Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.

Transoral robotic surgery adoption and safety in treatment of oropharyngeal cancers.

BACKGROUND: Transoral robotic surgery (TORS) was approved by the Food and Drug Administration in 2009 for the treatment of oropharyngeal cancers (oropharyngeal squamous cell carcinoma [OPSCC]). This study investigated the adoption and safety of TORS. METHODS: All patients who underwent TORS for OPSCC in the National Cancer Data Base from 2010 to 2016 were selected. Trends in the positive margin rate (PMR), 30-day unplanned readmission, and early postoperative mortality were evaluated. Outcomes after TORS, nonrobotic surgery (NRS), and nonsurgical treatment were compared with matched-pair survival analyses. RESULTS: From 2010 to 2016, among 73,661 patients with OPSCC, 50,643 were treated nonsurgically, 18,024 were treated with NRS, and 4994 were treated with TORS. TORS utilization increased every year from 2010 (n = 363; 4.2%) to 2016 (n = 994; 8.3%). The TORS PMR for base of tongue malignancies decreased significantly over the study period (21.6% in 2010-2011 vs 15.8% in 2015-2016; P = .03). The TORS PMR at high-volume centers (≥10 cases per year; 11.2%) was almost half that of low-volume centers (<10 cases per year; 19.3%; P < .001). The rates of 30-day unplanned readmission (4.1%) and 30-day postoperative mortality (1.0%) after TORS were low and did not vary over time. High-volume TORS centers had significantly lower rates of 30-day postoperative mortality than low-volume centers (0.5% vs 1.5%; P = .006). In matched-pair analyses controlling for clinicopathologic cofactors, 30-, 60-, and 90-day posttreatment mortality did not vary among patients with OPSCC treated with TORS, NRS, or nonsurgical treatment. CONCLUSIONS: TORS has become widely adopted and remains safe across the country with a very low risk of severe complications comparable to the risk with NRS. Although safety is excellent nationally, high-volume TORS centers have superior outcomes with lower rates of positive margins and early postoperative mortality.

Cytology-based Cancer Surgery of the Head and Neck (CyCaS-HN): a prospective, randomized, controlled clinical trial.

PURPOSE: Liquid-based cytology (LBC) is routinely used in gynecology but is rarely applied in head and neck oncology though many suspicious lesions are easily accessible. While several studies have evaluated the potential use of LBC for early detection and molecular characterization of head and neck squamous cell carcinomas (HNSCCs), no study investigated its potential role in surgical management and therapy planning so far. METHODS: Twenty-five patients with cT1-2 squamous cell carcinomas of the oral cavity and oropharynx were prospectively enrolled in this study and were randomized to two treatment arms: in the control arm, a diagnostic panendoscopy with incisional biopsy was followed by a second operation with transoral tumor resection ± neck dissection and tracheostomy. In the intervention arm, patients underwent LBC diagnostics and in case of a positive result received one single operation with panendoscopy and incisional biopsy for confirmation of LBC result by rapid section histology followed by transoral tumor resection ± neck dissection and tracheostomy in the same session. RESULTS: Time between clinical diagnosis and definitive surgical treatment was significantly shorter in the intervention group compared with the control group (p < 0.0001). Additionally, time of hospitalization (p < 0.0001) and cumulative operation time (p = 0.062) were shorter in the intervention group. No significant differences in overall, progression-free, and disease-specific survival were observed. CONCLUSION: Cytology-based cancer surgery is a promising therapeutic strategy that can potentially be considered for a well-defined group of early-stage HNSCC patients and help to avoid repetitive general anesthesia, shorten the diagnosis-to-treatment interval and spare operation as well as hospitalization time.

Nodal characteristics associated with adverse prognosis in oral cavity cancer are linked to host immune status.

