Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma.

Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, or JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T cell clones. A high ratio of regulatory T to T helper 17 cells in pretreatment blood predicts low T cell receptor repertoire diversity in pretreatment blood, a low cytolytic T cell signature in pretreatment tumors, and innate resistance. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for individuals with resectable head and neck cancer.

Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma.

Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear. Using a Simon's two-stage design, we present results of a single-arm phase-II trial where 12 patients with stage II-IVA OCSCC received 3 to 4 biweekly doses of 3 mg/kg nivolumab followed by definitive surgical resection with curative intent. Presurgical nivolumab therapy in this cohort shows an overall response rate of 33% (n = 4 patients; 95% CI: 12%-53%). With a median follow up of 2.23 years, 10 out of 12 treated patients remain alive. Neoadjuvant nivolumab is safe, well-tolerated, and is not associated with delays in definitive surgical treatment in this study. This work demonstrates feasibility and safety for incorporation of nivolumab in the neoadjuvant setting for OCSCC (ClinicalTrials.gov: NCT03021993).

IL6 Fuels Durable Memory for Th17 Cell-Mediated Responses to Tumors.

The accessibility of adoptive T-cell transfer therapies (ACT) is hindered by the cost and time required for product development. Here we describe a streamlined ACT protocol using Th17 cells expanded only 4 days ex vivo. While shortening expansion compromised cell yield, this method licensed Th17 cells to eradicate large tumors to a greater extent than cells expanded longer term. Day 4 Th17 cells engrafted, induced release of multiple cytokines including IL6, IL17, MCP-1, and GM-CSF in the tumor-bearing host, and persisted as memory cells. IL6 was a critical component for efficacy of these therapies via its promotion of long-term immunity and resistance to tumor relapse. Mechanistically, IL6 diminished engraftment of FoxP3+ donor T cells, corresponding with robust tumor infiltration by donor effector over regulatory cells for the Day 4 Th17 cell product relative to cell products expanded longer durations ex vivo. Collectively, this work describes a method to rapidly generate therapeutic T-cell products for ACT and implicates IL6 in promoting durable immunity of Th17 cells against large, established solid tumors. SIGNIFICANCE: An abbreviated, 4-day ex vivo expansion method licenses Th17 cells to confer long-lived immunity against solid malignancies via induction of systemic IL6 in the host.See related commentary by Fiering and Ho, p. 3795.

Immunological effects of nivolumab immunotherapy in patients with oral cavity squamous cell carcinoma.

BACKGROUND: Although checkpoint blockades have become widely used, the immunological impact in cancer patients, especially those with oral cavity squamous cell carcinoma (OCSCC), has not been well studied. METHODS: The present study assessed the immunological impact of anti-PD-1 (nivolumab) treatment in 10 patients with OCSCC. This involved phenotypic analyses of peripheral blood T-cell subpopulations and their expression of immune mediators prior to and following nivolumab treatment. The focus was on immunological effects of treatment without regard to possible clinical responses. RESULTS: Nivolumab caused a decline in the frequency of blood CD4+ cells but did not affect their expression of IFN-γ. However, nivolumab increased the proportion of CD4+ cells expressing the Treg-supporting factor Foxp3. Nivolumab treatment caused an increase in the proportion of CD8+ cells. While their expression of granzyme B increased, it did not attain significance. Analyses of CD8+ cell subpopulations showed nivolumab caused an increase in levels of unconventional CD8dimCD3+ T-cells. It also caused an increase in expression of granzyme B by these unconventional T-cells as well as by the conventional CD8hiCD3+ cells. The CD8hiCD3+ subpopulation also had a near-significant increase in IFN-γ expression. Treatment with nivolumab had no effect on the levels of the NK containing CD8dimCD3- subpopulation of cells or their expression of IFN-γ or granzyme B. CONCLUSIONS: These results show nivolumab causes opposing effects on CD4+ and CD8+ cell populations, with CD4+ cell levels declining but increasing the proportion of Treg cells, and unconventional CD8+ T-cell levels increasing with increased expression of immune mediators by CD8+ T-cell subpopulations.

