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Boldrini L, Charles-Davies D, Romano A, Mancino M, Nacci I, Tran HE, Bono F, Boccia E, Gambacorta MA, Chiloiro G. Response prediction for neoadjuvant treatment in locally advanced rectal cancer patients-improvement in decision-making: A systematic review. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024:109463. [PMID: 39562260 DOI: 10.1016/j.ejso.2024.109463] [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: 05/27/2024] [Revised: 09/26/2024] [Accepted: 11/13/2024] [Indexed: 11/21/2024]
Abstract
BACKGROUND Predicting pathological complete response (pCR) from pre or post-treatment features could be significant in improving the process of making clinical decisions and providing a more personalized treatment approach for better treatment outcomes. However, the lack of external validation of predictive models, missing in several published articles, is a major issue that can potentially limit the reliability and applicability of predictive models in clinical settings. Therefore, this systematic review described different externally validated methods of predicting response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) patients and how they could improve clinical decision-making. METHOD An extensive search for eligible articles was performed on PubMed, Cochrane, and Scopus between 2018 and 2023, using the keywords: (Response OR outcome) prediction AND (neoadjuvant OR chemoradiotherapy) treatment in 'locally advanced Rectal Cancer'. INCLUSION CRITERIA (i) Studies including patients diagnosed with LARC (T3/4 and N- or any T and N+) by pre-medical imaging and pathological examination or as stated by the author (ii) Standardized nCRT completed. (iii) Treatment with long or short course radiotherapy. (iv) Studies reporting on the prediction of response to nCRT with pathological complete response (pCR) as the primary outcome. (v) Studies reporting external validation results for response prediction. (vi) Regarding language restrictions, only articles in English were accepted. EXCLUSION CRITERIA (i) We excluded case report studies, conference abstracts, reviews, studies reporting patients with distant metastases at diagnosis. (ii) Studies reporting response prediction with only internally validated approaches. DATA COLLECTION AND QUALITY ASSESSMENT Three researchers (DC-D, FB, HT) independently reviewed and screened titles and abstracts of all articles retrieved after de-duplication. Possible disagreements were resolved through discussion among the three researchers. If necessary, three other researchers (LB, GC, MG) were consulted to make the final decision. The extraction of data was performed using the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS) template and quality assessment was done using the Prediction model Risk Of Bias Assessment Tool (PROBAST). RESULTS A total of 4547 records were identified from the three databases. After excluding 392 duplicate results, 4155 records underwent title and abstract screening. Three thousand and eight hundred articles were excluded after title and abstract screening and 355 articles were retrieved. Out of the 355 retrieved articles, 51 studies were assessed for eligibility. Nineteen reports were then excluded due to lack of reports on external validation, while 4 were excluded due to lack of evaluation of pCR as the primary outcome. Only Twenty-eight articles were eligible and included in this systematic review. In terms of quality assessment, 89 % of the models had low concerns in the participants domain, while 11 % had an unclear rating. 96 % of the models were of low concern in both the predictors and outcome domains. The overall rating showed high applicability potential of the models with 82 % showing low concern, while 18 % were deemed unclear. CONCLUSION Most of the external validated techniques showed promising performances and the potential to be applied in clinical settings, which is a crucial step towards evidence-based medicine. However, more studies focused on the external validations of these models in larger cohorts is necessary to ensure that they can reliably predict outcomes in diverse populations.
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Affiliation(s)
- Luca Boldrini
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy; Radiomics Core Research Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Diepriye Charles-Davies
- Radiomics Core Research Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.
| | - Angela Romano
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Matteo Mancino
- Istituto di Radiologia, Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Ilaria Nacci
- Istituto di Radiologia, Università Cattolica Del Sacro Cuore, Rome, Italy; Radiology Unit, Department of Medical Surgical Sciences and Translational Medicine, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Huong Elena Tran
- Radiomics Core Research Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Francesco Bono
- Radiomics Core Research Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Edda Boccia
- Radiomics Core Research Facility, Gemelli Science and Technology Park, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Maria Antonietta Gambacorta
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy; Istituto di Radiologia, Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Giuditta Chiloiro
- UOC Radioterapia Oncologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
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Subramaniyam K, Harihar S. An Overview on the Emerging Role of the Plasma Protease Inhibitor Protein ITIH5 as a Metastasis Suppressor. Cell Biochem Biophys 2024; 82:399-409. [PMID: 38355846 DOI: 10.1007/s12013-024-01227-7] [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: 01/30/2023] [Accepted: 02/02/2024] [Indexed: 02/16/2024]
Abstract
Most cancers are not detected until they have progressed to the point of becoming malignant and life-threatening. Chemotherapy and conventional medicines are often ineffective against cancer. Although we have made significant progress, new conceptual discoveries are still required to investigate new treatments. The role of metastasis suppressor genes as a therapeutic option for limiting tumor progression and metastasis has been on the anvil for some time. In this review, we discuss the role of ITIH5 as a metastasis suppressor gene and catalog its involvement in different cancers. We further shed light on the mode of action of ITIH5 based on the available data. The review will provide a new perspective on ITIH5 as an anti-metastatic protein and hopefully serve as an impetus for future studies towards the application of ITIH5 for clinical intervention in targeting metastatic cancers.
