillman Cancer Center Bioinformatics Core, Pittsburgh, PA
| | - Housayin Li
- Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh, Pittsburgh, PA
| | - James Ohr
- UPMC Hillman Cancer Center, Pittsburgh, PA
| | - Heath D Skinner
- UPMC Hillman Cancer Center, Pittsburgh, PA
- Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA
| | - Raja R Seethala
- UPMC Hillman Cancer Center, Pittsburgh, PA
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| | - Simion I Chiosea
- UPMC Hillman Cancer Center, Pittsburgh, PA
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| | | | - Julie E Bauman
- GW Cancer Center, The George Washington University School of Medicine and Health Sciences, Washington, DC
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16
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Aliotta E, Jeong J, Paudyal R, Grkovski M, Diplas B, Han J, Hatzoglou V, Aristophanous M, Riaz N, Schöder H, Lee NY, Shukla-Dave A, Deasy JO. Predicting and monitoring response to head and neck cancer radiotherapy using multimodality imaging and radiobiological digital twin simulations. Phys Med Biol 2025; 70:115016. [PMID: 40378867 DOI: 10.1088/1361-6560/add9de] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 05/16/2025] [Indexed: 05/19/2025]
Abstract
Objective.To predict radiotherapy treatment response for head and neck cancer (HNC) using multimodality imaging and personalized radiobiological modeling.Approach.A mechanistic radiobiological model was combined with multi-modality imaging data from diffusion weighted-magnetic resonance imaging and positron emission tomography scans with [18F]Fluorodeoxyglucose (FDG) and [18F]Fluoromisonidazole (FMISO) tracers to develop personalized treatment response models for human papilloma virus associated HNC patients undergoing chemo-radiotherapy. Models were initialized to incorporate patient-specific imaging and updated to reflect longitudinal measurements of nodal gross tumor volume throughout treatment. Prediction accuracy was assessed based on mean absolute error (MAE) of weekly volume predictions and in predicting locoregional recurrence (LRR) following treatment.Main results.Personalized modeling based on pretreatment imaging significantly improved longitudinal volume prediction accuracy and correlation with measurement compared with a generic population model (MAE = 23.4 ± 10.0% vs 24.9 ± 9.0%,p= 0.002 on pairedt-test,R= 0.82 vs 0.72). Adding volume measurements from weeks 1 and 2 further improved prediction accuracy for subsequent weeks (MAE = 12.5 ± 8.1%, 10.7 ± 9.9%). When incorporating feedback with longitudinal measurements, penalizing large deviations from pretreatment model parameters using a variational regularization method was necessary to maintain model stability. Model-predicted volumes based on baseline + week-1 information significantly improved LRR prediction compared with week-1 volume data alone (area under the curve, AUC = 0.83 vs 0.77,p= 0.03) and was similar to prediction using week-3 volume data (AUC = 0.83 vs 0.85,p= non-significant).Significance.The proposed approach, which integrates clinical imaging and radiobiological principles, could be a basis to guide pretreatment prescription personalization as well as on-treatment adaptations.
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Affiliation(s)
- Eric Aliotta
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Jeho Jeong
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Ramesh Paudyal
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Milan Grkovski
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Bill Diplas
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - James Han
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Vaios Hatzoglou
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Michalis Aristophanous
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Nadeem Riaz
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Nancy Y Lee
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Amita Shukla-Dave
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Joseph O Deasy
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
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17
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Santos-Silva AR, Witjes MJH, Shaw RJ, Kanatas A, Vissink A, Treister NS. Iatrogenic Head and Neck Necrosis of Bone and Soft Tissue in Cancer Patients. Oral Dis 2025. [PMID: 40411292 DOI: 10.1111/odi.15378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 04/15/2025] [Accepted: 04/27/2025] [Indexed: 05/26/2025]
Abstract
BACKGROUND Cancer patients are at risk of developing a wide range of treatment-related toxicities that may affect the head and neck region. Iatrogenic necrosis of bone and soft tissue in this area represents a distinct clinical entity characterized by significant complexities and challenges, arising as a consequence of radiotherapy (osteoradionecrosis) or the administration of bone-modifying and/or antiangiogenic therapies (medication-related osteonecrosis of the jaw). OBJECTIVE This review provides a comprehensive understanding of this potentially highly impactful complication of cancer therapy and antiresorptive therapy by examining its pathophysiology, risk factors, clinical presentation, and management strategies. RESULTS Risk factors associated with these conditions include radiotherapy-related variables, medication-related factors, and local predisposing conditions. CONCLUSION This review highlights the importance of preventive strategies, including comprehensive dental evaluations and the development of personalized treatment plans before, during, and after cancer therapy, as well as when patients are undergoing or are expected to undergo treatment with bone-modifying medications. By addressing these critical aspects, clinicians can better manage and mitigate the impact of this challenging complication on the quality of life and morbidity outcomes.
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Affiliation(s)
- Alan Roger Santos-Silva
- Oral Diagnosis Department, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil
| | - Max J H Witjes
- Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Richard J Shaw
- Department of Molecular and Clinical Cancer Medicine, Liverpool Head & Neck Centre, William Henry Duncan Building, University of Liverpool, Liverpool, UK
- Honorary Consultant in Oral & Maxillofacial, Head & Neck Surgery, Liverpool University Hospitals NHS Foundation Trust, Aintree Hospital, Liverpool, UK
| | - Anastasios Kanatas
- St. James Institute of Oncology, Leeds Dental Institute and Leeds General Infirmary, University of Leeds, Leeds, UK
| | - Arjan Vissink
- Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Nathaniel S Treister
- Division of Oral Medicine and Dentistry, Brigham and Women's Hospital/Dana Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA
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18
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Cai X, Wang D, Feng H, Xu S, Li F, Zhou W, Qin G. Transoral endoscopy-assisted low-temperature plasma for the treatment of oropharyngeal malignant tumours: Preliminary Reports from a Single-Centre Retrospective Analysis. World J Surg Oncol 2025; 23:202. [PMID: 40410912 PMCID: PMC12100998 DOI: 10.1186/s12957-025-03854-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 05/16/2025] [Indexed: 05/25/2025] Open
Abstract
OBJECTIVES This study investigated the characteristics and clinical efficacy of transoral endoscopy-assisted low-temperature plasma surgery for the treatment of oropharyngeal malignant tumours. METHODS The clinical data of 14 patients who underwent transoral endoscopy-assisted low-temperature plasma resection of oropharyngeal malignant tumours in the Department of Otolaryngology-Head and Neck Surgery from January 2017 to October 2024 were retrospectively analysed. The general characteristics, clinical pathology results, surgical methods, operative time, volume of blood loss, length of hospitalization, and follow-up status of the patients were analysed. RESULTS The 14 patients included 13 males and 1 female, and the average age was 60 ± 9 years. Three patients received flaps for wound repair (1 forearm flap, 1 platysma myocutaneous flap, and 1 submental flap), 6 patients underwent unilateral neck lymph node dissection, 5 patients underwent bilateral neck lymph node dissection, and 1 patient underwent preventive tracheotomy. The average duration of the operations was 231 ± 114 min, and the average duration of tumour resection was 53 ± 15 min. The average volume of blood loss was 66 ± 55 ml, and the average duration of hospitalization was 10 ± 5 days. Postoperative pathology confirmed that 13 patients had squamous cell carcinoma, and 1 patient had mucoepidermoid carcinoma. The average duration of postoperative follow-up was 20 ± 14 months. One patient developed multisystem metastases, and one patient experienced tumour recurrence. all other patients survived well. CONCLUSIONS Transoral surgery has become more common as a minimally invasive approach for treating oropharyngeal tumours. Transoral endoscopy-assisted low-temperature plasma-assisted resection of oropharyngeal malignant tumours may be used as a surgical approach.
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Affiliation(s)
- Xintao Cai
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Jiangyang District, Taiping Street, Luzhou, 646000, China
| | - Dingting Wang
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Jiangyang District, Taiping Street, Luzhou, 646000, China
| | - Huajun Feng
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Jiangyang District, Taiping Street, Luzhou, 646000, China
| | - Shengen Xu
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Jiangyang District, Taiping Street, Luzhou, 646000, China
| | - Fei Li
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Jiangyang District, Taiping Street, Luzhou, 646000, China
| | - Weihua Zhou
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Jiangyang District, Taiping Street, Luzhou, 646000, China
| | - Gang Qin
- Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, No. 25 Jiangyang District, Taiping Street, Luzhou, 646000, China.
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19
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Liu L, Oh C, Lim MA, Zheng S, Piao Y, Ohm S, Shan Y, Piao S, Shen S, Kim YI, Won HR, Chang JW, Kim MG, Kim DH, Kim JW, Jung SN, Koo BS. Dual blockage of P-cadherin and c-Met synergistically inhibits the growth of head and neck cancer. Cell Oncol (Dordr) 2025:10.1007/s13402-025-01061-w. [PMID: 40392501 DOI: 10.1007/s13402-025-01061-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 03/26/2025] [Indexed: 05/22/2025] Open
Abstract
PURPOSE P-cadherin (CDH3) is a transmembrane protein that plays a crucial role in maintaining the structural integrity of epithelial tissue and homeostasis. Its role in carcinogenesis remains a subject of debate, as its behavior can vary depending on the molecular context and the specific tumor cell model under study. In this study, we explored the role of P-cadherin in head and neck squamous cell carcinoma (HNSCC) and the mechanisms underlying its function. METHODS We analyzed P-cadherin expression in HNSCC patients using The Cancer Genome Atlas (TCGA), The Chungnam National University Hospital (CNUH) cohort and Gene Expression Omnibus (GEO) database. For in vitro functional analysis, we conducted proliferation, migration, invasion, and western blot assays after either suppressing or overexpressing P-cadherin. For in vivo functional analysis, we utilized mouse xenograft models. RESULTS P-cadherin was significantly overexpressed in tumor samples compared to normal samples in the TCGA-HNSCC and CNUH-HNSCC cohorts. P-cadherin knockdown resulted in decreased proliferation, migration, and invasion compared to control cells, while P-cadherin overexpression increased cell proliferation and migration in HNSCC cells. We discovered that c-Met functions as an upstream regulator of P-cadherin. Surprisingly, we found that P-cadherin knockdown increased the phosphorylation of c-Met and STAT3. Combining P-cadherin siRNA with the c-Met inhibitor SU11274 or c-Met siRNA resulted in a more effective reduction in HNSCC cell growth, both in vitro and in vivo, compared to either treatment alone. CONCLUSION Our study uncovered a previously unknown aspect of P-cadherin-mediated c-Met regulation. The enhanced activation of c-Met/STAT3 following P-cadherin inhibition could be responsible for the survival of resistant tumor cells. Therefore, dual inhibition of P-cadherin and c-Met may be an effective approach for treating HNSCC.
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Affiliation(s)
- Lihua Liu
- Department of Nutrition, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Chan Oh
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Mi Ae Lim
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Sicong Zheng
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Yudan Piao
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Sun Ohm
- Department of Biology, Temple University, Philadelphia, PA, 19122, USA
| | - Yujuan Shan
- Department of Nutrition, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Shuyu Piao
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Shan Shen
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Young Il Kim
- Department of Radiation Oncology, Chungnam National University Sejong Hospital, Sejong, 30099, Republic of Korea
| | - Ho-Ryun Won
- Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University Sejong Hospital, Sejong, Republic of Korea
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Jae Won Chang
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Min-Gyu Kim
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Doh Hoon Kim
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Ji Won Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University Sejong Hospital, Sejong, Republic of Korea
| | - Seung-Nam Jung
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.
| | - Bon Seok Koo
- Department of Nutrition, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China.
