|
1
|
Rödel F, Fleischmann M, Diefenhardt M, Dapper H, Hoffmann A, Rödel C, Martin D, Fokas E. Emerging advances and future opportunities in the molecular and therapeutic landscape of anal cancer. Nat Rev Clin Oncol 2025:10.1038/s41571-025-01025-x. [PMID: 40360682 DOI: 10.1038/s41571-025-01025-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2025] [Indexed: 05/15/2025]
Abstract
Anal squamous cell carcinoma (ASCC) is a rare malignancy with an increasing incidence. Primary chemoradiotherapy (CRT) is the standard-of-care treatment for patients with localized ASCC. In the metastatic setting, trials testing immune-checkpoint inhibitor monotherapy have demonstrated outcomes similar to those of patients receiving chemotherapy. Conversely, adding the anti-PD-1 antibody retifanlimab to chemotherapy in patients with recurrent or metastatic ASCC has been shown to significantly improve outcomes. Despite considerable efforts to develop personalized therapy, treatment guidance and prognosis remain reliant on baseline clinical characteristics. An improved understanding of the molecular characteristics of ASCC has provided insights into the mechanisms that mediate tumour progression and response to CRT. For example, human papillomavirus (HPV) infection is known to have an aetiological role in most ASCCs and can modulate cellular responses to CRT via several distinct mechanisms. In this Review, we summarize emerging advances in the molecular and therapeutic landscape of ASCC, including the implementation of biomarkers for treatment guidance and translation into new therapeutic approaches, with HPV infection constituting a global determinant of both tumour biology and clinical outcome. We also discuss the rationale for combining immune-checkpoint inhibitors with CRT in patients with HPV+ tumours.
Collapse
Affiliation(s)
- Franz Rödel
- Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany
| | - Maximilian Fleischmann
- Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany
| | - Markus Diefenhardt
- Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany
| | - Hendrik Dapper
- Department of Radiation Oncology, Cyberknife and Radiotherapy, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Annett Hoffmann
- Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
| | - Claus Rödel
- Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany
| | - Daniel Martin
- Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany
| | - Emmanouil Fokas
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany.
- German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany.
- Department of Radiation Oncology, Cyberknife and Radiotherapy, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.
| |
Collapse
|
|
2
|
Balci Topuz B, Sert F, Sezak M, Soylu M, Yalman D, Ozkok S. HPV status and immunohistochemical analysis of p16, p53 and PD‑L1 expression as prognostic biomarkers in patients with squamous cell anal cancer receiving definitive radiotherapy/chemoradiotherapy. Oncol Lett 2024; 28:395. [PMID: 38966586 PMCID: PMC11223008 DOI: 10.3892/ol.2024.14528] [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: 03/27/2024] [Accepted: 06/07/2024] [Indexed: 07/06/2024] Open
Abstract
Anal squamous cell carcinoma (SCC) treated with definitive radiotherapy (RT)/chemoradiotherapy (CRT) has shown high success rates, yet challenges such as treatment resistance and recurrence persist. The present study aimed to investigate the associations between immunohistochemical (IHC) evaluation, treatment response and prognosis in anal SCC. A retrospective cohort analysis included 42 patients with anal SCC treated at a single institution between 2006 and 2022. Human papillomavirus (HPV) status was determined, and the IHC analysis of p16, p53 and PD-L1 expression was conducted using formalin-fixed, paraffin-embedded biopsies. A complete response to RT/CRT was observed in 71.4% of patients. Recurrence occurred in 38.1% of cases, of which 7.1% had local-regional recurrence (LRR), 14.3% had distant recurrence (DR), and 16.7% had both LRR and DR. HPV positivity (71.4%) was significantly associated with p16 positivity. Lack of complete response was associated with HPV-negative status, p16-negative status, increased recurrence and DR. In addition, recurrence was significantly associated with p53-positive status, and p53 positivity was significantly associated with increased LRR. PD-L1 positivity, defined as a combined positive score (CPS) ≥1% was found in 73.8% of the patients, and exhibited significant associations with HPV positivity and p16 positivity. PD-L1 CPS ≥ 1% was also associated with an increased LRR. Univariate analysis revealed that age <65 years, a complete response and HPV positivity were associated with increased 5-year overall survival (OS), while a complete response, HPV positivity and p53-negative status were associated with increased 5-year disease-free survival (DFS). Multivariate analysis identified that age <65 years and HPV positivity are independent prognostic factors for 5-year OS, and a complete response and p53-negative status are independent prognostic factors for 5-year DFS. In conclusion, these findings suggust that the identification of HPV status and poor prognostic biomarkers at diagnosis may be used to guide personalized treatment strategies, with the combination of immunotherapy with standard CRT potentially providing improved outcomes.
Collapse
Affiliation(s)
- Beril Balci Topuz
- Department of Radiation Oncology, Ministry of Health Dr. Ersin Arslan Training and Research Hospital, Gaziantep 27090, Türkiye
| | - Fatma Sert
- Department of Radiation Oncology, Ege University Faculty of Medicine, Izmir 35100, Türkiye
| | - Murat Sezak
- Department of Pathology, Ege University Faculty of Medicine, Izmir 35100, Türkiye
| | - Mehmet Soylu
- Department of Microbiology, Ege University Faculty of Medicine, Izmir 35100, Türkiye
| | - Deniz Yalman
- Department of Radiation Oncology, Ege University Faculty of Medicine, Izmir 35100, Türkiye
| | - Serdar Ozkok
- Department of Radiation Oncology, Ege University Faculty of Medicine, Izmir 35100, Türkiye
| |
Collapse
|
|
3
|
Martin D, Rödel F, Hehlgans S, Looso M, Ziegler PK, Fleischmann M, Diefenhardt M, Fries L, Kalinauskaite G, Tinhofer I, Zips D, Gani C, Rödel C, Fokas E. Inflammatory pathways confer resistance to chemoradiotherapy in anal squamous cell carcinoma. NPJ Precis Oncol 2024; 8:93. [PMID: 38653773 DOI: 10.1038/s41698-024-00585-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/22/2024] [Indexed: 04/25/2024] Open
Abstract
Anal squamous cell carcinoma (ASCC) is associated with immunosuppression and infection with human papillomavirus (HPV). Response to standard chemoradiotherapy (CRT) varies considerably. A comprehensive molecular characterization of CRT resistance is lacking, and little is known about the interplay between tumor immune contexture, host immunity, and immunosuppressive and/or immune activating effects of CRT. Patients with localized ASCC, treated with CRT at three different sites of the German Cancer Consortium (DKTK) were included. Patient cohorts for molecular analysis included baseline formalin fixed paraffin embedded biopsies for immunohistochemistry (n = 130), baseline RNA sequencing (n = 98), peripheral blood immune profiling (n = 47), and serum cytokine measurement (n = 35). Gene set enrichment analysis showed that pathways for IFNγ, IFNα, inflammatory response, TNFα signaling via NF-κB, and EMT were significantly enriched in poor responders (all p < 0.001). Expression of interferon-induced transmembrane protein 1 (IFITM1), both on mRNA and protein levels, was associated with reduced Freedom from locoregional failure (FFLF, p = 0.037) and freedom from distant metastasis (FFDM, p = 0.014). An increase of PD-L1 expression on CD4+ T-cells (p < 0.001) and an increase in HLA-DR expression on T-cells (p < 0.001) was observed in the peripheral blood after CRT. Elevated levels of regulatory T-cells and CXCL2 were associated with reduced FFLF (p = 0.0044 and p = 0.004, respectively). Inflammatory pathways in tissue in line with elevated levels of regulatory T-cells and CXCL2 in peripheral blood are associated with resistance to CRT. To counteract this resistance mechanism, the RADIANCE randomized phase-2 trial currently tests the addition of the immune checkpoint inhibitor durvalumab to standard CRT in locally advanced ASCC.
Collapse
Affiliation(s)
- D Martin
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany.
- German Cancer Consortium (DKTK), Partner Site Frankfurt, A Partnership between DKFZ and University Hospital Frankfurt, Frankfurt, Germany.
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany.
| | - F Rödel
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, A Partnership between DKFZ and University Hospital Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
| | - S Hehlgans
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
| | - M Looso
- Max Planck Institute for Heart and Lung Research, Bioinformatics Core Unit, Bad Nauheim, Germany
| | - P K Ziegler
- German Cancer Consortium (DKTK), Partner Site Frankfurt, A Partnership between DKFZ and University Hospital Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
- Dr. Senckenberg Institute of Pathology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
| | - M Fleischmann
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, A Partnership between DKFZ and University Hospital Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
| | - M Diefenhardt
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, A Partnership between DKFZ and University Hospital Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
| | - L Fries
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
| | - G Kalinauskaite
- Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, A Partnership between DKFZ and Charité University Hospital Berlin, Berlin, Germany
| | - I Tinhofer
- Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, A Partnership between DKFZ and Charité University Hospital Berlin, Berlin, Germany
| | - D Zips
- Department of Radiooncology and Radiotherapy, Charité University Hospital Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, A Partnership between DKFZ and Charité University Hospital Berlin, Berlin, Germany
| | - C Gani
- Eberhard Karls University, Tübingen, University Hospital Tübingen, Department of Radiation Oncology, Tübingen, Germany
- German Cancer Consortium (DKTK), Partner Site Tübingen, A Partnership between DKFZ and University Hospital Tübingen, Tübingen, Germany
| | - C Rödel
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, A Partnership between DKFZ and University Hospital Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
| | - E Fokas
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, A Partnership between DKFZ and University Hospital Frankfurt, Frankfurt, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany
- Department of Radiation Oncology, Cyberknife and Radiotherapy, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany
| |
Collapse
|
|
4
|
Huffman BM, Singh H, Ali LR, Horick N, Wang SJ, Hoffman MT, Metayer KA, Murray S, Bird A, Abrams TA, Biller LH, Chan JA, Meyerhardt JA, McCleary NJ, Goessling W, Patel AK, Wisch JS, Yurgelun MB, Mouw K, Reardon B, Van Allen EM, Zerillo JA, Clark JW, Parikh A, Mayer RJ, Schlechter B, Ng K, Kumar S, Del Vecchio Fitz C, Kuperwasser C, Hanna GJ, Coveler AL, Rubinson DA, Welsh EL, Pfaff K, Rodig S, Dougan SK, Cleary JM. Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders. J Immunother Cancer 2024; 12:e008436. [PMID: 38272561 PMCID: PMC10824013 DOI: 10.1136/jitc-2023-008436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed. METHODS This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18). RESULTS In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder's TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response. CONCLUSIONS Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab.
Collapse
Affiliation(s)
- Brandon M Huffman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Harshabad Singh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Lestat R Ali
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Nora Horick
- Massachusetts General Hospital, Boston, Massachusetts, USA
| | - S Jennifer Wang
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Megan T Hoffman
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Katherine A Metayer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Shayla Murray
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Alexandra Bird
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Thomas A Abrams
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Leah H Biller
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Jennifer A Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Jeffrey A Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Nadine J McCleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Wolfram Goessling
- Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Anuj K Patel
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Jeffrey S Wisch
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Kent Mouw
- Harvard Medical School, Boston, Massachusetts, USA
| | | | - Eliezer M Van Allen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Jessica A Zerillo
- Harvard Medical School, Boston, Massachusetts, USA
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Jeffrey W Clark
- Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aparna Parikh
- Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Robert J Mayer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Benjamin Schlechter
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | | | - Glenn J Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew L Coveler
- University of Washington School of Medicine, Seattle, Washington, USA
| | - Douglas A Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Emma L Welsh
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Kathleen Pfaff
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Scott Rodig
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Stephanie K Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - James M Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
5
|
Haqshenas G, Garland SM, Balgovind P, Cornall A, Danielewski J, Molano M, Machalek DA, Murray G. Development of a touchdown droplet digital PCR assay for the detection and quantitation of human papillomavirus 16 and 18 from self-collected anal samples. Microbiol Spectr 2023; 11:e0183623. [PMID: 37962350 PMCID: PMC10714734 DOI: 10.1128/spectrum.01836-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 10/09/2023] [Indexed: 11/15/2023] Open
Abstract
IMPORTANCE The quantity of the human papillomavirus (HPV) is associated with disease outcome. We designed an accurate and precise digital PCR assay for quantitating HPV in anal samples, a sample type that is typically problematic due to the presence of PCR inhibitors.
Collapse
Affiliation(s)
- Gholamreza Haqshenas
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
- Centre for Women’s Infectious Diseases, The Royal Women’s Hospital, Melbourne, Victoria, Australia
- Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
| | - Suzanne M. Garland
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
- Centre for Women’s Infectious Diseases, The Royal Women’s Hospital, Melbourne, Victoria, Australia
- Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
| | - Prisha Balgovind
- Centre for Women’s Infectious Diseases, The Royal Women’s Hospital, Melbourne, Victoria, Australia
- Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
| | - Alyssa Cornall
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
- Centre for Women’s Infectious Diseases, The Royal Women’s Hospital, Melbourne, Victoria, Australia
- Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
| | - Jennifer Danielewski
- Centre for Women’s Infectious Diseases, The Royal Women’s Hospital, Melbourne, Victoria, Australia
- Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
| | - Monica Molano
- Centre for Women’s Infectious Diseases, The Royal Women’s Hospital, Melbourne, Victoria, Australia
| | - Dorothy A. Machalek
- Centre for Women’s Infectious Diseases, The Royal Women’s Hospital, Melbourne, Victoria, Australia
- Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
- The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Gerald Murray
- Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
- Centre for Women’s Infectious Diseases, The Royal Women’s Hospital, Melbourne, Victoria, Australia
- Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
| |
Collapse
|
|
6
|
Ranabhotu A, Habibian N, Patel B, Farrell E, Do J, Sedghi S, Sedghi L. Case Report: Resolution of high grade anal squamous intraepithelial lesion with antibiotics proposes a new role for syphilitic infection in potentiation of HPV-associated ASCC. Front Oncol 2023; 13:1226202. [PMID: 37854673 PMCID: PMC10580285 DOI: 10.3389/fonc.2023.1226202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/04/2023] [Indexed: 10/20/2023] Open
Abstract
Introduction Human Papillomavirus (HPV) is the primary risk factor for the development of anal intraepithelial neoplasia (AIN) and is a leading risk factor for anogenital squamous cell carcinoma (ASCC). Despite common shared risk factors for both HPV and syphilis, co-infection is not well documented, and the role of syphilitic infection in HPV-associated AIN and ASCC potentiation is not defined. Case description/methods A 72-year-old single male presented with complaints of mild rectal pain and intermittent rectal bleeding. A flexible sigmoidoscopy was performed, and a firm 4.5cm x 3cm perianal mass was detected and superficially biopsied. Pathology findings demonstrated evidence of a high grade squamous intraepithelial lesion (HGSIL, AIN II/III/AIS) with viral cytopathic effect, consistent with HPV infection. Much of the biopsied lesion showed acanthotic squamous mucosa with intraepithelial neutrophils and abundant submucosal plasma cells, suggesting possible syphilitic involvement. Subsequent immunohistochemical staining for p16 as a surrogate marker for HPV was positive, as was an immunohistochemical stain for spirochetes, supportive of co-infection with Treponema pallidum pallidum (T. pallidum), the causative agent in venereal syphilis. The patient was referred to an infectious disease specialist for syphilitic infection and was treated with penicillin with surprisingly complete resolution of the lesion. EUAs were performed 2- and 3-months following treatment without lesion recurrence. However, one year following diagnosis, a flexible sigmoidoscopy revealed a 5 mm recurrent HPV-related low-grade AIN 1 lesion at the dentate line. Discussion Resolution of the lesion by antibiotic treatment for syphilitic infection suggested that co-infection by T. pallidum may potentiate HPV-associated squamous cell carcinoma based on histological findings. Findings from this case, as well as a review of bacterial involvement and potentiation in various cancers, are reviewed here. Such findings offer new insight regarding the role of STI-associated bacteria and HPV co-infection in the establishment of AIN and may additionally propose new treatment modalities for ASCC.