Effect of a Standardized Electronic Medical Record Order Set on Opioid Prescribing after Tonsillectomy.

OBJECTIVE: Approximately 5% of children develop new persistent opioid use after tonsillectomy. Critical review of our prescribing practices revealed inconsistent and excessive opioid prescribing after this procedure in children. We sought to improve our practice by using a standardized electronic medical record (EMR)-based order set. METHODS: Retrospective chart review of outpatient tonsillectomy performed before and after institution of an EMR intervention with comparison of opioid and nonopioid analgesic (NOA) prescription characteristics as well as outcomes including hemorrhage and readmission. RESULTS: Analysis of 276 preorder set and 128 post-order set tonsillectomies revealed a significant increase in NOA utilization following initiation of the order set and a significant reduction in doses of opioid prescribed. Due to a change to a stronger opioid in the order set, morphine dose equivalents (MDEs) prescribed were not decreased in the post-order set cohort. Variability between prescriptions and providers was significantly decreased in the post-order set group in terms of doses and MDEs, and dangerously high outlier prescriptions were eliminated. No differences in pain control, postoperative hemorrhage, presentation to the emergency department, or readmission were identified. DISCUSSION: An EMR-based intervention improved the quality and safety of posttonsillectomy opioid prescribing at our institution. Moving forward, this order set provides a platform with which to titrate opioid prescriptions and NOA to optimal pain control and safety levels. IMPLICATIONS FOR PRACTICE: A standardized EMR-based order set can improve the quality of opioid prescribing after tonsillectomy.

Carotid-cochlear dehiscence: a dangerous mimicker of inner ear pathologies.

A 67-year-old woman was referred to the otolaryngology service after presenting to the emergency department for dizziness and loss of balance. She reported several similar episodes over the past years. Physical examination was unremarkable. A temporal bone CT scan revealed dehiscence between the bony carotid canal and the cochlea resulting in the diagnosis of carotid-cochlear dehiscence (CCD). CCD is an extremely rare condition involving the thinning of the bony canal separating the internal carotid artery from the cochlea. CCD is best diagnosed with temporal bone CT scan. Treatment options include observation as well as chemical or surgical labyrenthectomy. Despite similar clinical and diagnostic characteristics of reported CCD cases, general trends and consensus on treatment options cannot be ascertained due to the extreme rarity of this condition. Regardless of these limitations, CCD is a critical diagnosis as it mimics other inner ear conditions and poses a potential, significant surgical risk for the otolaryngologist.

Immune Evasion by Head and Neck Cancer: Foundations for Combination Therapy.

Head and neck cancer is disfiguring and deadly, and contemporary treatment has fallen short in terms of morbidity and mortality. The rich immune infiltrate within these tumors designates them as prime candidates for immunotherapy and success with these drugs has been documented for recurrent and metastatic head and neck cancer. Still, single-agent immunotherapy has generated either only transient responses or durable response in only a minority subset of patients. Mapping the immune escape mechanisms enacted by head and neck cancer within the tumor microenvironment allows for rational design of strategies to overcome this tolerance. We outline the immune pathway derangements within the head and neck cancer microenvironment and discuss combination treatment strategies to overcome the limitations of immunologic monotherapy.

Specialty-specific reduction in opioid prescribing after common pediatric surgical operations.