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
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20
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Barcellos-Hoff MH, Yom SS. Revisiting the TGFβ paradox: insights from HPV-driven cancer and the DNA damage response. Nat Rev Cancer 2025:10.1038/s41568-025-00819-6. [PMID: 40389543 DOI: 10.1038/s41568-025-00819-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/01/2025] [Indexed: 05/21/2025]
Abstract
The transforming growth factor-β (TGFβ) paradox refers to the well-established role of TGFβ in suppressing cancer in healthy tissues yet promoting malignancy in established cancers. Although this positioned TGFβ inhibitors as a potential therapeutic strategy for malignancy, therapuetic blockade has failed in multiple clinical trials. The general lack of selection principles for defining which patients would most benefit from the addition of a TGFβ inhibitor has probably hindered its deployment. Here, we highlight the therapeutic potential in TGFβ regulation of DNA repair using human papillomavirus (HPV)-driven head and neck squamous cell carcinoma (HNSCC) as an illustrative example. HPV inhibits TGFβ signalling, which in turn reduces DNA damage repair, ultimately conferring sensitivity to cancer treatments and thus contributing to the favourable prognosis of HPV-positive HNSCC. Here, we review the DNA repair deficit caused by a loss of TGFβ signalling and how this could be targeted to induce synthetic lethality. Moreover, we explore its role in predicting response to immune checkpoint inhibitors and the potential of biomarkers to select which patients with cancer could ultimately benefit from TGFβ inhibition.
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Affiliation(s)
| | - Sue S Yom
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA
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21
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Mueller M, Visini M, Mueller SA, Stadler T, Rajan GP, Morand GB, Hool SL, Schanne DH, Balermpas P, Limacher A, Chan S, Trelle S, Elicin O, Giger R. DeintensiF: Standard versus individualized deintensified follow-up after curative treatment in head and neck cancer: protocol of a randomized pilot study. Pilot Feasibility Stud 2025; 11:69. [PMID: 40380278 DOI: 10.1186/s40814-025-01651-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 04/28/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Around 70% of head and neck cancer (HNC) cases are diagnosed in an advanced stage. Improvements in treatment have led to a cure rate of up to 80-90% for early-stage and 40-50% for advanced-stage disease. However, routine follow-up involves social and financial burdens, including frequent imaging associated with radiation exposure and costs. Currently, there is no consensus on the follow-up strategy after HNC treatment, and no conclusive evidence shows a survival advantage for routine follow-up over symptom-driven self-referrals. The DeintensiF study aims to provide robust evidence, comparing standard follow-up with a tailored deintensified approach. Additionally, it seeks to explore whether early detection of recurrence/second primary malignancy in asymptomatic patients impacts survival and quality of life. The pilot phase aims to assess feasibility of patients' recruitment and adherence to the assigned follow-up strategy and patient-reported outcomes (PROs) questionnaire in the first 2 years. METHODS This randomized-controlled, multicenter, open-label, pilot study has the goal to randomize a minimum of 16 patients across three Swiss sites into two arms within 1 year. The Experimental Arm A: scheduled clinical exams every 6 months and monthly PRO with evaluation and possibility to alert for open urgent appointments; and the Control Arm B: regular visits every 3 months for the first 2 years and less frequent thereafter plus multiple scheduled imaging appointments for head and neck magnet resonance imaging (MRI) and computed tomography (CT) with contrast and chest CT scans. Patients' motivation for participation or not will be explored by additional questionnaire before randomization. The primary objective during the pilot phase is to evaluate the feasibility of recruiting and randomizing patients with complete remission 6 months after treatment of head and neck squamous cell carcinoma to a deintensified and to a conventional follow-up. The secondary objective is to assess adherence to the two different follow-up strategies. DISCUSSION If feasible, the DeintensiF pilot study will expand from the recruited patients (detailed in the "Methods" section) to a larger cohort of advanced HNC cases in the main trial, integrating electronic PRO tailored follow-up care. This approach aims to reshape follow-up practices, enhancing patient-centered strategies and outcomes in head and neck oncology. TRIAL-REGISTRATION ClinicalTrials.gov (NCT05388136); Swiss National Clinical Trial Portal (SNCTP000005198).
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Affiliation(s)
- M Mueller
- Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
- Private University in the Principality of Liechtenstein (UFL), Triesen, Liechtenstein
| | - M Visini
- Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - S A Mueller
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - T Stadler
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - G P Rajan
- Department of Otorhinolaryngology, Head and Neck Surgery, Lucerne Cantonal Hospital, Lucerne, Switzerland
| | - G B Morand
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Department of Otorhinolaryngology, Head and Neck Surgery, Lucerne Cantonal Hospital, Lucerne, Switzerland
| | - S-L Hool
- Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - D H Schanne
- Department of Radiation-Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - P Balermpas
- Department of Radiation-Oncology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - A Limacher
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - S Chan
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - S Trelle
- Department of Clinical Research, University of Bern, Bern, Switzerland
| | - O Elicin
- Department of Radiation-Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - R Giger
- Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
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22
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Sun F, Colevas AD. Update: Immunotherapeutic Strategies in HPV-Associated Head and Neck Squamous Cell Carcinoma. Viruses 2025; 17:712. [PMID: 40431723 PMCID: PMC12115775 DOI: 10.3390/v17050712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2025] [Revised: 05/14/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has increased substantially over the past three decades, and since 2017, it has been recognized in the AJCC staging system as distinct from its HPV-negative counterpart. The underlying mechanisms of HPV-associated carcinogenesis, tumor microenvironment, and host immune response represent opportunities for therapeutic development. While anti-PD-1 immunotherapy is now part of standard treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in general, there are no established immunotherapeutic strategies specifically for HPV-related HNSCC. In this context, multiple emerging approaches are being actively studied-among these are therapeutic vaccines with or without anti-PD-(L)1 adjuvants, peptide-HLA-based immunotherapeutic platforms, and adoptive cell therapies including tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR) therapy, and chimeric antigen receptor (CAR) T-cell therapy. Beyond further maturation of these novel immunotherapeutic strategies, additional work is needed to delineate the optimal disease state of application (localized versus recurrent/metastatic), as well as in the development of small molecule inhibitors targeting HPV-specific mechanisms of viral oncogenesis.
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Affiliation(s)
| | - A. Dimitrios Colevas
- Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA;
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23
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Mohebbi E, Guthrie G, Patil S, Benjamin W, Tan M, Giurintano JP, Witek ME, Ahn PH, Taylor K, Wolf G, Fan R, Rozek LS. Postdiagnosis Smoking Cessation and Survival Outcomes of Head and Neck Cancer Patients. Head Neck 2025. [PMID: 40370118 DOI: 10.1002/hed.28182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/01/2025] [Accepted: 04/28/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Post-diagnosis smoking remains prevalent among head and neck squamous cell carcinoma (HNSCC) patients. Smoking cessation may improve patient outcomes. METHODS A prospective longitudinal cohort study (2008-2014) included 835 newly diagnosed HNSCC patients and followed up for 7 years. Participants were categorized by smoking behavior (never smokers, former smokers, quitters, continuing smokers, and intermittent smokers). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). RESULTS Smoking cessation after diagnosis was associated with significantly improved OS. Quitters had a 61% reduction in mortality risk compared to continuing smokers (HR: 0.39, 95% CI: 0.22, 0.69), with the greatest benefit in oral cavity cancer patients (HR: 0.28, 95% CI: 0.12, 0.65). Intermittent smokers also showed improved survival (HR: 0.50, 95% CI: 0.31, 0.79). RFS did not significantly differ based on smoking behavior. CONCLUSIONS Smoking cessation post-diagnosis improves OS, particularly in oral cavity cancer patients, highlighting the importance of targeted smoking cessation interventions in HNSCC care.
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Affiliation(s)
- Elham Mohebbi
- Department of Oncology, School of Medicine, Georgetown University, Washington, District of Columbia, USA
| | - Garret Guthrie
- Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Siddhi Patil
- Department of Oncology, School of Medicine, Georgetown University, Washington, District of Columbia, USA
| | - William Benjamin
- Department of Otolaryngology, Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
| | - Ming Tan
- Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Jonathan P Giurintano
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Matthew E Witek
- Department of Radiation Medicine, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Peter H Ahn
- Department of Radiation Medicine, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Kathryn Taylor
- Department of Oncology, School of Medicine, Georgetown University, Washington, District of Columbia, USA
| | - Gregory Wolf
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Ruzong Fan
- Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Laura S Rozek
- Department of Oncology, School of Medicine, Georgetown University, Washington, District of Columbia, USA
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24
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Bzhilyanskaya V, Tong JY, Ferris MJ, Molitoris JK, Hatten KM. Nutritional Outcomes in HPV-Associated Oropharyngeal Squamous Cell Carcinoma After Transoral Robotic Surgery. Laryngoscope 2025. [PMID: 40359314 DOI: 10.1002/lary.32264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/09/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025]
Abstract
OBJECTIVES Nutritional outcomes following transoral robotic surgery (TORS) for human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) are poorly understood. This study evaluates how TORS, with or without adjuvant treatment, impacts swallowing and weight loss. METHODS All patients treated with TORS for HPV-associated OPSCC from January 2016 to December 2023 were included. Weight loss, functional oral intake, feeding tube dependence, patient demographics, and treatment course were collected from patients' electronic medical records. RESULTS In total, 160 patients with HPV-associated OSPCC treated with TORS were included. 87.5% were male, with a median age of 60.0 years. Most patients were diagnosed with pT1 (53.8%) or pT2 (40.0%) and pN1 (78.1%) disease. 31.9% underwent TORS alone, while 42.5% received adjuvant radiation and 25.6% adjuvant chemoradiation. The median follow-up time was 2.27 (range 0.26-7.56) years. 87.4% of patients underwent nasogastric tube placement during TORS. Prolonged postoperative nasogastric tube dependence was significantly associated with increased rates of feeding tube replacement (p < 0.001; 95% CI, 1.051-1.181) later during treatment. Weight loss from three months to three years postoperatively was significantly greater in patients who received adjuvant radiation and chemoradiation (p < 0.001), despite no significant difference in swallowing outcomes. There was no significant difference in weight loss between adjuvant radiation and chemoradiation groups. CONCLUSIONS Adjuvant treatment following TORS is associated with significantly greater long-term weight loss but does not significantly alter swallowing outcomes. Longer duration of nasogastric tube dependence in the postoperative period is associated with higher rates of enteral feeding dependence later in treatment. LEVEL OF EVIDENCE: 3
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Affiliation(s)
- Vera Bzhilyanskaya
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, School of Medicine, Baltimore, Maryland, USA
| | - Jane Y Tong
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, School of Medicine, Baltimore, Maryland, USA
| | - Matthew J Ferris
- Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland, USA
| | - Jason K Molitoris
- Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland, USA
| | - Kyle M Hatten
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, School of Medicine, Baltimore, Maryland, USA
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25
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Singh AK, Ma SJ, Blakaj D, Zhu S, Almeida ND, Koempel A, Yuan G, Wang G, Wooten K, Gupta V, McSpadden R, Kuriakose MA, Markiewicz MR, Yao S, Hicks WL, Seshadri M, Repasky EA, Bouchard EG, Farrugia MK, Yu H. An integrated machine learning-based prognostic model in head and neck cancer using the systemic inflammatory response index and correlations with patient reported financial toxicity. RESEARCH SQUARE 2025:rs.3.rs-6529613. [PMID: 40386418 PMCID: PMC12083689 DOI: 10.21203/rs.3.rs-6529613/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/02/2025]
Abstract
Objective : To investigate the prognostic utility of systemic inflammatory response index (SIRI) as a biological readout of stress associated immune modulation in head and neck cancer patients who underwent radiation therapy. Methods : Random survival forest machine learning was used to model survival in 568 head and neck cancer patients. SIRI was calculated via pre-treatment bloodwork. Model validation was performed in an external cohort of 345 patients. Baseline financial toxicity (FT) and SIRI were studied in 638 patients. Results : Incorporation of SIRI (with performance status and smoking history) into a machine learning model identified three risk-groups that significantly stratified overall survival (p<0.0001,) and these findings were validated in the external validation cohort (p<0.001.) Increasing levels of FT were significantly associated with increasing SIRI levels. (p=0.001.) Conclusions and Relevance : An integrated machine learning model using clinical features was successfully developed and externally validated. SIRI was significantly associated with increasing FT. Our findings highlight the potential utility of SIRI as a biological marker of FT in head and neck cancer patients.