Collapse
Affiliation(s)
- A. Ranabhotu
- Gatroenterology Associates of Central Georgia, Macon, GA, United States
| | - N. Habibian
- Gatroenterology Associates of Central Georgia, Macon, GA, United States
| | - B. Patel
- Gatroenterology Associates of Central Georgia, Macon, GA, United States
| | - E. Farrell
- Gatroenterology Associates of Central Georgia, Macon, GA, United States
- Mercer University School of Medicine, Macon, GA, United States
| | - J. Do
- Advanced Pathology Solutions, Department of Gastroenterology, Little Rock, AR, United States
| | - S. Sedghi
- Gatroenterology Associates of Central Georgia, Macon, GA, United States
- Mercer University School of Medicine, Macon, GA, United States
| | - L. Sedghi
- Department of Oral and Craniofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, CA, United States
| |
Collapse
|
|
7
|
Díez-Martínez M, Perpiñá-Galvañ J, Ferri J, Ventero M, Portilla J, Cabañero-Martínez MJ. Evaluation of the validity of the HPV viral load compared to conventional techniques for the detection of high-grade anal intraepithelial lesions in men with HIV who have sex with men. PeerJ 2023; 11:e15878. [PMID: 37637161 PMCID: PMC10460151 DOI: 10.7717/peerj.15878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/18/2023] [Indexed: 08/29/2023] Open
Abstract
Background The incidence of high-grade anal intraepithelial lesions (HSILs) has increased in recent years among men who have sex with men with human immunodeficiency virus (HIV). This work evaluated the validity of the human papilloma virus viral load (HPV-VL) versus cytological and qualitative HPV results to detect HSILs. Methods From May 2017 to January 2020, 93 men who have sex with men and HIV were included in an anal cancer screening program from the Infectious Diseases Unit at a tertiary-care hospital in Alicante (Spain). The gold-standard for the screening of anal HSILs is the anal biopsy using high-resolution anoscopy. The diagnostic methods compared against gold-standard were HPV-16-VL, HPV-18-VL, and HPV-16-18-VL co-testing, anal cytology, and qualitative HPV detection. The receiver operating characteristic (ROC) curve and cut-off points for HPV-VL were calculated. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Cohen's Kappa coefficient (κ) were also calculated. Results The mean patient age was 44.6 ± 9.5 years. All of them received antiretroviral treatment, 96.8% had an HIV viral load of <50 copies/mL and 17.2% had a previous diagnosis of AIDS. The diagnosis of the anal biopsies were: 19.4% (n = 18) HSIL, 29.1% (n = 27) LSIL, and 51.6% (n = 48) negative. An HPV-16-VL >6.2 copies/cell was detected in the HSIL biopsy samples (p = 0.007), showing a sensitivity of 100% and a specificity of 46.2%. HPV-18-VL and HPV16-18-VL co-testing showed a sensitivity of 75% and 76.9% and a specificity of 72.7% and 61.3%, respectively. The highest PPV was 50% obtained with the cytology and HPV-18-VL. The HPV-16-VL showed a NPV of 100%, followed by 88.9% in the HPV-18-VL and 87% in the abnormal cytology. Cohen's Kappa coefficient were: HPV-18-VL (κ = 0.412), abnormal cytology (κ = 0.353) and HPV-16-VL (κ = 0.338). Conclusions HPV-VL testing improved the detection sensitivity but not the specificity for HSIL biopsies compared to anal cytology and the qualitative detection of HPV. In men who have sex with men and HIV the HPV-VL could be an useful tool for diagnosis of HSILs in anal cancer screening programs. Further studies will be needed to evaluate the clinical implications of HPV-VL in these programs.
Collapse
Affiliation(s)
- Marcos Díez-Martínez
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Infectious Diseases Unit, Alicante University General Hospital, Alicante, Spain
- Spanish AIDS Research Network, Carlos III Health Institute, Madrid, Spain
| | - Juana Perpiñá-Galvañ
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Nursing Department, Alicante University, Alicante, Spain
| | - Joaquín Ferri
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Surgery Department, Alicante University General Hospital, Alicante, Spain
| | - Maripaz Ventero
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Microbiology Department, Alicante University General Hospital, Alicante, Spain
| | - Joaquin Portilla
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Infectious Diseases Unit, Alicante University General Hospital, Alicante, Spain
- Spanish AIDS Research Network, Carlos III Health Institute, Madrid, Spain
- Department of Clinical Medicine, Miguel Hernandez University, Elche, Alicante, Spain
| | - María José Cabañero-Martínez
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Nursing Department, Alicante University, Alicante, Spain
| |
Collapse
|
|
8
|
Yamada K, Shiraishi K, Takashima A, Takayanagi D, Saiki Y, Takano S, Tanaka M, Fukunaga M, Sugimoto K, Iwasaki Y, Nakamura Y, Kuwahara D, Tsuji Y, Takano M, Sugihara K, Ajioka Y. Characteristics of anal canal squamous cell carcinoma as an HPV-associated cancer in Japan. Int J Clin Oncol 2023; 28:990-998. [PMID: 37115427 DOI: 10.1007/s10147-023-02339-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023]
Abstract
The definition of the anal canal was revised in the TNM classification (8th edition). The Japanese Society for Cancer of the Colon and Rectum (JSCCR) conducted a retrospective multi-institutional study to clarify the characteristics of anal canal cancer (ACC) in Japan. The diagnoses of 1781 patients treated for ACC were squamous cell carcimoma (SCC; n = 428; 24.0%), adenosquamous cell carcinoma (n = 7; 0.4%), and adenocarcinoma (n = 1260; 70.7%). Anal carcinoma is associated with human papillomavirus (HPV) infection and is risk factor for anal SCC. Among 40 cases analyzed at Takano Hospital and 47 cases analyzed at National Cancer Center Hospital, 34 cases (85.0%) and 40 cases (85.1%), respectively were infected with HPV; HPV-16 was the most common genotype (79.4% and 82.5%). In the JSCCR retrospective multi-institutional study, the prognosis analysis by stage was performed for anal SCC cases (202 cases treated by CRT and 91 cases treated by surgery). The 5-year overall survival (OS) rates by stage did not differ between the two treatment groups to a statistically significant extent. Regarding the results of cancer treatment of patients who underwent HPV infection tests, although the 5-year OS rates by stage did not differ to a statistically significant extent due to the small number of cases, HPV-positive patients had better survival. While an HPV vaccine for anal canal SCC has already been approved internationally, HPV vaccination has already been implemented in Japan as a national immunization program for young women but not for men at present. An HPV vaccination for men is urgently needed.
Collapse
Affiliation(s)
- Kazutaka Yamada
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan.
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Atsuo Takashima
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Daisuke Takayanagi
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yasumitsu Saiki
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Shota Takano
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Masafumi Tanaka
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Mitsuko Fukunaga
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Kosuke Sugimoto
- Division of Medical Information Research, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Yuki Iwasaki
- Division of Medical Information Research, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Yasushi Nakamura
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Daisaku Kuwahara
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Yoriyuki Tsuji
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Masahiro Takano
- Department of Surgery, Coloproctology Center Takano Hospital, 3-2-55 Oe, Chuo-ku, Kumamoto, 862-0971, Japan
| | - Kenichi Sugihara
- Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, 757 Ichibancho, Asahimachi-dori, Chuo Ward, Niigata, 951-8510, Japan
| |
Collapse
|
|
9
|
Gysens L, Martens A, Haspeslagh M. Performance of fine-needle aspirate testing compared with superficial swab testing for quantification of BPV-1/-2 viral load in equine sarcoids. Res Vet Sci 2023; 159:101-105. [PMID: 37104992 DOI: 10.1016/j.rvsc.2023.04.014] [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: 12/07/2022] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023]
Abstract
Bovine papillomavirus (BPV) types 1 and 2 are causally associated with equine sarcoid, the most common mesenchymal neoplasm of horses, but the viral load (VL) differs between lesions. Sensitive and accurate BPV detection and quantification is essential for clinicians to confirm clinical suspicion, as well as in research settings for stratifying these skin lesions. Due to the limitations of histopathology in sarcoid diagnosis, PCR screening of superficial swabs constitutes the principal sampling method for BPV detection. This study aimed to investigate the ability of superficial swabs and fine-needle aspirates (FNA) to accurately detect the VL in equine sarcoids, considering the main clinical types: occult, nodular, verrucous and fibroblastic. Superficial swabs and FNAs from a series of sarcoid-affected horses were tested in parallel for BPV DNA quantification. Quantitative real-time PCR screening of postoperative tissue biopsies served as reference standard for the accuracy assessment of the viral titters. Our results indicate that VL is not a predictor of the clinical type. Student's t-test results gave evidence of a significant difference between both sample methods (P < 0.001) with FNA giving the best approximation of the actual VL (P < 0.01). In contrast to superficial swabs, the reference standard correlated moderately with FNA in general (P < 0.05; r = 0.39) and strongly with FNA results within the occult sarcoid group (P < 0.05; r = 0.59). In conclusion, the correlation of FNA with the reference standard was strong enough to suggest this is the preferred method for quantifying VL in sarcoids.
Collapse
Affiliation(s)
- Lien Gysens
- Department of Large Animal Surgery, Anaesthesia and Orthopaedics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke 9820, Belgium.
| | - Ann Martens
- Department of Large Animal Surgery, Anaesthesia and Orthopaedics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke 9820, Belgium
| | - Maarten Haspeslagh
- Department of Large Animal Surgery, Anaesthesia and Orthopaedics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke 9820, Belgium
| |
Collapse
|
|
10
|
Ito T, Takayanagi D, Sekine S, Hashimoto T, Shimada Y, Matsuda M, Yamada M, Hamamoto R, Kato T, Shida D, Kanemitsu Y, Boku N, Kohno T, Takashima A, Shiraishi K. Comparison of clinicopathological and genomic profiles in anal squamous cell carcinoma between Japanese and Caucasian cohorts. Sci Rep 2023; 13:3587. [PMID: 36869079 PMCID: PMC9984524 DOI: 10.1038/s41598-023-30624-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 02/27/2023] [Indexed: 03/05/2023] Open
Abstract
Anal squamous cell carcinoma (ASCC) is a rare tumor of the gastrointestinal tract. We aimed to compare the genetic backgrounds and their effect on clinical outcomes between Japanese and Caucasian patients with ASCC. Forty-one patients diagnosed with ASCC at the National Cancer Center Hospital were enrolled and evaluated for clinicopathological features, human papillomavirus (HPV) infection, HPV genotypes, p16 expression, PD-L1, and association of p16 status with the efficacy of concurrent chemoradiotherapy (CCRT). Target sequencing for hotspot mutations in 50 cancer-related genes was performed using genomic DNA from 30 available samples. Of 41 patients, 34 were HPV-positive (among them, HPV 16 was predominant; 73.2%); 38 patients were p16-positive (92.7%); and 39 patients received CCRT, of whom 36 were p16-positive and three p16-negative. p16-positive patients showed better complete response than p16-negative patients. Among 28 samples, 15 showed mutations in PIK3CA, FBXW7, ABL1, TP53, and PTEN; no difference in mutation profiles between the Japanese and Caucasian cohorts was observed. Actionable mutations were detected in both Japanese and Caucasian patients with ASCC. Genetic backgrounds, such as the HPV 16 genotype and PIK3CA mutations, were common regardless of ethnicity. p16 status may be a prognostic biomarker for CCRT in Japanese patients with ASCC.
Collapse
Affiliation(s)
- Takahiko Ito
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Daisuke Takayanagi
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Shigeki Sekine
- Department of Clinical Pathology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Taiki Hashimoto
- Department of Clinical Pathology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yoko Shimada
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Maiko Matsuda
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Masayoshi Yamada
- Endoscopy Division, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Ryuji Hamamoto
- Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- RIKEN Center for Advanced Intelligence Project, Cancer Translational Research Team, Hirosawa, Wako, Saitama, 351-0198, Japan
| | - Tomoyasu Kato
- Department of Gynecology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Dai Shida
- Department of Colorectal Surgery, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Division of Frontier Surgery, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Yukihide Kanemitsu
- Department of Colorectal Surgery, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Narikazu Boku
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Atsuo Takashima
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
| |
Collapse
|
|
11
|
Mazurek AM, Małusecka E, Jabłońska I, Vydra N, Rutkowski TW, Giglok M, Suwiński R. Circulating HPV16 DNA in Blood Plasma as Prognosticator and Early Indicator of Cancer Recurrence in Radio-Chemotherapy for Anal Cancer. Cancers (Basel) 2023; 15:cancers15030867. [PMID: 36765825 PMCID: PMC9913251 DOI: 10.3390/cancers15030867] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/20/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Implementation of anal squamous cell carcinoma (ASCC) treatment modifications requires reliable patient risk stratification. The circulating tumor-related human papillomavirus type 16 (ctHPV16) may play a role in predicting survival or assessing treatment response. METHODS The study included 62 ASCC patients treated with chemoradiotherapy. A threshold of 2.5 was used to determine the maximum standardized uptake value (SUVmax). The ctHPV16 viral load (VL) was quantified by qPCR. RESULTS In the multivariate Cox analysis, lower SUVmax (p = 0.047) and ctHPV16-positive (p = 0.054) proved to be independent prognostic factors for favorable overall survival (OS). In the subgroup with the higher SUVmax, ctHPV16 and nodal (N) status were independent prognostic factors with p = 0.022 for ctHPV16 and p = 0.053 for N. The best survival rate (95%) presented ctHPV16-positive/N-negative patients. High ctHPV16 VL tended to be slightly specific for patients younger than 63 years (p = 0.152). The decrease in ctHPV16 VL to undetectable level after the end of treatment correlated with the overall clinical response. CONCLUSIONS A prognostic stratification by SUVmax, ctHPV16 and N-positive status allows consideration of more aggressive treatment in high-risk patients (those with high SUVmax, ctHPV16-negative, and N-positive) or de-intensification of therapy in low-risk patients (those with low SUVmax, ctHPV16-positive and N-negative). However, prospective clinical trials on a large group are needed.