BACKGROUND: Opioid misuse has reached epidemic proportions, and postoperative opioids have been linked to overdose, diversion, and dependency. We recently found our opioid prescribing practices following common pediatric operations to be inconsistent and excessive. In this study, we evaluate the efficacy of an educational intervention on opioid prescriptions following tonsillectomy and hernia repair. METHODS: Retrospective chart review of prescriptions following outpatient tonsillectomies and hernia repairs at a single institution before and after an educational intervention was performed. The intervention consisted of a single campus-wide grand rounds presentation detailing the surgeon's role in the opioid epidemic. RESULTS: Postoperative opioid prescriptions were significantly reduced for hernia repair following the educational intervention: 4.2 ± 2.9 vs 2.7 ± 2.6 days' supply (p = 0.004). Such a reduction was not observed for post-tonsillectomy opioid prescriptions: 6.3 ± 4.4 vs 5.4 ± 3.0 days' supply (p = 0.226). A greater decrease in interprovider variation was observed for hernia providers after the educational intervention than for tonsillectomy providers, though significant variation continued to be present for both procedures after the intervention. CONCLUSIONS: The efficacy of an educational intervention at reducing postoperative pediatric opioid prescribing may be tied to the specialty-specific role model relationship of the educator to the prescriber. TYPE OF STUDY: retrospective comparative chart review. LEVEL OF EVIDENCE: IV.

Pharyngeal Flap Versus Sphincter Pharyngoplasty for Velopharyngeal Insufficiency: A Review of the 2014 and 2015 American College of Surgeons National Surgical Quality Improvement Project-Pediatrics Data.

The authors sought to compare hospital utilization and complications in patients undergoing pharyngeal flap (PF) or sphincter pharyngoplasty (SP) for velopharyngeal insufficiency (VPI). A retrospective analysis of the 2014 and 2015 American College of Surgeons National Surgical Quality Improvement Project-Pediatrics (ACS NSQIP-P) was performed. Current procedural terminology codes were used to identify children undergoing PF (42225, 42226) and SP (42950) for VPI (International Classification of Diseases version 9: 478.29, 528.9, or 750.29). Four hundred forty-six patients were treated for VPI with either PF (n = 250) or SP (n = 196). The groups were demographically similar in age, gender, race, and preoperative comorbidity. Pharyngeal flap was performed less often as an outpatient procedure than SP (96/250 [38.4%] vs 130/196 [66.3%], P < 0.0001) and had a longer total length of hospital stay (mean 1.76 ±â€Š1.29 vs 0.98 ±â€Š0.91 days, P < 0.0001). No difference in total complications (10/250 [4.0%] vs 3/196 [1.5%], P = 0.124) was identified. The reduction in hospital resource utilization (fewer admissions, shorter length of stay) is notable. No difference in complications was identified between the 2 procedures.

New predictors of complications in carotid body tumor resection.

OBJECTIVE: This study examined the relationship between two new variables, tumor distance to base of skull (DTBOS) and tumor volume, with complications of carotid body tumor (CBT) resection, including bleeding and cranial nerve injury. METHODS: Patients who underwent CBT resection between 2004 and 2014 were studied using a standardized, multi-institutional database. Demographic, perioperative, and outcomes data were collected. CBT measurements were determined from computed tomography, magnetic resonance imaging, and ultrasound examination. RESULTS: There were 356 CBTs resected in 332 patients (mean age, 51 years; 72% female); 32% were classified as Shamblin I, 43% as Shamblin II, and 23% as Shamblin III. The mean DTBOS was 3.3 cm (standard deviation [SD], 2.1; range, 0-10), and the mean tumor volume was 209.7 cm3 (SD, 266.7; range, 1.1-1642.0 cm3). The mean estimated blood loss (EBL) was 257 mL (SD, 426; range, 0-3500 mL). Twenty-four percent of patients had cranial nerve injuries. The most common cranial nerves injured were the hypoglossal (10%), vagus (11%), and superior laryngeal (5%) nerves. Both Shamblin grade and DTBOS were statistically significantly correlated with EBL of surgery and cranial nerve injuries, whereas tumor volume was statistically significantly correlated with EBL. The logistic model for predicting blood loss and cranial nerve injury with all three variables-Shamblin, DTBOS, and volume (R2 = 0.171, 0.221, respectively)-was superior to a model with Shamblin alone (R2 = 0.043, 0.091, respectively). After adjusting for Shamblin grade and volume, every 1-cm decrease in DTBOS was associated with 1.8 times increase in risk of >250 mL of blood loss (95% confidence interval, 1.25-2.55) and 1.5 times increased risk of cranial nerve injury (95% confidence interval, 1.19-1.92). CONCLUSIONS: This large study of CBTs demonstrates the value of preoperatively determining tumor dimensions and how far the tumor is located from the base of the skull. DTBOS and tumor volume, when used in combination with the Shamblin grade, better predict bleeding and cranial nerve injury risk. Furthermore, surgical resection before expansion toward the base of the skull reduces complications as every 1-cm decrease in the distance to the skull base results in 1.8 times increase in >250 mL of blood loss and 1.5 times increased risk of cranial nerve injury.

