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Introduction: Myelodysplastic syndromes (MDS) are a heterogenous group of blood disorders defined by peripheral cytopenia(s), bone marrow failure, morphological dysplasia, and risk of progression. To understand the genetic, epigenetic and biological factors associated with the initiation and progression of MDS, NHLBI created the National MDS Study (NCT02775383). This is a prospective cohort study conducted at 92 community hospitals and 29 academic centers enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasm (MPN) overlap syndrome. Eligible patients have yet to receive any therapy directed at their cytopenias. Previously untreated cytopenic participants underwent centralized histopathology and data review at the time of enrollment for assignment into distinct subcategories: MDS, MDS/MPN overlap, AML, and Other. Targeted exon sequencing of 96 genes was performed using marrow specimens from the first 300 consecutive individuals in the study. Here we report the genetic mutations for this cohort. Methods: NovaSeq 6000 was used for deep sequencing at a mean coverage of 1,286X and mean breadth (bases covered at ≥100X) of 99.8%. Reads were aligned against build GRCh38 using BWA-MEM, and VarScan2 was used to detect SNVs and INDELS. Variants were filtered for those with an allele base quality of >25 in combination with rule-based and manual review criteria. Subjects in the Other category without an identified malignancy were considered clonal cytopenias of undetermined significance (CCUS) when a mutation or a clonal cytogenetic change was present. Fisher's exact and Wilcoxon rank sum tests in combination with Bonferroni correction were applied to compare groups. Results : A total of 350 putative nonsynonymous pathogenic variants in 36 genes with an allele frequency of >.05 were identified across 150 patients (50%). At least one variant was noted in the following proportion of individuals: 61/72 (85%) with MDS, 13/13 (100%) with MDS/MPN, 15/17 (88%) with AML, and 61/198 (31%) in the Other category, of which 48 were CCUS and 13 were other cancers. Two CCUS patients only had a cytogenetic abnormality. Table 1 shows the distribution of variants in each subcategory of patients for the most commonly mutated genes in our cohort of 300 subjects. Mutations in these genes were enriched in specific groups: SF3B1, STAG2,TP53, and ASXL1 in MDS; TET2 in MDS/MPN; and IDH2 and TP53 in AML (one-sided p<0.0012). None were enriched in the Other group. Within the CCUS subset, 21 genes were mutated, with 37 of 50 (74%) patients having a mutation in TET2, ASXL1, SRSF2, SF3B1, or DNMT3A. The heatmap presented in Figure 1 summarizes variants by subject and allele frequency. Pair-wise comparisons of baseline characteristics of subjects between MDS, MDS/MPN, AML, or CCUS groups revealed no significant differences for age or sex. The CCUS group had significantly higher hemoglobins than the MDS group with median hemoglobin levels of 11.35 and 9.40 g/dL, respectively (p<0.0084). AML had significantly lower platelets compared to all other groups (median of 53 vs. > 110x109/L , respectively, p<0.0084). All groups significantly differed in their median ANC with AML having the lowest (0.8x109/L), followed by MDS (1.5x109/L), CCUS (2.45x109/L), and MDS/MPN overlap (5.95x109/L) (p<0.0084). There was no difference in the median number of variants per patient between groups or correlation with age (rs=0.11, p=0.18). The maximum variant allele frequency (maxVAF) per patient was highest in the MDS/MPN group (median = 0.42, range = 0.38-0.91) and lowest in the CCUS group (median = 0.37, range =0.06-0.98) with the MDS/MPN group having a significantly higher maxVAF compared to the MDS and the CCUS groups (p<0.0084). The proportions of subjects with mutations was similar for those who had abnormal (92% [34/37]) and normal (91% [80/88]) cytogenetics. Conclusions: Incorporation of gene-panel sequencing in the comprehensive evaluation of 300 adult cytopenic patients identified half of the cohort with potentially pathogenic variants. Ultimately, a diagnosis of CCUS was possible in 48 of 183 subjects (26%) not diagnosed with MDS, MDS/MPN overlap syndrome, AML, other cancers or clonal cytogenetics. This study continues to serially bank samples from patients with CCUS, in addition to MDS, MDS/MPN, and ICUS, with the goal to better understand the natural history of these diseases and their progression. Disclosures Lindsley: Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Bejar:Celgene: Consultancy; Takeda Pharmaceuticals: Research Funding; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy; Modus Outcomes: Consultancy; Daiichi-Sankyo: Consultancy. Al Baghdadi:Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Tracon: Equity Ownership; Epizyme: Equity Ownership; Bristol Myer Squibb: Consultancy, Honoraria; Sunesis: Equity Ownership; Portola: Equity Ownership; Heron therapeutics: Equity Ownership; Cardinal health: Consultancy, Honoraria; Bristol Myer Squibb: Equity Ownership; Celgene: Equity Ownership; Spectrum pharmaceutical: Equity Ownership; Astrazeneca: Equity Ownership; Seattle genetics: Equity Ownership; Roche: Consultancy, Honoraria. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Foran:Agios: Honoraria, Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Komrokji:DSI: Consultancy; Agios: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; celgene: Consultancy; Incyte: Consultancy; JAZZ: Consultancy. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Starczynowski:Kurome Therapeutics: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Background: Anaplastic thyroid cancer (ATC) has poor prognosis with median overall survival (OS) of ∼6 months. We previously reported high PD-1/PDL-1 staining in ATC, raising the possibility of the productive application of the immunotherapeutic pembrolizumab. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. Methods: An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 2 each IV weekly plus volumetric modulated arc therapy) was initiated as frontline therapy (with or without surgery) in ATC to assess efficacy and toxicities. Six-month OS was selected as the primary endpoint using a Simon's optimal design with interim analysis (targeting accrual of 25 patients; Cohort A: prior resection, Cohort B: no resection). Based on a prior patient cohort-treated similarly, but without pembrolizumab, the design was such that, if 6-month true survival is 75%, the probability of declaring the approach worthy of further pursuit would be 91%. Results: Three patients were enrolled, two with rapidly enlarging unresectable neck masses. Early tumor responses were favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation—one from pulmonary metastases and two from otherwise unexpected fatal pulmonary complications occurring subsequent to chemoradiotherapy completion—prompting study closure. Conclusions: Although initially tolerated and effective in terms of locoregional disease control, disappointing survival outcomes compared with historical controls raise uncertainty that the piloted approach merits further pursuit in ATC.