Collapse
Affiliation(s)
- Agnieszka M. Mazurek
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
- Correspondence: ; Tel.: +48-322789647; Fax: +48-322789840
| | - Ewa Małusecka
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
| | - Iwona Jabłońska
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
| | - Natalia Vydra
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
| | - Tomasz W. Rutkowski
- I Radiation and Clinical Oncology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
| | - Monika Giglok
- Radiotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
| | - Rafał Suwiński
- Radiotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
| |
Collapse
|
|
12
|
Guerendiain D, Grigorescu R, Kirk A, Stevenson A, Holden MTG, Pan J, Kavanagh K, Graham SV, Cuschieri K. HPV status and HPV16 viral load in anal cancer and its association with clinical outcome. Cancer Med 2022; 11:4193-4203. [PMID: 35785486 PMCID: PMC9678095 DOI: 10.1002/cam4.4771] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/22/2022] [Accepted: 04/06/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND The incidence of anal cancer is increasing globally. Evidence-based improvement in early detection and management of this morbid cancer is thus required. In other cancers associated with Human Papillomavirus (HPV), viral status and dynamics, including viral load (VL) has been shown to influence clinical outcome. Our aim was to determine the influence of HPV status and HPV16 VL on the clinical outcomes of anal cancer patients. METHODS A total of 185 anal cancer lesions were genotyped for HPV. Of the HPV16 positive component, VL was determined using a digital droplet PCR assay. The association of qualitative HPV status and VL (low (<12.3), medium (12.3-57) and high (>57 copies/cell)) on overall survival and hazard of death was assessed. RESULTS Of the 185 cases, 164 (88.6%) samples were HPV positive. HPV16 was detected in 154/185 samples (83.2%). HPV positive status was associated with improved overall survival in the univariate analysis [hazard ratio (HR) of 0.44, 0.23-0.82, p = 0.01]. When adjusted by age, sex, stage and response to treatment, the association of positive HPV status with improved survival remained (HR 0.24 [0.11-0.55] p < 0.001). High VL was associated with improved overall survival in the univariate analysis with a HR of 0.28 (0.11-0.71, p = 0.007). When adjusted only by age and sex, high VL was associated with better overall survival (HR 0.27, 0.11-0.68 p = 0.006). CONCLUSIONS HPV status appears to be independently associated with improved outcomes in anal cancer patients. Moreover, HPV viral load quantification may be informative for further risk stratification and warrants further investigation.
Collapse
Affiliation(s)
- Daniel Guerendiain
- Scottish HPV Reference Laboratory, NHS Lothian, Edinburgh, UK.,School of Medicine, University of St Andrews, St Andrews, UK
| | | | - Anna Kirk
- Centre for Virus Research, Institute of Infection Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Andrew Stevenson
- Centre for Virus Research, Institute of Infection Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | | | - Jiafeng Pan
- Department of Mathematics and Statistics, University of Strathclyde, Glasgow, UK
| | - Kim Kavanagh
- Department of Mathematics and Statistics, University of Strathclyde, Glasgow, UK
| | - Sheila V Graham
- Centre for Virus Research, Institute of Infection Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Kate Cuschieri
- Scottish HPV Reference Laboratory, NHS Lothian, Edinburgh, UK
| |
Collapse
|
|
13
|
Mathias-Machado MC, Peixoto RD, Moniz CMV, Jácome AA. Biomarkers in Anal Cancer: Current Status in Diagnosis, Disease Progression and Therapeutic Strategies. Biomedicines 2022; 10:2029. [PMID: 36009576 PMCID: PMC9405643 DOI: 10.3390/biomedicines10082029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/05/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022] Open
Abstract
Squamous cell carcinoma of the anal canal (SCCA) is a rare neoplasm, but with rising incidence rates in the past few decades; it is etiologically linked with the human papillomavirus (HPV) infection and is especially prevalent in immunocompromised patients, mainly those infected with HIV. Fluoropyrimidine-based chemoradiotherapy remains the cornerstone of the treatment of non-metastatic disease, but the locally advanced disease still presents high rates of disease recurrence and systemic therapy of SCCA is an unmet clinical need. Despite sharing common molecular aspects with other HPV-related malignancies, such as cervical and head and neck cancers, SCCA presents specific epigenomic, genomic, and transcriptomic abnormalities, which suggest that genome-guided personalized therapies should be specifically designed for this disease. Actionable mutations are rare in SCCA and immune checkpoint inhibition has not yet been proven useful in an unselected population of patients. Therefore, advances in systemic therapy of SCCA will only be possible with the identification of predictive biomarkers and the subsequent development of targeted therapies or immunotherapeutic approaches that consider the unique tumor microenvironment and the intra- and inter-tumoral heterogeneity. In the present review, we address the molecular characterization of SCCA and discuss potential diagnostic, predictive and prognostic biomarkers of this complex and challenging disease.
Collapse
Affiliation(s)
- Maria Cecília Mathias-Machado
- Department of Gastrointestinal Medical Oncology, Oncoclinicas, São Paulo 04538-132, Brazil
- Department of Oncology, ICESP—Instituto do Cancer do Estado de São Paulo, University of São Paulo, São Paulo 01246-000, Brazil
| | | | - Camila Motta Venchiarutti Moniz
- Department of Oncology, ICESP—Instituto do Cancer do Estado de São Paulo, University of São Paulo, São Paulo 01246-000, Brazil
| | - Alexandre A. Jácome
- Department of Gastrointestinal Medical Oncology, Oncoclinicas, Belo Horizonte 34000-000, Brazil
| |
Collapse
|
|
14
|
Principe DR, Cataneo JL, Timbers KE, Koch RM, Valyi-Nagy K, Mellgren A, Rana A, Gantt G. Leukocyte subtyping predicts for treatment failure and poor survival in anal squamous cell carcinoma. BMC Cancer 2022; 22:697. [PMID: 35751111 PMCID: PMC9229146 DOI: 10.1186/s12885-022-09742-7] [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: 11/09/2021] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background Anal squamous cell carcinoma (SCC) generally carries a favorable prognosis, as most tumors are highly sensitive to standard of care chemoradiation. However, outcomes are poor for the 20–30% of patients who are refractory to this approach, and many will require additional invasive procedures with no guarantee of disease resolution. Methods To identify the patients who are unlikely to respond to the current standard of care chemoradiation protocol, we explored a variety of objective clinical findings as a potential predictor of treatment failure and/or mortality in a single center retrospective study of 42 patients with anal SCC. Results Patients with an increase in total peripheral white blood cells (WBC) and/or neutrophils (ANC) had comparatively poor clinical outcomes, with increased rates of death and treatment failure, respectively. Using pre-treatment biopsies from 27 patients, tumors with an inflamed, neutrophil dominant stroma also had poor therapeutic responses, as well as reduced overall and disease-specific survival. Following chemoradiation, we observed uniform reductions in nearly all peripheral blood leukocyte subtypes, and no association between peripheral white blood cells and/or neutrophils and clinical outcomes. Additionally, post-treatment biopsies were available from 13 patients. In post-treatment specimens, patients with an inflamed tumor stroma now demonstrated improved overall and disease-specific survival, particularly those with robust T-cell infiltration. Conclusions Combined, these results suggest that routinely performed leukocyte subtyping may have utility in risk stratifying patients for treatment failure in anal SCC. Specifically, pre-treatment patients with a high WBC, ANC, and/or a neutrophil-dense tumor stroma may be less likely to achieve complete response using the standard of care chemoradiation regimen, and may benefit from the addition of a subsequent line of therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09742-7.
Collapse
Affiliation(s)
- Daniel R Principe
- Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA.,Department of Surgery, University of Illinois at Chicago, IL, Chicago, USA
| | - Jose L Cataneo
- Department of Surgery, University of Illinois at Chicago, IL, Chicago, USA
| | - Kaytlin E Timbers
- Department of Surgery, University of Illinois at Chicago, IL, Chicago, USA
| | - Regina M Koch
- Department of Surgery, University of Illinois at Chicago, IL, Chicago, USA
| | - Klara Valyi-Nagy
- Department of Pathology, University of Illinois at Chicago, IL, Chicago, USA
| | - Anders Mellgren
- Department of Surgery, Division of Colorectal Surgery, University of Illinois at Chicago, Chicago, IL, USA
| | - Ajay Rana
- Department of Surgery, University of Illinois at Chicago, IL, Chicago, USA.,Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Gerald Gantt
- Department of Surgery, Division of Colorectal Surgery, University of Illinois at Chicago, Chicago, IL, USA.
| |
Collapse
|
|
15
|
Metastatic Anal Squamous Cell Carcinoma Presenting as an Indeterminate Biliary Stricture Diagnosed By Cholangioscopy. ACG Case Rep J 2022; 9:e00785. [PMID: 35765678 PMCID: PMC9232361 DOI: 10.14309/crj.0000000000000785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 02/02/2022] [Indexed: 11/17/2022] Open
Abstract
Anal squamous cell carcinoma (SCC) rarely metastasizes outside the pelvis. Although liver involvement has been described, biliary strictures from metastatic disease are exceedingly rare. We report a case of a patient with metastatic anal SCC presenting as a biliary stricture, which was identified on endoscopic retrograde cholangiopancreatography with single-operator cholangioscopy. Direct visualization of the stricture with single-operator cholangioscopy may prove critical in obtaining a timely diagnosis. Therapeutic options for metastatic anal SCC are limited, but chemotherapy can be considered, and surgical resection is an option for limited disease.
Collapse
|
|
16
|
Sauerbrei W, Haeussler T, Balmford J, Huebner M. Structured reporting to improve transparency of analyses in prognostic marker studies. BMC Med 2022; 20:184. [PMID: 35546237 PMCID: PMC9095054 DOI: 10.1186/s12916-022-02304-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 02/17/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Factors contributing to the lack of understanding of research studies include poor reporting practices, such as selective reporting of statistically significant findings or insufficient methodological details. Systematic reviews have shown that prognostic factor studies continue to be poorly reported, even for important aspects, such as the effective sample size. The REMARK reporting guidelines support researchers in reporting key aspects of tumor marker prognostic studies. The REMARK profile was proposed to augment these guidelines to aid in structured reporting with an emphasis on including all aspects of analyses conducted. METHODS A systematic search of prognostic factor studies was conducted, and fifteen studies published in 2015 were selected, three from each of five oncology journals. A paper was eligible for selection if it included survival outcomes and multivariable models were used in the statistical analyses. For each study, we summarized the key information in a REMARK profile consisting of details about the patient population with available variables and follow-up data, and a list of all analyses conducted. RESULTS Structured profiles allow an easy assessment if reporting of a study only has weaknesses or if it is poor because many relevant details are missing. Studies had incomplete reporting of exclusion of patients, missing information about the number of events, or lacked details about statistical analyses, e.g., subgroup analyses in small populations without any information about the number of events. Profiles exhibit severe weaknesses in the reporting of more than 50% of the studies. The quality of analyses was not assessed, but some profiles exhibit several deficits at a glance. CONCLUSIONS A substantial part of prognostic factor studies is poorly reported and analyzed, with severe consequences for related systematic reviews and meta-analyses. We consider inadequate reporting of single studies as one of the most important reasons that the clinical relevance of most markers is still unclear after years of research and dozens of publications. We conclude that structured reporting is an important step to improve the quality of prognostic marker research and discuss its role in the context of selective reporting, meta-analysis, study registration, predefined statistical analysis plans, and improvement of marker research.
Collapse
Affiliation(s)
- Willi Sauerbrei
- Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.
| | - Tim Haeussler
- Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - James Balmford
- Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Marianne Huebner
- Department of Statistics and Probability, Michigan State University, East Lansing, MI, USA
| |
Collapse
|
|
17
|
Domröse CM, Wieland U, Pilch H, Einzmann T, Schömig-Markiefka B, Mallmann P, Silling S, Mallmann MR. Cervical Intraepithelial Neoplasia 3 (Cervical Intraepithelial Neoplasia 3/High-Grade Squamous Intraepithelial Lesion) in Human Papillomavirus-Vaccinated Women-Results From a Tertiary Referral Center. J Low Genit Tract Dis 2022; 26:122-126. [PMID: 35019900 DOI: 10.1097/lgt.0000000000000653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE High-grade cervical intraepithelial neoplasia (CIN 3) still develops in some vaccinated women despite established effectiveness of prophylactic human papillomavirus (HPV) vaccination. The purpose of this study was to define characteristics of women with CIN 3 after HPV vaccination referred to a gynecological dysplasia unit. MATERIALS AND METHODS Retrospective analysis of HPV-vaccinated women with CIN 3 in a single German center. Between July 2018 and September 2020, 791 women were referred to our university hospital-based dysplasia unit for colposcopic evaluation of abnormal cytological findings. Human papillomavirus vaccination status was retrieved. Human papillomavirus typing was performed in lesional biopsies and cervical swabs. RESULTS Nine women were identified who had previously been vaccinated with the quadrivalent HPV vaccine (Q-HPV) and were diagnosed with histologically confirmed CIN 3/high-grade squamous intraepithelial lesion. The Q-HPV had been administered between 12 and 28 years of age and 1-13 years before CIN 3 diagnosis. Nine different high-risk (HR)-HPV types were found in the CIN 3 biopsies, 6 monoinfections (twice HPV 16, once HPV 18, HPV 31, HPV 52, HPV 58, respectively) and 3 dual infections (HPV 33 + 52, HPV 51 + 52, HPV 53 + 66). Seven of these 9 HR-HPV types are not covered by Q-HPV, but only 2 CIN 3 lesions carried HR-HPV types not included in the nonavalent HPV vaccine. CONCLUSIONS It is important to implement vaccination recommendations and administer HPV vaccination as early as possible in HPV-naive individuals. Because not all HR-HPV types are covered by the available HPV vaccines, other types may still cause CIN 3/high-grade squamous intraepithelial lesion. This requires further screening after vaccination, especially in women who were previously vaccinated with the bivalent or the quadrivalent HPV vaccine.