Acute Aortic Dissection and Intramural Hematoma: A Systematic Review.

IMPORTANCE: Acute aortic syndrome (AAS), a potentially fatal pathologic process within the aortic wall, should be suspected in patients presenting with severe thoracic pain and hypertension. AAS, including aortic dissection (approximately 90% of cases) and intramural hematoma, may be complicated by poor perfusion, aneurysm, or uncontrollable pain and hypertension. AAS is uncommon (approximately 3.5-6.0 per 100,000 patient-years) but rapid diagnosis is imperative as an emergency surgical procedure is frequently necessary. OBJECTIVE: To systematically review the current evidence on diagnosis and treatment of AAS. EVIDENCE REVIEW: Searches of MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials for articles on diagnosis and treatment of AAS from June 1994 to January 29, 2016, were performed. Only clinical trials and prospective observational studies of 10 or more patients were included. Eighty-two studies (2 randomized clinical trials and 80 observational) describing 57,311 patients were reviewed. FINDINGS: Chest or back pain was the most commonly reported presenting symptom of AAS (61.6%-84.8%). Patients were typically aged 60 to 70 years, male (50%-81%), and had hypertension (45%-100%). Sensitivities of computerized tomography and magnetic resonance imaging for diagnosis of AAS were 100% and 95% to 100%, respectively. Transesophageal echocardiography was 86% to 100% sensitive, whereas D-dimer was 51.7% to 100% sensitive and 32.8% to 89.2% specific among 6 studies (n = 876). An immediate open surgical procedure is needed for dissection of the ascending aorta, given the high mortality (26%-58%) and proximity to the aortic valve and great vessels (with potential for dissection complications such as tamponade). An RCT comparing endovascular surgical procedure to medical management for uncomplicated AAS in the descending aorta (n = 61) revealed no dissection-related deaths in either group. Endovascular surgical procedure was better than medical treatment (97% vs 43%, P < .001) for the primary end point of "favorable aortic remodeling" (false lumen thrombosis and no aortic dilation or rupture). The remaining evidence on therapies was observational, introducing significant selection bias. CONCLUSIONS AND RELEVANCE: Because of the high mortality rate, AAS should be considered and diagnosed promptly in patients presenting with acute chest or back pain and high blood pressure. Computerized tomography, magnetic resonance imaging, and transesophageal echocardiography are reliable tools for diagnosing AAS. Available data suggest that open surgical repair is optimal for treating type A (ascending aorta) AAS, whereas thoracic endovascular aortic repair may be optimal for treating type B (descending aorta) AAS. However, evidence is limited by the paucity of randomized trials.

Delayed Extradural CSF Collection Following Pediatric Cochlear Implantation: Report of Two Cases.