AbstractBackgroundThe incidence of human papillomavirus (HPV)‐related oropharyngeal squamous cell carcinoma (OPSCC) is rising, even in elderly patients. The outcomes of transoral surgery (TOS) in this population are not entirely known.MethodsA retrospective review was performed at two institutions from October 2003 to September 2016 on patients 70 years or older with HPV‐related OPSCC treated with TOS.ResultsA total of 75 patients were included with a mean age of 74 years (70‐87 years). At a median follow‐up of 35.7 months, 3‐year overall survival was 81.5% and disease‐specific survival was 94.3%. Advanced cT stage (odds ratio, 2.74; 95% confidence interval, 1.13‐6.64) negatively impacted OS. Conjunctive consolidation was performed to create a staging system with patients older than 80 years, severe comorbidity, and cT3‐4 having worse survival.ConclusionsElderly patients with HPV‐related OPSCC treated with TOS have excellent survival and therefore should not be excluded from such therapy based on age alone.

PURPOSE The purpose of this study was to determine if dose de-escalation from 60 to 66 Gy to 30 to 36 Gy of adjuvant radiotherapy (RT) for selected patients with human papillomavirus–associated oropharyngeal squamous cell carcinoma could maintain historical rates for disease control while reducing toxicity and preserving swallow function and quality of life (QOL). PATIENTS AND METHODS MC1273 was a single-arm phase II trial testing an aggressive course of RT de-escalation after surgery. Eligibility criteria included patients with p16-positive oropharyngeal squamous cell carcinoma, smoking history of 10 pack-years or less, and negative margins. Cohort A (intermediate risk) received 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks along with 15 mg/m 2 docetaxel once per week. Cohort B included patients with extranodal extension who received the same treatment plus a simultaneous integrated boost to nodal levels with extranodal extension to 36 Gy in 1.8-Gy fractions twice per day. The primary end point was locoregional tumor control at 2 years. Secondary end points included 2-year progression-free survival, overall survival, toxicity, swallow function, and patient-reported QOL. RESULTS Accrual was from September 2013 to June 2016 (N = 80; cohort A, n = 37; cohort B, n = 43). Median follow-up was 36 months, with a minimum follow-up of 25 months. The 2-year locoregional tumor control rate was 96.2%, with progression-free survival of 91.1% and overall survival of 98.7%. Rates of grade 3 or worse toxicity at pre-RT and 1 and 2 years post-RT were 2.5%, 0%, and 0%. Swallowing function improved slightly between pre-RT and 12 months post-RT, with one patient requiring temporary feeding tube placement. CONCLUSION Aggressive RT de-escalation resulted in locoregional tumor control rates comparable to historical controls, low toxicity, and little decrement in swallowing function or QOL.