Collapse
Affiliation(s)
- Christian Markus Domröse
- Department of Obstetrics and Gynecology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Ulrike Wieland
- Institute of Virology, National Reference Center for Papilloma and Polyomaviruses, University of Cologne, Cologne, Germany
| | - Henryk Pilch
- Department of Obstetrics and Gynecology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Thomas Einzmann
- Department of Obstetrics and Gynecology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | | | - Peter Mallmann
- Department of Obstetrics and Gynecology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Steffi Silling
- Institute of Virology, National Reference Center for Papilloma and Polyomaviruses, University of Cologne, Cologne, Germany
| | - Michael Rudolf Mallmann
- Department of Obstetrics and Gynecology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| |
Collapse
|
|
18
|
Evaluation of prognostic factors after primary chemoradiotherapy of anal cancer: A multicenter study of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG). Radiother Oncol 2022; 167:233-238. [PMID: 34999135 DOI: 10.1016/j.radonc.2021.12.050] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/21/2021] [Accepted: 12/31/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND PURPOSE Prognosis after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) shows marked differences among patients according to TNM subgroups, however individualized risk assessment tools to better stratify patients for treatment (de-) escalation or intensified follow-up are lacking in ASCC. MATERIALS AND METHODS Patients' data from eight sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG), comprising a total of 605 patients with ASCC, treated with standard definitive CRT with 5-FU/Mitomycin C or Capecitabine/Mitomycin C between 2004-2018, were used to evaluate prognostic factors based on Cox regression models for disease-free survival (DFS). Evaluated variables included age, gender, Karnofsky performance score (KPS), HIV-status, T-category, lymph node status and laboratory parameters. Multivariate cox models were separately constructed for the whole cohort and the subset of patients with early-stage (cT1-2 N0M0) tumors. RESULTS After a median follow-up of 46 months, 3-year DFS for patients with early-stage ASCC was 84.9%, and 67.1% for patients with locally-advanced disease (HR 2.4, p < 0.001). T-category (HR vs. T1: T2 2.02; T3 2.11; T4 3.03), N-category (HR versus N0: 1.8 for N1-3), age (HR 1.02 per year), and KPS (HR 0.8 per step) were significant predictors for DFS in multivariate analysis in the entire cohort. The model performed with a C-index of 0.68. In cT1-2N0 patients, T-category (HR 2.14), HIV status (HR 2.57), age (1.026 per year), KPS (HR 0.7 per step) and elevated platelets (HR 1.3 per 100/nl) were associated with worse DFS (C-index of 0.7). CONCLUSION Classical clinicopathologic parameters like T-category, N-category, age and KPS remain to be significant prognostic factors for DFS in patients treated with contemporary CRT for ASCC. HIV and platelets were significantly associated with worse DFS in patients with early stage ASCC.
Collapse
|
|
19
|
Guerra GR, Kong JC, Millen RM, Read M, Liu DS, Roth S, Sampurno S, Sia J, Bernardi MP, Chittleborough TJ, Behrenbruch CC, Teh J, Xu H, Haynes NM, Yu J, Lupat R, Hawkes D, Di Costanzo N, Tothill RW, Mitchell C, Ngan SY, Heriot AG, Ramsay RG, Phillips WA. Molecular and genomic characterisation of a panel of human anal cancer cell lines. Cell Death Dis 2021; 12:959. [PMID: 34663790 PMCID: PMC8523722 DOI: 10.1038/s41419-021-04141-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 06/27/2021] [Accepted: 06/30/2021] [Indexed: 12/20/2022]
Abstract
Anal cancer is a rare disease that has doubled in incidence over the last four decades. Current treatment and survival of patients with this disease has not changed substantially over this period of time, due, in part, to a paucity of preclinical models to assess new therapeutic options. To address this hiatus, we set-out to establish, validate and characterise a panel of human anal squamous cell carcinoma (ASCC) cell lines by employing an explant technique using fresh human ASCC tumour tissue. The panel of five human ASCC cell lines were validated to confirm their origin, squamous features and tumourigenicity, followed by molecular and genomic (whole-exome sequencing) characterisation. This panel recapitulates the genetic and molecular characteristics previously described in ASCC including phosphoinositide-3-kinase (PI3K) mutations in three of the human papillomavirus (HPV) positive lines and TP53 mutations in the HPV negative line. The cell lines demonstrate the ability to form tumouroids and retain their tumourigenic potential upon xenotransplantation, with varied inducible expression of major histocompatibility complex class I (MHC class I) and Programmed cell death ligand 1 (PD-L1). We observed differential responses to standard chemotherapy, radiotherapy and a PI3K specific molecular targeted agent in vitro, which correlated with the clinical response of the patient tumours from which they were derived. We anticipate this novel panel of human ASCC cell lines will form a valuable resource for future studies into the biology and therapeutics of this rare disease.
Collapse
Affiliation(s)
- Glen R Guerra
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.
| | - Joseph C Kong
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Rosemary M Millen
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Matthew Read
- Department of Surgery, St Vincent's Hospital, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - David S Liu
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
- UGI Surgery Unit, Austin Hospital, 145 Studley Road, Heidelberg, Victoria, 3084, Australia
| | - Sara Roth
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Shienny Sampurno
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Joseph Sia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Division of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Maria-Pia Bernardi
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Timothy J Chittleborough
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Corina C Behrenbruch
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Jiasian Teh
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Huiling Xu
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Nicole M Haynes
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Jiaan Yu
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Richard Lupat
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - David Hawkes
- Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, 3010, Australia
- VCS Foundation, Carlton, VIC, 3053, Australia
- Department of Pathology, University of Malaya, Kuala Lumpur, Malaysia
| | - Natasha Di Costanzo
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Richard W Tothill
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Centre for Cancer Research, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Catherine Mitchell
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Samuel Y Ngan
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Division of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
| | - Alexander G Heriot
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Department of Surgery, St Vincent's Hospital, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Robert G Ramsay
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia
| | - Wayne A Phillips
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.
- Department of Surgery, St Vincent's Hospital, The University of Melbourne, Parkville, VIC, 3010, Australia.
| |
Collapse
|
|
20
|
Gerum S, Iglseder W, Schmid R, Peterka K, Knocke-Abulesz TH, Harl P, Schwaiger S, Reiter I, Salinger J, Venhoda C, Kurzweil G, Poetscher M, Jaeger R, Celedin B, Clemens P, Roeder F. Practice of radiation therapy for anal cancer in Austria-a survey on behalf of the Austrian radiation oncology society gastrointestinal tumor group (ÖGRO-GIT). Strahlenther Onkol 2021; 197:953-961. [PMID: 34591119 PMCID: PMC8547205 DOI: 10.1007/s00066-021-01842-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/09/2021] [Indexed: 11/23/2022]
Abstract
Purpose We conducted a patterns-of-care survey on chemoradiation for locoregionally confined anal cancer in Austria to evaluate areas of disagreement and to identify possible targets for further standardization. Methods An anonymous questionnaire comprising 38 questions was sent to all Austrian radiation oncology departments. Results were analyzed descriptively and compared to two international guidelines. Results The response rate was 93%. Work-up generally includes DRE, endoscopy, and cross-sectional imaging of chest/abdomen and pelvis. PET-CT is used by 38%. Screening for HIV and biopsies of suspicious lymph nodes are infrequently used. All centers perform IMRT, mainly with daily IGRT. Median doses to the primary are 54.7 Gy (T1–2) and 59.4 Gy (T3–4). Suspicious nodes receive a boost (median dose 54 Gy), while elective nodal areas are mainly treated with 45–50.4 Gy. Target delineation of elective nodal areas seems generally uniform, although disagreement exists regarding inclusion of the common iliac nodes. No agreement was found for OAR-delineation and dose constraints. Concurrent chemotherapy is mitomycin and 5‑FU/capecitabine. Supportive care beyond skin care is infrequently offered. Intensive follow-up is performed for at least 5 years. Treatment of T1N0 shows considerable disagreement. Conclusion We found a high rate of agreement between the centers and concordance with major guidelines. PET-CT, routine HIV testing, and biopsies of suspicious LN seem underrepresented. The largest controversy regarding target volumes concerns inclusion of the common iliac nodes. Prescribed doses are generally in line with the recommendations or higher. OAR delineation, dose constraints, supportive care, and treatment of early anal cancer represent areas for further standardization. Supplementary Information The online version of this article (10.1007/s00066-021-01842-w) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- S Gerum
- Universitätsklinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Uniklinikum der Paracelsus Medizinischen Universität, Müllner Hauptstraße 48, 5020, Salzburg, Austria.
| | - W Iglseder
- Universitätsklinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Uniklinikum der Paracelsus Medizinischen Universität, Müllner Hauptstraße 48, 5020, Salzburg, Austria
| | - R Schmid
- Universitätsklinik für Radioonkologie, Medizinische Universität Wien, Universitätsklinikum AKH Wien, Comprehensive Cancer Center Vienna, Währinger Gürtel 18-20, 1090, Wien, Austria
| | - K Peterka
- Institut für Radioonkologie, Kaiser-Franz-Josef-Spital/SMZ Süd-Klinik Favoriten, Kundratstraße 3, 1100, Wien, Austria
| | - T H Knocke-Abulesz
- Sonderabteilung Strahlentherapie, Wiener Gesundheitsverbund Klinik Hietzing, Wolkersbergenstraße 1, 1130, Wien, Austria
| | - P Harl
- Institut für Radioonkologie, SMZ - Ost Donauspital der Stadt Wien, Langobardenstraße 122, 1220, Wien, Austria
| | - S Schwaiger
- Institut für Radioonkologie, Klinik Ottakring, Wilhelminenspital der Stadt Wien, Montleartstraße 37, 1160, Wien, Austria
| | - I Reiter
- Institut für Radioonkologie und Strahlentherapie, Landesklinikum Wiener Neustadt, Corvinusring 3-5, 2700, Wiener Neustadt, Germany
| | - J Salinger
- Klinische Abteilung für Strahlentherapie - Radioonkologie, Universitätsklinikum Krems, Karl Landsteiner Privatuniversität für Gesundheitswissenschaften, Mitterweg 10, 3500, Krems an der Donau, Austria
| | - C Venhoda
- Klinik für Radioonkologie, Klinikum der Barmherzigen Schwestern, Ordensklinikum Linz, Seilerstätte 4, 4010, Linz, Austria
| | - G Kurzweil
- Klinik für Radioonkologie/Strahlentherapie, Salzkammergutklinikum Vöcklabruck, Dr.-Wilhelm-Boch-Straße 1, 4840, Vöcklabruck, Austria
| | - M Poetscher
- Universitätsklinik für Strahlentherapie - Radioonkologie, Comprehensive Cancer Center Graz, Medizinische Universität Graz, Auenbruggerplatz 32, 8036, Graz, Austria
| | - R Jaeger
- Universitätsklinik für Strahlentherapie - Radioonkologie, Medizinische Universität Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - B Celedin
- Institut für Strahlentherapie/Radioonkologie, Klinikum Klagenfurt am Wörthersee, Feschnigstraße 11, 9020, Klagenfurt, Austria
| | - P Clemens
- Institut für Radioonkologie und Strahlentherapie, Landeskrankenhaus Feldkirch, Carinagasse 47, 6807, Feldkirch, Austria
| | - F Roeder
- Universitätsklinik für Radiotherapie und Radio-Onkologie, Landeskrankenhaus Salzburg, Uniklinikum der Paracelsus Medizinischen Universität, Müllner Hauptstraße 48, 5020, Salzburg, Austria
| |
Collapse
|
|
21
|
Guren MG, Sebag-Montefiore D, Franco P, Johnsson A, Segelov E, Deutsch E, Rao S, Spindler KLG, Arnold D. Treatment of Squamous Cell Carcinoma of the Anus, Unresolved Areas and Future Perspectives for Research: Perspectives of Research Needs in Anal Cancer. Clin Colorectal Cancer 2021; 20:279-287. [PMID: 34645589 DOI: 10.1016/j.clcc.2021.09.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/30/2021] [Accepted: 09/09/2021] [Indexed: 01/12/2023]
Abstract
Anal cancer is a relatively rare, mostly HPV-related cancer. The curative treatment consists of concurrent chemoradiation delivered with modern radiotherapy techniques. The prognosis for most patients with early localized disease is very favourable; however patients with locally advanced disease and/or HPV negative tumours are at higher risk of locoregional and distant treatment failure. Tailored approaches are presently being investigated to determine the most suitable regimen in terms of radiotherapy dose prescription, target volume selection, normal tissue avoidance, and combination therapy. Metastatic anal cancer is treated with chemotherapy aiming at prolonged survival. The role of immune therapy in the clinical setting is being investigated. There is little knowledge on the biology of anal cancer, and an urgent need for more clinical and translational research dedicated to this disease. In this article, the evidence-base for the current treatment is briefly reviewed, and perspectives on future research needs are high-lighted.
Collapse
Affiliation(s)
| | | | - Pierfrancesco Franco
- Department of Translational Medicine, University of Eastern Piedmont and Department of Radiation Oncology, AOU ''Maggiore della Carità,'' Novara, Italy
| | - Anders Johnsson
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
| | - Eva Segelov
- School of Clinical Sciences, Faculty of Medicine, Monash University, Clayton, Australia and Department of Oncology, Monash Health Clayton, Australia
| | | | - Sheela Rao
- GI Unit, Royal Marsden Hospital, London, UK
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, AK Altona, Hamburg, Germany
| |
Collapse
|
|
22
|
Turchan WT, Liauw SL. Chemoradiation for Anal Cancer: Clinical Outcomes and Strategies to Optimize the Therapeutic Ratio According to HPV Status. Semin Radiat Oncol 2021; 31:349-360. [PMID: 34455990 DOI: 10.1016/j.semradonc.2021.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The incidence of anal cancer in the United States has increased in recent years, primarily related to the increasing incidence of HPV-associated anal squamous cell carcinoma, which is estimated to represent 80%-95% of anal cancers. Similar to head and neck cancer, HPV association has been demonstrated to be a strong positive prognostic factor in patients with anal cancer. Encouraging results from a number of studies investigating treatment de-escalation for HPV-associated oropharyngeal cancer support the notion that similar attempts may be feasible in HPV-associated anal cancer; however, the data to support this hypothesis are currently lacking. Studies are needed to determine how, if at all, HPV status should impact the management of patients with anal cancer. This review summarizes the relationship between HPV association and outcomes for patients with anal cancer, and how HPV status may impact the treatment of patients with anal cancer going forward.
Collapse
Affiliation(s)
| | - Stanley L Liauw
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL.
| |
Collapse
|
|
23
|
|
|
24
|
Wakeham K, Murray L, Muirhead R, Hawkins MA, Sebag-Montefiore D, Brown S, Murphy L, Thomas G, Bell S, Whibley M, Morgan C, Sleigh K, Gilbert DC. Multicentre Investigation of Prognostic Factors Incorporating p16 and Tumour Infiltrating Lymphocytes for Anal Cancer After Chemoradiotherapy. Clin Oncol (R Coll Radiol) 2021; 33:638-649. [PMID: 34024700 DOI: 10.1016/j.clon.2021.04.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/09/2021] [Accepted: 04/27/2021] [Indexed: 11/30/2022]
Abstract
AIMS Anal squamous cell carcinomas (ASCC) are strongly associated with human papillomaviruses. Standard of care is chemoradiotherapy at uniform doses with no treatment stratification. Immunohistochemical staining for p16INK4A (p16), a surrogate for human papillomaviruses, is prognostic for outcomes. We investigated this alongside clinical-pathological factors, including tumour infiltrating lymphocyte (TIL) scores. MATERIALS AND METHODS Using an independent, multicentre cohort of 257 ASCC treated with chemoradiotherapy, pretreatment biopsies were stained and scored for p16 and TIL. Kaplan-Meier curves were derived for outcomes (disease-free survival [DFS], overall survival and cancer-specific survival), by stage, p16 and TIL scores and Log-rank tests were carried out to investigate prognostic effect. A multivariate analysis was carried out using Cox regression. RESULTS Stage, sex, p16 and TILs were independently prognostic. Hazard ratios for death (overall survival) were 2.51 (95% confidence interval 1.36-4.63) for p16 negative versus p16 positive, 2.17 (1.34-3.5) for T3/4 versus T1/2, 2.42 (1.52-3.8) for males versus females and 3.30 (1.52-7.14) for TIL1 versus TIL3 (all P < 0.05). CONCLUSIONS We have refined prognostic factors in ASCC. p16 adds to stratification by stage with respect to DFS in early disease and overall survival/DFS in locally advanced cancers. Our data support the role of the host immune response in mediating outcomes. These factors will be prospectively evaluated in PLATO (ISRCTN88455282).