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Affiliation(s)
- Anurag K. Singh
- Department of Radiation Medicine Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Sung Jun Ma
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH, 43210, USA
| | - Dukagjin Blakaj
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH, 43210, USA
| | - Simeng Zhu
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH, 43210, USA
| | - Neil D. Almeida
- Department of Radiation Medicine Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Andrew Koempel
- Department of Radiation Oncology, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, 460 West 10th Avenue, Columbus, OH, 43210, USA
| | - Guangwei Yuan
- Department of Biostatistics and Bioinformatics Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Grace Wang
- Department of Biostatistics and Bioinformatics Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Kimberly Wooten
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Vishal Gupta
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Ryan McSpadden
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Moni A. Kuriakose
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Michael R. Markiewicz
- Department of Oral and Maxillofacial Surgery School of Dental Medicine University at Buffalo, The State University of New York 3435 Main Street Buffalo, NY 14214. USA
- Department of Neurosurgery Department of Surgery Jacobs School of Medicine and Biomedical Sciences University at Buffalo, The State University of New York 955 Main Street Buffalo, NY 14203. USA
| | - Song Yao
- Department of Cancer Prevention and Control Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Wesley L. Hicks
- Department of Head and Neck Surgery Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Mukund Seshadri
- Department of Oral Oncology Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Elizabeth A. Repasky
- Department of Immunology Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | | | - Mark K. Farrugia
- Department of Radiation Medicine Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
| | - Han Yu
- Department of Biostatistics and Bioinformatics Roswell Park Comprehensive Cancer Center Elm and Carlton Streets Buffalo, NY 14203. USA
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Bhethanabotla RM, Gulati A, Khalsa IK, Evans C, Perrin CE, Lappin JJ, Kidane J, Crosby TW, Chan JW, Yom SS, Young VN, Rosen CA, Schneider SL, Ha PK, Boscardin WJ, Laus J, Ryan WR, Ma Y. Swallowing Function Outcomes in Head and Neck Cancer Survivors Followed by a Long-Term Dysphagia Surveillance Protocol. Head Neck 2025. [PMID: 40325795 DOI: 10.1002/hed.28166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/25/2025] [Accepted: 04/03/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND This study aimed to evaluate swallow outcomes in head and neck cancer (HNC) survivors enrolled in a long-term dysphagia surveillance protocol following curative intent radiotherapy (RT). METHODS We conducted a retrospective review of videofluoroscopic swallow studies from 2015 to 2023 in HNC patients treated with RT. Swallow kinematics and function were assessed at baseline, 0-1, 1-2, 2-5, and 5+ years post-RT. Logistic regression models assessed kinematic deviations beyond 2SD from normative and dichotomized outcomes. RESULTS Among 638 patients with 1167 VFSS, 14.6% were 2 years post-RT, primarily oral cavity (29.6%) and oropharyngeal (46.7%) cancers treated with adjuvant (chemo) RT (53.3%). At 2 years, 51.3% exhibited abnormal hyolaryngeal movement, 27.5% had pharyngeal contraction abnormalities, and 9.0% had impaired pharyngoesophageal opening. Unsafe swallow was seen in 51.6% with moderate-to-profound dysphagia in 45%. CONCLUSION Dysphagia surveillance revealed significant swallowing impairments in HNC survivors, with unsafe swallowing prevalent in over half of cases 2 years post-RT.
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Affiliation(s)
- Rohith M Bhethanabotla
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA
| | - Arushi Gulati
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA
| | - Inderpreet K Khalsa
- University of California San Francisco School of Medicine, San Francisco, California, USA
| | - Cara Evans
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA
| | - Claire E Perrin
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA
| | - James J Lappin
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA
| | - Joseph Kidane
- Caruso Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles, California, USA
| | - Tyler W Crosby
- Voice and Swallowing Center, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Jason W Chan
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, California, USA
| | - Sue S Yom
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, California, USA
| | - VyVy N Young
- Voice and Swallowing Center, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Clark A Rosen
- Voice and Swallowing Center, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Sarah L Schneider
- Voice and Swallowing Center, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA
| | - Patrick K Ha
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA
| | - W John Boscardin
- Department of Medicine and Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, California, USA
| | - Joey Laus
- Department of Otolaryngology-Head and Neck Surgery, Emory University Hospital, Atlanta, Georgia, USA
| | - William R Ryan
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USA
| | - Yue Ma
- Voice and Swallowing Center, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California, USA
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27
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Prabhakar AT, Morgan IM. CK2 control of human papillomavirus life cycles. Biol Chem 2025:hsz-2024-0150. [PMID: 40311144 DOI: 10.1515/hsz-2024-0150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/20/2025] [Indexed: 05/03/2025]
Abstract
Human papillomaviruses are causative agents in around 5 % of all cancers, and in a number of other human diseases. While prophylactic vaccines will alleviate the HPV disease burden on future generations, there are currently no therapeutic anti-viral strategies for combating HPV infections or lesions. HPV induce the proliferation of infected epithelial cells and modulate the host differentiation response, and both of these controls are required for a successful viral life cycle. Enhanced understanding of viral-host interactions during the viral life cycle will identify potential novel anti-viral strategies for therapeutic development. This minireview will summarize the critical role of the host enzyme CK2 in regulating the function of the viral proteins E1, E2 and E7; such control makes CK2 a critical enzyme for regulating HPV life cycles. Therapeutic strategies blocking CK2 function to combat HPV infections and treat HPV diseases will be described.
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Affiliation(s)
- Apurva T Prabhakar
- 6889 Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry , Richmond, VA 23298, USA
| | - Iain M Morgan
- 6889 Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry , Richmond, VA 23298, USA
- 6889 Virginia Commonwealth University Massey Cancer Center , Richmond, VA 23298, USA
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28
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Palma DA, Prisman E, Berthelet E, Tran E, Hamilton S, Wu J, Eskander A, Higgins K, Karam I, Poon I, Husain Z, Enepekides D, Hier M, Richardson K, Mlynarek A, Johnson-Obaseki S, Gaudet M, Bayley A, Dowthwaite S, Jackson JE, Dzienis M, O'Neil J, Chandarana S, Banerjee R, Hart R, Chung J, Tenenholtz T, Le H, Yoo J, Mendez A, Winquist E, Kuruvilla S, Stewart P, Warner A, Mitchell S, Chen J, Parker C, Kwan K, Theurer J, Bahig H, Christopoulos A, Mendez LC, Sathya J, Hammond JA, Read N, Venkatesan V, Fung K, Nichols AC. Radiation vs. trans-oral surgery for treatment de-escalation in HPV-related oropharyngeal cancers: Primary analysis of the ORATOR2 randomized trial. Eur J Cancer 2025; 220:115343. [PMID: 40121836 DOI: 10.1016/j.ejca.2025.115343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/04/2025] [Accepted: 03/03/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND The optimal treatment de-escalation approach for HPV-related oropharyngeal squamous cell carcinomas (OPSCC) is unknown. The objective was to assess two de-escalation approaches: primary radiotherapy (RT) vs. transoral surgical (TOS). PATIENTS AND METHODS Patients with T1-T2 N0-2 HPV-related OPSCC were randomly assigned to primary RT (60 Gy with concurrent weekly cisplatin in node-positive) vs. TOS + neck dissection (ND) (and adjuvant reduced-dose RT depending on pathology). The primary endpoint was 2-year OS (hypothesized to be 94 % in each arm, compared to 84 %). Secondary endpoints included comparisons of survival and quality of life between arms. The trial was stopped early due to two treatment related deaths in the surgical arm. RESULTS Sixty-one patients were randomized (n = 30 in RT arm and n = 31 in TOS+ND arm), with a median age of 62 years (IQR: 57-68). The majority were male (n = 51) and never-smokers (n = 31). Median follow-up was 3.7 years (IQR: 3.1-4.5 years). In the RT arm, the primary endpoint for acceptability was met (p = 0.008), and two-year OS was 100 % (95 % confidence interval [CI]: 100-100 %). In the TOS+ND arm, the primary endpoint was not met (p = 0.296) and two-year OS was 90 % (95 % CI: 71-97 %), significantly worse than the RT arm (p = 0.041). Two-year progression-free survival (PFS) were 100 % (95 % CI: 100-100 %) vs. 86 % (95 % CI: 67-95 %) respectively (p = 0.012). Mean (± SD) 2-year MDADI total scores were 89 ± 13 vs. 83 ± 11, respectively (p = 0.11), and grade 2-5 toxicity rates were similar (n = 21 vs. n = 24 respectively, p = 0.51), with no additional grade 5 events. CONCLUSION For treatment de-escalation, a primary RT approach achieved excellent oncologic and functional outcomes and should be tested in phase III de-escalation trials. TRIAL REGISTRATION Clinicaltrials.gov NCT03210103.
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Affiliation(s)
- David A Palma
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada.