BACKGROUND AND OBJECTIVE: Nodal metastasis is one of the strongest predictors of outcomes in oral cavity squamous cell carcinomas (OSCC). The aim was to analyze the interplay of nodal characteristics in OSCC prognosis. METHODS: In this retrospective cohort study we included OSCC patients treated with primary surgery including neck dissection between 2005 and 2015 (n = 619). Disease-specific survival (DSS) was the primary endpoint. Optimal cutoffs were identified using recursive-partitioning analysis (RPA). A novel characteristic-metastatic focus-to-lymph node size ratio (MLR)-was introduced. We compared the American Joint Committee on Cancer, Eighth Edition (AJCC8) pN categories to a new categorization. RESULTS: Patients with higher neutrophil-to-lymphocyte ratio had more adverse nodal characteristics. All nodal characteristics were significant predictors of DSS in univariable analysis. In multivariable analysis, only number of positive nodes and MLR remained significant. An RPA including all nodal covariates confirmed the results. Compared with AJCC8, our RPA categorization had better hazard discrimination (0.681 vs. 0.598), but poorer balance value (0.783 vs. 0.708). CONCLUSION: Patients with higher neutrophil-to-lymphocyte ratio had more adverse nodal characteristics. Total number of metastatic lymph nodes is the strongest predictor of outcomes in OSCC. MLR is a more powerful predictor than metastatic lymph node size or metastatic focus size alone.

Life Expectancy and Treatment Patterns in Elderly Patients With Low-Risk Papillary Thyroid Cancer: A Population-Based Analysis.

OBJECTIVE: Guidelines endorse active surveillance for low-risk papillary thyroid carcinoma (PTC), but this is not commonly utilized. Those with limited life expectancy due to age and comorbidity may be best suited for active surveillance given their higher likelihood of other-cause mortality compared to disease-specific mortality. METHODS: Surveillance, epidemiology, and end results-Medicare was queried for patients >65 years with T1, N0, M0 PTC who received surgery. We evaluated the overall survival, disease-specific survival (DSS), and survival based on tumor size and extent of surgery (hemi- vs total thyroidectomy). We created a competing risk model to identify the cumulative incidence of other-cause mortality to define patient groups with life expectancies of less than 10 and 15 years. RESULTS: A total of 3280 patients were included. The 20-year overall survival and DSS were 38.2% and 98.5%, respectively. DSS was comparable between patients based on tumor size and surgery. The cancer cohort had better survival compared to matched controls (P < .001). Life expectancy was less than 15 years for any patient aged >80 years regardless of Charlson comorbidity score (CCS ≥ 0) and any patient aged >70 years with CCS ≥ 1. Life expectancy was less than 10 years for any patient a >80 years with CCS ≥ 1 and aged >70 years with CCS ≥ 3. CONCLUSION: Older patients with comorbidities have limited life expectancies but excellent DSS from low-risk PTC. Incorporating life expectancy into management decisions and guidelines would likely promote selection of less aggressive management for populations that are most suited for this approach.

Human papillomavirus and survival of patients with sinonasal squamous cell carcinoma.

BACKGROUND: To the authors' knowledge, the question of whether human papillomavirus (HPV) infection is associated with outcomes in patients with sinonasal squamous cell carcinoma (SNSCC) is not well studied at this time. In the current study, the authors investigated patterns of HPV testing and its association with survival in patients with SNSCC using the National Cancer Data Base. METHODS: The authors selected all SNSCC cases diagnosed between 2010 and 2016. HPV testing practices, clinicodemographic factors, treatments, and survival were analyzed. Multivariable Cox regression and propensity score-matched survival analyses were performed. RESULTS: A total of 6458 SNSCC cases were identified. Of these, only 1523 cases (23.6%) were tested for HPV and included in the current study. The median patient age was 64 years and the majority had advanced stage tumors (overall AJCC stage III-IV, 721 patients; 62.1%). HPV-positive SNSCC comprised 31.5% (447 of 1418 cases) of the final study cohort. Among 15 hospitals that routinely tested nonoropharyngeal SCCs for HPV, the percentage of HPV-positive SNSCCs was smaller (24.6%; P = .04). Patients with HPV-positive SNSCC were younger (aged 60 years vs 65 years; P < .001), with tumors that were more likely to be high grade (55.3% vs 41.7%; P < .001), and attributed to the nasal cavity (62.2% vs 44.0%; P < .001). HPV-positive SNSCC was associated with significantly improved overall survival in multivariable regression analysis (hazard ratio, 0.45; 95% CI, 0.28-0.72 [P = .001]) and propensity score-matched (hazard ratio, 0.61; 95% CI, 0.38-0.96 [P = .03]) analyses controlling for clinicodemographic and treatment factors. CONCLUSIONS: Currently, only a minority of patients with SNSCC are tested for HPV. However, a sizable percentage of SNSCC cases may be HPV related; furthermore, HPV-positive SNSCC is associated with improved overall survival. Routine HPV testing may be warranted in patients with SNSCC.