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Affiliation(s)
- Krishnaveni Subramaniyam
- Department of Genetic Engineering, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Sitaram Harihar
- Department of Biotechnology, GITAM School of Science, GITAM (Deemed to be) University, Visakhapatnam, 530045, Andhra Pradesh, India.
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Pervushin NV, Kopeina GS, Zhivotovsky B. Bcl-B: an "unknown" protein of the Bcl-2 family. Biol Direct 2023; 18:69. [PMID: 37899453 PMCID: PMC10614328 DOI: 10.1186/s13062-023-00431-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 10/31/2023] Open
Abstract
Bcl-B is a poorly understood protein of the Bcl-2 family that is highly expressed in many healthy tissues and tumor types. Bcl-B is considered an antiapoptotic protein, but many reports have revealed its contradictory roles in different cancer types. In this mini-review, we elucidate the functions of Bcl-B in normal conditions and various pathologies, its regulation of programmed cell death, its oncogene/oncosuppressor activity in tumorigenesis, its impact on drug-acquired resistance, and possible approaches to inhibit Bcl-B.
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Affiliation(s)
- N V Pervushin
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, 119991, Russia
| | - G S Kopeina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, 119991, Russia.
| | - B Zhivotovsky
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
- Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, 119991, Russia.
- Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute, Box 210, Stockholm, 17177, Sweden.
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Duong MQ, Gadet R, Treilleux I, Borel S, Nougarède A, Marcillat O, Gonzalo P, Mikaelian I, Popgeorgiev N, Rimokh R, Gillet G. Nrh L11R single nucleotide polymorphism, a new prediction biomarker in breast cancer, impacts endoplasmic reticulum-dependent Ca 2+ traffic and response to neoadjuvant chemotherapy. Cell Death Dis 2023; 14:392. [PMID: 37391438 PMCID: PMC10313725 DOI: 10.1038/s41419-023-05917-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 06/12/2023] [Accepted: 06/21/2023] [Indexed: 07/02/2023]
Abstract
Overexpression of Bcl-2 proteins such as Bcl2L10, also referred to as Nrh, is associated with resistance to therapy and poor survival in various cancers, including breast cancer, lung cancer, and leukemia. The single nucleotide polymorphism (SNP) of BCL2L10 in its BH4 domain at position 11 (BCL2L10 Leu11Arg, rs2231292), corresponding to position 11 in the Nrh open reading frame, is reported to lower resistance towards chemotherapy, with patients showing better survival in the context of acute leukemia and colorectal cancer. Using cellular models and clinical data, we aimed to extend this knowledge to breast cancer. We report that the homozygous status of the Nrh Leu11Arg isoform (Nrh-R) is found in 9.7-11% percent of the clinical datasets studied. Furthermore, Nrh-R confers higher sensitivity towards Thapsigargin-induced cell death compared to the Nrh-L isoform, due to altered interactions with IP3R1 Ca2+ channels in the former case. Collectively, our data show that cells expressing the Nrh-R isoform are more prone to death triggered by Ca2+ stress inducers, compared to Nrh-L expressing cells. Analysis of breast cancer cohorts revealed that patients genotyped as Nrh-R/Nrh-R may have a better outcome. Overall, this study supports the notion that the rs2231292 Nrh SNP could be used as a predictive tool regarding chemoresistance, improving therapeutic decision-making processes. Moreover, it sheds new light on the contribution of the BH4 domain to the anti-apoptotic function of Nrh and identifies the IP3R1/Nrh complex as a potential therapeutic target in the context of breast cancer.
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Affiliation(s)
- Minh Quang Duong
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France
| | - Rudy Gadet
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France
| | | | - Stéphane Borel
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France
| | - Adrien Nougarède
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France
- Division for Biology and Healthcare Technologies, CEA-LETI, MINATEC Campus, F-38054, Grenoble, France
| | - Olivier Marcillat
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France
| | - Philippe Gonzalo
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France
- Laboratoire de Biochimie, CHU de Saint-Etienne, Université de Lyon, Lyon, France
| | - Ivan Mikaelian
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France
| | - Nikolay Popgeorgiev
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France
| | - Ruth Rimokh
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France.
| | - Germain Gillet
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France.
- Hospices civils de Lyon, Centre de Biologie Sud, Centre Hospitalier Lyon Sud, chemin du Grand Revoyet, 69495, Pierre Bénite, France.
