Survival trends of patients with subglottic squamous cell carcinoma: A population based cohort study

Background: Subglottic squamous cell carcinoma is a rare subsite of laryngeal cancer, which is believed to behave more aggressively and portend a worse prognosis than other laryngeal cancer subsites (supraglottis and glottis). Our objective was to utilize a population-based cancer registry to report the overall survival and laryngectomy-free survival in patients diagnosed with subglottic squamous cell carcinoma, and to examine trends in outcomes over time. We also compared overall survival in patients treated with primary laryngectomy versus radiation. Methods: We carried out a retrospective population-based study of patients with a new diagnosis of squamous cell carcinoma in the province of Ontario, Canada over a 15-year period (1995-2009). We identified patients with a new diagnosis of subglottic squamous cell carcinoma using the Ontario Cancer Registry. We determined demographics, comorbidity measures, staging, survival and primary treatment with laryngectomy using the linked population-based healthcare databases in Ontario. We first determined the overall survival and laryngectomy free survival of patients with subglottic cancer. In a secular trends study, we then examined the trends in overall survival and laryngectomy-free survival over the study period. Results: A total of 4927 cases of laryngeal carcinoma were identified, with 89 patients defined as primary subglottic carcinoma (1.8%). Among the subglottic cohort, 68 (76.4%) were male, and the mean (25th, 75th percentile) age at diagnosis was 68 (60- 77 years). The 5-year overall survival was 47.2%, while the 5-year laryngectomy-free survival was 31.5%. No differences were observed in overall survival (OS) or laryngectomy-free survival (LFS) across years over the 15-year study period (p=0.42 OS, p=0.83 LFS). Thirteen patients (15%) were treated with primary laryngectomy. Primary treatment with laryngectomy was not associated with a different risk of mortality compared with radiation. Conclusions: The overall survival and laryngectomy-free survival of patients with subglottic carcinoma is poor and has remained stable over time (1995-2009). Primary treatment with laryngectomy does not appear to improve overall survival compared with primary radiation

Utility of clinical features with fine needle aspiration biopsy for diagnosis of Warthin tumor.

BACKGROUND:Conservative management of Warthin tumor (WT) may be a viable alternative to surgery, but there are concerns of missed malignancies on fine needle aspiration biopsy (FNAB). The purpose of this study is to measure the sensitivity and positive predictive value of FNAB for WT, and to identify clinical features associated with WT that can aid in this diagnosis. METHODS: Retrospective analysis of patients from January 1, 2006 to April 30, 2017 at a tertiary care center in London, Ontario, Canada. All patients with a diagnosis of WT on FNAB or resection were included. Electronic medical records were identified for 177 patients that fit the criteria. Study outcomes included the sensitivity and positive predictive value of FNAB alone for WT, and, when including clinical features associated with WT. RESULTS: The mean age of patients in this study was 63.2 years (SD 10.4); 115 (65%) were male, and 157 (89%) were past or present smokers. The measured sensitivity and positive predictive value of FNAB for WT were 95.8 and 97.2% respectively. Two cases were classified as WT on FNAB but confirmed at resection as mucoepidermoid carcinoma and acinic cell carcinoma. When only patients with multifocal, bilateral or incidental tumors were assessed, sensitivities and positive predictive values for each were 100%. Isolating for inferior pole location also resulted in a positive predictive value of 100%. CONCLUSIONS: The sensitivity and positive predictive value of FNAB for WT in this study are high, with two false negatives on FNAB. Multifocal, bilateral, incidentaloma and inferior pole location were identified as potential clinical features that may increase the diagnostic confidence for WT, strengthening the argument for conservative management in these patients. Overall, this study serves as an initial exploration into whether clinical features may be included with FNAB results to improve the sensitivity and positive predictive value of diagnosing WT. Further research is necessary before these findings can be translated into clinical practice

Functional outcomes in early (T1/T2) supraglottic cancer: a systematic review

ObjectivesOrgan preserving surgery (OPS) and radiotherapy (RT) are both accepted treatment options for early stage supraglottic cancer (SGC). Radiation has supplanted surgery in most cases, because of the perception that surgery results in poorer functional outcomes. However, evidence suggests that OPS with a neck dissection may be associated with improved survival. Our objective was to conduct a systematic review of the literature to compare functional outcomes of OPS and RT for early SGC.MethodsWe searched Medline, EMBASE and Cochrane Central Register of Controlled Trials to identify studies. Studies were included if they reported functional outcomes on 10 or more patients with early stage SGC treated with radiation or OPS, including open partial laryngectomy, transoral laser microsurgery (TLM) or transoral robotic surgery (TORS). Two reviewers independently screened articles for relevance using pre-determined criteria.ResultsFrom 7720 references, we included 10 articles (n=640 patients). 50% (n=320) of patients were treated with surgery. Three head-to-head RT versus OPS papers were included, however different outcome measures were used for each group. Intractable aspiration management (including total laryngectomy or permanent tracheostomy) following OPS was reported in five papers representing 186 patients; the definitive intractable aspiration management rate was 2.6% (95% CI 1.0-6.8%). Four papers reported permanent G-tube rate for the surgical group (n=198), calculating a rate of 5.3% (95% CI 2.6-10.5%), this was not reported for the RT group in any papers. One study reported quality of life. Two studies reported objective voice measures.ConclusionsThis systematic review revealed a paucity of objective measures and significant data heterogeneity, rendering the comparison of functional outcomes following OPS versus RT for early SGC limited. Future research should include objective measures of functional outcomes including laryngectomy rate, g-tube rate, tracheostomy dependence, quality of life, and voice quality measures

