Immune-related adverse events are associated with improved response, progression-free survival, and overall survival for patients with head and neck cancer receiving immune checkpoint inhibitors.

BACKGROUND: The authors hypothesized that patients developing immune-related adverse events (irAEs) while receiving immune checkpoint inhibition (ICI) for recurrent/metastatic head and neck cancer (HNC) would have improved oncologic outcomes. METHODS: Patients with recurrent/metastatic HNC received ICI at 2 centers. Univariate and multivariate logistic regression, Kaplan-Meier methods, and Cox proportional hazards regression were used to associate the irAE status with the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in cohort 1 (n = 108). These outcomes were also analyzed in an independent cohort of patients receiving ICI (cohort 2; 47 evaluable for irAEs). RESULTS: The median follow-up was 8.4 months for patients treated in cohort 1. Sixty irAEs occurred in 49 of 108 patients with 5 grade 3 or higher irAEs (10.2%). ORR was higher for irAE+ patients (30.6%) in comparison with irAE- patients (12.3%; P = .02). The median PFS was 6.9 months for irAE+ patients and 2.1 months for irAE- patients (P = .0004), and the median OS was 12.5 and 6.8 months, respectively (P = .007). Experiencing 1 or more irAEs remained associated with ORR (P = .03), PFS (P = .003), and OS (P = .004) in multivariate analyses. The association between development of irAEs and prolonged OS persisted in a 22-week landmark analysis (P = .049). The association between development of irAEs and favorable outcomes was verified in cohort 2. CONCLUSIONS: The development of irAEs was strongly associated with an ICI benefit, including overall response, PFS, and OS, in 2 separate cohorts of patients with recurrent/metastatic HNC.

The REASON score: an epigenetic and clinicopathologic score to predict risk of poor survival in patients with early stage oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a capricious cancer with poor survival rates, even for early-stage patients. There is a pressing need to develop more precise risk assessment methods to appropriately tailor clinical treatment. Genome-wide association studies have not produced a viable biomarker. However, these studies are limited by using heterogeneous cohorts, not focusing on methylation although OSCC is a heavily epigenetically-regulated cancer, and not combining molecular data with clinicopathologic data for risk prediction. In this study we focused on early-stage (I/II) OSCC and created a risk score called the REASON score, which combines clinicopathologic characteristics with a 12-gene methylation signature, to predict the risk of 5-year mortality. METHODS: We combined data from an internal cohort (n = 515) and The Cancer Genome Atlas (TCGA) cohort (n = 58). We collected clinicopathologic data from both cohorts to derive the non-molecular portion of the REASON score. We then analyzed the TCGA cohort DNA methylation data to derive the molecular portion of the risk score. RESULTS: 5-year disease specific survival was 63% for the internal cohort and 86% for the TCGA cohort. The clinicopathologic features with the highest predictive ability among the two the cohorts were age, race, sex, tobacco use, alcohol use, histologic grade, stage, perineural invasion (PNI), lymphovascular invasion (LVI), and margin status. This panel of 10 non-molecular features predicted 5-year mortality risk with a concordance (c)-index = 0.67. Our molecular panel consisted of a 12-gene methylation signature (i.e., HORMAD2, MYLK, GPR133, SOX8, TRPA1, ABCA2, HGFAC, MCPH1, WDR86, CACNA1H, RNF216, CCNJL), which had the most significant differential methylation between patients who survived vs. died by 5 years. All 12 genes have already been linked to survival in other cancers. Of the genes, only SOX8 was previously associated with OSCC; our study was the first to link the remaining 11 genes to OSCC survival. The combined molecular and non-molecular panel formed the REASON score, which predicted risk of death with a c-index = 0.915. CONCLUSIONS: The REASON score is a promising biomarker to predict risk of mortality in early-stage OSCC patients. Validation of the REASON score in a larger independent cohort is warranted.

Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone. METHODS: The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment. RESULTS: Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated. CONCLUSION: These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer. TRIAL REGISTRATION NUMBER: This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.

Transoral robotic surgery and neck dissection for HPV-positive oropharyngeal carcinoma: Importance of nodal count in survival.

BACKGROUND: In this study we determine the survival in patients with HPV-positive oropharyngeal carcinoma treated with transoral robotic surgery (TORS), neck dissection and risk-adapted adjuvant therapy. METHODS: We retrospectively identified 122 patients with HPV-positive oropharyngeal carcinoma treated with TORS and neck dissection between 2011 and 2018. Survival probability was calculated. We determined the effect of the type of neck dissection performed (modified radical neck dissection-MRND vs. selective neck dissection - SND), extranodal extension (ENE), margin status, and presence of ≥ 5 metastatic nodes on survival. RESULTS: Our patient population had a five-year overall survival of 91.0% (95% C.I. 85-97%). The five-year probability of recurrence or cancer-associated death was 0.0977 (95% C.I. 0.0927-0.1027). The five-year probability of cancer-associated death was 0.0528 (95% C.I. 0.048-0.0570). All patients who died of their disease had distant metastasis. Our PEG dependence rate was 0%. Patients with ENE and positive margins who underwent adjuvant chemoradiation did not have worse survival. Presence of ≥ 5 metastatic nodes portended worse survival after controlling for age, positive ENE and margins. Low yield (<18 nodes) on neck dissection worsened DFS on multivariable analysis. Furthermore, patients who underwent SND did not have worse OS than those who underwent MRND. CONCLUSION: Our study demonstrates that surgery could be simplified by performing TORS with SND rather than MRND. The one true poor prognostic factor in HPV-positive oropharyngeal carcinoma patients who undergo surgery is high nodal burden. Patients with high nodal burden are much more likely to die from their disease.

Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance.

BACKGROUND: The risk of delayed autoimmunity occurring months or years after discontinuation of immunotherapy is frequently asserted in the literature. However, specific cases were rarely described until 2018, when a wave of reports surfaced. With expanding I-O indications in the adjuvant/neoadjuvant curative setting, growing numbers of patients will receive limited courses of immunotherapy before entering routine surveillance. In this context, under-recognition of DIRE could pose a growing clinical hazard. METHODS: The aim of this study was to characterize DIRE through identification of existing reports of delayed post-treatment irAE in cancer patients treated with immunotherapy. We performed a PubMed literature review from 2008 through 2018 to determine the median data safety reporting window from existing I-O clinical trials, which we then applied to define the DIRE cutoff, and collated all qualifying reports over the same time span. DIRE was defined as new immune-related adverse events (irAE) manifesting ≥90 days after discontinuation of immunotherapy. RESULTS: Median duration of I-O clinical trials data safety reporting was 90 days (82% ≤ 90 days). DIRE cutoff was thus set as ≥90 days post-immunotherapy. We identified 23 qualifying cases; 21 by literature review and 2 from our institution. Median off-treatment interval to DIRE was 6 months (range: 3 to 28). Median cumulative immunotherapy exposure was 4 doses (range: 3 to 42). Involvement included endocrine, neurologic, GI, pulmonary, cardiac, rheumatologic and dermatologic irAE. CONCLUSIONS: As immunotherapy indications expand into the curative setting, often with brief exposure and potentially sequenced with multimodality treatments, it will be necessary to recognize an emerging diagnostic complex, which we have termed delayed immune-related events (DIRE). Clinical vigilance has the potential to reduce morbidity from diagnostic delay, as irAE are generally manageable with prompt initiation of treatment - or from misdiagnosis - as misattribution can lead to unnecessary or harmful interventions as we describe. DIRE should therefore figure prominently in the differential diagnosis of patients presenting with illnesses of unclear etiology, irrespective of intervening treatments or interval post-immunotherapy, both of which can confound diagnosis. Increased recognition will rest on delineation of DIRE as a clinical diagnostic entity.

A Survey of Sleep Medicine Physician Perceptions on the Surgical Treatment of Obstructive Sleep Apnea.

PURPOSE: Surgical treatment for obstructive sleep apnea (OSA) varies by specialty. Our survey sought to answer 3 principal questions: 1) To which surgical specialists are sleep physicians referring patients for upper airway surgery? 2) Which surgical treatment do sleep specialists find to be most effective in treating OSA? 3) Do sleep medicine physicians believe that maxillomandibular advancement (MMA) is worthwhile to patients who are surgical candidates? MATERIALS AND METHODS: We formulated a cross-sectional survey. The study sample was obtained by identifying all practices that advertised as sleep medicine specialists in Houston, Texas, by using Internet searches. Physicians who treated children were excluded. Seventy-nine surveys were hand delivered to offices in the greater Houston area; the survey included 6 questions to determine referral and surgical preferences for OSA. Variable responses included years in practice, specialty, and a comments section. A 10-point Likert scale was used to assess sleep medicine physicians' referral patterns and perceptions regarding surgical treatment of OSA. Numerical data were analyzed by calculating mean values and by dividing responses into "disagree" (<5), "neutral" (5), and "agree" (>5). RESULTS: Twenty-six surveys were returned. More sleep medicine physicians referred patients to ear, nose, and throat surgeons (52%) than to oral and maxillofacial surgeons (20%). MMA was viewed as the most effective surgery (72%), followed by "none" (16%), "other" (8%), and uvulopalatopharyngoplasty (4%). More respondents viewed the benefits versus risks as favorable for MMA (44%) than for uvulopalatopharyngoplasty (29%). CONCLUSIONS: The results of this survey show that sleep medicine physicians in the greater Houston area view MMA as the most favorable and effective surgical option for treating OSA. Although MMA was most often referred for, more respondents refer patients to ear, nose, and throat surgeons than to oral and maxillofacial surgeons for surgical management of OSA. Years in practice displayed no correlation in referral patterns or preference for type of OSA surgery.

Regeneration of a Tooth in a Tissue-Engineered Mandible After Resection of a Central Giant Cell Tumor. Demonstrating Evidence of Functional Matrix Theory and Ectodermal Origin of Teeth in a Human Model-A Case Report.

Central giant cell tumors (CGCTs) are uncommon lesions occurring in the jaw. They are benign but locally destructive osteolytic lesions. They usually occur in pediatric patients 5 to 15 years of age. Multiple noninvasive modalities of treatment (intralesional steroids, interferon, calcitonin, and denosumab) have been described for those lesions, but for those that are refractory to treatment, enucleation and curettage or resection is a curative surgery. This case report describes a pediatric patient who was diagnosed with an aggressive CGCT of the left mandible encompassing the right angle to the condyle. The lesion became refractory to noninvasive treatments and immediate resection and reconstruction was performed using principles of tissue engineering. After 5 years of close observation, the patient showed normal morphology and growth of his mandible, but surprisingly developed a left mandibular third molar (tooth 17) in the site of the mandibular resection and reconstruction. This is the first case report in the literature to show the spontaneous development of teeth in a human reconstructed mandible, contributing evidence toward the functional matrix theory of mandibular growth and ectodermal origin of teeth.