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Lee TH, Jang B, Chang JH, Kim E, Park JH, Chie EK. Genomic landscape of locally advanced rectal adenocarcinoma: Comparison between before and after neoadjuvant chemoradiation and effects of genetic biomarkers on clinical outcomes and tumor response. Cancer Med 2023; 12:15664-15675. [PMID: 37260182 PMCID: PMC10417181 DOI: 10.1002/cam4.6169] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 03/05/2023] [Accepted: 05/18/2023] [Indexed: 06/02/2023] Open
Abstract
PURPOSE To explore genomic biomarkers in rectal cancer by performing whole-exome sequencing. MATERIALS AND METHODS Pre-chemoradiation (CRT) biopsy and post-CRT surgical specimens were obtained from 27 patients undergoing neoadjuvant CRT followed by definitive resection. Exomes were sequenced to a mean coverage of 30×. Somatic single-nucleotide variants (SNVs) and insertions/deletions (indels) were identified. Tumor mutational burden was defined as the number of SNVs or indels. Mutational signatures were extracted and fitted to COSMIC reference signatures. Tumor heterogeneity was quantified with a mutant-allele tumor heterogeneity (MATH) score. Genetic biomarkers and frequently occurred copy number alterations (CNAs) were compared between pre- and post-CRT specimens. Their associations with tumor regression grade (TRG) and clinical outcomes were explored. RESULTS Top five mutated genes were APC, TP53, NF1, KRAS, and NOTCH1 for pre-CRT samples and APC, TP53, NF1, CREBBP, and ATM for post-CRT samples. Several gene mutations including RUNX1, EGFR, and TP53 in pre-CRT samples showed significant association with clinical outcomes, but not with TRG. However, no such association was found in post-CRT samples. Discordance of driver mutation status was found between pre- and post-CRT samples. In tumor mutational burden analysis, higher number of SNVs or indels was associated with worse treatment outcomes. Six single-base substitution (SBS) signatures identified were SBS1, SBS30, SBS29, SBS49, SBS3, and SBS44. The MATH score decreased after CRT on paired analysis. Less than half of CNAs frequent in post-CRT samples were present in pre-CRT samples. CONCLUSION Pre- and post-CRT samples showed different genomic landscape. Potential genetic biomarkers of pre-CRT samples found in the current analysis call for external validation.
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Affiliation(s)
- Tae Hoon Lee
- Department of Radiation OncologySeoul National University HospitalSeoulRepublic of Korea
- Department of Clinical Medical ScienceSeoul National University College of MedicineSeoulRepublic of Korea
| | - Bum‐Sup Jang
- Department of Radiation OncologySeoul National University HospitalSeoulRepublic of Korea
| | - Ji Hyun Chang
- Department of Radiation OncologySeoul National University HospitalSeoulRepublic of Korea
| | - Eunji Kim
- Department of Radiation OncologySeoul Metropolitan Government‐Seoul National University Boramae Medical CenterSeoulRepublic of Korea
| | - Jeong Hwan Park
- Department of PathologySeoul Metropolitan Government‐Seoul National University Boramae Medical CenterSeoulRepublic of Korea
| | - Eui Kyu Chie
- Department of Radiation OncologySeoul National University HospitalSeoulRepublic of Korea
- Department of Clinical Medical ScienceSeoul National University College of MedicineSeoulRepublic of Korea
- Department of Radiation OncologySeoul National University College of MedicineSeoulRepublic of Korea
- Medical Research Center, Institute of Radiation MedicineSeoul National UniversitySeoulRepublic of Korea
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Li SF, Wei R, Yu GH, Jiang Z. Predictive value of indirect bilirubin before neoadjuvant chemoradiotherapy in evaluating prognosis of local advanced rectal cancer patients. World J Gastrointest Oncol 2022; 14:2224-2237. [PMID: 36438711 PMCID: PMC9694265 DOI: 10.4251/wjgo.v14.i11.2224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/25/2022] [Accepted: 10/02/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Many biomarkers have predictive value for overall survival (OS) and disease-free survival (DFS) in tumor patients. However, the role of indirect bilirubin (IBIL) in local advanced rectal cancer (LARC) patients treated with neoadjuvant chemoradiotherapy (nCRT) has not been studied. AIM To explore the predictive value of IBIL before nCRT (pre-IBIL) for the OS and DFS of LARC patients treated with nCRT. METHODS A total of 324 LARC patients undergoing nCRT with total mesorectal excision (TME) were enrolled. Preoperative clinical features and postoperative pathological characteristics were collected. Cox regression analysis was performed, and a Cox-based nomogram was developed to predict OS and DFS. We also assessed the predictive performance of the nomogram with calibration plots and receiver operating characteristic (ROC) curves. RESULTS Among 324 patients, the median pre-IBIL was 6.2 μmol/L (interquartile range: 4.6 μmol/L-8.4 μmol/L). In the Cox multivariate regression analysis, we found that pre-IBIL, smoking history, tumor regression grade (TRG), vascular invasion, and carbohydrate antigen 19-9 before nCRT (pre-CA19-9) were predictors of OS. Additionally, pre-IBIL, body mass index (BMI), nCRT with surgery interval, TRG, and vascular invasion were predictors of DFS. Predictive nomograms were developed to predict 5-year OS and 5-year DFS with area under the ROC curve values of 0.7518 and 0.7355, respectively. Good statistical performance on internal validation was shown by calibration plots and ROC curves. CONCLUSION This study demonstrated that pre-IBIL was an independent prognostic factor for OS and DFS in LARC patients treated with nCRT followed by TME. Nomograms incorporating pre-IBIL, BMI, smoking history, nCRT with surgery interval, TRG, vascular invasion, and pre-CA19-9 could be helpful to predict OS and DFS.