6071 Background: Phase III data suggests a benefit of HDC in the adjuvant setting, but the effect of HDC and WC on long term survival and for HPV+ HNSCC is unknown. Methods: Data from a published retrospective study (Geiger Oral Onc 2013) of HDC vs WC in resected HNSCC was updated. Overall survival (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier method for all pts and by HPV status. Multivariate analyses were performed to assess impact of HPV status, smoking, age, HDC vs WC, and cumulative cisplatin dose ( < 200mg/m2 vs ≥200 mg/m2). Results: 51 patients (pts) received HDC and 53 WC. Median follow-up was 8.7 yrs (0.8-13.7). For the whole cohort, HDC had significantly improved OS over WC (p = 0.0095; 5- and 10-yr OS 84% and 80% vs 72% and 60%). No OS benefit for HDC was seen in pts with HPV+HNSCC (5- and 10-yr OS 90% and 87% for HDC and 81% and 81% for WC; p = 0.51). For HPV-negative HNSCC, OS had borderline significance with HDC vs WC (5- and 10-yr OS 73% and 68% vs 65% and 44%; p = 0.06). For the whole cohort, there was no difference in 5- and 10-yr RFS (78% and 74% for HDC vs 72% and 62% for WC; p = 0.32). When analyzed by HPV status, there was no difference in RFS with HDC or WC for either HPV+ (p = 0.43) or HPV-negative HNSCC (p = 0.97). On multivariate analyses of OS for all pts, only HPV status was significant (p = 0.0011; HR 0.27, CI 0.12-0.62). For HPV+ HNSCC, there was no significant predictor of OS. For non-HPV HNSCC, the benefit of HDC approached significance with a decreased risk of death (HR 0.38; p = 0.07). For all pts, those who received ≥200mg/m2 had significantly improved OS (5-yr 90% vs 72% and 10-yr 86% vs 61%; p = 0.004). By HPV status, cumulative dose had no significant effect on OS. Conclusions: OS is better with HDC and with cumulative dose > 200 mg/m2 in unselected patients. The benefit of cisplatin is likely higher for non-HPV HNSCC. A difference in OS with no difference in RFS suggests non cancer-related causes of death in the WC cohort. Ability to receive HDC could be a surrogate marker of comorbidity. [Table: see text]

Objectives/HypothesisSinonasal mucosal melanoma (SNMM) is a rare malignant neoplasm. No study to date has analyzed the impact that nodal metastases and distant metastases at diagnosis have on overall survival (OS) and disease‐specific survival (DSS).Study DesignRetrospective database review.MethodsThe Surveillance, Epidemiology, and End Results database was queried for cases of SNMM. Descriptive statistics were used analyze patient demographic and clinicopathologic variables. The Kaplan‐Meier model was used to analyze survival, and the Cox proportional hazards model was used for multivariate analysis.ResultsThree hundred twenty‐eight cases of SNMM were identified. The most frequent sinonasal anatomic location was the nasal cavity in 279 (73.0%) patients, followed by the maxillary sinus in 60 (15.7%) patients. Regional nodal metastases at diagnosis occurred in 33 (8.6%) patients, whereas distant metastases at diagnosis occurred in 41 (10.7%) patients. Five‐year OS was 22.7%, and 5‐year DSS was 26.8%. The presence of positive nodes at diagnosis (OS P < .0001, DSS P < .0001), distant metastases at diagnosis (OS P = .0442, DSS P = .0442), primary tumor site (OS P < .0001, DSS P < .0001), and increasing age (OS P = .0012, DSS P = .0016) were found to be significant as negative predictors of OS and DSS.ConclusionsSNMM is a rare pathologic entity with a poor prognosis. The presence of nodal and distant metastases at diagnosis are negative prognostic factors in OS and DSS. These factors can be used in the development of new models of risk stratification and to inform treatment strategies and surveillance patterns.Level of EvidenceNALaryngoscope, 130:622–627, 2020

Objectives Determine the effect of endoscopic skull base surgery (ESBS) on long‐term olfactory outcomes after surgery. Methods An English‐language search was conducted using the Cochrane, MEDLINE, Scopus, and Embase databases from January 2000 to October 2017 for adult patients undergoing ESBS with subjective and objective olfaction outcomes. Two authors independently examined articles to identify those meeting inclusion criteria. Studies examining objective olfactory outcomes after ESBS were included in the meta‐analysis. A random‐effects meta‐analysis of patients undergoing sellar and parasellar ESBS was conducted to compare preoperative and postoperative olfactory outcomes using the University of Pennsylvania Smell Identification Test (UPSIT) and Cross‐Cultural Smell Identification Test (CCSIT). Results Among 339 eligible articles, 29 articles met inclusion criteria. Twenty‐five of these focused on sellar and parasellar tumors. Individual articles not meeting criteria for meta‐analysis were qualitatively reported. Meta‐analysis showed there was no difference in preoperative and postoperative olfactory function after sellar and parasellar ESBS based on the UPSIT (five studies, mean difference [MD] = −1.03; 95% CI: −3.98, 1.93; P = .50) and the CCIST (three studies, MD = −0.77; 95% CI: −3.03, 1.49; P = .50). A pooled overall meta‐analysis revealed similar results (eight studies, effect size = −0.30; 95% CI: −0.79, 0.18; P = .22). However, heterogeneity for all meta‐analyses was high ( I 2 > 95%, P < .01), suggesting significant variation in the included studies. Conclusions Based on published objective olfaction outcomes after sellar and parasellar ESBS, there was no significant difference between preoperative and postoperative olfaction. Further prospective studies using validated objective measures of olfaction are required to improve our understanding on this subject. Level of Evidence 2a Laryngoscope , 129:1998–2007, 2019