| | - Eitan Prisman
- Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Eric Berthelet
- Department of Radiation Oncology, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec, Canada
| | - Eric Tran
- Division of Radiation Oncology, Department of Oncology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Sarah Hamilton
- Division of Radiation Oncology, Department of Oncology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jonn Wu
- Division of Radiation Oncology, Department of Oncology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Antoine Eskander
- Department of Otolaryngology - Head and Neck Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Kevin Higgins
- Department of Otolaryngology - Head and Neck Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Irene Karam
- Department of Radiation Oncology, Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Ian Poon
- Department of Radiation Oncology, Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Zain Husain
- Department of Radiation Oncology, Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Danny Enepekides
- Department of Otolaryngology - Head and Neck Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Michael Hier
- Department of Otolaryngology - Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
| | - Keith Richardson
- Department of Otolaryngology - Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
| | - Alex Mlynarek
- Department of Otolaryngology - Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
| | | | - Marc Gaudet
- Division of Radiation Oncology, University of Ottawa, Ottawa, Ontario, Canada
| | - Andrew Bayley
- Department of Radiation Oncology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Samuel Dowthwaite
- Department of Otolaryngology - Head and Neck Surgery, Gold Coast University Hospital, Southport, Queensland, Australia
| | - James E Jackson
- Icon Cancer Centre, Gold Coast University Hospital, Southport, Queensland, Australia
| | - Marcin Dzienis
- Department of Medical Oncology, Gold Coast University Hospital, Southport, Queensland, Australia
| | - John O'Neil
- Department of Otolaryngology - Head and Neck Surgery, Gold Coast University Hospital, Southport, Queensland, Australia
| | - Shamir Chandarana
- Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of Calgary, Calgary, Alberta, Canada
| | - Robyn Banerjee
- Division of Radiation Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Robert Hart
- Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of Calgary, Calgary, Alberta, Canada
| | - Jeffson Chung
- Department of Otolaryngology - Head and Neck Surgery, West Virginia University, Morgantown, WV, United States
| | - Todd Tenenholtz
- Department of Radiation Oncology, West Virginia University, Morgantown, WV, United States
| | - Hien Le
- Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide, Australia
| | - John Yoo
- Department of Otolaryngology - Head and Neck Surgery, Western University, London, Ontario, Canada
| | - Adrian Mendez
- Department of Otolaryngology - Head and Neck Surgery, Western University, London, Ontario, Canada
| | - Eric Winquist
- Division of Medical Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Sara Kuruvilla
- Division of Medical Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Paul Stewart
- Division of Medical Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Andrew Warner
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Sylvia Mitchell
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Jeff Chen
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Christina Parker
- Department of Audiology, London Health Sciences Centre, London, Ontario, Canada
| | - Keith Kwan
- Department of Pathology, Western University, London, Ontario, Canada
| | - Julie Theurer
- School of Communication Sciences and Disorders, Western University, London, Ontario, Canada
| | - Houda Bahig
- Department of Radiology, Radio-Oncology and Nuclear Medicine, Division of Radio-Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal, Montréal, Quebec, Canada
| | - Apostolos Christopoulos
- Division of Otorhinolaryngology-Head and Neck Surgery, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal, Montréal, Quebec, Canada
| | - Lucas C Mendez
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Jinka Sathya
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - J Alex Hammond
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Nancy Read
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Varagur Venkatesan
- Division of Radiation Oncology, Department of Oncology, Western University, London, Ontario, Canada
| | - Kevin Fung
- Department of Otolaryngology - Head and Neck Surgery, Western University, London, Ontario, Canada
| | - Anthony C Nichols
- Department of Otolaryngology - Head and Neck Surgery, Western University, London, Ontario, Canada
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Kim HK, Lee YP, Kim H, Yang Y, Kwon J, Lee KH, Son SM, Han HS. Differential diagnosis of synchronous double primary squamous cell carcinomas of the esophagus and occult primary oropharynx through HPV testing: A case report. Medicine (Baltimore) 2025; 104:e42243. [PMID: 40324276 PMCID: PMC12055166 DOI: 10.1097/md.0000000000042243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 12/05/2024] [Accepted: 12/09/2024] [Indexed: 05/07/2025] Open
Abstract
RATIONALE Esophageal and head and neck cancers often coexist due to field cancerization, which causes multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract. However, guidelines for the differential diagnosis and optimal treatment of synchronous esophageal and head and neck SCC are lacking. This study highlights the diagnostic and therapeutic challenges of these coexisting malignancies. PATIENT CONCERNS A 52-year-old man presenting with dysphagia was diagnosed with esophageal SCC, and an incidental retropharyngeal tumorous lesion was found during staging. DIAGNOSES Biopsy revealed SCC in both lesions. To differentiate between metastatic disease and a second primary SCC, immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed. The retropharyngeal SCC showed strong p16 staining, indicating human papilloma virus (HPV)-related origin, while the esophageal SCC was p16-negative. NGS revealed distinct genetic profiles for each lesion, confirming synchronous double primary SCCs. INTERVENTIONS The patient underwent definitive concurrent chemoradiotherapy for both SCCs. OUTCOMES The patient achieved a complete response for both lesions and remains recurrence-free 1 year after treatment. LESSONS This case underscores the importance of HPV testing and/or NGS in patients with multiple SCCs in the upper aerodigestive tract to accurately differentiate primary cancers from metastases.
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Affiliation(s)
- Hee Kyung Kim
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Yong-Pyo Lee
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Hongsik Kim
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Yaewon Yang
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Jihyun Kwon
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Ki Hyeong Lee
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Seung-Myoung Son
- Department of Pathology, Chungbuk National University Hospital, Cheongju, Republic of Korea
- Department of Pathology, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
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30
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Lee DY, Pan A, Yaskolko M, Chiorazzi M, Bhatia A, Burtness B, Ishizuka JJ. Real world treatment patterns for recurrent and metastatic head and neck cancer in the post-KEYNOTE 048 era. Front Oncol 2025; 15:1577509. [PMID: 40416868 PMCID: PMC12099209 DOI: 10.3389/fonc.2025.1577509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Accepted: 03/31/2025] [Indexed: 05/27/2025] Open
Abstract
Background While KEYNOTE-048 established anti-PD1 with or without chemotherapy as first-line treatment for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) with combined positive score (CPS) ≥ 1, treatment choice remains ambiguous given additional toxicity of combination treatment. Methods Patients treated first-line with anti-PD1 monotherapy, anti-PD1+chemotherapy, or cetuximab+chemotherapy in the Flatiron Health database were included. Treatment group differences were assessed with chi-squared and t-tests, and selection factors were analyzed with logistic regressions. Survival was assessed with Kaplan-Meier curves, log-rank tests, and Cox regressions. Results Of 2577 patients included, Anti-PD1 monotherapy (n=1410) improved survival over cetuximab+chemotherapy (n=577, median survival 14.6 vs. 12.6 months, p=0.015), while anti-PD1+chemotherapy (n=590) showed a nonsignificant trend towards improvement (median survival 14.3 vs. 12.6 months, p=0.053). In HPV-associated disease, survival was equal between regimens. Addition of chemotherapy improved survival over anti-PD1 monotherapy in non-HPV associated tumors with CPS 1-9 (median survival 18.0 vs. 10.3 months, p=0.029) and in oral cavity primaries (median survival 10.3 vs. 7.6 months, p=0.003). Conclusions Subgroups of patients with recurrent or metastatic HNSCC, including non-HPV associated disease with CPS 1-9 and oral cavity primaries, may derive benefits from the addition of chemotherapy to anti-PD1 therapy.
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Affiliation(s)
- Daniel Y. Lee
- Department of Internal Medicine (Oncology), Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, United States
| | - Alexander Pan
- Department of Internal Medicine (Oncology), Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, United States
| | - Maxim Yaskolko
- Department of Internal Medicine (Oncology), Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, United States
| | - Michael Chiorazzi
- Department of Internal Medicine (Oncology), Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, United States
| | - Aarti Bhatia
- Department of Internal Medicine (Oncology), Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, United States
| | - Barbara Burtness
- Department of Internal Medicine (Oncology), Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, United States
| | - Jeffrey J. Ishizuka
- Department of Internal Medicine (Oncology), Smilow Cancer Center at Yale New Haven Hospital, New Haven, CT, United States
- Department of Pathology, Yale School of Medicine, New Haven, CT, United States
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, United States
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31
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Wang L, Ingle M, Oo L, Bains A, Lam F, James A, Podesta C, Virk J, Awad Z, Gujral D. Management of Head and Neck Squamous Cell Carcinoma With N3 Nodal Disease. Clin Oncol (R Coll Radiol) 2025; 41:103794. [PMID: 40086028 DOI: 10.1016/j.clon.2025.103794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/09/2025] [Accepted: 02/20/2025] [Indexed: 03/16/2025]
Abstract
AIMS Radical management of the N3 neck for head and neck squamous cell cancer (HNSCC) remains unclear. We aimed to investigate the use of primary surgery including neck dissection versus primary radiotherapy followed by imaging. MATERIALS AND METHODS We retrospectively reviewed consecutive patients with HNSCC and N3 nodal disease, excluding nasopharyngeal primaries. Patients had either surgical management of the primary and neck dissection followed by postoperative radiotherapy or primary radiotherapy followed by surveillance if complete response was found on post-treatment imaging. Patients were imaged at a mean of 16 weeks post radiotherapy. Patients identified with presence of resectable residual disease on imaging were treated with neck dissection. RESULTS Between July 2012 and February 2023, 53 patients with T0-4N3M0 HNSCC were treated radically. The median (range) follow-up was 25.5 (3-146) months, with an opportunity for follow-up of 64 (19-147) months. Twenty-two patients had primary surgical management and 31 had primary radiotherapy. Two-year overall survival was 64% in patients treated with primary surgery, 55% in patients treated with primary radiotherapy, 87% in patients with complete response after radiotherapy, and 92% in complete responders who were p16 positive. Response assessment was done with positron emission tomography-computed tomography (PET-CT) in 77% of patients and predicted subsequent disease-free survival better than computed tomography (CT). p16-positive patients were more likely to achieve complete response (63% vs 25%), but extracapsular spread was not predictive of response. CONCLUSION Surveillance for patients with complete response on postradiotherapy PET-CT is a reasonable approach, especially for p16-positive patients, sparing them the morbidity of neck dissection. Patients with p16-negative disease are less likely to achieve a complete response and may be better managed with primary neck dissection.
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Affiliation(s)
- L Wang
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK.
| | - M Ingle
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK
| | - L Oo
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK
| | - A Bains
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK; Department of Radiation Physics and Radiobiology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK
| | - F Lam
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK
| | - A James
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK
| | - C Podesta
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK
| | - J Virk
- Department of Otolaryngology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK
| | - Z Awad
- Department of Otolaryngology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK; Department of Surgery and Cancer, Imperial College, London, UK
| | - D Gujral
- Department of Clinical Oncology, Imperial College Healthcare NHS Trust, Fulham Palace Road, London, W6 8RF, UK; Department of Surgery and Cancer, Imperial College, London, UK
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32
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Rosenberg AJ, Juloori A, Jelinek MJ, Agrawal N, Cursio JF, Cipriani N, Lingen MW, Izumchenko E, Katipally R, Chin J, Ginat D, Pasternak-Wise O, Gooi Z, Blair E, Pearson AT, Haraf DJ, Vokes EE. Neoadjuvant Nivolumab Plus Chemotherapy Followed by Response-Stratified Chemoradiation Therapy in HPV-Negative Head and Neck Cancer: The DEPEND Phase 2 Nonrandomized Clinical Trial. JAMA Oncol 2025; 11:492-501. [PMID: 40048190 PMCID: PMC11886870 DOI: 10.1001/jamaoncol.2025.0081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/09/2025] [Indexed: 03/09/2025]
Abstract
Importance Neoadjuvant immunotherapy in human papillomavirus (HPV)-negative locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) appears promising, yet its role in nonsurgical treatment for head and neck cancer remains undefined. Neoadjuvant nivolumab plus chemotherapy followed by response-stratified de-escalated chemoradiation therapy (CRT) in HPV-negative LA stage IVa/b HNSCC may improve treatment efficacy while reducing treatment-related toxic effects. Objective To determine the deep response rate and tolerability of neoadjuvant nivolumab plus chemotherapy followed by response-stratified CRT in nonvirally mediated stage IVa/b HNSCC. Design, Setting, and Participants In this investigator-initiated phase 2 nonrandomized clinical trial conducted at a single academic center, patients with stage IVa/b (American Joint Committee on Cancer Tumor Classification, 8th edition) HPV-negative LA HNSCC were enrolled between 2019 and 2022. Data were analyzed from February 2023 to January 2024. Interventions The DEPEND trial evaluated neoadjuvant nivolumab plus carboplatin and paclitaxel, followed by response-stratified CRT. Patients with 50% or greater reduction per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 received de-escalated CRT to 66 Gy with elimination of elective nodal volumes; patients with less than 50% reduction received standard CRT to 70 to 75 Gy. Adjuvant nivolumab was administered for 9 cycles. Main Outcomes and Measures The primary end point was deep response rate (DRR; 50% or greater shrinkage per RECIST version 1.1) following neoadjuvant nivolumab plus chemotherapy. Secondary end points included progression-free survival (PFS), overall survival (OS), locoregional control, and distant control. Exploratory end points included acute toxic effects in patients who received response-adapted de-escalated CRT. Results Of 36 included patients, 28 (78%) were male, and the median (range) age was 58.9 (27-77) years. All patients started treatment and were available for analysis. The median (range) follow-up was 20 (13-40) months. The primary end point was met, with a DRR following neoadjuvant nivolumab/chemotherapy of 53% (95% CI, 35-70). The objective response rate was 86% (95% CI, 71-95). A total of 19 received de-escalated CRT and 16 received standard CRT. PFS and OS at 2 years were 66% (95% CI, 34-76) and 73% (95% CI, 52-86), respectively. The most common treatment-emergent adverse events for de-escalated and standard CRT were mucositis (14 of 19 [74%] and 15 of 16 [94%], respectively), radiation dermatitis (13 of 19 [68%] and 14 of 16 [88%], respectively), and dry mouth (7 of 19 [37%] and 10 of 16 [63%], respectively). Conclusions and Relevance In this phase 2 nonrandomized clinical trial, neoadjuvant nivolumab/chemotherapy led to deep responses in 53% of patients with HPV-negative LA stage IVa/b HNSCC, and response-adapted de-escalated CRT led to favorable survival with lower acute toxic effects among deep responders. Trial Registration ClinicalTrials.gov Identifier: NCT03944915.
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Affiliation(s)
- Ari J. Rosenberg
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
| | - Aditya Juloori
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois
| | | | - Nishant Agrawal
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Section of Otolaryngology-Head and Neck Surgery, University of Chicago, Chicago, Illinois
| | - John F. Cursio
- Department of Public Health Sciences, University of Chicago, Chicago, Illinois
| | - Nicole Cipriani
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Mark W. Lingen
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Evgeny Izumchenko
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
| | - Rohan Katipally
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois
| | - Jeffrey Chin
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois
| | - Daniel Ginat
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Department of Radiology, University of Chicago, Chicago, Illinois
| | - Olga Pasternak-Wise
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Department of Radiology, University of Chicago, Chicago, Illinois
| | - Zhen Gooi
- Section of Otolaryngology-Head and Neck Surgery, University of Chicago, Chicago, Illinois
| | - Elizabeth Blair
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Section of Otolaryngology-Head and Neck Surgery, University of Chicago, Chicago, Illinois
| | - Alexander T. Pearson
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
| | - Daniel J. Haraf
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois
| | - Everett E. Vokes
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois
- University of Chicago Comprehensive Cancer Center, Chicago, Illinois
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Chen AM. HPV-Mediated Radiosensitivity in Oropharyngeal Squamous Cell Carcinoma: Molecular Mechanisms and Cellular Pathways. Curr Oncol Rep 2025; 27:634-641. [PMID: 40214894 DOI: 10.1007/s11912-025-01666-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2025] [Indexed: 05/16/2025]
Abstract
PURPOSE OF REVIEW While the oncogenic potential of HPV has been well-established in other disease sites (e.g. cervix, vulva, anus), it is increasingly evident that a significant proportion of oropharyngeal cancer cases are related to the virus. Although considerable progress has been made in the understanding of this disease with respect to its underlying biology and clinical behavior, numerous questions persist. From a therapeutic standpoint, HPV-positive oropharyngeal cancer has been shown to be more radiosensitive than HPV-negative disease. However, how HPV mediates this radiosensitivity is relatively uncertain. RECENT FINDINGS Given that it has been firmly established that patients with HPV-positive oropharyngeal cancer have a significantly improved prognosis as a result of their exquisite response to radiation and can be treated with less-than-standard doses, logical questions pertain to how HPV confers this benefit to infected patients. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, multiple theories have been proposed. Indeed, it is likely that no single explanation exists for the increased radiosensitivity, and instead, HPV likely exerts its influence through a cascade of activated pathways at both the cellular level and tumor microenvironment. As will be discussed in this review, the proposed mechanisms for HPV-induced radiation response have generally centered on the disruption of such cellular pathways as DNA repair, cell cycle checkpoints, metabolic-induced stress, immunology, and cancer stem cells. Given that HPV-positive oropharyngeal cancer is increasingly recognized as a public health problem, the search to better understand its unique biological radiosensitivity has important societal and treatment-related implications.
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Affiliation(s)
- Allen M Chen
- Department of Radiation Oncology, Irvine, Chao Family Comprehensive Cancer Center, University of California, 101 The City Drive, Building 23, Orange, CA, 92868, USA.
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Lander DP, Vettikattu N, Sawaf T, Wang N, Patel MR, Kaka AS, Bur AM, Jackson RS. Submandibular Gland Flap Reconstruction for Oropharyngeal Defects After Transoral Robotic Surgery (TORS). Head Neck 2025; 47:1440-1446. [PMID: 39739241 DOI: 10.1002/hed.28051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/23/2024] [Accepted: 12/16/2024] [Indexed: 01/02/2025] Open
Abstract
BACKGROUND To describe utilization and outcomes of submandibular gland flap (SGF) reconstruction after transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC). METHODS A multi-institutional retrospective case series of patients who underwent TORS for OPSCC followed by SGF reconstruction with harvest via transcervical approach from 1/1/2016 to 4/1/2023. RESULTS In total, 14 patients underwent SGF reconstruction after TORS for OPSCC. All patients had HPV-positive disease, predominantly in early local (N = 10 with pT1/pT2 disease, 71%) and regional stages (N = 11 with pN0/pN1 disease, 79%). Most patients received adjuvant radiation treatment (N = 9, 64%). Median hospital LOS after surgery was 4 days (IQR 2 days) with median functional oral intake scale (FOIS) score of 5 (IQR 0.8) at 1-3 weeks after surgery. CONCLUSIONS SGF reconstruction is a useful technique for closure of appropriately selected TORS defects requiring reconstruction beyond healing by secondary intention and mobilization of adjacent tissue but not large enough to warrant free flap reconstruction.
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Affiliation(s)
- Daniel P Lander
- Department of Otolaryngology-Head & Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Nikhil Vettikattu
- Department of Otolaryngology-Head & Neck Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Tuleen Sawaf
- Department of Otolaryngology-Head & Neck Surgery, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Naomi Wang
- Department of Otolaryngology-Head & Neck Surgery, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Mihir R Patel
- Department of Otolaryngology-Head & Neck Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Azeem S Kaka
- Department of Otolaryngology-Head & Neck Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Andrés M Bur
- Department of Otolaryngology-Head & Neck Surgery, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Ryan S Jackson
- Department of Otolaryngology-Head & Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
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Swiecicki PL, Yilmaz E, Rosenberg AJ, Fujisawa T, Bruce JY, Meng C, Wozniak M, Zhao Y, Mihm M, Kaplan J, Gorla S, Geiger JL. Reply to: Enfortumab Vedotin: A Promising Therapy for Head and Neck Cancer With Potential Links to Human Papillomavirus. J Clin Oncol 2025; 43:1611-1612. [PMID: 39970368 DOI: 10.1200/jco-25-00028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 02/21/2025] Open
Affiliation(s)
- Paul L Swiecicki
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Emrullah Yilmaz
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Ari Joseph Rosenberg
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Takao Fujisawa
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Justine Yang Bruce
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Changting Meng
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Michele Wozniak
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Yongyun Zhao
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Michael Mihm
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Jason Kaplan
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Seema Gorla
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Jessica L Geiger
- Paul L. Swiecicki, MDDepartment of Internal Medicine, Division of Hematology/Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, Emrullah Yilmaz, MD, PhD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, Ari Joseph Rosenberg, MDDepartment of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, Takao Fujisawa, MD, Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan, Justine Bruce, Yang MD, University of Wisconsin Carbone Cancer Center, Madison, WI, Changting Meng, MD, Pfizer, Bothell, WA, Michele, Wozniak PhD, Yongyun Zhao, PhD, Michael Mihm, PhD, Jason Kaplan, MD, and Seema Gorla, MD Astellas Pharma, Inc, Northbrook, IL and Jessica L. Geiger MD, Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
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Cheng D, Rao Y, Qiu J, Song Y, Pang W, Qiu K, Dong Y, Liu Q, Zhao Y, Liu J, Xu W, Ren J. Survival Outcomes Related to Treatment Modalities in Patients With Oropharyngeal Squamous Cell Carcinoma. EAR, NOSE & THROAT JOURNAL 2025; 104:NP270-NP277. [PMID: 35839478 DOI: 10.1177/01455613221115608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BackgroundMore patients with oropharyngeal squamous cell carcinoma (OPSCC) in Eastern countries receive surgically inclusive treatment (SIT), while most patients in Western countries receive nonsurgical treatment (NST). The optimal treatment modality for OPSCC patients remains controversial.MethodsA total of 153 consecutive OPSCC cases diagnosed between 2009 and 2019 in West China Hospital (WCH) and 15,400 OPSCC cases from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2017) were obtained. Clinical characteristics, treatments, and survival outcomes were retrospectively collected. We constructed Kaplan-Meier curves and performed univariate (UVA) and multivariate (MVA) analyses to compare the prognosis of OPSCC patients among the WCH, SEER Asian, and SEER all ethnic populations by different treatment modality, human papilloma virus (HPV) infection status, age, and tumor stage.ResultsOverall, the proportions of patients with younger age, advanced tumors and HPV-negative status, and receiving SIT in WCH population were higher than those in the SEER all ethnic population, while the proportions in the SEER Asian population were between those of the other two populations. We observed consistent beneficial effects of SIT on the overall survival (OS) in OPSCC patients in all three populations (SEER Asian: MVA, hazard ratio (HR): 0.2, p < .001; SEER all ethnic: MVA, HR: 0.46, p < .001; WCH: UVA, HR: 0.62, p = .071), and HPV-negative Asian patients showed greater benefits from the SIT than HPV-positive Asian patients (HPV Negative: HR: 0.16, p = .005; HPV positive: HR = 0.28, p = .059). Male was a risk factor for reduced OS in OPSCC patients in the WCH population (HR: 3.17, p = .043), but was a protective factor in the SEER population (HR: 0.8, p = .002), which might be related to the differences of HPV infection status.ConclusionsEven though differences in patient characteristics existed between the Chinese, American, and Asian American populations, our ten-year real-world data and SEER data suggested that patients with OPSCC who received SIT had a better prognosis than those who received NST.
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Affiliation(s)
- Danni Cheng
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Yufang Rao
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Jianqing Qiu
- Department of Biostatistics, Princess Margaret Cancer Centre and Dalla Lana School of Public Health, Toronto, ON, Canada
| | - Yao Song
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Wendu Pang
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Ke Qiu
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Yijun Dong
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiurui Liu
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Zhao
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jun Liu
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Xu
- Department of Biostatistics, Princess Margaret Cancer Centre and Dalla Lana School of Public Health, Toronto, ON, Canada
| | - Jianjun Ren
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
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Jin Y, Jiang H, Sun Q, Li F, Wu X, Huang Z. A retrospective review of treatment approach and outcomes for locally advanced head and neck squamous cell cancer. J Cancer Res Ther 2025; 21:381-388. [PMID: 40317142 DOI: 10.4103/jcrt.jcrt_1332_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 02/28/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND We sought to provide clinicians with important insights into the best treatment plans for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) by examining the treatment trends and outcomes of the disease. METHODS Data pertaining to 158 patients with stage III to IVB LA-HNSCC who received treatment at our hospital from October 2019 to October 2021 were examined in this study. The clinical results of various treatment approaches were compared among the patients. RESULTS Of the 158 patients, 42 (26.6%) received definitive concurrent chemoradiotherapy (CCRT), 41 (36%) received induction chemotherapy (IC), and 95 (60.1%) underwent surgery. The 1-, 2-, and 3-year survival rates were 84.8%, 70.7%, and 59.3%, respectively, with a median follow-up of 36 months. No discernible difference in overall survival was observed between the CCRT and surgical groups (P = 0.397). CONCLUSIONS The decision regarding definitive CCRT, IC followed by definitive CCRT, surgery followed by adjuvant CCRT, or radiotherapy for patients with LA-HNSCC should be made in consultation with the multidisciplinary team. Furthermore, the decision should take into account the patient's overall health and the diagnosis, stage, developmental tendency, preferences, and prognosis of the disease. The most suitable overall treatment strategy for the patient must be formulated.