Collapse
Affiliation(s)
- K Wakeham
- Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - L Murray
- Leeds Institute of Medical Research, University of Leeds, Leeds Cancer Centre, Leeds, UK
| | - R Muirhead
- Oxford University Hospitals NHS Trust, Department of Oncology, Churchill Hospital, Oxford, UK
| | - M A Hawkins
- University College London, Medical Physics and Biomedical Engineering, London, UK
| | - D Sebag-Montefiore
- Leeds Institute of Medical Research, University of Leeds, Leeds Cancer Centre, Leeds, UK
| | - S Brown
- Clinical Trials Research Unit, University of Leeds, Leeds, UK
| | - L Murphy
- MRC Clinical Trials Unit at UCL, London, UK
| | - G Thomas
- Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - S Bell
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - M Whibley
- Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, UK
| | - C Morgan
- Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, UK
| | - K Sleigh
- Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, UK
| | - D C Gilbert
- MRC Clinical Trials Unit at UCL, London, UK.
| |
Collapse
|
|
25
|
Braun SA, Silling S, Schloer SM, Hofmann SC, Fritzen B, Oellig F, Lehmann P, Homey B, Assaf C, Emmert S, Fölster-Holst R, Tigges C, Wieland U, Kreuter A. Human Papillomavirus-type distribution in anogenital lesions of prepubertal children. J Eur Acad Dermatol Venereol 2021; 35:1219-1225. [PMID: 33428291 DOI: 10.1111/jdv.17114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/10/2020] [Indexed: 11/27/2022]
Abstract
BACKGROUND In contrast to adults, only limited data are available on the human papillomavirus (HPV)-type spectrum in anogenital warts (AGW) of children. OBJECTIVE This study aimed to evaluate the HPV-type spectrum in AGW of prepubertal children. MATERIALS & METHODS In a retrospective German multicentre study, HPV genotyping was performed in AGW biopsies of 55 1- to 12-year-old children using HPV group-specific PCRs followed by hybridization with type-specific probes or sequence analysis. RESULTS Human papillomavirus-DNA was found in 53 of the 55 AGW. In 58.5% (31/53) of the HPV-positive AGW, mucosal HPV types were detected. HPV6 (27/53, 50.9%) was the predominant type. 43.4% (23/53) of the lesions were induced by cutaneous HPV types (HPV2, HPV27, HPV57). Mucosal HPV types were significantly more common in children under 5 years of age than in children 5 years of age and older (22/25, 88.0% [95% CI: 70.0-95.8] vs. 9/28, 32.1% [95% CI: 17.9-50.7], P < 0.001). In contrast, cutaneous HPV types were significantly more prevalent in the 5- to 12-year age group (4/25, 16.0% [95% CI 6.4-34.7] vs. 19/28, 67.9% [95% CI 49.3-82.1], P < 0.001). CONCLUSION Anogenital warts in 5- to 12-year-old children are frequently associated with cutaneous HPV types, possibly due to horizontal transmission. HPV typing, in addition to comprehensive clinical and psychosocial evaluation, can potentially help in the assessment of these cases.
Collapse
Affiliation(s)
- S A Braun
- Department of Dermatology, University Hospital Muenster, Muenster, Germany.,Department of Dermatology, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany
| | - S Silling
- Institute of Virology, National Reference Center for Papilloma and Polyomaviruses, University of Cologne, Cologne, Germany
| | - S M Schloer
- Center for Molecular Biology of Inflammation, Institute of Medical Biochemistry, University of Muenster, Muenster, Germany
| | - S C Hofmann
- Department of Dermatology, Allergology, und Dermatosurgery, HELIOS University Hospital Wuppertal, University of Witten-Herdecke, Wuppertal, Germany
| | - B Fritzen
- Department of Dermatology and Venereology, HELIOS Hospital Krefeld, Krefeld, Germany
| | - F Oellig
- Institute of Pathology, Mülheim a.d.R., Germany
| | - P Lehmann
- Department of Dermatology, Allergology, und Dermatosurgery, HELIOS University Hospital Wuppertal, University of Witten-Herdecke, Wuppertal, Germany
| | - B Homey
- Department of Dermatology, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany
| | - C Assaf
- Department of Dermatology and Venereology, HELIOS Hospital Krefeld, Krefeld, Germany
| | - S Emmert
- Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, Rostock, Germany
| | - R Fölster-Holst
- Department of Dermatology, Christian-Albrechts-University, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - C Tigges
- Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital Oberhausen, University of Witten-Herdecke, Oberhausen, Germany
| | - U Wieland
- Institute of Virology, National Reference Center for Papilloma and Polyomaviruses, University of Cologne, Cologne, Germany
| | - A Kreuter
- Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital Oberhausen, University of Witten-Herdecke, Oberhausen, Germany
| |
Collapse
|
|
26
|
Bruyere D, Monnien F, Colpart P, Roncarati P, Vuitton L, Hendrick E, Lepinoy A, Luquain A, Pilard C, Lerho T, Molimard C, Maingon P, Arnould L, Bone-Lepinoy MC, Dusserre L, Martin L, Reynders C, Ancion M, Peiffert D, Leroux A, Hubert P, Delhorme JB, Ghnassia JP, Woronoff AS, Delvenne P, Prétet JL, Bosset JF, Peulen O, Mougin C, Valmary-Degano S, Herfs M. Treatment algorithm and prognostic factors for patients with stage I-III carcinoma of the anal canal: a 20-year multicenter study. Mod Pathol 2021; 34:116-130. [PMID: 32728225 DOI: 10.1038/s41379-020-0637-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/15/2020] [Accepted: 07/15/2020] [Indexed: 01/01/2023]
Abstract
Despite a growing incidence in developed countries and a recent improved understanding of its pathogenesis, anal cancer management has not evolved over the past decades and drug combination used as first-line regimen still largely depends on clinician preferences. Aiming at paving the way for precision medicine, a large cohort of 372 HIV-negative patients diagnosed over a 20-year time period with locally advanced anal carcinoma was collected and carefully characterized at the clinical, demographic, histopathologic, immunologic, and virologic levels. Both the prognostic relevance of each clinicopathological parameter and the efficacy of different concurrent chemoradiation strategies were determined. Overall, the incidence of anal cancer peaked during the sixth decade (mean: 63.4) and females outnumbered males (ratio: 2.51). After completion of treatment, 95 (25.5%) patients experienced progression of persistent disease or local/distant recurrence and 102 (27.4%) died during the follow-up period (median: 53.8 months). Importantly, uni-multivariate analyses indicated that both negative HPV/p16ink4a status and aberrant p53 expression were far better predictors for reduced progression-free survival than traditional risk factors such as tumor size and nodal status. As for overall survival, the significant influences of age at diagnosis, p16ink4a status, cTNM classification as well as both CD3+ and CD4+ T-cell infiltrations within tumor microenvironment were highlighted. Cisplatin-based chemoradiotherapy was superior to both radiotherapy alone and other concurrent chemoradiation therapies in the treatment of HPV-positive tumors. Regarding their HPV-uninfected counterparts, frequent relapses were observed, whatever the treatment regimen administered. Taken together, our findings reveal that current anal cancer management and treatment have reached their limits. A dualistic classification according to HPV/p53 status should be considered with implications for therapy personalization and optimization.
Collapse
Affiliation(s)
- Diane Bruyere
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | - Franck Monnien
- Department of Pathology, University Hospital of Besançon, 25000, Besançon, France
| | - Prudence Colpart
- Department of Pathology, University Hospital of Besançon, 25000, Besançon, France
| | - Patrick Roncarati
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | - Lucine Vuitton
- Department of Gastroenterology, University Hospital of Besançon, 25000, Besançon, France.,EA3181, University Bourgogne Franche-Comté, LabEx LipSTIC ANR-11-LABX-0021, 25000, Besançon, France
| | - Elodie Hendrick
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | | | - Alexandra Luquain
- Department of Pathology, University Hospital of Besançon, 25000, Besançon, France
| | - Charlotte Pilard
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | - Thomas Lerho
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | - Chloé Molimard
- Department of Pathology, University Hospital of Besançon, 25000, Besançon, France
| | - Philippe Maingon
- Department of Radiation Oncology, Georges-François Leclerc Center, 21000, Dijon, France.,Department of Radiation Oncology, La Pitié Salpêtrière University Hospital, Sorbonne University, 75013, Paris, France
| | - Laurent Arnould
- Department of Biology and Pathology of Tumors, Georges-François Leclerc Center, 21000, Dijon, France
| | | | | | - Laurent Martin
- Department of Pathology, University Hospital of Dijon, 21000, Dijon, France
| | - Celia Reynders
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | - Marie Ancion
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | - Didier Peiffert
- Department of Radiation Oncology, Lorraine Institute of Oncology, 54519, Vandœuvre-lès-Nancy, France
| | - Agnès Leroux
- Department of Pathology, Lorraine Institute of Oncology, 54519, Vandœuvre-lès-Nancy, France
| | - Pascale Hubert
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | - Jean-Baptiste Delhorme
- Department of Digestive Surgery, University Hospital of Strasbourg, 67200, Strasbourg, France
| | | | - Anne-Sophie Woronoff
- Doubs and Belfort Territory Cancer Registry, University Hospital of Besançon, 25000, Besançon, France
| | - Philippe Delvenne
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium.,Department of Pathology, University Hospital of Liege, 4000, Liege, Belgium
| | - Jean-Luc Prétet
- EA3181, University Bourgogne Franche-Comté, LabEx LipSTIC ANR-11-LABX-0021, 25000, Besançon, France.,CNR Papillomavirus, University Hospital of Besançon, 25000, Besançon, France
| | - Jean-François Bosset
- Department of Radiation Oncology, University Hospital of Besançon, 25000, Besançon, France
| | - Olivier Peulen
- Metastasis Research Laboratory, GIGA-Cancer, University of Liege, 4000, Liege, Belgium
| | - Christiane Mougin
- EA3181, University Bourgogne Franche-Comté, LabEx LipSTIC ANR-11-LABX-0021, 25000, Besançon, France.,CNR Papillomavirus, University Hospital of Besançon, 25000, Besançon, France
| | - Séverine Valmary-Degano
- Department of Pathology, University Hospital of Besançon, 25000, Besançon, France.,EA3181, University Bourgogne Franche-Comté, LabEx LipSTIC ANR-11-LABX-0021, 25000, Besançon, France.,Department of Pathology, University Hospital of Grenoble-Alps, 38043, Grenoble cedex 9, France
| | - Michael Herfs
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000, Liege, Belgium.
| |
Collapse
|
|
27
|
Marônek M, Link R, Monteleone G, Gardlík R, Stolfi C. Viruses in Cancers of the Digestive System: Active Contributors or Idle Bystanders? Int J Mol Sci 2020; 21:ijms21218133. [PMID: 33143318 PMCID: PMC7663754 DOI: 10.3390/ijms21218133] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/29/2020] [Indexed: 12/13/2022] Open
Abstract
The human virome, which is a collection of all the viruses that are present in the human body, is increasingly being recognized as an essential part of the human microbiota. The human gastrointestinal tract and related organs (e.g., liver, pancreas, and gallbladder)-composing the gastrointestinal (or digestive) system-contain a huge number of viral particles which contribute to maintaining tissue homeostasis and keeping our body healthy. However, perturbations of the virome steady-state may, both directly and indirectly, ignite/sustain oncogenic mechanisms contributing to the initiation of a dysplastic process and/or cancer progression. In this review, we summarize and discuss the available evidence on the association and role of viruses in the development of cancers of the digestive system.
Collapse
Affiliation(s)
- Martin Marônek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia; (M.M.); (R.G.)
| | - René Link
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, 040 11 Košice, Slovakia;
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Roman Gardlík
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia; (M.M.); (R.G.)
| | - Carmine Stolfi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
- Division of Clinical Biochemistry and Clinical Molecular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Correspondence: ; Tel.: +39-06-72596163
| |
Collapse
|
|
28
|
Lee G, Kim DW, Muralidhar V, Mitra D, Horick NK, Eyler CE, Hong TS, Drapek LC, Allen JN, Blaszkowsky LS, Giantonio B, Parikh AR, Ryan DP, Clark JW, Wo JY. Chemoradiation-Related Lymphopenia and Its Association with Survival in Patients with Squamous Cell Carcinoma of the Anal Canal. Oncologist 2020; 25:1015-1022. [PMID: 32827337 DOI: 10.1634/theoncologist.2019-0759] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 07/29/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Although treatment-related lymphopenia (TRL) is common and associated with poorer survival in multiple solid malignancies, few data exist for anal cancer. We evaluated TRL and its association with survival in patients with anal cancer treated with chemoradiation (CRT). MATERIALS AND METHODS A retrospective analysis of 140 patients with nonmetastatic anal squamous cell carcinoma (SCC) treated with definitive CRT was performed. Total lymphocyte counts (TLC) at baseline and monthly intervals up to 12 months after initiating CRT were analyzed. Multivariable Cox regression analysis was performed to evaluate the association between overall survival (OS) and TRL, dichotomized by grade (G)4 TRL (<0.2k/μL) 2 months after initiating CRT. Kaplan-Meier and log-rank tests were used to compare OS between patients with versus without G4 TRL. RESULTS Median time of follow-up was 55 months. Prior to CRT, 95% of patients had a normal TLC (>1k/μL). Two months after initiating CRT, there was a median of 71% reduction in TLC from baseline and 84% of patients had TRL: 11% G1, 31% G2, 34% G3, and 8% G4. On multivariable Cox model, G4 TRL at two months was associated with a 3.7-fold increased risk of death. On log-rank test, the 5-year OS rate was 32% in the cohort with G4 TRL versus 86% in the cohort without G4 TRL. CONCLUSION TRL is common and may be another prognostic marker of OS in anal cancer patients treated with CRT. The association between TRL and OS suggests an important role of the host immunity in anal cancer outcomes. IMPLICATIONS FOR PRACTICE This is the first detailed report demonstrating that standard chemoradiation (CRT) commonly results in treatment-related lymphopenia (TRL), which may be associated with a poorer overall survival (OS) in patients with anal squamous cell carcinoma. The association between TRL and worse OS observed in this study supports the importance of host immunity in survival among patients with anal cancer. These findings encourage larger, prospective studies to further investigate TRL, its predictors, and its relationship with survival outcomes. Furthermore, the results of this study support ongoing efforts of clinical trials to investigate the potential role of immunotherapy in anal cancer.