Pretreatment peripheral blood leukocytes are independent predictors of survival in oral cavity cancer.

BACKGROUND: Inflammation and immune surveillance evasion are cancer hallmarks. Peripheral blood leukocytes (PBLs) represent both. The aim of the current study was to examine PBLs as predictors of outcomes in oral cavity squamous cell carcinoma (OSCC), and to find specific cutoffs with the goal of including PBLs as host factor in patients' preoperative risk assessment. METHODS: Previously established head and neck squamous cell carcinoma (HNSCC) cutoffs were examined in an independent cohort of 1369 OSCC patients. Then optimal OSCC cutoffs were found and validated in the subset of patients with OSCC (n = 119) from the external HNSCC cohort. The PBLs analyzed were neutrophils, monocytes, and lymphocytes individually, the neutrophil-to-lymphocyte ratio (NLR), and a combined index using all PBLs called Systemic Inflammation Response Index (SIRI). RESULTS: All parameters were significant predictors of survival using the previous cutoffs. However, OSCC cutoffs stratified survival outcomes better. Considering neutrophils ≤4.8 × 109 /L as reference, patients with 4.8-9.1 × 109 /L neutrophils had 1.536 times higher risk of death (95% CI, 1.295-1.822), and patients with ≥9.1 × 109 /L had 3.076 times higher risk (95% CI: 2.170-4.360). All PBLs maintained independent prognostic capacity in multivariable analysis. Neutrophils, NLR, and SIRI were significant predictors of survival when validating OSCC cutoffs in the external validation cohort. CONCLUSIONS: Pretreatment peripheral blood neutrophils, NLR, and SIRI are the most robust independent predictors of overall survival among all PBLs in OSCC. The authors report externally validated cutoffs that demonstrate the feasibility of including PBLs as host features in the preoperative prognostication of OSCC.

Identification of prognostic molecular biomarkers in 157 HPV-positive and HPV-negative squamous cell carcinomas of the oropharynx.

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing due to high-risk HPV infection. We explored the significance of genetic alterations in HPV-positive (HPV-P) and HPV-negative (HPV-N) OPSCC patients on long-term outcome. A total of 157 cases of primary resected OPSCC diagnosed from 1978 to 2005 were subjected to a targeted exome sequencing by MSK-IMPACT™ interrogating somatic mutations in 410 cancer-related genes. Mutational profiles were correlated to recurrence and survival outcomes. OPSCC included 47% HPV-positive (HPV-P) and 53% HPV-negative (HPV-N) tumors arising in the base of tongue (BOT, 43%), palatine tonsil (30%) and soft palate (SP, 27%). HPV negative status, SP location and smoking were associated with poorer outcome. Poorer overall survival was found in NOTCH1-mutated HPV-P (p = 0.039), and in SOX2-amplified HPV-N cases (p = 0.036). Chromosomal arm gains in 8p and 8q, and 16q loss were more common in HPV-P (p = 0.005, 0.04 and 0.01, respectively), while 9p, 18q and 21q losses were more frequent in HPV-N OPSCC (p = 0.006, 0.002 and 0.01, respectively). Novel, potentially functional JAK3, MYC and EP300 intragenic deletions were found in HPV-P, and FOXP1, CDKN2A, CCND1 and RUNX1 intragenic deletions and one FGFR3 inversion were detected in HPV-N tumors. HPV-N/TP53-wild-type OPSCC harbored recurrent mutations in NOTCH1/3/4 (39%), PIK3CA, FAT1 and TERT. In comparison to their oral and laryngeal counterparts, HPV-N OPSCC were genetically distinct. In OPSCC, HPV status, tumor subsite and smoking determine outcome. Risk-stratification can be further refined based on the mutational signature, namely, NOTCH1 and SOX2 mutation status.

Periodontal pathogens are a risk factor of oral cavity squamous cell carcinoma, independent of tobacco and alcohol and human papillomavirus.

Over the past decade, there has been a change in the epidemiology of oral cavity squamous cell cancer (OC-SCC). Many new cases of OC-SCC lack the recognized risk factors of smoking, alcohol and human papilloma virus. The aim of this study was to determine if the oral microbiome may be associated with OC-SCC in nonsmoking HPV negative patients. We compared the oral microbiome of HPV-negative nonsmoker OC-SCC(n = 18), premalignant lesions(PML) (n = 8) and normal control patients (n = 12). Their oral microbiome was sampled by oral wash and defined by 16S rRNA gene sequencing. We report that the periodontal pathogens Fusobacterium, Prevotella, Alloprevotella were enriched while commensal Streptococcus depleted in OC-SCC. Based on the four genera plus a marker genus Veillonella for PML, we classified the oral microbiome into two types. Gene/pathway analysis revealed a progressive increase of genes encoding HSP90 and ligands for TLRs 1, 2 and 4 along the controls→PML → OC-SCC progression sequence. Our findings suggest an association between periodontal pathogens and OC-SCC in non smoking HPV negative patients.

IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype.

Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.

Neck dissection for salivary gland malignancies.

Salivary gland carcinomas are diverse, and their biological behavior and surgical management are also variable and somewhat controversial. Cervical lymph node status is an important prognostic variable for salivary gland malignancies. Neck dissection should be undertaken if there is clinical or radiographic evidence of associated nodal metastasis in the neck. However, indications for elective neck dissections in a clinically N0 neck remains a controversial topic. This article describes indications for elective neck dissection in salivary gland malignancies, provides a detailed review of the neck dissection technique, and discusses postoperative management of these patients.

Therapeutic targeting of tumor suppressor genes.

Carcinogenesis is a multistep process attributable to both gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes. Currently, most molecular targeted therapies are inhibitors of oncogenes, because inactivated tumor suppressor genes have proven harder to "drug." Nevertheless, in cancers, tumor suppressor genes undergo alteration more frequently than do oncogenes. In recent years, several promising strategies directed at tumor suppressor genes, or the pathways controlled by these genes, have emerged. Here, we describe advances in a number of different methodologies aimed at therapeutically targeting tumors driven by inactivated tumor suppressor genes.

Increasing diagnosis of subclinical thyroid cancers leads to spurious improvements in survival rates.

BACKGROUND: Survival rates are commonly used to measure success in treating cancer, but can be misleading. Modern diagnostic practices can lead to the appearance of improving cancer survival, as tumors are diagnosed earlier (lead-time bias) or as an increasing proportion are slow-growing (length bias), whereas the actual burden of cancer deaths is unchanged. Increasingly, more subclinical thyroid cancers are being diagnosed. The objective of the current study was to determine whether thyroid cancer survival rates have been affected by this phenomenon. METHODS: The authors analyzed survival data from patients with thyroid cancer who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) from 1950 to 2005, and United States population-based incidence, prevalence, and survival data from 1973 to 2009 in the Surveillance, Epidemiology, and End Results data set. RESULTS: US thyroid cancer incidence has increased 3-fold from 1975 to 2009. Over time, the proportion of thyroid cancers that are subcentimeter in size has increased from 23% (1983) to 36% (2009). At MSKCC, this percentage rose from 20% (1950) to 35% (2005). The incidence rates of large tumors (>6 cm) and distant metastasis have not changed. In the United States, 10-year relative survival improved from 95.4% to 98.6% (1983-1999). At MSKCC, 10-year disease-specific survival improved from 91.1% to 96.1% (1950-2005). However, when stratified by tumor size and stage, no changes in survival outcomes were observed. US thyroid cancer mortality rates have remained stable (1975-2009). CONCLUSIONS: Modern medical practices increasingly uncover small, asymptomatic thyroid cancers. Survival rates appear improved, but this finding is spurious, attributable instead to shifts in the characteristics of disease being diagnosed. Relying on survival rates to measure success in treating thyroid cancer may reinforce inappropriately aggressive management. Treatment decisions in thyroid cancer should be made based on mortality, not survival data.

Wide Inter-institutional Variation in Performance of a Molecular Classifier for Indeterminate Thyroid Nodules.

BACKGROUND: The Afirma gene expression classifier (GEC) is used to assess malignancy risk in indeterminate thyroid nodules (ITNs) classified as Bethesda category III/IV. Our objective was to analyze GEC performance at two institutions with high thyroid cytopathology volumes but differing prevalence of malignancy. METHODS: Retrospective analysis of all ITNs evaluated with the GEC at Memorial Sloan Kettering Cancer Center (MSK; n = 94) and Mount Sinai Beth Israel (MSBI; n = 71). These institutions have differing prevalences of malignancy in ITNs: 30-38 % (MSK) and 10-19 % (MSBI). Surgical pathology was correlated with GEC findings for each matched nodule. Performance characteristics were estimated using Bayes Theorem. RESULTS: Patient and nodule characteristics were similar at MSK and MSBI. The GEC-benign call rates were 38.3 % (MSK) and 52.1 % (MSBI). Of the GEC-benign nodules, 8.3 % (MSK) and 13.5 % (MSBI) were treated surgically. Surgical pathology indicated that all of GEC-benign nodules were benign. Of the GEC-suspicious nodules, 60.0 % (MSK) and 61.7 % (MSBI) underwent surgery. Positive predictive values (PPVs) for GEC-suspicious results were 57.1 % (95 % CI 41.0-72.3) at MSK and 14.3 % (95 % CI 0.2-30.2) at MSBI. The estimated negative predictive values (NPVs) were 86-92 % at MSK and 95-98 % at MSBI. CONCLUSIONS: There were wide variations in the Afirma GEC-benign call rate, PPV, and NPV between MSBI (a comprehensive health system) and MSK (a tertiary referral cancer center), which had differing rates of malignancy in ITNs. The GEC could not routinely alter management in either institution. We believe that this assay would be expected to be most informative in practice settings where the prevalence of malignancy is 15-21 %, such that NPV >95 % and PPV >25 % would be anticipated. Knowing the prevalence of malignancy in ITNs at a particular institution is critical for reliable interpretation of GEC results.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: THE INCREASING INCIDENCE OF THYROID CANCER.

OBJECTIVE: (1) Describe current epidemiology of thyroid cancer in the United States; (2) evaluate hypothesized causes of the increased incidence of thyroid cancer; and (3) suggest next steps in research and clinical action. METHODS: Analysis of data from Surveillance, Epidemiology and End Results System and the National Center for Vital Statistics. Literature review of published English-language articles through December 31, 2013. RESULTS: The incidence of thyroid cancer has tripled over the past 30 years, whereas mortality is stable. The increase is mainly comprised of smaller tumors. These facts together suggest the major reason for the increased incidence is detection of subclinical, nonlethal disease. This has likely occurred through: health care system access, incidental detection on imaging, more frequent biopsy, greater volumes of and extent of surgery, and changes in pathology practices. Because larger-size tumors have increased in incidence also, it is possible that there is a concomitant true rise in thyroid cancer incidence. The only clearly identifiable contributor is radiation exposure, which has likely resulted in a few additional cases annually. The contribution of the following causes to the increasing incidence is unclear: iodine excess or insufficiency, diabetes and obesity, and molecular disruptions. The following mechanisms do not currently have strong evidence to support a link with the development of thyroid cancer: estrogen, dietary nitrate, and autoimmune thyroid disease. CONCLUSION: Research should focus on illuminating which thyroid cancers need treatment. Patients should be advised of the benefits as well as harms that can occur with treatment of incidentally identified, small, asymptomatic thyroid cancers.

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers.

Activation of the PI3K and epidermal growth factor receptor (EGFR) pathway is able to drive oncogenesis in multiple human cancers, including head and neck squamous cell carcinoma. Targeted agents such as cetuximab and erlotinib are currently used in patients with head and neck squamous cell carcinoma, but, in this disease, the genomic alterations that cause pathway activation and determine response to pharmacologic inhibition remain ill-defined. Here, we present a detailed dissection of the EGFR/PI3K pathway, composed of sequencing of the core pathway components, and high-resolution genomic copy number assessment. Mutations were found in PIK3CA (6%), but no point mutations were observed in other pathway genes such as PTEN and EGFR. In contrast, we observed frequent copy number alterations of genes in the pathway, including PIK3CA, EGFR, protein tyrosine phosphatase receptor S (PTPRS), and RICTOR. In total, activating genetic pathway alterations were identified in 74% of head and neck tumors. Importantly, intragenic microdeletions of the EGFR phosphatase PTPRS were frequent (26%), identifying this gene as a target of 19p13 loss. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations. These findings have important implications for our understanding of head and neck cancer tumorigenesis and for the use of targeted agents for this malignancy.

Reduced impact of nodal metastases as a prognostic factor for tonsil cancer in the HPV era.