Rapid standardized operating rooms (RAPSTOR) in thyroid and parathyroid surgery

Objective: To evaluate the impact of a high efficiency rapid standardized OR (RAPSTOR) for hemithyroid/parathyroid surgery using standardized equipment sets (SES) and consecutive case scheduling (CCS) on turnover times (TOT), average case volumes, patient outcomes, hospital costs and OR efficiency/stress. Methods: Patients requiring hemithyroidectomy (primary or completion) or unilateral parathyroidectomy in a single surgeon’s practice were scheduled consecutively with SES. Retrospective control groups were classified as sequential (CS) or non-sequential (CNS). A survey regarding OR efficiency/stress was administered. Phenomenography and descriptive statistics were conducted for time points, cost and patient outcome variables. Hospital cost minimization analysis was performed. Results: The mean TOT of RAPSTOR procedures (16 min; n = 27) was not significantly different than CS (14 min, n = 14) or CNS (17 min, n = 6). Mean case number per hour was significantly increased in RAPSTOR (1.2) compared to both CS (0.9; p \u3c 0.05) and CNS (0.7; p \u3c 0.05). Average operative time was significantly reduced in RAPSTOR (32 min; n = 28) compared to CNS (48 min; p \u3c 0.05) but not CS (33 min; p = 0.06). Time to discharge was reduced in RAPSTOR (595 min) compared to CNS (1210 min, p \u3c 0.05). There was no difference in complication rate between all groups (p = 0.27). Survey responses suggested improved efficiency, teamwork and workflow. Furthermore, there is associated decrease in direct operative costs for RAPSTOR vs. CS. Conclusion: A high efficiency standardized OR for hemithyroid and parathyroid surgery using SES and CCS is associated with improved efficiency and, in this study, led to increased capacity at reduced cost without compromising patient safety. Level of evidence: Level 2. Graphical abstract: [Figure not available: see fulltext.

High-throughput testing in head and neck squamous cell carcinoma identifies agents with preferential activity in human papillomavirus-positive or negative cell lines.

Head and neck squamous cell carcinoma (HNSCC) is a common cancer diagnosis worldwide. Despite advances in treatment, HNSCC has very poor survival outcomes, emphasizing an ongoing need for development of improved therapeutic options. The distinct tumor characteristics of human papillomavirus (HPV)-positive vs. HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status. High-throughput robotic screening of 1,433 biologically and pharmacologically relevant compounds at a single dose (4 μM) was carried out against 6 HPV-positive and 20 HPV-negative HNSCC cell lines for preliminary identification of therapeutically relevant compounds. Statistical analysis was further carried out to differentiate compounds with preferential activity against cell lines stratified by the HPV-status. These analyses yielded 57 compounds with higher activity in HPV-negative cell lines, and 34 with higher-activity in HPV-positive ones. Multi-point dose-response curves were generated for six of these compounds (Ryuvidine, MK-1775, SNS-032, Flavopiridol, AZD-7762 and ARP-101), confirming Ryuvidine to have preferential potency against HPV-negative cell lines, and MK-1775 to have preferential potency against HPV-positive cell lines. These data comprise a valuable resource for further investigation of compounds with therapeutic potential in the HNSCC

Repurposing Albendazole: new potential as a chemotherapeutic agent with preferential activity against HPV-negative head and neck squamous cell cancer.

Albendazole is an anti-helminthic drug that has been shown to exhibit anti-cancer properties, however its activity in head and neck squamous cell cancer (HNSCC) was unknown. Using a series of in vitro assays, we assessed the ability of albendazole to inhibit proliferation in 20 HNSCC cell lines across a range of albendazole doses (1 nM-10 μM). Cell lines that responded to treatment were further examined for cell death, inhibition of migration and cell cycle arrest. Thirteen of fourteen human papillomavirus-negative HNSCC cell lines responded to albendazole, with an average IC50 of 152 nM. In contrast, only 3 of 6 human papillomavirus-positive HNSCC cell lines responded. Albendazole treatment resulted in apoptosis, inhibition of cell migration, cell cycle arrest in the G2/M phase and altered tubulin distribution. Normal control cells were not measurably affected by any dose tested. This study indicates that albendazole acts to inhibit the proliferation of human papillomavirus-negative HNSCC cell lines and thus warrants further study as a potential chemotherapeutic agent for patients suffering from head and neck cancer

A case report and genetic characterization of a massive acinic cell carcinoma of the parotid with delayed distant metastases.

We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure

TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma.

BACKGROUND: Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs). METHODS: Five unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance. RESULTS: Prolonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20-35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib. CONCLUSIONS: We have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients

Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models

Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC