Hyperbaric Oxygen as Radiation Sensitizer for Locally Advanced Squamous Cell Carcinoma of the Oropharynx: A Phase 1 Dose-Escalation Study.

PURPOSE: To explore, in a dose-escalation study, the feasibility of hyperbaric oxygen (HBO) treatments immediately before intensity modulated radiation therapy in conjunction with cisplatinum chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Eligible patients presented with SCCHN (stage III-IV [M0]), life expectancy >6 months, and Karnofsky performance status ≥70. Enrollees received intensity modulated radiation therapy, 70 Gy in 35 fractions over 7 weeks with weekly cisplatinum. Patients received HBO-100% oxygen, 2.4 atmospheres absolute (ATA) for 30 minutes-twice per week initially. Subsequent patients were escalated to 3 and then 5 times per week. Intensity modulated radiation therapy began within 15 minutes after HBO. Patients were followed for 2 years after RT with quality-of-life questionnaires (Performance Status Scale-Head and Neck Cancer and the Functional Assessment of Cancer Therapy-Head and Neck Cancer) and for 5+ years for local recurrence, distant metastases, disease-specific survival, and overall survival. RESULTS: Twelve subjects enrolled from 3 centers. Two withdrew during radiation therapy and 1 within 14 weeks after radiation therapy. The remaining 9 had primary oropharyngeal disease and were stage IVA (7) or IVB (2). No dose-limiting toxicities were observed with daily HBO. Two patients (22%) required pressure equalization tubes. The average time between HBO and radiation therapy was 8.5 minutes, with 2 of 231 administrations delivered beyond 15 minutes (0.5%). Per-protocol analysis showed a clinical complete response in 7 and a pathologic complete response without tumor in salvage neck dissections in 2. With minimum follow-up of 61 months, per-protocol 5-year overall survival was 100%, local recurrence 0%, and distant metastases 11%. Patient-reported outcomes for quality of life (Functional Assessment of Cancer Therapy-Head and Neck Cancer) were comparable to published results for chemoradiotherapy without HBO. CONCLUSIONS: While acknowledging the study's small size and early attrition of 3 patients, our in-depth review of the acquired data indicates the feasibility of combining HBO with chemoradiation.

Methicillin-resistant Staphylococcus aureus (MRSA) nasal real-time PCR: a predictive tool for contamination of the hospital environment.

OBJECTIVE We sought to determine whether the bacterial burden in the nares, as determined by the cycle threshold (CT) value from real-time MRSA PCR, is predictive of environmental contamination with MRSA. METHODS Patients identified as MRSA nasal carriers per hospital protocol were enrolled within 72 hours of room admission. Patients were excluded if (1) nasal mupirocin or chlorhexidine body wash was used within the past month or (2) an active MRSA infection was suspected. Four environmental sites, 6 body sites and a wound, if present, were cultured with premoistened swabs. All nasal swabs were submitted for both a quantitative culture and real-time PCR (Roche Lightcycler, Indianapolis, IN). RESULTS At study enrollment, 82 patients had a positive MRSA-PCR. A negative correlation of moderate strength was observed between the CT value and the number of MRSA colonies in the nares (r=-0.61; P<0.01). Current antibiotic use was associated with lower levels of MRSA nasal colonization (CT value, 30.2 vs 27.7; P<0.01). Patients with concomitant environmental contamination had a higher median log MRSA nares count (3.9 vs 2.5, P=0.01) and lower CT values (28.0 vs 30.2; P<0.01). However, a ROC curve was unable to identify a threshold MRSA nares count that reliably excluded environmental contamination. CONCLUSIONS Patients with a higher burden of MRSA in their nares, based on the CT value, were more likely to contaminate their environment with MRSA. However, contamination of the environment cannot be predicted solely by the degree of MRSA nasal colonization.

Addressing distress in patients with head and neck cancers: a mental health quality improvement project.

This study sought to improve mental health care for patients with head and neck cancers (HNCs) through the implementation of an evidence-based process for identifying and managing psychological distress. This process in an HNC medical oncology clinic was assessed and redesigned using quality improvement (QI) methods from November 2010 through April 2012. The redesign, starting in January 2011, involved a 2-component QI intervention: the validated NCCN Distress Thermometer and an evidence-based treatment decision algorithm. Screening processes were improved through Plan-Do-Study-Act (PDSA) cycles. Before January 2011, distress identification was based on a provider's clinical assessment. Cause-effect diagramming suggested that lack of a formalized process for distress assessment contributed to missed diagnoses. Providers were also unfamiliar with mental health resources. After implementing process changes, biweekly distress screening rates rose from 0% to 38% between January and July 2011. Furthermore, with additional PDSA cycles, these rates increased to 74% between October 2011 and April 2012. Similar to proposed benchmarks, 84% (n=47) of newly diagnosed patients (n=56) were screened. Improvement in screening was attributed to process changes and involvement of senior leadership. QI principles can be applied to the cancer setting in order to create systems of care which more reliably identify and address the needs of patients with psychological distress.

Use of a linear array for the detection of human papillomavirus genotypes in head and neck cancer.

CONTEXT: Tumors of the head and neck commonly arise from the squamous and respiratory mucosa that lines the nasal and oral cavity, sinuses, pharynx, and larynx. The rate of oropharyngeal cancers diagnosed among Americans younger than 50 years is increasing. Infection of the oropharynx and tonsils by the human papillomavirus (HPV) has been linked to preneoplasia and cancer. OBJECTIVES: To evaluate the Roche Linear Array HPV Genotyping test kit to identify, and then specifically genotype, HPV in formalin-fixed, paraffin-embedded tissues. DESIGN: We evaluated the performance of this assay for accuracy, for intra-assay and interassay precision, and for its limit of detection, using materials with known HPV status. Sixteen tumor tissues with the following origins were evaluated: 1 ocular, 1 hypopharynx, 8 tonsil, 1 retromolar trigone, 3 tongue, 1 anal, and 1 lymph node. DNA from formalin-fixed, paraffin-embedded tumor sections was isolated and amplified in duplicate, with positive and negative controls, using primers specific to the polymorphic L1 region of the HPV genome. Thirty-seven genotypes were tested using the linear array. The amplified product (450 base pairs) was visualized by gel electrophoresis and, if positive, reflexed to HPV genotyping. RESULTS: Nine of the 16 tumors analyzed were HPV positive. The detected genotypes included HPV 6, 16, and 69. CONCLUSIONS: The Roche Linear Array HPV Genotyping test is an easy-to-use method for determining HPV genotype in the routine analysis of formalin-fixed, paraffin-embedded tumors. This assay is robust and can be performed routinely in a clinical laboratory setting.

A dose escalation trial of biweekly docetaxel and gemcitabine with filgrastim or pegfilgrastim for the treatment of patients with advanced solid tumors.

BACKGROUND/AIMS: A single-institution phase I trial to determine the feasibility of using filgrastim or pegfilgrastim to increase the dose intensity of biweekly docetaxel and gemcitabine. METHODS: Patients with metastatic solid tumors received gemcitabine 3,000 mg/m(2) and increasing doses of docetaxel (55 mg/m(2) in 10 mg/m(2) increments) every 14 days with filgrastim or pegfilgrastim. RESULTS: 35 patients enrolled, median 2 prior therapies, 158 cycles of therapy. There was 1 dose-limiting toxicity (DLT) (sepsis) at docetaxel 55 mg/m(2), 1 DLT (sepsis/diarrhea) at docetaxel 65 mg/m(2), and no DLT at docetaxel 75 mg/m(2). At docetaxel 85 mg/m(2), 2/4 patients had DLT (fatigue/dyspnea, diarrhea). The maximum tolerated dose (MTD) of docetaxel was 75 mg/m(2). 1/12 patients treated at MTD experienced DLT (sepsis/dyspnea). The initial 25 patients received filgrastim (average 7 doses/cycle), the last 10 received pegfilgrastim. CONCLUSIONS: The MTD for docetaxel was 75 mg/m(2) with gemcitabine 3,000 mg/m(2) given every 14 days with filgrastim or pegfilgrastim. This regimen was well tolerated with signs of clinical activity. We found no significant differences in toxicities or effectiveness between daily filgrastim and pegfilgrastim given 13 days before the next chemotherapy. The use of granulocyte growth factors allowed increased dose intensity of docetaxel and gemcitabine. This regimen warrants further study in chemotherapy-naïve patients and patients with earlier stages.