Collapse
Affiliation(s)
- Grace Lee
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Daniel W Kim
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Vinayak Muralidhar
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Devarati Mitra
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Nora K Horick
- Massachusetts General Hospital Biostatistics Center, Boston, Massachusetts, USA
| | - Christine E Eyler
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lorraine C Drapek
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jill N Allen
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lawrence S Blaszkowsky
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Bruce Giantonio
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aparna R Parikh
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David P Ryan
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jeffrey W Clark
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| |
Collapse
|
|
29
|
Dahl O, Myklebust MP, Dale JE, Leon O, Serup-Hansen E, Jakobsen A, Pfeiffer P, Løes IM, Pfeffer F, Spindler KLG, Guren MG, Glimelius B, Johnsson A. Evaluation of the stage classification of anal cancer by the TNM 8th version versus the TNM 7th version. Acta Oncol 2020; 59:1016-1023. [PMID: 32574087 DOI: 10.1080/0284186x.2020.1778180] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Background: The UICC TNM 7th edition introduced stage groups for anal cancer which in 2019 has not yet come into general use. The new TNM 8th edition from 2016 defines 7 sub-stages. Background data for these changes are lacking. We aimed to investigate whether the new classification for anal cancer reliably predict the prognosis in the different stages.Patients and methods: The Nordic Anal Cancer Group (NOAC) conducted a large retrospective study of all anal cancers in Norway, Sweden and most of Denmark in 2000-2007. From the Nordic cohort 1151 anal cancer patients with follow-up data were classified by the TNM 4th edition which has identical T, N and M definitions as the TNM 7th edition, and therefore also can be classified by the TNM 7th stage groups. We used the Nordic cohort to translate the T, N and M stages into the TNM 8th stages and sub-stages. Overall survival for each stage was assessed.Results: Although the summary stage groups for TNM 8th edition discriminates patients with different prognosis reasonably well, the analyses of the seven sub-stages show overlapping overall survival: HR for stage IIA 1.30 (95%CI 0.80-2.12) is not significantly different from stage I (p = .30) and HR for stage IIB 2.35 (95%CI 1.40-3.95) and IIIA 2.48 (95%CI 1.43-4.31) are also similar as were HRs for stage IIIB 3.41 (95%CI 1.99-5.85) and IIIC 3.22 (95%CI 1.99-5.20). Similar overlapping was shown for local recurrence and distant spread.Conclusion: The results for the sub-stages calls for a revision of the staging system. We propose a modification of the TNM 8th edition for staging of anal cancer into four stages based on the T, N and M definitions of the TNM 8th classification.
Collapse
Affiliation(s)
- Olav Dahl
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, Medical Faculty, University of Bergen, Bergen, Norway
| | | | - Jon Espen Dale
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Otilia Leon
- Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Eva Serup-Hansen
- Department of Oncology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Anders Jakobsen
- Department of Oncology, Vejle Hospital, University of Southern Denmark, Vejle, Denmark
| | - Per Pfeiffer
- Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense C, Denmark
| | - Inger Marie Løes
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Frank Pfeffer
- Department of Gastroenterological Surgery, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Karen-Lise Garm Spindler
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - Marianne Grønlie Guren
- Department of Oncology and K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Anders Johnsson
- Department of Oncology, Skåne University Hospital, Lund, Sweden
| |
Collapse
|
|
30
|
Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1. Cells 2020; 9:cells9051235. [PMID: 32429458 PMCID: PMC7291120 DOI: 10.3390/cells9051235] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/14/2020] [Accepted: 05/15/2020] [Indexed: 01/13/2023] Open
Abstract
NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.
Collapse
|
|
31
|
Małusecka E, Chmielik E, Suwiński R, Giglok M, Lange D, Rutkowski T, Mazurek AM. Significance of HPV16 Viral Load Testing in Anal Cancer. Pathol Oncol Res 2020; 26:2191-2199. [PMID: 32266586 PMCID: PMC7471158 DOI: 10.1007/s12253-020-00801-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 03/04/2020] [Indexed: 11/26/2022]
Abstract
Human papilloma virus (HPV) is highly frequent among patients with anal squamous cell carcinoma, but the viral load (VL) differs between patients. This study aimed to compare the rate of HPV positivity, HPV16VL, p16INK4A and p53 expression between treatment naive and recurrent anal cancer patients. HPV was genotyped via AmpliSens® HPV HCR-genotype-titre-FRT kit. HPV16 VL was determined via quantitative polymerase chain reaction-based in-house test. p16INK4A and p53 expression was tested via immunohistochemistry. The cohort comprised 13 treatment-naive and 17 recurrent anal SCC patients. High-risk HPV was detected in 87% of cases, and HPV16 (73%) was the predominant genotype. The rate of HPV positivity was higher among women and nonsmokers, and majority of HPV-positive cases were also p16INK4A-positive. All p53-negative tumors were HPV16-positive. The most predominant p53 staining pattern in the HPV-positive group was scattered type, whereas it was diffuse type in the HPV-negative group. The HPV16 VL was higher in the treatment-naive group. Further, in the treatment-naive group, cases with scattered staining pattern of p53 had higher HPV16 VL than cases with diffuse staining pattern. The opposite result was noted in the recurrent cancer group. Moreover, p16-positive cases with scattered p53 staining pattern in the treatment naive group had higher HPV16 VL than their counterparts in the recurrent cancer group. In conclusion, the HPV VL, as is the association between VL and p16INK4A /p53, is in an inversed trend in treatment naive and recurrent cancer patients, highlighting the importance of HPV VL measurement in anal SCC.
Collapse
Affiliation(s)
- Ewa Małusecka
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102, Gliwice, Poland.
| | - Ewa Chmielik
- Tumor Pathology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland
| | - Rafał Suwiński
- II Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland
| | - Monika Giglok
- II Radiotherapy and Chemotherapy Clinic and Teaching Hospital, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland
| | - Dariusz Lange
- Tumor Pathology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland
| | - Tomasz Rutkowski
- I Radiation and Clinical Oncology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland
| | - Agnieszka M Mazurek
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, 44-102, Gliwice, Poland
| |
Collapse
|
|
32
|
Urbute A, Rasmussen CL, Belmonte F, Obermueller T, Prigge ES, Arbyn M, Verdoodt F, Kjaer SK. Prognostic Significance of HPV DNA and p16 INK4a in Anal Cancer: A Systematic Review and Meta-Analysis. Cancer Epidemiol Biomarkers Prev 2020; 29:703-710. [PMID: 32051192 DOI: 10.1158/1055-9965.epi-19-1259] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/16/2019] [Accepted: 01/27/2020] [Indexed: 12/24/2022] Open
Abstract
We conducted a systematic review and meta-analysis of observational studies evaluating survival in patients with anal cancer, according to human papillomavirus (HPV) DNA, p16INK4a, and combined HPV DNA/p16INK4a status. We systematically searched PubMed, EMBASE, and Cochrane Library databases to identify studies published in English until July 25, 2018, directly providing or allowing estimation of survival of patients with anal cancer according to the presence of HPV DNA and/or overexpression of p16INK4a We estimated pooled HRs and 95% confidence intervals (CI) for overall survival (OS) using a random-effects model. We included 16 studies, comprising 1,724 patients with anal cancer tested for HPV DNA (65% positive), and 567 patients tested for p16INK4a (87% positive). The pooled HR for OS was 0.54 (95% CI, 0.33-0.89) for HPV DNA positive versus negative, 0.37 (95% CI, 0.24-0.57) for p16INK4a positive versus negative, and 0.36 (95% CI, 0.22-0.58) for HPV DNA positive/p16INK4a positive versus HPV DNA positive/p16INK4a negative patients with anal cancer. Patients with HPV DNA or p16INK4a positive anal cancer have significantly better OS compared with HPV DNA or p16INK4a negative. This points to the possible value of HPV DNA and/or p16INK4a testing when planning the management and follow-up strategy for patients diagnosed with anal cancer.
Collapse
Affiliation(s)
- Aivara Urbute
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | | | - Federica Belmonte
- Unit of Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Theresa Obermueller
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elena-Sophie Prigge
- Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marc Arbyn
- Unit of Cancer Epidemiology, Belgian Cancer Centre, Sciensano, Brussels, Belgium
| | - Freija Verdoodt
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Susanne K Kjaer
- Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. .,Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
33
|
Kim KS, Chang AR, Kim K, Koh HK, Jang WI, Park HJ, Chang JH, Kim MS. Post-operative radiation therapy with or without chemotherapy for anal squamous cell carcinoma incidentally discovered after local excision: a propensity score matched analysis of retrospective multicenter study. Br J Radiol 2020; 93:20190667. [PMID: 31825665 PMCID: PMC7055428 DOI: 10.1259/bjr.20190667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/29/2019] [Accepted: 12/06/2019] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE To evaluate the results of post-operative radiation therapy (RT) for anal squamous cell carcinoma (ASCC) incidentally detected after excision, and compare these outcomes with those of definitive RT without excision for exploring the possibility of treatment de-intensification. METHODS AND MATERIALS A total of 25 patients with T1-2N0-1 ASCC who underwent RT following incidental tumor resection were selected from multicenter retrospective database. And, we selected one-to-one matched 25 patients receiving definitive RT from the same database using propensity score matching method, and the outcomes were compared. RESULTS Median age was 60 years (range, 30-76), and 18 patients (72%) were female. 19 patients (76%) had T0/1 tumors and four patients (16%) had regional lymph node metastases. Hemorrhoidectomy was performed in eight patients (32%) and the others underwent local excision. 12 patients (48%) had microscopic or gross residual diseases. Median RT dose to the primary lesion was 50.4 Gy (range, 40-60). Concurrent chemotherapy was delivered to 23 patients (92%). Median follow-up period was 71 months (range, 4.5-203.1 months). None of the patients showed recurrence during follow-up. However, one patient died after 6 months due to the chemotherapy-related hematologic toxicity. When compared with those patients receiving definitive RT, clinicopathological variables were well-balanced between the two groups. While matched paired patients treated with definitive RT received a higher median RT dose of 54 Gy (range, 45-61.2) and concurrent chemotherapy was given to 22 patients (88%), overall survival was not significantly different (p = 0.262). CONCLUSION Patients treated with RT for early stage ASCC after local excision showed favorable treatment outcomes. Further study is warranted to justify the de-intensification of the treatment for these patients. ADVANCES IN KNOWLEDGE Post-operative RT can achieve favorable treatment outcomes in incidental ASCC with residual diseases after local excision.
Collapse
Affiliation(s)
| | - Ah Ram Chang
- Department of Radiation Oncology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea
| | - Kyubo Kim
- Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Hyeon Kang Koh
- Department of Radiation Oncology, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Won Il Jang
- Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
| | - Hae Jin Park
- Department of Radiation Oncology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Ji Hyun Chang
- Department of Radiation Oncology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Mi-Sook Kim
- Department of Radiation Oncology, Konkuk University School of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
34
|
Parwaiz I, MacCabe T, Thomas M, Messenger D. A Systematic Review and Meta-Analysis of Prognostic Biomarkers in Anal Squamous Cell Carcinoma Treated With Primary Chemoradiotherapy. Clin Oncol (R Coll Radiol) 2019; 31:e1-e13. [DOI: 10.1016/j.clon.2019.06.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 05/15/2019] [Accepted: 05/21/2019] [Indexed: 01/22/2023]
|
|
35
|
Martin D, Rödel F, Balermpas P, Winkelmann R, Fokas E, Rödel C. C-Reactive Protein-to-Albumin Ratio as Prognostic Marker for Anal Squamous Cell Carcinoma Treated With Chemoradiotherapy. Front Oncol 2019; 9:1200. [PMID: 31788452 PMCID: PMC6856140 DOI: 10.3389/fonc.2019.01200] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 10/22/2019] [Indexed: 12/23/2022] Open
Abstract
Background: Definitive chemoradiotherapy (CRT) is the primary treatment for non-metastatic anal squamous cell carcinoma (ASCC). Despite favorable treatment outcomes in general, failure rates up to 40% occur in locally advanced disease. For treatment escalation or de-escalation strategies easily assessable and valid biomarkers are needed. Methods: We identified 125 patients with ASCC treated with standard CRT at our department. C-reactive protein (CRP) to albumin ratio (CAR) was calculated dividing baseline CRP by baseline albumin levels. We used maximally selected rank statistics to dichotomize patients to high and low risk groups. Associations of CAR with clinicopathologic parameters were evaluated and the prognostic impact was tested using univariate and multivariate cox regression analysis. In a subset of 78 patients, pretreatment tumor tissue was available and CD8+ tumor infiltrating lymphocytes (TILs) and p16INK4a status were scored by immunohistochemistry and correlated with CAR. Results: Advanced T-stage and male gender were significantly associated with higher baseline CAR. Using the calculated cutoff of 0.117, a high baseline CAR was also associated with worse locoregional control (p = 0.002), distant metastasis-free survival (p = 0.01), disease-free survival (DFS, p = 0.002) and overall survival (OS, p < 0.001). A combined risk score incorporating N-stage and CAR, termed N-CAR score, was associated with worse outcome across all endpoints and in multivariate analysis independent of T-stage and Gender (HR 4.27, p = 0.003). In the subset of 78 patients, a strong infiltration with intratumoral CD8+ TIL was associated with a significantly lower CAR (p = 0.007). CAR is an easily accessible biomarker that is associated with DFS. Our study revealed a possible link between chronic systemic inflammation and an impaired intratumoral immune response.
Collapse
Affiliation(s)
- Daniel Martin
- Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany.,Frankfurt Cancer Institute (FCI), Frankfurt, Germany
| | - Franz Rödel
- Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany.,Frankfurt Cancer Institute (FCI), Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Partner Site Frankfurt am Main, German Cancer Consortium (DKTK), Frankfurt, Germany
| | - Panagiotis Balermpas
- Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany.,Department of Radiation Oncology, University Hospital Zürich, Zurich, Switzerland
| | - Ria Winkelmann
- Senckenberg Institute for Pathology, University of Frankfurt, Frankfurt, Germany
| | - Emmanouil Fokas
- Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany.,Frankfurt Cancer Institute (FCI), Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Partner Site Frankfurt am Main, German Cancer Consortium (DKTK), Frankfurt, Germany
| | - Claus Rödel
- Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany.,Frankfurt Cancer Institute (FCI), Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Partner Site Frankfurt am Main, German Cancer Consortium (DKTK), Frankfurt, Germany
| |
Collapse
|
|
36
|
Russo S, Anker CJ, Abdel-Wahab M, Azad N, Bianchi N, Das P, Dragovic J, Goodman KA, Jones W, Kennedy T, Kumar R, Lee P, Sharma N, Small W, Suh WW, Jabbour SK. Executive Summary of the American Radium Society Appropriate Use Criteria for Treatment of Anal Cancer. Int J Radiat Oncol Biol Phys 2019; 105:591-605. [PMID: 31288054 PMCID: PMC11101015 DOI: 10.1016/j.ijrobp.2019.06.2544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 10/26/2022]
Affiliation(s)
- Suzanne Russo
- Case Western Reserve University School of Medicine and University Hospitals, Cleveland Ohio
| | | | - May Abdel-Wahab
- International Atomic Energy Agency, Division of Human Health, New York City, New York
| | - Nilofer Azad
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nancy Bianchi
- University of Vermont Cancer Center, Burlington, Vermont
| | - Prajnan Das
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | | | - William Jones
- UT Health Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | | | - Rachit Kumar
- Banner MD Anderson Cancer Center, Gilbert, Arizona
| | - Percy Lee
- University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, California
| | - Navesh Sharma
- Milton S. Hershey Cancer Institute, Hershey, Pennsylvania
| | | | - W Warren Suh
- Ridley-Tree Cancer Center, Sansum Clinic, Santa Barbara, California
| | - Salma K Jabbour
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
| |
Collapse
|
|
37
|
Chamseddin BH, Lee EE, Kim J, Zhan X, Yang R, Murphy KM, Lewis C, Hosler GA, Hammer ST, Wang RC. Assessment of circularized E7 RNA, GLUT1, and PD-L1 in anal squamous cell carcinoma. Oncotarget 2019; 10:5958-5969. [PMID: 31666927 PMCID: PMC6800260 DOI: 10.18632/oncotarget.27234] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 09/23/2019] [Indexed: 12/14/2022] Open
Abstract
Anal squamous cell carcinoma (ASCC) is a rare, potentially fatal malignancy primarily caused by high-risk human papillomaviruses (HPV). The prognostic implication of programmed death-ligand 1 (PD-L1) expression remains controversial, and glucose transporter 1 (GLUT1) expression has never been examined in ASCC. Covalently closed circular RNAs have recently been shown to be widespread in cancers and are proposed to be biomarkers. We discovered HPV16 expresses a circular E7 RNA (circE7) which has not been assessed as a potential biomarker. A retrospective, translational case series at UT Southwestern was conducted to analyze PD-L1, GLUT1, HPV-ISH, and HPV circE7 in relation to the clinical features and overall survival of patients with ASCC. Twenty-two (22) subjects were included in the study. Improved overall survival was predicted by basaloid histology (p= 0.013), PD-L1 expression (p= 0.08), and HPV-ISH positivity (p
& 0.001), but not GLUT1 expression. High levels of circE7 by quantitative RT-PCR predicted improved overall survival in ASCC (p= 0.023) and analysis of The Cancer Genome Atlas sequencing from HPV-positive head and neck cancer and cervical cancer suggested high circE7 marked improved survival in 875 subjects (p= 0.074). While our study suggests that circE7 levels correlate with improved survival in ASCC, larger, prospective studies are necessary to confirm the potential role of circE7 as a biomarker.
Collapse
Affiliation(s)
- Bahir H Chamseddin
- Department of Dermatology, UT Southwestern Medical Center, Dallas, 75390, TX, USA
| | - Eunice E Lee
- Department of Dermatology, UT Southwestern Medical Center, Dallas, 75390, TX, USA
| | - Jiwoong Kim
- Department of Clinical Science, UT Southwestern Medical Center, Dallas, 75390, TX, USA
| | - Xiaowei Zhan
- Department of Clinical Science, UT Southwestern Medical Center, Dallas, 75390, TX, USA
| | - Rong Yang
- Department of Dermatology, UT Southwestern Medical Center, Dallas, 75390, TX, USA
| | | | - Cheryl Lewis
- Harold C. Simmons Center, UT Southwestern Medical Center, Dallas, 75390, TX, USA
| | - Gregory A Hosler
- Department of Dermatology, UT Southwestern Medical Center, Dallas, 75390, TX, USA.,ProPath Dermatopathology, Dallas, 75247, TX, USA.,These authors contributed equally to this work
| | - Suntrea T Hammer
- Department of Pathology, UT Southwestern Medical Center, Dallas, 75390, TX, USA.,These authors contributed equally to this work
| | - Richard C Wang
- Department of Dermatology, UT Southwestern Medical Center, Dallas, 75390, TX, USA.,ProPath Dermatopathology, Dallas, 75247, TX, USA.,These authors contributed equally to this work
| |
Collapse
|
|
38
|
Fleischmann M, Martin D, Peña-Llopis S, Oppermann J, von der Grün J, Diefenhardt M, Chatzikonstantinou G, Fokas E, Rödel C, Strebhardt K, Becker S, Rödel F, Tselis N. Association of Polo-Like Kinase 3 and PhosphoT273 Caspase 8 Levels With Disease-Related Outcomes Among Cervical Squamous Cell Carcinoma Patients Treated With Chemoradiation and Brachytherapy. Front Oncol 2019; 9:742. [PMID: 31475104 PMCID: PMC6702309 DOI: 10.3389/fonc.2019.00742] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 07/23/2019] [Indexed: 12/22/2022] Open
Abstract
Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT. Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset. Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses. Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.
Collapse
Affiliation(s)
- Max Fleischmann
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Daniel Martin
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Samuel Peña-Llopis
- Division of Solid Tumor Translational Oncology, West German Cancer Center, Essen University Hospital, Essen, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK) Partner Site, Essen/Düsseldorf, Germany
| | - Julius Oppermann
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Jens von der Grün
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Markus Diefenhardt
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | | | - Emmanouil Fokas
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Frankfurt Cancer Institute (FCI), University of Frankfurt, Frankfurt, Germany.,German Cancer Consortium (DKTK) Partner Site, Frankfurt/Mainz, Germany
| | - Claus Rödel
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Frankfurt Cancer Institute (FCI), University of Frankfurt, Frankfurt, Germany.,German Cancer Consortium (DKTK) Partner Site, Frankfurt/Mainz, Germany
| | - Klaus Strebhardt
- German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK) Partner Site, Frankfurt/Mainz, Germany.,Department of Gynecology, Goethe-University, Frankfurt, Germany
| | - Sven Becker
- Department of Gynecology, Goethe-University, Frankfurt, Germany
| | - Franz Rödel
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Frankfurt Cancer Institute (FCI), University of Frankfurt, Frankfurt, Germany.,German Cancer Consortium (DKTK) Partner Site, Frankfurt/Mainz, Germany
| | - Nikolaos Tselis
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| |
Collapse
|
|
39
|
Rising Incidence and Improved Survival of Anal Squamous Cell Carcinoma in Norway, 1987-2016. Clin Colorectal Cancer 2019; 18:e96-e103. [DOI: 10.1016/j.clcc.2018.10.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/08/2018] [Accepted: 10/09/2018] [Indexed: 01/29/2023]
|
|
40
|
Otter S, Whitaker S, Chatterjee J, Stewart A. The Human Papillomavirus as a Common Pathogen in Oropharyngeal, Anal and Cervical Cancers. Clin Oncol (R Coll Radiol) 2019; 31:81-90. [DOI: 10.1016/j.clon.2018.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/07/2018] [Accepted: 09/10/2018] [Indexed: 12/21/2022]
|
|
41
|
Modulation of radiation sensitivity and antitumor immunity by viral pathogenic factors: Implications for radio-immunotherapy. Biochim Biophys Acta Rev Cancer 2018; 1871:126-137. [PMID: 30605716 DOI: 10.1016/j.bbcan.2018.12.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 11/17/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023]
Abstract
Several DNA viruses including Human Papillomavirus (HPV), Epstein-Barr virus (EBV), and Human cytomegalovirus (HCMV) are mechanistically associated with the development of human cancers (HPV, EBV) and/or modulation of the immune system (HCMV). Moreover, a number of distinct mechanisms have been described regarding the modulation of tumor cell response to ionizing radiation and evasion from the host immune system by viral factors. There is further accumulating interest in the treatment with immune-modulatory therapies such as immune checkpoint inhibitors for malignancies with a viral etiology. Also, patients with HPV-positive tumors have a significantly improved prognosis that is attributable to increased intrinsic radiation sensitivity and may also arise from modulation of a cytotoxic T cell response in the tumor microenvironment (TME). In this review, we will highlight recent advances in the understanding of the biological basis of radiation response mediated by viral pathogenic factors and evasion from and modulation of the immune system by viruses.
Collapse
|
|
42
|
Zhu Y, Deng S, Zhang Y, Jiang Q. Comparative study of ultrasonic elastography and conventional ultrasound in diagnosis of malignant anus neoplasm. Exp Ther Med 2018; 15:2343-2346. [PMID: 29456640 PMCID: PMC5795467 DOI: 10.3892/etm.2018.5720] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 12/12/2017] [Indexed: 12/26/2022] Open
Abstract
The application value of conventional ultrasound and ultrasonic elastography (UE) in preoperative diagnosis and combined diagnosis of malignant anus neoplasms was investigated. One hundred and twenty patients, whose mass was detected by digital rectal examination, were examined using UE and conventional ultrasound before operation, and the results were compared with those of histopathological examinations after operation, so that the accuracy and imaging features of UE as well as UE combined with conventional ultrasound in diagnosing malignant anus neoplasm were analyzed. Among the 120 patients, 77 were diagnosed with benign lesions and 43 were diagnosed with malignant lesions via pathological diagnosis for anal canal lesion surgery. Conventional ultrasound before operation showed that 53 patients were diagnosed with benign lesions and 26 with malignant lesions. Compared with that in the pathological diagnosis results, the diagnostic accordance rate in preoperative conventional ultrasound was 65.8%. Through UE diagnosis, 66 patients had benign lesions and 39 patients had malignant lesions. Compared with that in the pathological diagnosis results, the diagnostic accordance rate in preoperative UE was 87.5%. After the examination via UE combined with conventional ultrasound before operation, 71 patients were diagnosed with benign lesions and 40 patients were diagnosed with malignant lesions; compared with that in the pathological diagnosis results, the diagnostic accordance rate was 92.5%. In terms of mass qualitative diagnosis, the sensitivity and specificity of conventional ultrasound were 60.5 and 68.8%, respectively; those of UE were 90.7 and 85.7%, respectively, and those of UE combined with conventional ultrasound were 93.0 and 92.2%, respectively. According to the analysis results of receiver operating characteristic (ROC) curve, the area under curve (AUC) of malignant anus neoplasm diagnosed via UE was 0.732 [95% confidence interval (95% CI), 0.211-2.534], the AUC via conventional ultrasound was 0.695 (95% CI, 0.517-0.932), and that via UE combined with conventional ultrasound was 0.823 (95% CI, 0.146-4.643). In conclusion, examinations utilizing UE combined with conventional ultrasound can increase the preoperative diagnostic accordance rate in malignant anus neoplasm, which can be used as an effective method for preoperative diagnosis of malignant anus neoplasm.
Collapse
Affiliation(s)
- Yicheng Zhu
- Department of Ultrasound, Shanghai Pudong New Area People's Hospital, Shanghai 201299, P.R. China
| | - Shuhao Deng
- Department of Ultrasound, Shanghai Pudong New Area People's Hospital, Shanghai 201299, P.R. China
| | - Yuan Zhang
- Department of Ultrasound, Shanghai Pudong New Area People's Hospital, Shanghai 201299, P.R. China
| | - Quan Jiang
- Department of Ultrasound, Shanghai Pudong New Area People's Hospital, Shanghai 201299, P.R. China
| |
Collapse
|
|
43
|
Soares PC, Abdelhay ES, Thuler LCS, Soares BM, Demachki S, Ferro GVR, Assumpção PP, Lamarão LM, Ribeiro Pinto LF, Burbano RMR. HPV positive, wild type TP53, and p16 overexpression correlate with the absence of residual tumors after chemoradiotherapy in anal squamous cell carcinoma. BMC Gastroenterol 2018; 18:30. [PMID: 29466950 PMCID: PMC5822520 DOI: 10.1186/s12876-018-0758-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 02/13/2018] [Indexed: 01/05/2023] Open
Abstract
Background Anal residual tumors are consensually identified within six months of chemoradiotherapy and represent a persistent lesion that may have prognostic value for overall survival. The aim of this study was to evaluate the association of HPV and HIV status, p16 expression level and TP53 mutations with the absence of residual tumors (local response) in Squamous Cell Carcinoma (SCC) of the anal canal after chemoradiotherapy. Methods We performed a study on 78 patients with SCC of the anal canal who submitted to chemoradiotherapy and were followed for a six-month period to identify the absence or presence of residual tumors. HPV DNA was identified by polymerase chain reaction and direct sequencing, HIV RNA was detected by TaqMan amplification, p16 expression was detected by western blotting, and the mutational analysis of TP53 was performed by direct sequencing; additionally, samples carrying mutations underwent fluorescent in sit hybridization. The evaluation of the tumor response to treatment was conducted six months after the conclusion of chemoradiotherapy. The following classifications were used to evaluate the outcomes: a) no response (presence of residual tumor) and b) complete response (absence of residual tumor). Results The significant variables associated with the absence of residual tumors were HPV positive, p16 overexpressed, wild-type TP53, female gender, and stages I and II. Only the presence of HPV was independently correlated with the clinical response; this variable increased the chances of a response within six months by 31-fold. Conclusions The presence of HPV in tumor cells was correlated with the absence of a residual tumor. This correlation is valuable and can direct future therapeutic approaches in the anal canal.
Collapse
Affiliation(s)
- Paulo C Soares
- Hospital Ophir Loyola, Belém, Pará, 66060-281, Brazil. .,Universidade do Estado do Pará, Belém, Pará, Brazil.
| | | | | | - Bruno Moreira Soares
- Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Belém, Pará, Brazil
| | - Samia Demachki
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, Brazil
| | | | - Paulo P Assumpção
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, Brazil
| | | | | | - Rommel Mario Rodríguez Burbano
- Hospital Ophir Loyola, Belém, Pará, 66060-281, Brazil.,Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Belém, Pará, Brazil
| |
Collapse
|
|
44
|
Polo-like kinase 3 and phosphoT273 caspase-8 are associated with improved local tumor control and survival in patients with anal carcinoma treated with concomitant chemoradiotherapy. Oncotarget 2018; 7:53339-53349. [PMID: 27462786 PMCID: PMC5288191 DOI: 10.18632/oncotarget.10801] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 07/13/2016] [Indexed: 12/11/2022] Open
Abstract
We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro-apoptotic function. In the present study we aimed to investigate the clinical relevance of Plk3 expression and phosphorylation of caspase-8 at T273 in patients with anal squamous cell carcinoma (SSC) treated with 5-fluorouracil and mitomycin C-based chemoradiotherapy (CRT). Immunohistochemical detection of the markers was performed in pretreatment biopsy specimens of 95 patients and was correlated with clinical/histopathologic characteristics including HPV-16 virus load/p16INK4a expression and cumulative incidence of local and distant failure, cancer specific survival (CSS), and overall survival (OS). We observed significant positive correlations between Plk3 expression, pT273 caspase-8 signal, and levels of HPV-16 virus DNA load/p16INK4a detection. Patients with high scores of Plk3 and pT273 caspase-8 showed increased local control (p = 0.011; p = 0.001), increased CSS (p = 0.011; p = 0.013) and OS (p = 0.024; p = 0.001), while the levels of pT273 caspase-8 were significantly associated (p = 0.033) with distant metastases. In multivariate analyses Plk3 expression remained significant for local failure (p = 0.018), CSS (p = 0.016) and OS (p = 0.023). Moreover, a combined HPV16 DNA load and Plk3 or pT273 caspase-8 variable revealed a significant correlation to decreased local failure (p = 0.001; p = 0.009), increased CSS (p = 0.016; p = 0.023) and OS (p = 0.003; p = 0.003). In conclusion these data indicate that elevated levels of Plk3 and pT273 caspase-8 are correlated with favorable clinical outcome in patients with anal SCC treated with concomitant CRT.
