PHASE I/II STUDY OF ERLOTINIB COMBINED WITH CISPLATIN AND RADIOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Purpose: Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. Methods and Materials: In this Phase I/II trial 100 mg/m(2) of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuing during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase 11 was initiated 8 weeks after the last Phase I enrollment. Results: The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase 11 dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%-86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months` follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. Conclusions: This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC. (C) 2010 Elsevier Inc.

Peginterferon alfa-2b and Ribavirin: Effective in Patients With Hepatitis C Who Failed Interferon alfa/Ribavirin Therapy

Background & Aims: Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. Methods: This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 mu g/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigator`s request. Results: Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (<= 600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. Conclusions: Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.

A randomized controlled trial comparing a computer-assisted insulin infusion protocol with a strict and a conventional protocol for glucose control in critically ill patients

Purpose: The objective of this study is to evaluate blood glucose (BG) control efficacy and safety of 3 insulin protocols in medical intensive care unit (MICU) patients. Methods: This was a multicenter randomized controlled trial involving 167 MICU patients with at least one BG measurement +/- 150 mg/dL and one or more of the following: mechanical ventilation, systemic inflammatory response syndrome, trauma, or burns. The interventions were computer-assisted insulin protocol (CAIP), with insulin infusion maintaining BG between 100 and 130 mg/dL; Leuven protocol, with insulin maintaining BG between 80 and 110 mg/dL; or conventional treatment-subcutaneous insulin if glucose > 150 mg/dL. The main efficacy outcome was the mean of patients` median BG, and the safety outcome was the incidence of hypoglycemia (<= 40 mg/dL). Results: The mean of patients` median BG was 125.0, 127.1, and 158.5 mg/dL for CAIP, Leuven, and conventional treatment, respectively (P = .34, CAIP vs Leuven; P < .001, CAIP vs conventional). In CAIP, 12 patients (21.4%) had at least one episode of hypoglycemia vs 24 (41.4%) in Leuven and 2 (3.8%) in conventional treatment (P = .02, CAIP vs Leuven; P = .006, CAIP vs conventional). Conclusions: The CAIP is safer than and as effective as the standard strict protocol for controlling glucose in MICU patients. Hypoglycemia was rare under conventional treatment. However, BG levels were higher than with IV insulin protocols. (C) 2009 Elsevier Inc. All rights reserved.

Technical modifications in stabilisers and in bar removal in the Nuss procedure

Pectus excavatum is a congenital deformity that can require surgical treatment. Since Nuss proposed a correction technique, several modifications have been proposed in order to achieve more safety and efficiency in the placement and removal of both bars. Our objective is to describe the technique of placing and removing the bars by proposing three technical modifications: two in bar placement and one in the bar removal. We describe two cases where Nuss bars were placed and one case where the bar was removed as per the technical modification proposed herein. According to the original technique, bar stabilisers. were placed close to the lateral bar edges. We propose a more medial position in order to reduce bar displacement. New stabilisers were designed with central grooves in the posterior surface, which allow better sliding. The technical modification suitable for bar removal was the use of a protective film around the bars to protect the surrounding tissues from the sharp edges, and thereby minimise the risk of injuries. All the proposed modifications were performed without any additional surgical risk or perioperative complication. These three technical modifications can be easily and safety performed, and seem to reduce the risk of bleeding with no additional perioperative complications. (C) 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Is Silver Nitrate Pleurodesis for Patients with Malignant Pleural Effusion Feasible and Safe When Performed in an Outpatient Setting?

The purpose of this study was to analyze the effectiveness and safety of silver nitrate pleurodesis (SNP) in patients with recurrent malignant pleural effusion (RMPE) when performed in an outpatient setting. Prospective study including patients with RMPE recruited in a tertiary university-based hospital from February 2008 to June 2009. Elected patients underwent pleural catheter insertion (Day 1) followed by 0.5% SNP (Day 2), and on 7th day the drain was removed. All procedures were performed in an outpatient facility. Pleurodesis was considered successful when no additional pleural procedure was necessary by the 30th day. Complications were registered and graded according to the CTCAE3.0. Quality of life was evaluated before and 30 days after SNP. A total of 68 patients (54 female, 14 male, mean age: 57.3 years) were included. In addition, 7 had bilateral pleural effusions; therefore, 75 hemithoraces were drained. Also, 5 were excluded, and 70 hemithoraces (63 patients) underwent SNP. During the period of 30 days postpleurodesis, 8 deaths not related to the procedure occurred, and we lost contact with 10 patients who were followed elsewhere. At the 30th day, 48 hemithoraces (45 patients) were reevaluated, and 2 recurrences observed. The most frequent complication was pain-graded as 3 or more in 7 patients; infection occurred in 2 patients. Physical and environmental aspects of quality of life improved significantly after pleurodesis. In this study, SNP could be performed safely in an outpatient setting, with pain the most frequent complication. Recurrences occurred in 4% of the patients.

Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity

center dot Pharmacokinetic interactions between albendazole and praziquantel are based on plasma concentrations of the enantiomeric mixture of both drugs with contradictory data, although the antiparasitic activity arises from (-)-(R)-praziquantel and (+)-albendazole sulfoxide. WHAT THIS STUDY ADDS center dot The pharmacokinetic interaction between albendazole and praziquantel is enantioselective. Praziquantel increased the plasma concentrations of (+)-albendazole sulfoxide more than those of (-)-albendazole sulfoxide and the administration of albendazole did not change the kinetic disposition of (+)-(S)-praziquantel, but increased the plasma concentration of (-)-(R)-praziquantel. AIM This study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers. METHODS A randomized crossover study was carried out in three phases (n = 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0-48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P < 0.05. RESULTS The administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 mu g ml-1 h), (-)-ASOX by 358% (0.14 vs. 0.50 mu g ml-1 h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 mu g ml-1 h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (-)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (-)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 mu g ml-1 h). CONCLUSIONS The pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (-)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination.

Glaucoma and Keratoprosthesis Surgery Role of Adjunctive Cyclophotocoagulation

Purpose: To evaluate the efficacy and safety of diode laser transscleral cyclophotocoagulation (DLTSC) to control intraocular pressure (IOP) in keratoprosthesis patients with uncontrolled glaucoma. Patients and Methods: Between 1993 and 2007, 18 eyes of 18 patients underwent DLTSC, either before (n = 3), during (n = I), or after (n = 14) keratoprosthesis surgery. Keratoprosthesis type 1 was used in 72%. All but one of these patients received an Ahmed Glaucoma Valve, either with or after the keratoprosthesis placement. Best-corrected visual acuity, IOP (assessed by digital palpation), number of medications, and complications were recorded preoperatively, at day 7, at 1, 3, and 6 months then every 6 months postoperatively. Results: Mean follow-tip was 26.6 +/- 19.6 months (mean +/- SD) and mean age was 50.1 +/- 15.6 years. Glaucoma was identified in 1 I eyes before keratoprosthesis surgery and in 7 eyes after. Mean postoperative IOP was significantly reduced at 6, 12, 24, 36, and 48 months after DLTSC. DLTSC was repeated in 6 eyes. At final visit, mean best-corrected visual acuity was not decreased and there were no statistically significant differences in the number of glaucoma medications. Two patients had complications after DLTSC: a conjunctival dehiscence and a fungal endophthalmitis. Conclusions: DLTSC has beneficial long-term effects in the control of IOP and can be considered in the management of keratoprosthesis patients with refractory glaucoma.

Industrial relations decentralisation and the growth of 12-hour shifts in Australia

In the last two decades, increasing numbers of workplaces in Australia have introduced 12-hour shifts. This increase is due, in part, to government policies aimed at promoting labour flexibility. The purpose of this paper is to examine the cover afforded by the Workplace Relations Act 1996 and other industrial relations legislation in terms of shift-workers’ health and safety. Particular reference is made to the broader social, economic and political context surrounding the introduction and use of 12-hour shifts, as it is this context that shapes the constraints and opportunities facing employers and employees in the work arrangements they choose and how they are negotiated. We conclude that the current system of regulating industrial relations in Australia is largely outcome-focused and inadequate. The bargaining process receives little regulation in terms of considering how changes could affect health and safety in the workplace or how changes might affect individual workers. As a result, the increased introduction of unsafe shiftworking arrangements is a worrying, and likely, prospect.

Being breastfed in infancy and breast cancer incidence in adult life: Results from the two Nurses' Health studies

Events during perinatal and early life may influence the incidence of breast cancer in adult life, and some case-control studies suggest that having been breastfed may reduce breast cancer risk. The authors studied this association among premenopausal and postmenopausal women by using data from the two Nurses' Health Studies, the Nurses' Health Study (using data from 1992 to 1996) and the Nurses' Health Study II (using data from 1991 to 1997). A history of being breastfed was self-reported by the study participants. During a total of 695,655 person-years, 1,073 cases of invasive breast cancer were diagnosed. The authors did not observe any important overall association between having been breastfed and the development of breast cancer later in life among premenopausal women (covariate-adjusted relative risk = 0.97, 95% confidence interval (CI): 0.78, 1.20) or postmenopausal women (covariate-adjusted relative risk = 1.12, 95% CI: 0.92, 1.37). No significant trend was observed with increasing duration of breastfeeding. The authors also used data on breastfeeding retrospectively collected from 2,103 mothers of participants of the two Nurses' Health Studies. With the mothers' reports, the covariate-adjusted odds ratio of breast cancer was 1.11 (95% CI: 0.88, 1.39) for women who were breastfed compared with those who were not. Data from these two large cohorts do not support the hypothesis that being breastfed confers protection against subsequent breast cancer.