Problem-based learning of research skills.

PURPOSE: To determine whether a short-term, problem-based educational intervention leads to increased research activity among health care practitioners. SUBJECTS AND METHODS: Participant's success was evaluated as a composite of 2 outcomes. These were (1) reporting results for the project designed during the practicum and (2) conducting subsequent research activities. The study population included 36 clinical research outcomes projects developed by clinical practitioners, postgraduate trainees, and medical students during 6 separate practicums. All project teams received the same educational intervention, an "outcomes research practicum" that was divided into 4 primary learning modules administered over a 1 to 4 month period. Each module included a preparatory videotape lecture, supplemental readings, and a 90-minute interactive laboratory session during which faculty members worked with participants to develop answers to a series of predefined questions relating to the design of clinical outcomes research projects. Follow-up continued for a minimum of 12 months and a maximum of 36 months. RESULTS: Eighty-three percent of project teams completed all 4 practicum modules, and 69% completed one of the study outcomes (50% completed their research project and 47% completing a subsequent research activity). Practitioners were more likely to complete subsequent research activities, whereas trainees were more likely to complete their study project. DISCUSSION: This short-term, problem-based educational intervention was successful in increasing the collective research activities of participants. Further, more rigorous structured research is needed to determine the ultimate impact on practice change and patient outcomes.

Epidermal growth factor receptor tyrosine kinase inhibition represses cyclin D1 in aerodigestive tract cancers.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are active in cancer therapy. Mechanisms engaged during these clinical responses need to be determined. We reported previously that epidermal growth factor stimulation markedly increased cyclin D1 protein expression in human bronchial epithelial (HBE) cells, and this was opposed by chemoprevention with all-trans-retinoic acid. The current study sought to determine whether the EGFR TKI erlotinib repressed cyclin D1 protein expression in immortalized HBE cells, lung cancer cell lines, and clinical aerodigestive tract cancers. EXPERIMENTAL DESIGN: The BEAS-2B immortalized HBE cell line was exposed to varying concentrations of erlotinib, and effects on proliferation, cell cycle distribution, G1 cyclin expression, and cyclin D1 reporter activity were measured. Non-small-cell lung cancer cell lines were also evaluated for changes in proliferation and cyclin protein expression after erlotinib treatments. A proof of principle clinical trial was conducted. During this study, patients underwent a 9-day course of erlotinib treatment. Pretreatment and posttreatment tumor biopsies were obtained, and changes in candidate biomarkers were determined by immunostaining. Plasma pharmacokinetics and tumor tissue erlotinib concentrations were measured. RESULTS: Erlotinib, at clinically achievable dosages, repressed BEAS-2B cell growth, triggered G1 arrest, and preferentially reduced cyclin D1 protein expression and transcriptional activation. Erlotinib also preferentially repressed proliferation and cyclin D1 protein expression in responsive, but not resistant, non-small-cell lung cancer cell lines. This occurred in the presence of wild-type EGFR sequence at exons 18, 19, and 21. Five patients were enrolled onto an erlotinib proof of principle clinical trial, and four cases were evaluable. Pharmacokinetic studies established therapeutic erlotinib plasma levels in all patients, but tissue levels exceeding 2 micromol/L were detected in only two cases. Notably, these cases had pathological evidence of response (necrosis) in posttreatment biopsies as compared with pretreatment biopsies. In these cases, marked repression of cyclin D1 and the proliferation marker Ki-67 was detected by immunohistochemical assays. Cases without pathological response to erlotinib did not exhibit changes in cyclin D1 or Ki-67 immunohistochemical expression and had much lower erlotinib tissue levels than did responding cases. CONCLUSIONS: Taken together, these in vitro and in vivo findings provide direct evidence for repression of cyclin D1 protein as a surrogate marker of response in aerodigestive tract cancers to erlotinib treatment. These findings also provide a rationale for combining an EGFR TKI with an agent that would cooperatively repress cyclin D1 expression in clinical trials for aerodigestive tract cancer therapy or chemoprevention.