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Affiliation(s)
- Yidi Jin
- Department of Radiation Therapy, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China
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Sim ES, Nguyen HCB, Hanna GJ, Uppaluri R. Current Progress and Future Directions of Immunotherapy in Head and Neck Squamous Cell Carcinoma: A Narrative Review. JAMA Otolaryngol Head Neck Surg 2025; 151:521-528. [PMID: 40048196 DOI: 10.1001/jamaoto.2024.5254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
Importance For decades, the 3 therapeutic pillars for head and neck squamous cell carcinoma (HNSCC) have been radiation therapy, chemotherapy, and surgery. In recent years, a fourth pillar, immunotherapy, has shifted the existing paradigm of oncologic care by improving survival outcomes. This narrative review highlights key completed and ongoing clinical trials that have led to new therapeutic approaches and are aiming to further alter the current standard of care. Observations Immunotherapy in HNSCC first saw success in phase 3 clinical trials with immune checkpoint inhibitors (ICIs) for programmed cell death 1 protein in patients with recurrent or metastatic (R/M) disease. However, only approximately 15% to 20% of patients with R/M HNSCC achieve durable responses. Subsequent trials aimed to broaden ICIs to the definitive or curative setting, in combination with established chemoradiation modalities. These studies have yielded disappointing results, raising concerns that concurrent administration of ICI with chemoradiation- or radiation-induced attenuation of immune responses may contribute to lack of efficacy. Therefore, recent studies have attempted to introduce ICI sequentially, either prior to standard of care surgery in the neoadjuvant setting or following definitive treatment in the adjuvant or maintenance setting. These trials have demonstrated mixed results but with promising initial results from early phase neoadjuvant trials demonstrating early signals of response. Further trials are currently underway with various combinatorial approaches in the neoadjuvant and adjuvant settings to assess response rates and survival. Conclusions and Relevance The introduction of ICIs has brought a dramatic shift in the treatment landscape of HNSCC. Completed trials have provided new hope for patients, but failures in several settings suggest that further studies based on a biologic understanding of immune responses are required to expand immunotherapeutic approaches.
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Affiliation(s)
- Edward S Sim
- Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts
- Division of Otolaryngology-Head and Neck Surgery, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Head and Neck Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Hoang C B Nguyen
- Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts
- Division of Otolaryngology-Head and Neck Surgery, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Head and Neck Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Glenn J Hanna
- Center for Head and Neck Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ravindra Uppaluri
- Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts
- Division of Otolaryngology-Head and Neck Surgery, Brigham and Women's Hospital, Boston, Massachusetts
- Center for Head and Neck Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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Hausmann P, Zschaeck S, Furth C, Nikulin P, Cegla P, Roohani S, Lombardo E, Kazmierska J, Albert NL, Holzgreve A, Strouthos I, Belka C, Landry G, Cholewinski W, Kotzerke J, Baumann M, Krause M, Zips D, van den Hoff J, Hofheinz F. Tumor Asphericity in FDG PET Is an Independent Prognostic Parameter Improving Risk Stratification in Patients with Head and Neck Squamous Cell Carcinoma. J Nucl Med 2025; 66:686-691. [PMID: 40081960 PMCID: PMC12051765 DOI: 10.2967/jnumed.124.268972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 02/07/2025] [Indexed: 03/16/2025] Open
Abstract
Tumor asphericity in 18F-FDG PET is a prognostic marker that has been investigated in small pilot studies of patients with head and neck squamous cell carcinoma (HNSCC). Here, we investigated the prognostic role of asphericity in a large multicenter database of patients with HNSCC treated with primary radiotherapy or chemoradiation and assessed its independent prognostic value. Methods: In total, 1,104 patients were included in this analysis. All received pretreatment 18F-FDG PET scans. Clinical risk factors were evaluated, and quantitative PET parameters SUVmax, metabolic tumor volume (MTV), total lesion glycolysis, and asphericity were calculated. Primary study endpoints were overall survival (OS) and locoregional control (LRC). Uni- and multivariate Cox regression analyses were performed. Additionally, asphericity was combined with the best-established quantitative PET parameter of MTV, and the combinatory approach of using asphericity and MTV was compared with the use of only asphericity or MTV by bootstrap analyses. Results: Asphericity showed only a modest correlation with the established PET parameters of MTV, SUVmax, and total lesion glycolysis. On univariate testing asphericity was strongly associated with the outcome of patients (LRC and OS with P < 0.001). In multivariate testing of all imaging parameters that were not highly correlated, both MTV and asphericity showed a significant association with LRC (P < 0.001 for MTV and P = 0.021 for asphericity) and OS (P < 0.001 for MTV and asphericity). Asphericity and MTV were binarized and combined for risk stratification, and the prognostic value of the combination was compared with the prognostic value of individual parameters. Bootstrapping revealed significantly better performance by the combinatory approach when compared with MTV (P = 0.012 for LRC and P < 0.001 for OS) and asphericity with regard to OS (P < 0.001) but not for LRC (P = 0.53). Conclusion: We were able to show that asphericity bears independent prognostic value and significantly improves risk stratification when combined with MTV in a comprehensive retrospective cohort of HNSCC patients.
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Affiliation(s)
- Patrick Hausmann
- Department of Radiation Oncology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany;
| | - Sebastian Zschaeck
- Department of Radiation Oncology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- BIH Charité (Junior) Clinician Scientist Program, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, Berlin, Germany
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium, partner site Dresden, and German Cancer Research Center, Heidelberg, Germany
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Christian Furth
- Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Pavel Nikulin
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Paulina Cegla
- Department of Nuclear Medicine, Greater Poland Cancer Centre, Poznan, Poland
| | - Siyer Roohani
- Department of Radiation Oncology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- BIH Charité (Junior) Clinician Scientist Program, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, Berlin, Germany
- German Cancer Consortium, partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Elia Lombardo
- Department of Radiation Oncology, LMU University Hospital, LMU Munich, Munich, Germany
| | - Joanna Kazmierska
- Electroradiology Department, University of Medical Sciences, Poznan, Poland
- Radiotherapy Department II, Greater Poland Cancer Centre, Poznan, Poland
| | - Nathalie L Albert
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Adrien Holzgreve
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Iosif Strouthos
- Department of Radiation Oncology, German Oncology Center, European University Cyprus, Limassol, Cyprus
| | - Claus Belka
- Department of Radiation Oncology, LMU University Hospital, LMU Munich, Munich, Germany
- Bavarian Cancer Research Center, partner site Munich, Munich, Germany
- German Cancer Consortium, partner site Munich, Munich, Germany
| | - Guillaume Landry
- Department of Radiation Oncology, LMU University Hospital, LMU Munich, Munich, Germany
- Bavarian Cancer Research Center, partner site Munich, Munich, Germany
- German Cancer Consortium, partner site Munich, a partnership between DKFZ and LMU University Hospital Munich, Munich, Germany
| | - Witold Cholewinski
- Department of Nuclear Medicine, Greater Poland Cancer Centre, Poznan, Poland
- Electroradiology Department, University of Medical Sciences, Poznan, Poland
| | - Jorg Kotzerke
- Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Michael Baumann
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Division of Radiooncology/Radiobiology, German Cancer Research Center, Heidelberg, Germany
| | - Mechthild Krause
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium, partner site Dresden, and German Cancer Research Center, Heidelberg, Germany
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- National Center for Tumor Diseases, partner site Dresden, Dresden, Germany, German Cancer Research Center, Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and Helmholtz Association/Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology, Dresden, Germany; and
| | - Daniel Zips
- Department of Radiation Oncology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- German Cancer Consortium, partner site Dresden, and German Cancer Research Center, Heidelberg, Germany
- German Cancer Consortium, partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, Berlin, Germany
- National Tumor Center Berlin, partner site Berlin, Berlin, Germany, German Cancer Research Center, Heidelberg, Germany, Charité Comprehensive Cancer, Charité-Universitätsmedizin Berlin, Berlin, Germany, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany, and Max-Delbrück-Centrum für Molekulare Medizin, Helmholtz Association, Berlin, Germany
| | - Jörg van den Hoff
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Bavarian Cancer Research Center, partner site Munich, Munich, Germany
- German Cancer Consortium, partner site Munich, Munich, Germany
| | - Frank Hofheinz
- Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
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Donachie M, Horackiewicz J, Philp N, Slim MAM, Hurley R, Douglas C. Oropharyngeal Squamous Cell Carcinoma in the West of Scotland: A Retrospective Analysis of 1001 Patients From 2012 to 2020. Clin Otolaryngol 2025; 50:573-581. [PMID: 39853714 DOI: 10.1111/coa.14282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/27/2024] [Accepted: 01/05/2025] [Indexed: 01/26/2025]
Affiliation(s)
- Matthew Donachie
- Department of Otolaryngology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Jan Horackiewicz
- School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK
| | - Nichola Philp
- Department of Otolaryngology, Queen Elizabeth University Hospital, Glasgow, UK
| | | | - Rhona Hurley
- Department of Otolaryngology, Queen Elizabeth University Hospital, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Catriona Douglas
- Department of Otolaryngology, Queen Elizabeth University Hospital, Glasgow, UK
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Bartemes KR, Moore RM, Novotny BC, Pavelko KD, Sherman WA, Rivera M, Garcia JJ, Yin LX, Ma DJ, Moore EJ, Van Abel KM, Routman DM. Increased Interaction between B Cells and CD3+ T Cells in Nonprogressors with Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma. Clin Cancer Res 2025; 31:1719-1729. [PMID: 39964349 DOI: 10.1158/1078-0432.ccr-24-2425] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/08/2024] [Accepted: 02/14/2025] [Indexed: 05/02/2025]
Abstract
PURPOSE Tumor-infiltrating lymphocytes are associated with a decreased risk of recurrence in human papillomavirus-associated oropharyngeal squamous cell carcinoma. The composition and spatial distribution of tumor-infiltrating lymphocytes and tumor-infiltrating immune cells are not well characterized. EXPERIMENTAL DESIGN Formalin-fixed, paraffin-embedded primary and lymph node (LN) tumor tissues from 10 progressors (cases) and 10 matched nonprogressors (controls) were interrogated by imaging mass cytometry. Immune, stromal, and tumor cells were quantified from selected regions of interest using machine learning. Nearest neighbors, cell-cell interactions, and niche analyses were performed. RESULTS In primary regions of interest, immune cell, lymphocyte, T cell, CD8+ T cell, and innate cell prevalence was significantly greater in controls. High prevalence of immune cells, lymphocytes, innate cells, and CD4+ T cells in primary tissues was significantly associated with increased time to event (TTE). Although primary and LN prevalence of T cells, CD4+ T cells, CD8+ T cells, macrophages, and tumor cells were significantly correlated, differences in LNs were neither significant nor associated with TTE. Average distances between T cells and the nearest B cells and between lymphocytes and the nearest tumor cells were decreased in control primary tissues. Interactions between B and T cells were less organized in primary tissues from cases. A niche predominantly comprising lymphocytes was associated with longer TTE. CONCLUSIONS In human papillomavirus-associated oropharyngeal squamous cell carcinoma, immune cell subset prevalence in primary tumors differs with outcome and is associated with TTE. Interactions between B cells and both T-cell subsets are associated with longer TTE, underscoring the importance of active intratumoral immune responses in outcomes.
