Dm M. Hartl

Bio: Dm M. Hartl is an academic researcher from Institut Gustave Roussy. The author has contributed to research in topics: Head and neck squamous-cell carcinoma & Oropharyngeal Carcinoma. The author has an hindex of 1, co-authored 1 publications receiving 179 citations.

Treatment de-escalation in HPV-positive oropharyngeal carcinoma: Ongoing trials, critical issues and perspectives

Abstract: Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High-risk human papillomavirus (HR-HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de-escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de-escalation in HPV-positive OPSCC.

Human papillomavirus testing in head and neck carcinomas guideline from the college of American pathologists

Abstract: Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell ca...

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Abstract: Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.

Diagnostic accuracy of p16INK4a immunohistochemistry in oropharyngeal squamous cell carcinomas: A systematic review and meta-analysis.

Abstract: The accurate diagnosis of human papillomavirus (HPV) causality in oropharyngeal squamous cell carcinomas (OPSCC) is likely to influence therapeutic decisions in affected patients in the near future. We conducted a systematic review and meta-analysis to determine the diagnostic accuracy of p16INK4a immunohistochemistry (IHC) to identify HPV-induced OPSCC. We identified all studies that performed p16INK4a IHC (index test) and HPV E6/E7 mRNA detection using an amplification-based method (gold standard to indicate a transforming relevance of HPV) in OPSCC. Testing with one or more comparator tests (HPV DNA PCR, HPV DNA in situ hybridization (ISH) and p16INK4a IHC/HPV DNA PCR combined testing) was an optional criterion for inclusion. Among 1,636 retrieved studies 24 fulfilled the inclusion criteria. The pooled sensitivity of p16INK4a IHC, HPV DNA PCR, HPV DNA ISH and p16INK4a IHC/HPV DNA PCR combined testing was 94% (95%-confidence interval (CI) 91-97%), 98% (CI 94-100%), 85% (CI 76-92%) and 93% (CI 87-97%), respectively. The pooled specificity was 83% (CI 78-88%), 84% (CI 74-92%), 88% (CI 78-96%) and 96% (CI 89-100%), respectively. p16INK4a IHC/HPV DNA PCR combined testing was as sensitive as either p16INK4a IHC or HPV DNA PCR alone but significantly more specific than either separate test. In conclusion, p16INK4a IHC is highly sensitive but moderately specific to diagnose HPV-transformed OPSCC when used as a single test. Combined p16INK4a IHC and HPV DNA PCR testing significantly enhances specificity while maintaining high sensitivity. This diagnostic test combination thus represents an attractive testing strategy for the reliable diagnosis of HPV-induced OPSCC in the clinical setting and may constitute an inclusion criterion for future therapeutic trials.

The head and neck cancer cell oncogenome: A platform for the development of precision molecular therapies

Abstract: // Daniel Martin 1 , Martin C. Abba 2 , Alfredo A. Molinolo 1 , Lynn Vitale-Cross 1 , Zhiyong Wang 1 , Moraima Zaida 1 , Naomi C. Delic 4, 5 , Yardena Samuels 3 , J. Guy Lyons 4, 5 , J. Silvio Gutkind 1 1 Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA 2 CINIBA, Facultad de Ciencias Medicas, Universidad Nacional de La Plata, La Plata, Argentina 3 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel 4 Dermatology, University of Sydney, Camperdown, Australia 5 Cancer Services, Royal Prince Alfred Hospital, Camperdown, Australia Correspondence to: Silvio Gutkind, e-mail: sg39v@nih.gov Keywords: HNSCC, Sequencing, Exome, RNAseq, Cancer Received: July 11, 2014 Accepted: August 28, 2014 Published: November 04, 2014 ABSTRACT The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53 , FAT1 , CDK2NA , CASP8 , and NOTCH1 , and copy number variations (CNVs) and mutations in PIK3CA , HRAS , and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV + HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV + HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration.

HPV-Associated Head and Neck Cancer.

Abstract: Over the last two decades, it has been recognized that head and neck cancers, primarily in the oropharynx, can be a distinct entity that is causally related to human papilloma virus (HPV). Fakhry et al. established in 2008 that such tumors have a strikingly better prognosis with improved responsiveness to chemotherapy as well as chemoradiotherapy and favorable survival rates. Since then, new studies have contributed to our increased understanding of this new entity, ranging from a detailed understanding of the genetic fingerprint and risk modifiers such as smoking to successful early attempts to personalize therapy with de-escalation in the definitive intent treatment setting and specific evaluation of targeted therapies in this patient population. This Commentary seeks to summarize the state of the art of our understanding of HPV-associated head and neck cancers that has emerged since the publication of seminal findings by Fakhry et al.