Metastatic lymph nodes (LN) are an adverse prognostic factor in head and neck squamous cell carcinoma (SCC). In this study, we tested the hypothesis that nodal metastases have reduced impact on survival in tonsil cancer in the HPV-predominant era. Incidence and mortality data of tonsil and oral cavity SCC between 1988 and 2007 were obtained from the SEER database. Based on published literature, we considered cases of tonsil cancer from 1988 to 1997 as the pre-HPV cohort (N = 752), and 1998-2007 as the HPV-predominant cohort (N = 2,755). Comparing the two cohorts, Kaplan-Meier 5-year overall survival (OS) for tonsil SCC improved from 54.0 to 74.3 % (p < 0.0001), and cancer-specific survival (CSS) improved from 66.0 to 82.9 % (p < 0.0001). Stratifying by LN involvement showed improved OS in the HPV-predominant cohort with one (63.6 vs. 79.7 %, p < 0.0001), two to three (54.2 vs. 75.9 %, p < 0.0001), four to eight (40.3 vs. 68.9 %, p < 0.0001), and greater than eight positive nodes (25.5 vs. 41.9 %, p < 0.0001). While metastatic LNs still negatively affect prognosis, their impact on OPC survival has diminished in the HPV-predominant era. This finding provides a rationale for additional studies of the prognostic significance of LN metastases in OPC cohorts of defined HPV status, and supports the concept that HPV-related OPC is a disease distinct from "classical" OPC, with unique prognostic features.

Loss of Human Leukocyte Antigen and Immune Escape in Head and Neck Cancer.

OBJECTIVES/HYPOTHESIS: Cancer cells evade recognition by the immune system to survive. Head and neck squamous cell carcinoma (HNSCC) is characterized by high levels of immune infiltration and mutation-associated neoantigens; therefore, immune evasion is likely to be an important mechanism in HNSCC tumorigenesis and progression. A commonly employed mechanism of immune evasion is downregulation of human leukocyte antigen (HLA) or loss of heterozygosity (LOH) in tumor cells. The objective of this study was to integrate multi-dimensional genomic and transcriptomic data from HNSCC tumors to better understand the clinical and immunologic implications of HLA LOH. STUDY TYPE/DESIGN: Cross-sectional integrated clinical and genomic analysis. METHODS: Whole-exome sequencing and RNA-sequencing data from 522 tumors profiled in The Cancer Genome Atlas HNSCC cohort were analyzed and integrated with secondary analyses including immune cell deconvolution data. Associations were analyzed with categorical hypothesis testing and multivariable logistic and Cox regression. RESULTS: HLA LOH was a prevalent event that was identified in 53% of HNSCC tumors; in many cases, more than one class I HLA gene was targeted for LOH. HLA LOH was more common in advanced-stage tumors. Tumors with somatic HLA LOH had tumor microenvironments defined by decreased lymphocyte and T cell infiltration. CONCLUSIONS: HLA LOH is one of the most prevalent genetic alterations in HNSCC, and is associated with a cold immune microenvironment, suggesting that HLA LOH is a means of immune evasion. It may have value as a predictive biomarker or potential as a cancer cell-specific therapeutic target. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:160-165, 2024.

Skin cancer screening recommendations by U.S. cancer centers: Inconsistency with national guidelines.

OBJECTIVE: The incidence of melanoma has increased dramatically over the past four decades, while overall mortality has remained stable. This increase in incidence without a change in overall mortality may be due to overdiagnosis through skin cancer screening. Despite the USPSTF citing insufficient evidence for or against professional skin cancer screening in average-risk adults, U.S. skin cancer screening practices may be leading to overdiagnosis of skin cancers. METHODS: Two reviewers examined the online recommendations for skin cancer screening of 1113 U.S. cancer centers accredited by the Commission on Cancer, including 66 designated by the National Cancer Institute (NCI). Recommendations on skin cancer screening, such as age, frequency, and patient population (i.e. high-risk of developing skin cancer, "people of color") were documented. RESULTS: We found that 18% of centers (202) recommended professional screening in average-risk adults, 35.8% (399) advised regular self-examination, and only 3.4% (38) cited insufficient evidence for screening practices; 49% of NCI centers (32/66) recommended screening in high-risk adults compared to 13% of non-NCI centers (135/1047; p = 0.0004); 0.45% of centers (5) mentioned the potential harms of screening, while 3.5% (39) specifically recommended screening for people of color. CONCLUSION: Our study reveals that many U.S. cancer centers advise some form of skin cancer screening despite a lack of evidence for or against these practices. Few centers mentioned the potential harms of screening, including overdiagnosis. This indicates a need for stronger evidence for specific screening guidelines and for greater public awareness of the potential benefits and harms of routine skin cancer screening.