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Affiliation(s)
- Shuo-Feng Li
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ran Wei
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Guan-Hua Yu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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7
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Takenaka IKTM, Bartelli TF, Defelicibus A, Sendoya JM, Golubicki M, Robbio J, Serpa MS, Branco GP, Santos LBC, Claro LCL, Dos Santos GO, Kupper BEC, da Silva IT, Llera AS, de Mello CAL, Riechelmann RP, Dias-Neto E, Iseas S, Aguiar S, Nunes DN. Exome and Tissue-Associated Microbiota as Predictive Markers of Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer. Front Oncol 2022; 12:809441. [PMID: 35392220 PMCID: PMC8982181 DOI: 10.3389/fonc.2022.809441] [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: 11/05/2021] [Accepted: 02/17/2022] [Indexed: 11/13/2022] Open
Abstract
The clinical and pathological responses to multimodal neoadjuvant therapy in locally advanced rectal cancers (LARCs) remain unpredictable, and robust biomarkers are still lacking. Recent studies have shown that tumors present somatic molecular alterations related to better treatment response, and it is also clear that tumor-associated bacteria are modulators of chemotherapy and immunotherapy efficacy, therefore having implications for long-term survivorship and a good potential as the biomarkers of outcome. Here, we performed whole exome sequencing and 16S ribosomal RNA (rRNA) amplicon sequencing from 44 pre-treatment LARC biopsies from Argentinian and Brazilian patients, treated with neoadjuvant chemoradiotherapy or total neoadjuvant treatment, searching for predictive biomarkers of response (responders, n = 17; non-responders, n = 27). In general, the somatic landscape of LARC was not capable to predict a response; however, a significant enrichment in mutational signature SBS5 was observed in non-responders (p = 0.0021), as well as the co-occurrence of APC and FAT4 mutations (p < 0.05). Microbiota studies revealed a similar alpha and beta diversity of bacteria between response groups. Yet, the linear discriminant analysis (LDA) of effect size indicated an enrichment of Hungatella, Flavonifractor, and Methanosphaera (LDA score ≥3) in the pre-treatment biopsies of responders, while non-responders had a higher abundance of Enhydrobacter, Paraprevotella (LDA score ≥3) and Finegoldia (LDA score ≥4). Altogether, the evaluation of these biomarkers in pre-treatment biopsies could eventually predict a neoadjuvant treatment response, while in post-treatment samples, it could help in guiding non-operative treatment strategies.
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Affiliation(s)
| | - Thais F Bartelli
- Medical Genomics Laboratory, International Center for Research, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Alexandre Defelicibus
- Laboratory of Bioinformatics and Computational Biology, International Center for Research, A.C. Camargo Cancer Center, São Paulo, Brazil
| | - Juan M Sendoya
- Laboratorio de Terapia Molecular y Celular - Genomics Unit, Fundación Instituto Leloir, Buenos Aires, Argentina.,Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Mariano Golubicki
- Oncology Unit, Hospital de Gastroenterología Carlos Bonorino Udaondo, Buenos Aires, Argentina.,Clinical Oncology, Intergrupo Argentino para el Tratamiento de los Tumores Gastrointestinales (IATTGI), Buenos Aires, Argentina
| | - Juan Robbio
- Clinical Oncology, Intergrupo Argentino para el Tratamiento de los Tumores Gastrointestinales (IATTGI), Buenos Aires, Argentina
| | - Marianna S Serpa
- Medical Genomics Laboratory, International Center for Research, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Gabriela P Branco
- Medical Genomics Laboratory, International Center for Research, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Luana B C Santos
- Medical Genomics Laboratory, International Center for Research, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Laura C L Claro
- Department of Pathology, A.C.Camargo Cancer Center, São Paulo, Brazil
| | | | - Bruna E C Kupper
- Colorectal Cancer Department, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Israel T da Silva
- Laboratory of Bioinformatics and Computational Biology, International Center for Research, A.C. Camargo Cancer Center, São Paulo, Brazil
| | - Andrea S Llera
- Laboratorio de Terapia Molecular y Celular - Genomics Unit, Fundación Instituto Leloir, Buenos Aires, Argentina.,Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Celso A L de Mello
- Department of Clinical Oncology, A.C.Camargo Cancer Center, São Paulo, Brazil
| | | | - Emmanuel Dias-Neto
- Medical Genomics Laboratory, International Center for Research, A.C.Camargo Cancer Center, São Paulo, Brazil.,Laboratory of Neurosciences (LIM-27) Alzira Denise Hertzog Silva, Institute of Psychiatry, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Soledad Iseas
- Oncology Unit, Hospital de Gastroenterología Carlos Bonorino Udaondo, Buenos Aires, Argentina
| | - Samuel Aguiar
- Colorectal Cancer Department, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Diana Noronha Nunes
- Medical Genomics Laboratory, International Center for Research, A.C.Camargo Cancer Center, São Paulo, Brazil.,National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation (INCITO), São Paulo, Brazil
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Nikolic A, Krivokapic Z. Nucleic acid-based markers of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Surg Oncol 2022; 41:101743. [PMID: 35358913 DOI: 10.1016/j.suronc.2022.101743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 03/03/2022] [Accepted: 03/22/2022] [Indexed: 10/18/2022]
Abstract
The progress that has been made in the treatment of rectal cancer has mostly resulted from multimodality strategy approach that combines surgery, chemotherapy and radiotherapy. In locally advanced rectal cancer (LARC), surgery remains the primary treatment, while neoadjuvant chemoradiotherapy (nCRT) is used to downsize or downstage the tumor before surgical resection. Highly variable response to nCRT observed in LARC patients raises the need for biomarkers to enable prediction and evaluation of treatment response in a more efficient and timely manner than currently available tools. The search for predictive biomarkers continues beyond blood proteins, which have failed in subsequent validation studies. This review presents nucleic acids-based markers and their predictive potential in LARC patients. Most of the candidate biomarkers come from relatively small single-institution studies. The only candidate biomarker that emerged as relevant in more than a single study was elevated levels of Fusobacterium nucleatum nucleic acids in tumor tissue. Considering that this marker is easily accessible through non-invasive analysis of faecal samples, its predictive potential is worth further validation. The other candidate nucleic acid-based biomarkers require more consistent studies on larger cohorts before they can be considered for use in clinical setting.