Collapse
|
|
45
|
Sun G, Dong X, Tang X, Qu H, Zhang H, Zhao E. The prognostic value of HPV combined p16 status in patients with anal squamous cell carcinoma: a meta-analysis. Oncotarget 2017; 9:8081-8088. [PMID: 29487716 PMCID: PMC5814283 DOI: 10.18632/oncotarget.23545] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 12/15/2017] [Indexed: 12/25/2022] Open
Abstract
Human papillomavirus (HPV) DNA and p16 expression have been identified to be related to the progression of anal squamous cell carcinoma (ASCC). However, the prognostic relevance of combined detection, particularly HPV-/p16+ and HPV+/p16- signatures, is unknown. A meta-analysis of epidemiologic studies was therefore conducted to address this issue. Data were collected from studies comparing overall survival (OS) and disease-free survival (DFS) / disease-specific survival (DSS) / relapse-free survival (RFS) / progression-free survival (PFS) in ASCC patients with HPV and p16 status. The electronic databases of MEDLINE and EMBASE were searched from their inception till 31 May 2017. Study-specific risk estimates were pooled using a fixed-effects model for OS and DFS/DSS/RFS/PFS. Four studies involving a total of 398 ASCC cases were included in this meta-analysis. The pooled results showed that HPV+/p16+ cancers were significantly associated with improved OS (HR = 0.30, 95% CI: 0.17-0.51) and DFS/DSS/RFS/PFS (HR = 0.23, 95% CI: 0.14-0.36). However, patients with HPV-/p16+ or HPV+/p16- do not have a comparably good prognosis compared with HPV+/p16+ patients. The meta-analysis indicated that concomitant detection of HPV-DNA and p16 expression may be of prognostic or therapeutic utility in the evaluation of factors contributing to ASCC. Testing tumor specimens for HPV-DNA and p16 expression might indirectly affect treatment decisions.
Collapse
Affiliation(s)
- Guorui Sun
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
| | - Xiaoyuan Dong
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
| | - Xiaolong Tang
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
| | - Hui Qu
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
| | - Hao Zhang
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
| | - Ensheng Zhao
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
| |
Collapse
|
|
46
|
Jhaveri J, Rayfield L, Liu Y, Chowdhary M, Cassidy RJ, Madden NA, Tanenbaum DG, Gillespie TW, Patel PR, Patel KR, Landry JC. Prognostic relevance of human papillomavirus infection in anal squamous cell carcinoma: analysis of the national cancer data base. J Gastrointest Oncol 2017; 8:998-1008. [PMID: 29299360 DOI: 10.21037/jgo.2017.10.05] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background To examine the prognostic relevance of human papillomavirus (HPV) infection for anal squamous cell carcinoma (ASCC) patients treated with chemoradiation (CRT) in the National Cancer Data Base (NCDB). Methods The 2014 NCDB was queried for non-metastatic, histologically confirmed, ASCC patients diagnosed between 2004 and 2013. Patients were required to have HPV status documented in order to be eligible. Patients were then stratified into two groups: HPV+ and HPV-. Univariate analysis (UVA) was performed using the χ2 test for categorical covariates and ANOVA for numerical covariates. Multivariable analysis (MVA) was performed using Cox proportional hazard model for overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated for each covariate. To minimize selection bias, propensity score (PS) weighting was implemented to balance OS related variables between the groups including: age, education level, stage, diagnosis year, insurance type, and agent of chemotherapy. Results A total of 1,063 patients were eligible. Patients were stratified into HPV+ (n=498, 46.8%) and HPV- (n=565, 53.2%). After PS weighting, MVA for OS showed that for men, HPV infection was associated with better OS (HR: 0.60, 95% CI: 0.38-0.96; P=0.034). However, for women, HPV infection did not significantly influence survival (HR: 1.47, 95% CI: 0.96-2.25; P=0.074). Conclusions To our knowledge, this is the largest patient series evaluating the impact of HPV infection on OS in patients with anal cancer. We found that HPV infection is associated with a statistically significant better survival for men with ASCC. In contrast, for women, HPV infection did not significantly influence survival.
Collapse
Affiliation(s)
- Jaymin Jhaveri
- Department of Radiation Oncology and Winship Cancer Institute, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Lael Rayfield
- Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Yuan Liu
- Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Mudit Chowdhary
- Department of Radiation Oncology, Rush University, Chicago, IL, USA
| | - Richard J Cassidy
- Department of Radiation Oncology and Winship Cancer Institute, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Nicholas A Madden
- Department of Radiation Oncology and Winship Cancer Institute, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Daniel G Tanenbaum
- Department of Radiation Oncology and Winship Cancer Institute, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | | | - Pretesh R Patel
- Department of Radiation Oncology and Winship Cancer Institute, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Kirtesh R Patel
- Department of Radiation Oncology and Winship Cancer Institute, Winship Cancer Institute, Emory University, Atlanta, GA, USA.,Department of Therapeutic Radiology, Yale University, New Haven, CT, USA
| | - Jerome C Landry
- Department of Radiation Oncology and Winship Cancer Institute, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| |
Collapse
|
|
47
|
Rödel F, Steinhäuser K, Kreis NN, Friemel A, Martin D, Wieland U, Rave-Fränk M, Balermpas P, Fokas E, Louwen F, Rödel C, Yuan J. Prognostic impact of RITA expression in patients with anal squamous cell carcinoma treated with chemoradiotherapy. Radiother Oncol 2017; 126:214-221. [PMID: 29122359 DOI: 10.1016/j.radonc.2017.10.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 09/13/2017] [Accepted: 10/21/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signalling pathway and its deregulation is involved in the pathogenesis of several tumour entities. RITA's impact on the response of anal squamous cell carcinoma (SCC) to anticancer treatment, however, remains elusive. MATERIALS AND METHODS In our retrospective study immunohistochemical evaluation of RITA was performed on 140 pre-treatment specimens and was correlated with clinical and histopathologic characteristics and clinical endpoints cumulative incidence of local control (LC), distant recurrence (DC), disease-free survival (DFS) and overall survival (OS). RESULTS We observed significant inverse correlations between RITA expression and tumour grading, the levels of HPV-16 virus DNA load, CD8 (+) tumour infiltrating lymphocytes and programmed death protein (PD-1) immunostaining. In univariate analyses, elevated levels of RITA expression were predictive for decreased local control (p = 0.001), decreased distant control (p = 0.040), decreased disease free survival (p = 0.001) and overall survival (p < 0.0001), whereas in multivariate analyses RITA expression remained significant for decreased local control (p = 0.009), disease free survival (p = 0.032) and overall survival (p = 0.012). CONCLUSION These data indicate that elevated levels of pretreatment RITA expression are correlated with unfavourable clinical outcome in anal carcinoma treated with concomitant chemoradiotherapy.
Collapse
Affiliation(s)
- Franz Rödel
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany.
| | - Kerstin Steinhäuser
- Department of Gynecology and Obstetrics, Goethe-University, Frankfurt, Germany
| | - Nina-Naomi Kreis
- Department of Gynecology and Obstetrics, Goethe-University, Frankfurt, Germany
| | - Alexandra Friemel
- Department of Gynecology and Obstetrics, Goethe-University, Frankfurt, Germany
| | - Daniel Martin
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany
| | - Ulrike Wieland
- Institute of Virology, National Reference Centre for Papilloma- and Polyomaviruses, University of Cologne, Germany
| | - Margret Rave-Fränk
- Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Germany
| | - Panagiotis Balermpas
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany
| | - Emmanouil Fokas
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany
| | - Frank Louwen
- Department of Gynecology and Obstetrics, Goethe-University, Frankfurt, Germany
| | - Claus Rödel
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany
| | - Juping Yuan
- Department of Gynecology and Obstetrics, Goethe-University, Frankfurt, Germany.
| |
Collapse
|
|
48
|
Biesaga B, Mucha-Małecka A, Janecka-Widła A, Kołodziej-Rzepa M, Szostek S, Słonina D, Kowalczyk A, Halaszka K, Przewoźnik M. Differences in the prognosis of HPV16-positive patients with squamous cell carcinoma of head and neck according to viral load and expression of P16. J Cancer Res Clin Oncol 2017; 144:63-73. [PMID: 29043437 PMCID: PMC5756549 DOI: 10.1007/s00432-017-2531-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 10/05/2017] [Indexed: 12/11/2022]
Abstract
Purpose To evaluate the impact of HPV16 load (VL—the number of virus genome copies per cell) and P16 expression on prognosis of patients with squamous cell carcinomas (SCCs) of head and neck (HN). Materials and methods HPV16 presence was assessed in the group of 109 patients with HNSCCs by quantitative polymerase chain reaction (qPCR). VL (assessed by qPCR) and P16 expression (evaluated by immunohistochemistry) were analysed only in the subgroup of HPV16-positive tumours. These features were correlated with 5-year overall survival (OS) and disease-free survival (DFS). Results HPV16 infection was found in 36 tumours (33.0%). Virus-positive patients had better OS and DFS than those without infection (P = 0.041 and 0.005). Among HPV16-positive HNSCCs, 18 (50.0%) had higher VL (median value > 6764.3 copies/cell) and 25 (73.5%) P16 over expression. The significant differences in OS and DFS (P = 0.008 and 0.004) were noticed according to VL, wherein 100% DFS was found for patients with higher VL. According to P16 expression, significant difference was found only for OS (P = 0.020). In multivariate analysis, VL (P = 0.045; HR = 2.795; CI 0.121–1.060) and the level of smoking (P = 0.023, HR = 2.253; CI 1.124–4.514) were independent factors affecting DFS of HPV16-positive patients. Conclusion On the basis of viral load, it is possible to differentiate prognosis of patients with HPV16-positive HNSCCs. In this subgroup, viral load has stronger prognostic potential than P16 expression.
Collapse
Affiliation(s)
- Beata Biesaga
- Department of Applied Radiobiology, Maria Sklodowska-Curie Institute-Oncology Center, Cracow Branch, 11 Garncarska Street, 31-115, Cracow, Poland.
| | - Anna Mucha-Małecka
- Department of Radiation Oncology, Maria Sklodowska-Curie Institute-Oncology Center, Cracow Branch, 11 Garncarska Street, 31-115, Cracow, Poland
| | - Anna Janecka-Widła
- Department of Applied Radiobiology, Maria Sklodowska-Curie Institute-Oncology Center, Cracow Branch, 11 Garncarska Street, 31-115, Cracow, Poland
| | - Marta Kołodziej-Rzepa
- Department of Surgical Oncology, Maria Sklodowska-Curie Institute-Oncology Center, Cracow Branch, 11 Garncarska Street, 31-115, Cracow, Poland
| | - Sława Szostek
- Department of Virology, Chair of Microbiology, Jagiellonian University Medical College, 18 Czysta Street, 31-121, Cracow, Poland
| | - Dorota Słonina
- Department of Applied Radiobiology, Maria Sklodowska-Curie Institute-Oncology Center, Cracow Branch, 11 Garncarska Street, 31-115, Cracow, Poland
| | - Aleksandra Kowalczyk
- Department of Applied Radiobiology, Maria Sklodowska-Curie Institute-Oncology Center, Cracow Branch, 11 Garncarska Street, 31-115, Cracow, Poland
| | - Krzysztof Halaszka
- Department of Tumour Pathology, Maria Sklodowska-Curie Institute-Oncology Center, Cracow Branch, 11 Garncarska Street, 31-115, Cracow, Poland
| | - Marcin Przewoźnik
- Department of Tumour Pathology, Maria Sklodowska-Curie Institute-Oncology Center, Cracow Branch, 11 Garncarska Street, 31-115, Cracow, Poland
| |
Collapse
|
|
49
|
Martin D, Rödel F, Winkelmann R, Balermpas P, Rödel C, Fokas E. Peripheral Leukocytosis Is Inversely Correlated with Intratumoral CD8+ T-Cell Infiltration and Associated with Worse Outcome after Chemoradiotherapy in Anal Cancer. Front Immunol 2017; 8:1225. [PMID: 29085358 PMCID: PMC5649213 DOI: 10.3389/fimmu.2017.01225] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 09/15/2017] [Indexed: 12/11/2022] Open
Abstract
Peripheral blood leukocytosis has been implicated in promoting tumor progression leading to worse survival, but the mechanisms behind this phenomenon remain unexplored. Here, we examined the prognostic role of pretreatment white blood cell (WBC) count and clinicopathologic parameters in the context of CD8+ tumor-infiltrating lymphocytes (TIL) and myeloperoxidase+ tumor-associated neutrophils (TANs) in patients with anal squamous cell carcinoma (ASCC) treated with definitive chemoradiotherapy (CRT). After a median follow-up of 26 months, leukocytosis correlated with advanced T-stage (p < 0.001) and N-stage (p < 0.001), and predicted for worse distant-metastasis-free survival (p = 0.006), disease-free-survival (DFS, p = 0.029), and overall survival (p = 0.013). Importantly, leukocytosis was associated with a lower intraepithelial CD8+ TIL density (p = 0.014), whereas low CD8+ TIL expression in the intraepithelial compartment was associated with worse DFS (p = 0.028). Additionally, high TAN expression in the peritumoral compartment was associated with a significantly lower density of CD8+ TIL (p = 0.039), albeit, TAN expression lacked prognostic value. In conclusion, leukocytosis constitutes an important prognostic marker in ASCC patients treated with CRT. In conjunction with intratumoral TIL and TAN, these data provide for the first time important insight on the correlation of peripheral blood leukocytosis with the intratumoral immune contexture and could be relevant for future patient stratification using immunotherapies in ASCC.
Collapse
Affiliation(s)
- Daniel Martin
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt, Germany
| | - Franz Rödel
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner Site Frankfurt am Main, Frankfurt, Germany
| | - Ria Winkelmann
- Senckenberg Institute for Pathology, Goethe University Frankfurt, Frankfurt, Germany
| | - Panagiotis Balermpas
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner Site Frankfurt am Main, Frankfurt, Germany
| | - Claus Rödel
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner Site Frankfurt am Main, Frankfurt, Germany
| | - Emmanouil Fokas
- Department of Radiotherapy and Oncology, Goethe University Frankfurt, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner Site Frankfurt am Main, Frankfurt, Germany
| |
Collapse
|
|
50
|
Martin D, Rödel F, Balermpas P, Rödel C, Fokas E. The immune microenvironment and HPV in anal cancer: Rationale to complement chemoradiation with immunotherapy. Biochim Biophys Acta Rev Cancer 2017; 1868:221-230. [DOI: 10.1016/j.bbcan.2017.05.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 05/03/2017] [Indexed: 02/07/2023]
|