Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1.

Mechanisms of treatment resistance in head and neck squamous cell carcinoma (HNSCC) are not well characterized. In this study, HNSCC tumors from a cohort of prospectively enrolled subjects on an ongoing tissue banking study were divided into those that persisted or recurred locoregionally (n=23) and those that responded without recurrence (n=35). Gene expression was evaluated using llumina HumanHT-12-v3 Expression BeadChip microarrays. Sparse Partial Least Squares - Discriminant Analysis (sPLS-DA) identified 135 genes discriminating treatment-resistant from treatment-sensitive tumors. BCL-xL was identified among 23% of canonical pathways derived from this set of genes using Ingenuity Pathway analysis. The BCL-xL protein was expressed in 8 HNSCC cell lines examined. Cells were treated with the BCL-xL inhibitor, ABT-263 (navitoclax): the average half maximal inhibitory concentration (IC50) was 8.9µM (range 6.6µM - 13.9µM). Combining ABT-263 did not significantly increase responses to 2 Gy radiation or cisplatin in the majority of cell lines. MCL-1, a potential mediator of resistance to ABT-263, was expressed in all cell lines and HNSCC patient tumors, in addition to BCL-xL. Treatment with the MCL-1 inhibitor, A-1210477, in HNSCC cell lines showed an average IC50 of 10.7µM (range, 8.8µM to 12.7µM). Adding A-1210477 to ABT-263 (navitoclax) treatment resulted in an average 7-fold reduction in the required lethal dose of ABT-263 (navitoclax) when measured across all 8 cell lines. Synergistic activity was confirmed in PCI15B, Detroit 562, MDA686LN, and HN30 based on Bliss Independence analysis. This study demonstrates that targeting both BCL-xL and MCL-1 is required to optimally inhibit BCL-family pro-survival molecules in HNSCC, and co-inhibition is synergistic in HNSCC cancer cells.

Randomized Controlled Trial Assessing the Feasibility of Shortened Fasts in Intubated ICU Patients Undergoing Tracheotomy.

OBJECTIVE: American Society of Anesthesiology guidelines recommend preoperative fasts of 6 hours after light snacks and 8 hours after large meals. These guidelines were designed for healthy patients undergoing elective procedures but are often applied to intubated intensive care unit (ICU) patients. ICU patients undergoing routine procedures may be subjected to unnecessary prolonged fasts. This study tests whether shorter fasts allow for better nutrition delivery and patient outcomes without increasing the risk. STUDY DESIGN: Randomized blinded controlled trial. SETTING: Tertiary academic medical center. SUBJECTS: ICU patients undergoing bedside tracheotomy. METHODS: Intubated ICU patients who were receiving enteral feeding and for whom bedside tracheotomy was indicated were enrolled prospectively and randomly allocated to 2 parallel preoperative fasting regimens: a 6-hour fast (control) and a 45-minute fast (intervention). Patients were assessed for aspiration, caloric delivery, metabolic markers, and infectious and noninfectious complications. RESULTS: Twenty-four patients were enrolled and randomized. There were no complications related to the procedure. There were no cases of intraoperative aspiration identified. There was a single postoperative pneumonia in the control group. Median (interquartile range) length of fast and caloric delivery were significantly different between the control group and the shortened fast group: 22 hours (18, 34) vs 14 hours (5, 25; P < .001) and 429 kcal (57, 1125) vs 1050 kcal (825, 1410; P = .01), respectively. CONCLUSIONS: Shortening preoperative fasts in intubated ICU patients allowed for better caloric delivery in the preoperative period.

Comorbidity, human papillomavirus infection and head and neck cancer survival in an ethnically diverse population.

OBJECTIVE: To demonstrate the importance of comorbid conditions in head and neck squamous cell carcinoma (HNSCC), we assessed the association between comorbidity and survival in an inner-city population of HNSCC patients. PATIENTS AND METHODS: Comorbid status at diagnosis was derived using medical records and the Adult Comorbidity Evaluation-27 (ACE-27) index on 288 patients with histologically confirmed HNSCC from Montefiore Medical Center in the Bronx (NY) between 2002 and 2011. The association between comorbidity, tumor human papillomavirus (HPV) status and overall and disease specific survival was assessed by Kaplan-Meier analysis and multivariable Cox regression adjusting for clinico-pathologic factors. RESULTS: The study population consisted of primary oropharyngeal (36%), laryngeal (33%) and oral cavity cancer patients (31%). Overall, 19% had no comorbidity, 43% mild comorbidity, 29% moderate comorbidity, and 9% severe comorbidity. The most common comorbid conditions were hypertension, diabetes mellitus, respiratory disease, other malignancies, and illicit drug use. Survival analyses revealed that increased comorbidity at diagnosis was significantly related to poorer overall survival (p=0.016), but not to cancer survival (p=0.369) or recurrence (p=0.652). Oropharyngeal cancer patients with HPV DNA positive tumors and lower levels of comorbidity had significantly better overall survival compared to patients with HPV negative tumors (hazard ratio=0.2, 95%CI: 0.04-0.8), however there was no significant difference in overall (or disease specific) survival by HPV status among patients with higher levels of comorbidity at diagnosis (hazard ratio=0.7, 95%CI: 0.2-2.8). CONCLUSION: In an inner-city predominantly minority population, comorbidity at HNSCC diagnosis is relatively common and associated with poor overall survival, but not cancer survival or recurrence. Interestingly, the relationship between HPV and improved survival appears to be specific to patients with low comorbidity at diagnosis.

Transoral robotic total laryngectomy.

OBJECTIVES/HYPOTHESIS: Minimally invasive surgery has become the standard of care in many organ systems. Head and neck surgery has incorporated transoral surgery, either laser microsurgery or robotic resection, in the management of pharyngeal and laryngeal cancers. To date, the laryngeal procedures have taken the form of partial laryngectomy, as transoral approaches have not allowed reconstruction following total laryngectomy. We present the first series of transoral total laryngectomies. STUDY DESIGN: Multinational, multi-institutional prospective consecutive case series. METHODS: Case series of completed and attempted transoral robotic surgery (TORS) total laryngectomy performed under an institutional review board protocol. The procedure was developed in the cadaver laboratory and applied to selected individuals requiring total laryngectomy for recurrent laryngeal cancer or post-therapeutic organ dysfunction. RESULTS: TORS total laryngectomy was successfully performed in five patients and was unsuccessful in two others. Two of the patients had postoperative fistulae, and all seven are without evidence of recurrent cancer and are swallowing orally without gastrostomy supplementation. CONCLUSIONS: TORS total laryngectomy is feasible and can be taught to other surgeons. Potential benefits of this approach are present for patients undergoing salvage laryngectomy and include improved wound healing and functional results. This procedure further extends the applications of robotic head and neck surgery.

Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer.

OBJECTIVES: Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors. METHODS: A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m(2) as a 4-h intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks. RESULTS: Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21(Waf1/Cip1) characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors. CONCLUSIONS: Single agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.

High-dose-rate brachytherapy plus neck dissection for nodal disease.

BACKGROUND: Regional control for advanced nodal disease has been only marginally affected by concurrent chemoradiation, hyperfractionation, concomitant boost, or accelerated external radiation. METHODS: Twenty-five necks in 24 patients received brachytherapy treatment (20 Gy in 10 twice-daily fractions) in addition to external radiation, neck dissection +/- chemotherapy. Indications for brachytherapy included initial treatment of bulky disease (n = 12), recurrence of neck disease in a previously treated patient with at least a 3-month disease-free interval (n = 6), persistent disease after a curative efforts (n = 4), inadequate external radiation (ie, <40 Gy) due to either intolerance or noncompliance (n = 3). RESULTS: Overall actuarial regional control was 67% at 2 years. Regional control for those receiving brachytherapy as part of their initial treatment was 82% despite a mean nodal diameter of 8.7 cm (range, 5-15 cm). The 2-year actuarial regional control was 56% for the patients with a disease-free interval of at least 3 years. CONCLUSION: High-dose-rate brachytherapy produced excellent regional control. (c) 2008 Wiley Periodicals, Inc. Head Neck, 2008.

Phase II study of weekly docetaxel alone or in combination with trastuzumab in patients with metastatic breast cancer.

This study was designed to determine the efficacy and toxicity of weekly docetaxel in metastatic breast cancer when given alone (for HER2/neu negative disease) or with trastuzumab (for HER2/neu overexpressing disease). Patients with metastatic breast carcinoma received docetaxel given on 2 different schedules (group 1A, 33 mg/m2 weekly [n = 21]; group 1B, 40 mg/m2 weekly for 3 weeks with 1 week off [n = 14]). Patients with HER2/neu overexpressing disease also received trastuzumab 4 mg/kg on day 1, then 2 mg/kg on days 8 and 15 of each 28-day cycle (group 2). Fifty-two patients were treated with docetaxel alone (group 1A/B, n = 35) or in combination with trastuzumab (group 2, n = 17). Prior taxane therapy given every 3 weeks had been used for metastatic disease in 19 of 35 patients (54%) in group 1A/B and in 2 of 17 patients (12%) in group 2. The mean delivered dose intensity of docetaxel was 29 mg/m2 per week. Partial response occurred in 7 of 35 patients (21%; 95% exact binomial confidence interval [CI], 9%-38%) treated with docetaxel alone, including 3 of 19 taxane-pretreated patients (16%) and 4 of 16 taxane-naive patients (25%). Partial response occurred in 10 of 17 patients (59%; 95% CI, 34%-82%) treated with docetaxel/trastuzumab. The most common grade 3/4 toxicities, occurring in more than or equal to 10% of patients, included neutropenia (21%), pulmonary toxicity (12%), and hyperglycemia (10%). The median times to disease progression were 4.5 months (95% CI, 2.5-6.5 months) in the docetaxel group and 8.5 months (95% CI, 4.5-12.5 months) in the docetaxel/trastuzumab group. Weekly docetaxel/trastuzumab is an effective regimen for patients with HER2/neu overexpressing metastatic breast cancer. Weekly docetaxel may be effective in as many as 20% of patients who had progressive disease after treatment with taxanes given every 3 weeks.

Phase I trial of fludarabine and paclitaxel in non-Hodgkin's lymphoma.

Fludarabine is an active agent in low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Paclitaxel is also active in patients with refractory lymphoma, and preclinical data suggest an additive effect with fludarabine in vitro. We performed a phase I trial of fludarabine (25 mg/m(2) d 1-3) plus a 3-h infusion of paclitaxel (125, 150, or 175 mg/m(2)) on d 3 every 28 d in 13 patients with non-Hodgkin's lymphoma. The paclitaxel dose was escalated in cohorts of 3-4 patients using standard phase I design schema. Dose-limiting toxicity was defined as febrile neutropenia, platelet nadir less than 50,000/microL, or grade 3-4 nonhematologic toxicity. Thirteen patients were accrued to the study, 8 of these 13 patients (62%) had received prior chemotherapy. At the 125-, 150-, and 175-mg/m(2) dose levels of paclitaxel, dose-limiting toxicity occurred in 1/4, 0/4, and 0/4 patients, respectively. The single patient with dose-limiting toxicity had febrile neutropenia. Partial response occurred in two of eight patients with low-grade lymphoma and none of five patients with other types of lymphoma. A paclitaxel dose of 175 mg/m(2) given as a 3-h infusion on d 3 in conjunction with fludarabine (25 mg/m(2) d 1-3 every 4 wk) is a well-tolerated regimen for non-Hodgkin's lymphoma. Further study will be required in order to determine whether the fludarabine paclitaxel is more active than fludarabine alone in patients with low-grade lymphoma and chronic lymphocytic leukemia