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Affiliation(s)
- Aleksandra Nikolic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
| | - Zoran Krivokapic
- Clinic for Digestive Surgery, Clinical Center of Serbia, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Serbian Academy of Sciences and Arts, Belgrade, Serbia
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Del Bufalo D, Di Martile M, Valentini E, Manni I, Masi I, D'Amore A, Filippini A, Nicoletti C, Zaccarini M, Cota C, Castro MV, Quezada MJ, Rosanò L, Lopez-Bergami P, D'Aguanno S. Bcl-2-like protein-10 increases aggressive features of melanoma cells. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:11-26. [PMID: 36046354 PMCID: PMC9400776 DOI: 10.37349/etat.2022.00068] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 12/20/2021] [Indexed: 11/29/2022] Open
Abstract
Aim: B-cell lymphoma-2 (Bcl-2)-like protein-10 (Bcl2L10) is the less studied
member of Bcl-2 family proteins, with the controversial role in different
cancer histotypes. Very recently, Bcl2L10 expression in melanoma tumor
specimens and its role in melanoma response to therapy have been
demonstrated. Here, the involvement of Bcl2L10 on the in
vitro and in vivo properties associated with
melanoma aggressive features has been investigated. Methods: Endogenous Bcl2L10 protein expression was detected by western blotting
analysis in a panel of patient-derived and commercially available human
melanoma cells. In vitro assays to evaluate clonogenicity,
cell proliferation, cell migration, cell invasion, and in
vitro capillary-like structure formation [vasculogenic
mimicry (VM)] have been performed by using human melanoma cells
stably overexpressing Bcl2L10 or transiently transfected for loss/gain
function of Bcl2L10, grown under two- or three-dimensional (3D) conditions
Xenograft melanoma model was employed to evaluate in vivo
tumor growth and angiogenesis. Results: Results demonstrated that Bcl2L10 acts as an inducer of in
vitro cell migration, invasion, and VM, while in
vitro cell proliferation, in vivo tumor
growth, as well as colony formation properties were not affected. Dissecting
different signaling pathways, it was found that Bcl2L10 positively affects
the phosphorylation of extracellular-signal-regulated kinase (ERK) and the
expression of markers of cell invasion, such as urokinase plasminogen
activator receptor (uPAR) and matrix metalloproteinases (MMPs). Of note,
Bcl2L10-dependent in vitro migration, invasion, and VM are
linked to uPAR. Bcl2L10 also negatively regulates the intracellular calcium
level. Finally, reduced invasion capability in 3D spheroid invasion assay of
melanoma cells transiently overexpressing Bcl2L10 was observed after
treatment with inhibitors of MMPs and uPAR. Conclusions: Overall, data reported in this paper provide evidence supporting a positive
role of Bcl2L10 in melanoma aggressive features.
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Affiliation(s)
- Donatella Del Bufalo
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Marta Di Martile
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Elisabetta Valentini
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Isabella Manni
- SAFU Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Ilenia Masi
- Institute of Molecular Biology and Pathology, National Research Council, 00161 Rome, Italy
| | - Antonella D'Amore
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, 00161 Rome, Italy
| | - Antonio Filippini
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, 00161 Rome, Italy
| | - Carmine Nicoletti
- Unit of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University, 00161 Rome, Italy
| | - Marco Zaccarini
- Genetic Research, Dermatological Molecular Biology and Dermatopathology Unit, IRCCS San Gallicano Dermatological Institute, 00144 Rome, Italy
| | - Carlo Cota
- Genetic Research, Dermatological Molecular Biology and Dermatopathology Unit, IRCCS San Gallicano Dermatological Institute, 00144 Rome, Italy
| | - Maria Victoria Castro
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo, Universidad Maimónides, Buenos Aires C1405BCK, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires C1405BCK, Argentina
| | - María Josefina Quezada
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo, Universidad Maimónides, Buenos Aires C1405BCK, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires C1405BCK, Argentina
| | - Laura Rosanò
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council, 00161 Rome, Italy
| | - Pablo Lopez-Bergami
- Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo, Universidad Maimónides, Buenos Aires C1405BCK, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires C1405BCK, Argentina
| | - Simona D'Aguanno
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
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10
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Marei HE, Althani A, Afifi N, Hasan A, Caceci T, Felsani A, Tringali G, Cifola I, Pozzoli G, Cenciarelli C. Exome sequencing of glioblastoma-derived cancer stem cells reveals rare clinically relevant frameshift deletion in MLLT1 gene. Cancer Cell Int 2022; 22:9. [PMID: 34996478 PMCID: PMC8740446 DOI: 10.1186/s12935-021-02419-4] [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: 07/30/2021] [Accepted: 12/19/2021] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is a heterogeneous CNS neoplasm which causes significant morbidity and mortality. One reason for the poor prognostic outcome of GBM is attributed to the presence of cancer stem cells (CSC) which confer resistance against standard chemo- and radiotherapeutics modalities. Two types of GBM-associated CSC were isolated from the same patient: tumor core- (c-CSC) and peritumor tissue-derived cancer stem cells (p-CSC). Our experiments are focused on glioblastoma-IDH-wild type, and no disease-defining alterations were present in histone, BRAF or other genes. METHODS In the present study, potential differences in genetic variants between c-CSC versus p-CSC derived from four GBM patients were investigated with the aims of (1) comparing the exome sequences between all the c-CSC or p-CSC to identify the common variants; (2) identifying the variants affecting the function of genes known to be involved in cancer origin and development. RESULTS By comparative analyses, we identified common gene single nucleotide variants (SNV) in all GBM c-CSC and p-CSC, a potentially deleterious variant was a frameshift deletion at Gln461fs in the MLLT1 gene, that was encountered only in p-CSC samples with different allelic frequency. CONCLUSIONS We discovered a potentially harmful frameshift deletion at Gln461fs in the MLLT1 gene. Further investigation is required to confirm the presence of the identified mutations in patient tissue samples, as well as the significance of the frameshift mutation in the MLLT1 gene on GBM biology and response to therapy based on genomic functional experiments.
