Hypoxia-selective targeting by the bioreductive prodrug AQ4N in patients with solid tumors: results of a phase I study.

PURPOSE: AQ4N is a novel bioreductive prodrug under clinical investigation. Preclinical evidence shows that AQ4N penetrates deeply within tumors and undergoes selective activation to form AQ4, a potent topoisomerase II inhibitor, in hypoxic regions of solid tumors. This proof-of-principle, phase I study evaluated the activation, hypoxic selectivity, and safety of AQ4N in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Thirty-two patients with cancer (8 glioblastoma, 9 bladder, 8 head and neck, 6 breast, and 1 cervix) received a single 200 mg/m(2) dose of AQ4N before elective surgery. AQ4 and AQ4N levels in 95 tissues (tumor, healthy tissue) were assessed by liquid chromatography-tandem mass spectrometry. Tissue sections were also analyzed for AQ4 fluorescence using confocal microscopy, and for expression of the hypoxia-regulated glucose transporter, Glut-1. RESULTS: Activated AQ4 was detected in all tumor samples with highest levels present in glioblastoma (mean 1.2 microg/g) and head and neck (mean 0.65 microg/g) tumors; 22 of 32 patients had tumor AQ4 concentrations > or = 0.2 microg/g, levels previously shown to be active in preclinical studies. In 24 of 30 tumor samples, AQ4 was detected at higher concentrations than in adjacent normal tissue (tumor to normal ratio range 1.1-63.6); distant skin samples contained very low concentrations of AQ4 (mean 0.037 microg/g). Microscopic evaluation of tumor sections revealed that AQ4 colocalized within regions of Glut-1+ hypoxic cells. CONCLUSIONS: AQ4N was activated selectively in hypoxic regions in human solid tumors. Intratumoral concentrations of AQ4 exceeded those required for activity in animal models and support the evaluation of AQ4N as a novel tumor-targeting agent in future clinical studies.

Parotid cancer treatment with surgery followed by radiotherapy in Oxford over 15 years.

INTRODUCTION: Primary parotid malignancies represent a rare diagnosis, making high-quality comparative research unfeasible. There is little U.K.-based evidence to guide practice. A review was therefore undertaken of a large series of patients treated by a multidisciplinary team in a National Health Service tertiary referral centre. PATIENTS AND METHODS: Retrospective patient record review at the John Radcliffe Hospital in Oxford identified 401 patients who had undergone parotidectomy between 1995 and 2010, of whom 50 subjects were given a definitive diagnosis of primary parotid malignancy, treated with surgery and postoperative radiotherapy. Case notes, histology and imaging were reviewed by the study team. RESULTS: The median follow up for the cohort was 60 months (range: 1-108 months). Facial nerve function was preserved in all patients undergoing partial or total conservative parotidectomy. Although histology showed microscopically close or positive margins in 82% of cases, all patients underwent postoperative radiotherapy and locoregional recurrence was identified in only two (4%) patients. CONCLUSIONS: The data presented demonstrate a reasonable and practical multidisciplinary approach to a complex management problem. Facial nerve sparing surgery and postoperative radiotherapy result in good control of locoregional disease.

Predicting occult malignancy in nipple discharge.

BACKGROUND: This study was a retrospective analysis of patients who underwent minor or major duct surgery for pathological nipple discharge. The results of clinical examination, mammography, ultrasonography and cytodiagnosis of the nipple discharge were studied in order to predict those patients at risk of underlying or occult malignancy. METHODS: Between January 2004 and December 2006, 55 female patients aged between 24 and 82 years old underwent major or minor duct excision, 49 of which were for pathological nipple discharge. Results of several preoperative investigations were compared with the surgical pathology to determine how their sensitivity and specificity faired in predicting malignant ductal pathology. RESULTS: Of the 49 patients undergoing surgery for nipple discharge, 21 were diagnosed with intraductal papilloma, 19 with duct ectasia, 6 with carcinoma, 2 with benign breast disease and 1 with lobular carcinoma in situ. In all of the patients determined to have malignancy, none demonstrated malignant changes on mammography or ultrasonography. Only 2 of the 6 patients with malignancy were found to have atypical cells on cytological analysis. The sensitivity of blood detected in nipple discharge at predicting malignancy was 0.83, specificity of 0.53, positive predictive value of 0.20 and negative predictive value 0.96. CONCLUSIONS: Despite the various tests used in the assessment of pathological nipple discharge, this study highlights their limited help at predicting the cause. This, together with several other studies, demonstrates that ductal surgery remains the only reliable way of providing a diagnosis, in addition to being the major therapeutic measure.

Patient attitudes to clinical trials: development of a questionnaire and results from asthma and cancer patients.

OBJECTIVE: To develop a questionnaire to assess patients' views of clinical trials, and to report the results from the questionnaire in two patient groups: asthma and cancer. DESIGN: A 43 item questionnaire asking patients about their views to clinical trials was developed on the basis of interviews with trialists and focus groups with patients. The questionnaire was mailed to patients with a diagnosis of either asthma or cancer. A set of items was then selected, via statistical analyses, to form the core of the questionnaire. PARTICIPANTS: Patients with a diagnosis of cancer in one NHS Hospital Trust, and patients with a diagnosis of asthma in two NHS Hospital Trusts. RESULTS: Completed questionnaires were received from 353 cancer patients and 578 asthma patients. Factor analyses of the data indicated that 22 items contributed to five dimensions: 'positive beliefs', 'safety', 'information needs', 'negative expectations' and 'patient involvement'. Differences between asthma and cancer patients on these dimensions were small. A regression of these dimension scores against a variable asking if patients would be willing to take part in trials found that 'safety' and 'information needs' did not contribute significantly to the model for either asthma or cancer patients. CONCLUSIONS: A questionnaire has been developed for use in assessing patients' views towards clinical trials. Results from the surveys reported here suggest that patient views about the importance of trials and beliefs about the value of patient involvement are likely to be predictive of whether or not patients will agree to take part in a study.