INTRODUCTION: Although rare, complications in cochlear implantation may result from surgical or technical mishaps, reaction to the foreign body, infection, or mechanical device failure. Delayed cerebrospinal fluid (CSF) leak is a rarely reported condition that may present with asymptomatic swelling over the receiver-stimulator (RS). In our practice, meticulous drilling of a bony well is important in preventing device migration and maintaining a low device profile but there is the potential for immediate or delayed complication from this technique. OBJECTIVE: We report two cases of the diagnosis and management of delayed extradural CSF collection of the RS bony well and describe its successful management. PATIENTS: Two pediatric cochlear implant patients, 10 and 17 months of age with devices from different manufacturers. INTERVENTION(S): Operative exploration and repair without device removal. MAIN OUTCOME AND RESULTS: Although the initial postoperative course was uncomplicated with both patients receiving benefit from their device, both presented at varying intervals month(s) later with swelling over the RS. There were no signs of infection but the swelling prevented use of the device. Extradural CSF collection was suspected, confirmed operatively, and repaired with complete resolution without the need for reimplantation. CONCLUSION: Delayed CSF leak may present as an asymptomatic swelling over the RS after cochlear implantation. Sterile fluid aspiration may confirm the diagnosis and management can proceed conservatively or with operative exploration and repair. Future device designs with lower profiles may facilitate device fixation while allowing for a more shallow well, further reducing the risk of this rare complication.

Rapid and robust reversion to essential thrombocythemia on treatment with Decitabine in a case of hydroxyurea-induced t-MDS/AML.

Rapid remission of MDS/AML may be induced with Decitabine; however, significant megakaryocyte expansion and subsequent thrombocytosis may occur. Decitabine-mediated reversion of the MDS to benign ET via hypomethylation of JAK/STAT pathway repressors is one potential mechanism to explain this observed phenomenon.

Endovascular Repair of Type A Aortic Dissection: Current Experience and Technical Considerations.

Dissection of the ascending aorta, type A aortic dissection (TAAD), represents a surgical emergency with high morbidity and mortality. Current open surgical techniques, although state-of-the-art procedures and having improved outcomes for patients with TAAD over the last decades, confer significant risk of complications and death. Recently, endovascular techniques for repair of both the abdominal and thoracic aorta have gained acceptance within the vascular and cardiovascular surgical communities as a useful tool in select pathologies and patient populations. As development of endovascular technology proceeds ever closer to the aortic valve, thoracic endovascular repair for TAAD deserves special investigation. A comprehensive literature search for studies reporting outcomes of endovascular repair in the ascending aorta was performed. In this review, we compile the worldwide experience of thoracic endovascular repair for TAAD as well as imaging studies for patient selection and the use of hybrid (open plus endovascular) techniques. The authors discuss the remaining challenges that preclude its broader adoption in this role, namely patient selection and device specificity.

The kinetic characterization and X-ray structure of a putative benzoylformate decarboxylase from M. smegmatis highlights the difficulties in the functional annotation of ThDP-dependent enzymes.

Benzoylformate decarboxylase (BFDC) is a thiamin diphosphate (ThDP)-dependent enzyme that catalyzes the nonoxidative decarboxylation of benzoylformate. It is the penultimate enzyme in both the mandelate pathway and the d-phenylglycine degradation pathway. The ThDP-dependent Enzyme Engineering Database (TEED) now lists more than 800 sequences annotated as BFDCs, including one from Mycobacterium smegmatis (MsBFDC). However, there is no evidence that either pathway for benzoylformate formation exists in the M. smegmatis genome. Further, sequence alignments of MsBFDC with the well characterized enzyme isolated from Pseudomonas putida (PpBFDC) indicate that there will be active site substitutions in MsBFDC likely to reduce activity with benzoylformate. Taken together these data would suggest that the annotation is unlikely to be correct. To test this hypothesis the putative MsBFDC was cloned, expressed, purified, and the X-ray structure was solved to a resolution of 2.2Å. While showing no evidence for ThDP in the active site, the structure was very similar to that of PpBFDC. A number of 2-oxo acids were tested as substrates. For MsBFDC the K(m) value for benzoylformate was ~23 mM, nearly 100-fold greater than that of PpBFDC while the k(cat) value was reduced 60-fold. These values would suggest that benzoylformate is not the physiological substrate for this enzyme, and that annotation as a 2-oxo acid decarboxylase may be more appropriate.