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Affiliation(s)
- Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35116, Egypt.
| | - Asmaa Althani
- Biomedical Research Center, Qatar University, Doha, Qatar
| | | | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
| | - Thomas Caceci
- Biomedical Sciences, Virginia Maryland College of Veterinary Medicine, Blacksburg, VA, USA
| | - Armando Felsani
- Genomnia S.R.L, Via Ludovico Ariosto, Bresso, MI, 20091, USA
| | - Giuseppe Tringali
- Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy
| | - Ingrid Cifola
- Institute for Biomedical Technologies (ITB), National Research Council (CNR), Milan, Italy
| | - Giacomo Pozzoli
- Pharmacology Unit, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere, 100, 00133, Rome, Italy
| | - Carlo Cenciarelli
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere, 100, 00133, Rome, Italy.
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11
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Xiao WW, Li M, Guo ZW, Zhang R, Xi SY, Zhang XG, Li Y, Wu DQ, Ren YF, Pang XL, Wan XB, Li K, Zhou CL, Zhai XM, Liang ZK, Wang QX, Zeng ZF, Zhang HZ, Yang XX, Wu YS, Li M, Gao YH. A Genotype Signature for Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer. Int J Radiat Oncol Biol Phys 2021; 110:482-491. [PMID: 33434612 DOI: 10.1016/j.ijrobp.2021.01.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE To construct and validate a predicting genotype signature for pathologic complete response (pCR) in locally advanced rectal cancer (PGS-LARC) after neoadjuvant chemoradiation. METHODS AND MATERIALS Whole exome sequencing was performed in 15 LARC tissues. Mutation sites were selected according to the whole exome sequencing data and literature. Target sequencing was performed in a training cohort (n = 202) to build the PGS-LARC model using regression analysis, and internal (n = 76) and external validation cohorts (n = 69) were used for validating the results. Predictive performance of the PGS-LARC model was compared with clinical factors and between subgroups. The PGS-LARC model comprised 15 genes. RESULTS The area under the curve (AUC) of the PGS model in the training, internal, and external validation cohorts was 0.776 (0.697-0.849), 0.760 (0.644-0.867), and 0.812 (0.690-0.915), respectively, and demonstrated higher AUC, accuracy, sensitivity, and specificity than cT stage, cN stage, carcinoembryonic antigen level, and CA19-9 level for pCR prediction. The predictive performance of the model was superior to clinical factors in all subgroups. For patients with clinical complete response (cCR), the positive prediction value was 94.7%. CONCLUSIONS The PGS-LARC is a reliable predictive tool for pCR in patients with LARC and might be helpful to enable nonoperative management strategy in those patients who refuse surgery. It has the potential to guide treatment decisions for patients with different probability of tumor regression after neoadjuvant therapy, especially when combining cCR criteria and PGS-LARC.
