IMPORTANCE Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit. DESIGN, SETTING, AND PARTICIPANTSIn this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (ՆT2, or clinically node positive) were enrolled between 2016 to 2019.INTERVENTIONS Treatment was administered with nivolumab, 3 mg/kg, weeks 1 and 3, or nivolumab and ipilimumab (ipilimumab, 1 mg/kg, given week 1 only). Patients had surgery 3 to 7 days following cycle 2.MAIN OUTCOMES AND MEASURES Safety and volumetric response determined using bidirectional measurements. Secondary end points included pathologic and objective response, progression-free survival (PFS), and overall survival. Multiplex immunofluorescence was used to evaluate primary tumor immune markers.RESULTS Fourteen patients were randomized to nivolumab (N) and 15 patients to nivolumab/ipilimumab (N+I) (mean [SD] age, 62 [12] years; 18 men [62%] and 11 women [38%]). The most common subsite was oral tongue (n = 16). Baseline clinical staging included patients with T2 (n = 20) or greater (n = 9) T stage and 17 patients (59%) with node-positive disease. Median time from cycle 1 to surgery was 19 days (range, 7-21 days); there were no surgical delays. There were toxic effects at least possibly related to study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N+I) patients. One patient died of conditions thought unrelated to study treatment (postoperative flap failure, stroke). There was evidence of response in both the N and N+I arms (volumetric response 50%, 53%; pathologic downstaging 53%, 69%; RECIST response 13%, 38%; and pathologic response 54%, 73%, respectively). Four patients had major/complete pathologic response greater than 90% (N, n = 1; N+I, n = 3). With 14.2 months median follow-up, 1-year progression-free survival was 85% and overall survival was 89%.CONCLUSIONS AND RELEVANCE Treatment with N and N+I was feasible prior to surgical resection. We observed promising rates of response in both arms, supporting further neoadjuvant studies with these agents.

◥Purpose: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC.Patients and Methods: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (Clin-icalTrials.gov NCT02296684).Results: Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNg activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients.Conclusions: Among patients with locally advanced, HPVunrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.

Background: Human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (OPSCC) is increasing in the United States. Current epidemiologic assessments of the national burden of HPV-positive OPSCC are needed.Methods: The Surveillance Epidemiology and End Results HPV Status Database included 12,017 patients with head and neck squamous cell carcinoma of pharyngeal subsites, including OPSCC and non-OPSCC head and neck cancer subsites (hypopharynx, nasopharynx, and "other pharynx"), diagnosed from 2013 to 2014. Age-adjusted incidence rates per 100,000 persons by HPV status were calculated. An exploratory Fine-Gray competing-risks regression determined the associations between HPV status and cancer-specific mortality.Results: From 2013 to 2014, the U.S. incidence of HPVpositive OPSCC was 4.62 [95% confidence interval (CI), 4.51-4.73] versus 1.82 (95% CI, 1.75-1.89) per 100,000 persons for HPV-negative OPSCC. The incidence of HPV-positive versus negative non-OPSCC of the head and neck was 0.62 (95% CI, 0.58-0.66) versus 1.38 (95% CI, 1.32-1.44). White race (5.47) and male sex (8.00) had the highest incidences of HPV-positive OPSCC, with a unimodal age incidence distribution peaking at ages 60 to 64 years (27.23). HPV positivity was associated with lower cancer-specific mortality than HPV-negative disease for OPSCC [adjusted HR (aHR), 0.40; P < 0.001], but not non-OPSCC (aHR, 1.08; P ¼ 0.81), P interaction ¼ 0.002.Conclusions: The U.S. incidence of HPV-positive OPSCC was 4.62 per 100,000 persons. Most cases were found in white male patients younger than 65 years, where it represents the sixth most common incident nonskin cancer. The favorable prognosis associated with HPV appears to be limited to the oropharynx.Impact: This large population-based epidemiologic assessment of the U.S. population defines the incidence and demographic burden of HPV-positive OPSCC.