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Affiliation(s)
- Kathleen R Bartemes
- Department of Otolaryngology-Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
- Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Raymond M Moore
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Brenna C Novotny
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | | | - Will A Sherman
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Michael Rivera
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Joaquin J Garcia
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Linda X Yin
- Department of Otolaryngology-Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
| | - Daniel J Ma
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Eric J Moore
- Department of Otolaryngology-Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
| | - Kathryn M Van Abel
- Department of Otolaryngology-Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
| | - David M Routman
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
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Gayà J, Rubio D, Valero C, Vázquez-López C, Holgado A, Quer M, León X. Association of human papillomavirus (HPV) infection with the occurrence of second neoplasms and their prognostic impact in patients with oropharyngeal carcinoma. ACTA OTORRINOLARINGOLOGICA ESPANOLA 2025; 76:512237. [PMID: 40127862 DOI: 10.1016/j.otoeng.2025.512237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 02/04/2025] [Indexed: 03/26/2025]
Abstract
INTRODUCTION This study analyses the incidence of second neoplasms in patients with oropharyngeal carcinoma according to human papillomavirus (HPV) status and its impact on survival. MATERIAL AND METHODS A retrospective analysis of 583 patients with oropharyngeal cancer treated between 1991 and 2023 was performed. A total of 112 patients (19.2%) had HPV-positive tumours. RESULTS During the follow-up, 181 patients (31.0%) had a second neoplasm. The 5-year and 10-year second neoplasm-free survival for HPV-negative patients were 60.5% and 37.5%, significantly lower than in HPV-positive patients, which were 88.2% and 70.8%, respectively (p=.0001). The 84.4% of second and subsequent neoplasms in HPV-negative patients occurred in locations associated with tobacco and alcohol use, compared to 65.5% in HPV-positive patients (p=.001). In comparison to HPV-positive patients with no history of toxics consumption, HPV-positive patients with severe toxics consumption had a significantly higher risk of second neoplasms in locations associated with tobacco and alcohol use (p=.003). The competitive mortality associated with the appearance of second and subsequent neoplasms was significantly higher for patients with HPV-negative tumours (p=.0001). CONCLUSIONS Patients with HPV-positive oropharyngeal carcinomas have a lower risk of second neoplasms and lower competitive mortality associated with the appearance of second neoplasms compared with HPV-negative patients.
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Affiliation(s)
- Julia Gayà
- Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - David Rubio
- Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Cristina Valero
- Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Cristina Vázquez-López
- Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Anna Holgado
- Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Miquel Quer
- Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
| | - Xavier León
- Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain; UVIC. Universitat Central de Catalunya, Vic, Spain.
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Cooke PV, Chennareddy S, Kraft DO, Kappauf C, Lam AS, Chen S, Sindhu KK, Berger MH, Ferrandino RM, Kulkarni R, Tang M, Ghesani N, Misiukiewicz K, Bakst RL, Posner MR, Genden EM, Chai RL, Roof SA. Pretreatment Liquid Biopsy and Clinicopathologic Features in HPV-Associated Oropharyngeal Squamous Cell Carcinoma. JAMA Otolaryngol Head Neck Surg 2025; 151:433-440. [PMID: 40079946 PMCID: PMC11907365 DOI: 10.1001/jamaoto.2024.5549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 12/31/2024] [Indexed: 03/15/2025]
Abstract
Importance Despite the favorable prognosis for HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC), efforts to de-escalate treatment intensity, while maintaining low recurrence and mortality rates, have proven challenging. Identifying appropriate prognostic factors remains elusive; however, the association of pretreatment circulating tumor tissue viral-modified HPV (TTMV-HPV) DNA level with known characteristics of disease burden-clinical staging, characteristics of pretreatment imaging, and aggressive histopathologic features of surgical specimen-may offer insights that could shift treatment paradigms for HPV+ OPSCC. Objective To investigate the association of pretreatment TTMV-HPV DNA levels with clinical, radiologic, histopathologic, and outcome metrics in patients with HPV+ OPSCC. Design, Setting, and Participants This cohort study of patients with HPV+ OPSCC and positive test results for pretreatment TTMV-HPV DNA fragment levels used data from a single tertiary center from April 2020 to September 2023. TTMV-HPV DNA fragments levels were categorized into 3 cohorts: low (≤99 fragments/mL), moderate (100-999/mL), and high (≥1000/mL). Main Outcomes and Measures Association of clinical tumor (cT) and nodal (cN) staging with TTMV-HPV DNA fragment level. Secondary outcomes included the association between TTMV-HPV DNA fragment level and positive emission tomography-computed tomography (PET-CT) characteristics as well as histopathologic features of surgical specimen. The association of pretreatment fragment level with receiving adjuvant therapy for surgical patients was also analyzed. Recurrence-free survival and disease-specific survival were also assessed. Results The study population included 203 patients (mean [SD] age, 62 [10] years; 24 [12%] females and 179 males [88%]), 58 (29%) of whom were in the low, 73 (36%) in the moderate, and 72 (35%) in the high TTMV-HPV DNA fragment-level cohort. Compared to patients with cT0/1 stage, those with cT2 stage and cT3/4 stage had increased odds of higher TTMV-HPV DNA levels, with adjusted odds ratios (aORs) of 2.33 (95% CI, 1.24-4.46) and 2.51 (95% CI, 1.17-5.46), respectively. Compared to patients with cN0 stage, those with cN1 stage and cN2/3 stage also had increased odds of higher TTMV-HPV DNA levels, with aORs of 4.26 (95% CI, 1.82-10.34) and 3.64 (95% CI, 1.46-9.36), respectively. In adjusted analysis of pretreatment PET-CT characteristics, total primary tumor plus nodal volume was associated with higher TTMV-HPV DNA levels, with an aOR of 1.04 (95% CI, 1.02-1.07). Among 94 surgical patients, no significant association was found between pretreatment fragment level and lymphovascular invasion, perineural invasion, pathologic T stage, number of positive nodes, or extranodal extension on pathological analysis of surgical specimen. No significant differences in recurrence-free survival or disease-specific survival were found. Conclusion and Relevance This cohort study found that higher pretreatment TTMV-HPV DNA fragment levels were associated with more advanced clinical staging and higher aggregate primary and cervical nodal volume on PET-CT results. Future studies are needed to explore how pretreatment fragment level may influence treatment decisions.
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Affiliation(s)
- Peter V. Cooke
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Susmita Chennareddy
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Daniel O. Kraft
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Catharine Kappauf
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Austin S. Lam
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sida Chen
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kunal K. Sindhu
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Michael H. Berger
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Rocco M. Ferrandino
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Raksha Kulkarni
- Division of Nuclear Medicine, Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Megan Tang
- Division of Nuclear Medicine, Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nasrin Ghesani
- Division of Nuclear Medicine, Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Krzysztof Misiukiewicz
- Department of Hematology/Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Richard L. Bakst
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Marshall R. Posner
- Department of Hematology/Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Eric M. Genden
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Raymond L. Chai
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Scott A. Roof
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York
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Saba NF, Harrington K, Licitra L, Machiels JP, He C, Jew T, Andrianov V, Haddad R. STELLAR-305: phase II/III study of zanzalintinib plus pembrolizumab versus pembrolizumab alone in patients with HNSCC. Future Oncol 2025; 21:1349-1356. [PMID: 40248950 PMCID: PMC12057161 DOI: 10.1080/14796694.2025.2485015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 03/24/2025] [Indexed: 04/19/2025] Open
Abstract
TWEETABLE ABSTRACT STELLAR-305: design of an ongoing phase III #clinicaltrial, assessing the multi-targeted tyrosine kinase inhibitor, zanzalintinib, in combination with pembrolizumab in previously untreated recurrent/metastatic #HNSCC. CLINICAL TRIAL REGISTRATION NCT06082167 (ClinicalTrials.gov).
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Affiliation(s)
- Nabil F. Saba
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Kevin Harrington
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
- Head and Neck Unit, The Royal Marsden Hospital, London, UK
| | - Lisa Licitra
- Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
| | - Jean-Pascal Machiels
- Institut de Recherche Expérimentale et Clinique, Pôle MIRO, Université catholique de Louvain, Brussels, Belgium
- Department of Medical Oncology, Institut Roi Albert II & Cliniques universitaires Saint-Luc, Brussels, Belgium
| | | | | | | | - Robert Haddad
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
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Takhar A, Wilkie MD, Srinivasan D, King E. Head and Neck Squamous Cell Carcinoma of Unknown Primary-Who Can Be Offered Surgery as the Sole Treatment Modality? A Systematic Review. Clin Otolaryngol 2025; 50:399-414. [PMID: 39800989 DOI: 10.1111/coa.14279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 09/13/2024] [Accepted: 12/16/2024] [Indexed: 04/08/2025]
Abstract
OBJECTIVE Evaluate the role of surgery as the sole treatment modality for patients with cervical head and neck squamous cell carcinoma of unknown primary (HNSCCUP). DESIGN Systematic review of observational cohort studies with qualitative synthesis. SETTING PubMed, Ovid EMBASE, and Cochrane Controlled register of Trials (CENTRAL) were screened from January 2000 up to October 2021. PARTICIPANTS Patients with HNSCCUP after completing diagnostic workup subsequently treated with single-modality surgery. MAIN OUTCOME MEASURES The primary outcome was 3-year overall survival (OS). Secondary outcomes included disease-free survival (DFS), primary emergence, regional recurrence, and distant metastasis. RESULTS Fourteen eligible studies were identified, including 1780 patients, of whom 294 received surgery as their sole treatment (seven studies) with 3-year OS ranging from 43.9% to 100%. 3-year DFS was reported in four studies (n = 62) ranging from 42.8% to 67.0%. 5-year OS and DFS were available in three studies (n = 31), ranging from 36.6% to 75.0%, and 43.6% to 67.0%, respectively. The rate of primary emergence ranged from 11.1% to 33.3% (seven studies, n = 157), regional relapse from 0.0% to 50.0% (five studies, n = 60) and distant metastasis from 0.0% to 3.3% (three studies, n = 45). Patients undergoing surgery as a sole treatment had predominantly p16/HPV positive N1 (TNM7) disease without ECS. CONCLUSION Outcomes for HNSCCUP patients undergoing surgery alone range widely in the literature but may be reasonable in a subset of patients with early-stage p16/HPV positive disease. Data is lacking for p16/HPV negative disease where the potential primary site is more varied and primary emergence appears more common.