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Affiliation(s)
- Wei-Wei Xiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Min Li
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Guangzhou Darui Biotechnology Co, Ltd High-Tech Development Zone, Guangzhou, Guangdong, China; Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhi-Wei Guo
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Rong Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Endoscopy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Shao-Yan Xi
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xiang-Guo Zhang
- Department of Radiation Oncology, Affiliated Yuebei People Hospital of Shantou University Medical College, ShaoGuan, Guangdong, China
| | - Yong Li
- Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - De-Qing Wu
- Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Yu-Feng Ren
- Department of Radiation Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiao-Lin Pang
- Department of Radiation Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiang-Bo Wan
- Department of Radiation Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Kun Li
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Chun-Lian Zhou
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiang-Ming Zhai
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhi-Kun Liang
- Guangzhou Darui Biotechnology Co, Ltd High-Tech Development Zone, Guangzhou, Guangdong, China
| | - Qiao-Xuan Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zhi-Fan Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Hui-Zhong Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xue-Xi Yang
- Guangzhou Darui Biotechnology Co, Ltd High-Tech Development Zone, Guangzhou, Guangdong, China; Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Ying-Song Wu
- Guangzhou Darui Biotechnology Co, Ltd High-Tech Development Zone, Guangzhou, Guangdong, China; Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Ming Li
- Guangzhou Darui Biotechnology Co, Ltd High-Tech Development Zone, Guangzhou, Guangdong, China
| | - Yuan-Hong Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
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12
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Liu H, Wei R, Li C, Zhao Z, Guan X, Yang M, Liu Z, Wang X, Jiang Z. BMI May Be a Prognostic Factor for Local Advanced Rectal Cancer Patients Treated with Long-Term Neoadjuvant Chemoradiotherapy. Cancer Manag Res 2020; 12:10321-10332. [PMID: 33116887 PMCID: PMC7586017 DOI: 10.2147/cmar.s268928] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE This study aims to develop feasible nomograms to predict the overall survival (OS) and cancer-specific survival (CSS) of the local advanced rectal cancer (LARC) patients who were treated with neoadjuvant chemoradiotherapy (nCRT) and operation. METHODS A total of 243 LARC patients undergoing nCRT followed by total mesorectal excision (TME) were enrolled. Preoperative clinical features and postoperative pathological characteristics were collected. A Cox regression analysis was performed, and Cox-based nomograms were developed to predict the OS and CSS. We assessed the predictive performance of the nomogram with concordance index and calibration plots. RESULTS A total of 243 patients were included with a median follow-up period of 46 months (range from 9 to 86 months). Cox regression analysis showed that low BMI (BMI < 18.5, HR= 21.739, P < 0.05), high level of preoperative CA19-9 (HR = 3.369, P = 0.036), high ypStage (HR = 19.768, P < 0.001), positive neural invasion (HR = 4.218, P = 0.026) and no adjuvant chemotherapy (HR = 5.495, P < 0.001) were independent predictors of poor OS. Age ≥70 (HR = 2.284, P <0.001), low BMI (BMI < 18.5, HR = 3.906, P < 0.05), positive preoperative CA19-9 (HR = 1.920, P = 0.012), high ypStage (HR = 5.147, P <0.001) and positive neural invasion (HR = 2.873, P = 0.022) were independent predictors of poor CSS. The predictive nomograms were developed to predict the OS and CSS with a C-index of 0.837 and 0.760. Good statistical performance on internal validation was shown by calibration plots. CONCLUSION In conclusion, this study demonstrated that BMI was an independent prognostic factor for OS and CSS in LARC patients treated with nCRT followed TME. A nomogram incorporating BMI, neural invasion, pre-CA19-9, ypStage, age, and adjuvant chemotherapy could be helpful to predict the OS and CSS.
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Affiliation(s)
- Hengchang Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
| | - Ran Wei
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
| | - Zhixun Zhao
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
| | - Xu Guan
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
| | - Ming Yang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
| | - Zheng Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
| | - Xishan Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100021, People’s Republic of China
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13
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Sun Y, Zhang Y, Wu X, Chi P. A Four Gene-Based Risk Score System Associated with Chemoradiotherapy Response and Tumor Recurrence in Rectal Cancer by Co-Expression Network Analysis. Onco Targets Ther 2020; 13:6721-6733. [PMID: 32753901 PMCID: PMC7354918 DOI: 10.2147/ott.s256696] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022] Open
Abstract
Aim Resistance to neoadjuvant chemoradiotherapy (NCRT) and tumor recurrence presents a major clinical problem in locally advanced rectal cancer (LARC) patients. This study aimed to explore a genetic risk score related to NCRT response and tumor recurrence in rectal cancer after NCRT. Materials and Methods Weighted gene co-expression network analysis was employed to identify hub genes associated with NCRT response from the GSE93375 dataset. Prognostic hub genes were determined using Cox regression analysis and associated with disease-free survival (DFS). A risk score system was constructed and the prognostic significance of the risk score was validated in our patient cohort. A predictive nomogram for DFS was developed and validated internally. Results The Tan module had the highest correlations with NCRT response. Ten hub genes (COL15A1, THBS2, ITGB1, MMP2, CD34, SPARC, NOTCH3, PDGFRB, DCN, and SERPINH1) were associated with NCRT response. Immunostaining expression of four genes (NOTCH3, SPARC, DCN, and ITGB1) was found to be significantly associated with both NCRT response and DFS in our patient cohort and was selected to build a prognostic risk score for DFS as follows: risk score= (0.6188×Exp NOTCH3 ) + (0.6511×Exp SPARC ) + (-0.2976×Exp DCN ) + (1.0035×Exp ITGB1 ). Using this risk score, patients could be separated into high- and low-risk groups for tumor recurrence. A nomogram that incorporated the risk score, ypTNM stage, and tumor regression grade (TRG) was constructed and utilized to predict DFS in LARC patients. Conclusion The four-gene expression-based risk score system presented here could be potentially used for predicting tumor recurrence in LARC patients after NCRT.
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Affiliation(s)
- Yanwu Sun
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China
| | - Yiyi Zhang
- Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China
| | - Xuejing Wu
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China
| | - Pan Chi
- Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China
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14
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De Mattia E, Roncato R, Palazzari E, Toffoli G, Cecchin E. Germline and Somatic Pharmacogenomics to Refine Rectal Cancer Patients Selection for Neo-Adjuvant Chemoradiotherapy. Front Pharmacol 2020; 11:897. [PMID: 32625092 PMCID: PMC7311751 DOI: 10.3389/fphar.2020.00897] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 06/02/2020] [Indexed: 12/25/2022] Open
Abstract
Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the standard of care for patients with Locally Advanced Rectal Cancer (LARC). Current selection for nCRT is based on clinical criteria regardless of any molecular marker. Pharmacogenomics may be a useful strategy to personalize and optimize nCRT in LARC. This review aims to summarize the most recent and relevant findings about the role of germline and somatic pharmacogenomics in the prediction of nCRT outcome in patients with LARC, discussing the state of the art of their application in the clinical practice. A systematic literature search of the PubMed database was completed to identify relevant English-language papers published up to January 2020. The chemotherapeutic backbone of nCRT is represented by fluoropyrimidines, mainly metabolized by DPD (Dihydro-Pyrimidine Dehydrogenase, DPYD). The clinical impact of testing DPYD*2A, DPYD*13, c.2846A > T and c.1236G > A-HapB3 before a fluoropyrimidines administration to increase treatment safety is widely acknowledged. Other relevant target genes are TYMS (Thymidylate Synthase) and MTHFR (Methylene-Tetrahydro-Folate Reductase), whose polymorphisms were mainly studied as potential markers of treatment efficacy in LARC. A pivotal role of a TYMS polymorphism in the gene promoter region (rs34743033) was reported and was pioneeringly used to guide nCRT treatment in a phase II study. The pharmacogenomic analysis of other pathways mostly involved in the cellular response to radiation damage, as the DNA repair and the activation of the inflammatory cascade, provided less consistent results. A high rate of somatic mutation in genes belonging to PI3K (Phosphatidyl-Inositol 3-Kinase) and MAPK (Mitogen-Activated Protein Kinase) pathways, as BRAF (V-raf murine sarcoma viral oncogene homolog B1), KRAS (Kirsten Rat Sarcoma viral oncogene homolog), NRAS (Neuroblastoma RAS viral (v-ras) oncogene homolog), PIK3CA (Phosphatidyl-Inositol-4,5-bisphosphate 3-Kinase, Catalytic Subunit Alpha), as well as TP53 (Tumor Protein 53) was reported in LARC. Their pharmacogenomic role, already defined in colorectal cancer, is under investigation in LARC with promising results concerning specific somatic mutations in KRAS and TP53, as predictors of tumor response and prognosis. The availability of circulating tumor DNA in plasma may also represent an opportunity to monitor somatic mutations in course of therapy.
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Affiliation(s)
- Elena De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Rossana Roncato
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Elisa Palazzari
- Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Giuseppe Toffoli
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
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15
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Yuan Y, Li L, Cheng Q, Diao F, Zeng Q, Yang X, Wu Y, Zhang H, Huang M, Chen J, Zhou Q, Zhu Y, Hua R, Tian J, Wang X, Zhou Z, Hao J, Yu J, Hua D, Liu J, Guo X, Zhou Q, Sha J. In vitro testicular organogenesis from human fetal gonads produces fertilization-competent spermatids. Cell Res 2020; 30:244-255. [PMID: 32086476 DOI: 10.1038/s41422-020-0283-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 02/03/2020] [Indexed: 01/18/2023] Open
Abstract
Unlike most organs that mature during the fetal period, the male reproductive system reaches maturity only at puberty with the commencement of spermatogenesis. Robust modelling of human testicular organogenesis in vitro would facilitate research into mechanisms of and factors affecting human spermatogenic failure and male fertility preservation in prepubertal tumor patients. Here, we report successful recapitulation of human testicular organogenesis in vitro from fetal gonadal ridge. Our model displayed the formation of mature seminiferous epithelium and self-renewing spermatogonia. Remarkably, in vitro-derived haploid spermatids have undergone meiotic recombination, and showed increased genetic diversity as indicated by genetic analysis. Moreover, these spermatids were able to fertilize oocytes and support subsequent blastocyst formation. The in vitro testicular organogenesis system described here will play an important role in elucidating the regulation of human testis development and maintaining male fertility in prepubertal cancer patients.
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Affiliation(s)
- Yan Yuan
- Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, 214062, Wuxi, Jiangsu, China.,State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Laihua Li
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Qing Cheng
- State Key Laboratory of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Medical University, 210029, Nanjing, Jiangsu, China
| | - Feiyang Diao
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, 210029, Nanjing, Jiangsu, China
| | - Qiao Zeng
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, 210029, Nanjing, Jiangsu, China
| | - Xiaoyu Yang
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, 210029, Nanjing, Jiangsu, China
| | - Yibo Wu
- Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, 214062, Wuxi, Jiangsu, China
| | - Hao Zhang
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Mingqian Huang
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Junqing Chen
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Quan Zhou
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Yunfei Zhu
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Rong Hua
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Jianyu Tian
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Xin Wang
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Zuomin Zhou
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China
| | - Jie Hao
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China
| | - Jinjin Yu
- Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, 214062, Wuxi, Jiangsu, China
| | - Dong Hua
- Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, 214062, Wuxi, Jiangsu, China
| | - Jiayin Liu
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, 210029, Nanjing, Jiangsu, China
| | - Xuejiang Guo
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China.
| | - Qi Zhou
- State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China.
| | - Jiahao Sha
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China. .,State Key Laboratory of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Medical University, 210029, Nanjing, Jiangsu, China.
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