Subthalamic neurons display uncommon intrinsic behaviors that are likely to contribute to the motor and cognitive functions of the basal ganglia and to many of its disorders. Here, we report silent plateau potentials in these cells. These plateau responses start with a transient burst of action potentials that quickly diminish in amplitude because of spike inactivation and current shunt. The resulting interruption of spiking reveals a stable depolarization (up state) that clamps the cell membrane potential near ؊40 mV for several seconds. These plateau potentials coexist in single subthalamic neurons with more familiar patterns of burst and pacemaker firing. Within a narrow range of baseline membrane potentials (؊67 to ؊60 mV), depolarization abruptly switches single cells from bistable to rhythmic bursts or tonic firing modes, thus selecting entirely distinct algorithms for integrating cortical and pallidal synaptic inputs.basal ganglia ͉ bistability ͉ cortex S ubthalamic neurons contribute to the motor (1, 2) and limbic (3, 4) functions of the basal ganglia. Their importance is particularly obvious in Parkinson's disease, in which symptoms improve with high-frequency subthalamic stimulation (5) or subthalamic lesion (6). Thus, there is considerable interest in understanding the synaptic and intrinsic mechanisms that control firing in these cells.At rest, subthalamic neurons display a regular pacemaker activity maintained by sustained (7,8) and resurgent (9) voltagegated Na currents. However, there is little consensus on their firing patterns when they are hyperpolarized.Studies in whole-cell or perforated-patch configurations have reported a quasilinear modulation of cell firing by current injection, excitatory postsynaptic potentials (EPSPs), or inhibitory postsynaptic potentials (IPSPs) (8,(10)(11)(12), with nonlinearities limited to small rebound bursts after IPSPs (13). Consistent with these findings, the in vivo subthalamic responses to cortical stimulation (14-17), their synchronization to cortical slow oscillations (18), and spike-wave discharges (19) are readily explained by the summating contributions of direct cortical inputs and indirect pathways (18,20,21).Studies in whole-cell or cell-attached configurations have revealed more complex bursts of action potentials or spikegenerating plateau potentials that switch to pacemaker firing with membrane depolarization (22-26). These bursts may occur spontaneously (23, 24), generating rhythms strikingly similar to the multisecond-long oscillations reported in subthalamic neurons of locally anesthetized rats (27) and awake monkeys (28).In this study, we investigated the intrinsic behaviors of subthalamic neurons challenged with a wide range of synaptic and current stimuli, during whole-cell, perforated-patch, or cellattached recordings. We found an unexpected homogeneity and complexity in their firing patterns. Independent of the recording conditions, subthalamic neurons display the following four selfsustaining regimes: a resting down state, a quiescent pla...

IMPORTANCE Data regarding outcomes after major head and neck ablation and reconstruction in the growing geriatric population (specifically Ն80 years of age) are limited. Such information would be extremely valuable in preoperative discussions with elderly patients about their surgical risks and expected functional outcomes.OBJECTIVES To identify patient and surgical factors associated with 30-day postoperative complications, 90-day mortality, and 90-day functional decline; to explore whether an association exists between the type of reconstructive procedure and outcome; and to create a preoperative risk stratification system for these outcomes. DESIGN, SETTING, AND PARTICIPANTSThis retrospective, multi-institutional cohort study included patients 80 years or older undergoing pedicle or free-flap reconstruction after an ablative head and neck surgery from January 1, 2015, to December 31, 2017, at 17 academic centers. Data were analyzed from February 1 through April 20, 2019. MAIN OUTCOMES AND MEASURESThirty-day serious complication rate, 90-day mortality, and 90-day decline in functional status. Preoperative comorbidity and frailty were assessed using the American Society of Anesthesiologists classification, Adult Comorbidity Evaluation-27 score, and Modified Frailty Index. Multivariable clustered logistic regressions were performed. Conjunctive consolidation was used to create a risk stratification system. RESULTS Among 376 patients included in the analysis (253 [67.3%] men), 281 (74.7%) underwent free-flap reconstruction. The median age was 83 years (range, 80-98 years). A total of 193 patients (51.3%) had 30-day serious complications, 30 (8.0%) died within 90 days, and 36 of those not dependent at baseline declined to dependent status (11.0%). Type of flap (free vs pedicle, bone vs no bone) was not associated with these outcomes. Variables associated with worse outcomes were age of at least 85 years (odds ratio [OR] for 90-day mortality, 1.19 [95% CI 1.14-1.26]), moderate or severe comorbidities (OR for 30-day complications, 1.80 [95% CI, 1.34-2.41]; OR for 90-day mortality, 3.33 [95% CI, 1.29-8.60]), body mass index (BMI) of less than 25 (OR for 30-day complications, 0.95 [95% CI, 0.91-0.99]), high frailty (OR for 30-day complications, 1.72 [95% CI, 1.10-2.67]), duration of surgery (OR for 90-day functional decline, 2.94 [95% CI, 1.81-4.79]), flap failure (OR for 90-day mortality, 3.56 [95% CI, 1.47-8.62]), additional operations (OR for 30-day complications, 5.40 [95% CI, 3.09-9.43]; OR for 90-day functional decline, 2.94 [95% CI, 1.81-4.79]), and surgery of the maxilla, oral cavity, or oropharynx (OR for 90-day functional decline, 2.51 [95% CI, 1.30-4.85]). Age, BMI, comorbidity, and frailty were consolidated into a novel 3-tier risk classification system.CONCLUSIONS AND RELEVANCE Important demographic, clinical, and surgical characteristics were found to be associated with postoperative complications, mortality, and functional decline in patients 80 years or older undergoing major head and neck surgery. Fre...

For patients with a true penicillin allergy, we recommend broader gram-negative coverage with alternative antibiotics, such as cefuroxime, when undergoing free tissue transfer in the head and neck.

Evaluation of the utility of localized adjuvant radiation for node-negative primary cutaneous squamous cell carcinoma with clear histologic margins.

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