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Affiliation(s)
- Arunjit Takhar
- Consultant ENT/Head and Neck Surgeon, Department of Otolaryngology/Head and Neck Surgery, St George's & Epsom University Hospitals NHS Trust, London, United Kingdom
| | - Mark D Wilkie
- Consultant ENT/Head & Neck Surgeon, Liverpool Head and Neck Centre, University Hospital Aintree, Liverpool, United Kingdom
| | - Devraj Srinivasan
- Consultant Clinical Oncologist, Department of Oncology, NHS Lothian, United Kingdom
| | - Emma King
- Consultant ENT/Head and Neck Surgeon, Department of Otolaryngology/Head and Neck Surgery, University Hospitals Dorset NHS Foundation Trust. Professor of Head and Neck Surgical Oncology, University of Southampton, United Kingdom
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Salati V, Adamowicz M, McKean L, Noble D, Srinivasan D, MacKenzie J, Linton S, Callaghan C, Robert C, Cuschieri K, Conn B, Hay A, Aitman TJ, Nixon IJ. Prognostic Implications of HPV Cell-Free DNA Serial Testing During Follow-Up of p16 Positive Oropharyngeal Squamous Cell Carcinoma After Curative-Intent Treatment. Clin Oncol (R Coll Radiol) 2025; 41:103807. [PMID: 40199234 DOI: 10.1016/j.clon.2025.103807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 01/31/2025] [Accepted: 03/14/2025] [Indexed: 04/10/2025]
Abstract
INTRODUCTION Plasma circulating HPV cell-free DNA has high sensitivity and specificity for the detection of HPV-mediated oropharyngeal squamous cell carcinoma. We investigated the clinical significance of serial testing after curative-intent treatments. MATERIALS AND METHODS Patients with concordant p16 positive tumour or neck node biopsy and positive high-risk HPV plasma cell-free DNA were prospectively recruited. HPV cell-free DNA were obtained using digital droplet polymerase chain reaction (ddPCR) and were collected at diagnosis and at every clinical follow-up. Three months after completion of curative-intent treatments, patients were stratified according to treatment response on computed tomography. Complete responders (CR) were followed-up clinically, partial responders (PR) underwent further imaging and surgical/medical management if appropriate, patients with progressive disease (PD) received palliative treatments. RESULTS A hundred and fourteen patients were included and 717 HPV cfDNA ddPCR samples were analysed during a median follow-up of 103 weeks (IQR, 40.2-147.8). Ninety (78.9%) patients were classified as CR, 18 (15.8%) as PR and all except one, who was rapidly diagnosed with PD, had negative HPV ddPCR at 12 weeks follow-up; 6 (5.3%) had PD and all except one had positive HPV ddPCR. Eleven had recurrent disease, 6 in the CR group (6.6%) and 5 among PR (27.7%). Ninety patients had consistently negative HPV ddPCR at all time points and one developed a recurrence (NPV 99%, 95% C.I., 93.2-99.8%). Eighteen patients developed positive HPV ddPCR and 10 developed recurrent disease (PPV 55%, 95% C.I., 38.6-71.4%). Ten patients had two consecutively positive HPV ddPCR and all had proven disease (PPV 100%, 95% C.I., 69.2-100%). Nine patients had transiently positive HPV ddPCR and none developed disease at that time. CONCLUSIONS Post-treatment HPV ddPCR reflected treatment response on imaging and serial testing had high PPV and NPV in detecting recurrent disease.
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Affiliation(s)
- V Salati
- Department of Otolaryngology and Head and Neck Surgery, NHS Lothian, Lauriston Place, Edinburgh, EH3 9HX, UK; NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK; Department of Otolaryngology and Head and Neck Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), 1011 Lausanne, Switzerland
| | - M Adamowicz
- NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - L McKean
- Department of Clinical Oncology, Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - D Noble
- NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK; Department of Clinical Oncology, Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - D Srinivasan
- Department of Clinical Oncology, Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - J MacKenzie
- Department of Clinical Oncology, Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - S Linton
- Department of Otolaryngology and Head and Neck Surgery, NHS Lothian, Lauriston Place, Edinburgh, EH3 9HX, UK; NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - C Callaghan
- Department of Otolaryngology and Head and Neck Surgery, NHS Lothian, Lauriston Place, Edinburgh, EH3 9HX, UK; NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - C Robert
- NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - K Cuschieri
- Scottish HPV Reference Laboratory, Department of Laboratory Medicine, NHS Lothian, Royal Infirmary of Edinburgh, EH16 4SA, UK
| | - B Conn
- Department of Pathology, NHS Lothian, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, EH16 4SA, UK
| | - A Hay
- Department of Otolaryngology and Head and Neck Surgery, NHS Lothian, Lauriston Place, Edinburgh, EH3 9HX, UK; NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - T J Aitman
- NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
| | - I J Nixon
- Department of Otolaryngology and Head and Neck Surgery, NHS Lothian, Lauriston Place, Edinburgh, EH3 9HX, UK; NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK
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47
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Rao YJ. Biomarkers of Radioresistance in Head and Neck Cancer: A New Beginning. Clin Cancer Res 2025; 31:1563-1565. [PMID: 39964362 DOI: 10.1158/1078-0432.ccr-24-4223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/17/2025] [Accepted: 01/31/2025] [Indexed: 05/02/2025]
Abstract
The development of biomarkers of radioresistance in head and neck cancer may help personalize treatment. This commentary puts in context the findings of a secondary analysis of NRG/RTOG 9512, a trial of fractionation in T2N0 glottic cancer, which observed that NFE2L2/KEAP1/CUL3 mutations are correlated with local recurrence and disease-free survival. See related article by Guan et al., p. 1615.
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Affiliation(s)
- Yuan James Rao
- Division of Radiation Oncology, The George Washington University, Washington, District of Columbia
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48
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Huang CC, Ayala-Peacock DN, Stephens SJ, Chino JP. Recent advances in gynecologic radiation oncology. Cancer 2025; 131:e35888. [PMID: 40318035 DOI: 10.1002/cncr.35888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/17/2025] [Accepted: 03/31/2025] [Indexed: 05/07/2025]
Abstract
Significant advances have been made in the treatment of patients with gynecologic malignancies in the past few years. Integration of molecular testing in endometrial cancer now allows for more accurate risk stratification and personalized treatment recommendations for patients, with PORTEC-4a investigating outcomes after treatment de-escalation based on molecular subgroup. In several clinical trials, mismatch repair-deficiency (MMR-d) status has been proven to be a strong predictor for response to immunotherapy in the advanced/metastatic setting, and the role of immunotherapy in early-stage endometrial cancer is now being investigated. For patients with locally advanced cervical cancer, results from INTERLACE demonstrate that induction chemotherapy is now a viable treatment option, and KEYNOTE A-18 shows promise for the addition of concurrent and maintenance pembrolizumab to chemoradiation. Meanwhile, EMBRACE 1 and 2 have demonstrated the benefits of high-quality image guided brachytherapy, providing patients with locally advanced cervical cancer excellent control with improved toxicity. For patients with vulvar cancer, GOG279 demonstrated that addition of multi-agent chemotherapy with intensity modulated radiation therapy resulted in high rates of complete pathologic response, and GROINS-V III is currently investigating the role of chemotherapy and nodal radiation for patients with macrometastases on sentinel lymph node biopsy. This work summarizes the findings of recent landmark trials in endometrial, cervical, and vulvar cancer and their implications for the radiation oncologist.
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Affiliation(s)
- Christina C Huang
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA
| | - Diandra N Ayala-Peacock
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA
| | - Sarah J Stephens
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA
| | - Junzo P Chino
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA
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49
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Choulli M, Kubrak C, Morey F, Brenes J, Tous S, Quirós B, Wang X, Pavón MA, Gomà M, Taberna M, Alemany L, Oliva M, Mena M, Jha N, Scrimger R, Debenham B, Chua N, Walker J, Mesia R, Baracos V, Arribas L. Nutritional characterization of patients with oropharyngeal cancers: impact of human papillomavirus status. Eur J Clin Nutr 2025; 79:467-474. [PMID: 39738840 DOI: 10.1038/s41430-024-01556-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 11/19/2024] [Accepted: 12/06/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Oropharyngeal squamous cell carcinoma (OPSCC) of human papillomavirus (HPV)-positive status is increasing relative to HPV-negative disease. Nutritional features of OPSCC patients according to HPV status is unclear. SUBJECTS/METHODS Canadian and Spanish patients with OPSCC were assessed for body mass index (BMI), weight loss grade (WLG), and computed tomography-defined skeletal muscle index (SMI). Chi-square, t-test, Mann-Whitney-U, Kruskal-Wallis tests were conducted to compare HPV positive and negative groups. Overall survival (OS) was assessed by univariable Kaplan-Meier and Cox proportional hazard methods. RESULTS No differences in BMI, WLG, SMI, and adipose tissue index between the 308 (Canada) and 134 (Spain) patients according to HPV status; hence cohorts were pooled (n = 442). HPV-positive patients (n = 317) were overweight/obese (72.8%), had WLG of 0/1 (59.6%) and high SMI (83.4%) while HPV-negative patients were normal/underweight (61.5%), had high WLG 3/4 (50.8%), and moderate/severe SMI depletion (46.9%) (p < 0.003). These overall differences notwithstanding, there was crossover i.e. 35% of HPV-positive patients had high WLG and/or moderate/severe muscle depletion and 29% of HPV-negative patients had minimal weight loss and high SMI. HPV-negative patients had a higher risk of mortality (HR 3.78, 95% CI 2.70-5.29, P < 0.001) and this difference was retained after multivariable adjustment for WLG, SMI, age, disease stage, and planned treatment (HR 3.30, 95% CI 2.17-5.02, P < 0.001). CONCLUSION Nutrition features of patients with OPSCC did not differ between Canada and Spain. Distinctive nutrition features exist in patients according to HPV status. The high heterogeneity of individual nutritional profiles invites an individualized approach to nutrition care.
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Affiliation(s)
- Maryam Choulli
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
- Clinical Nutrition Unit, Catalan Institute of Oncology (ICO), Barcelona, Spain
| | - Catherine Kubrak
- Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada
| | - Francisca Morey
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
| | - Jesús Brenes
- Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, Barcelona, Spain
| | - Sara Tous
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
- Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Beatriz Quirós
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
- Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Xin Wang
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
| | - Miquel Angel Pavón
- Infections and Cancer Laboratory (INCALAB), Catalan Institute of Oncology (ICO), Barcelona, Spain
| | - Montserrat Gomà
- Pathology Department, Bellvitge University Hospital, Barcelona, Spain
| | - Miren Taberna
- Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, Barcelona, Spain
| | - Laia Alemany
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
- Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Marc Oliva
- Medical Oncology Department, Catalan Institute of Oncology (ICO), ONCOBELL, Barcelona, Spain
| | - Marisa Mena
- Unit of Molecular Epidemiology and Genetics (UNICEMG), Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
- Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Naresh Jha
- Department of Oncology, Division of Radiation Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada
| | - Rufus Scrimger
- Department of Oncology, Division of Radiation Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada
| | - Brock Debenham
- Department of Oncology, Division of Radiation Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada
| | - Neil Chua
- Department of Oncology, Division of Medical Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada
| | - John Walker
- Department of Oncology, Division of Medical Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada
| | - Ricard Mesia
- Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona, B-ARGO Group, IGTP, Barcelona, Spain
| | - Vickie Baracos
- Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada.
| | - Lorena Arribas
- Clinical Nutrition Unit, Catalan Institute of Oncology (ICO), Barcelona, Spain.
- Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
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50
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Hopkins BD, Bates JE. The role of biomarkers in the management of HPV-related oropharyngeal cancer. Curr Opin Oncol 2025; 37:203-208. [PMID: 40026007 DOI: 10.1097/cco.0000000000001126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
PURPOSE OF REVIEW Patients with HPV-related oropharyngeal cancer have very good survival outcomes but a high burden of toxicity. This has led to significant efforts to attempt to use a variety of biomarkers to select patients who are candidates for de-escalated treatment. RECENT FINDINGS Initially, the field used HPV status alone as a biomarker to select patients with oropharyngeal cancer for de-escalation, however, the recently presented results of NRG Oncology HN005 showed that this is an insufficient strategy to select patients for potential de-escalation as patients in that study who received 60 Gy rather than the standard 70 Gy of radiation had diminished progression-free survival. This has led to a myriad of other strategies to potentially identify patients who may be able to receive less intense treatment but maintain a high rate of cure. SUMMARY Many biomarker options exist to try and select patients for potential treatment de-escalation. We anxiously await the results of multiple ongoing phase II studies regarding many of these biomarkers and believe that the future of treatment for oropharyngeal cancer will be significantly more personalized.
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Affiliation(s)
- Benjamin D Hopkins
- Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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