Phase II trial of trimelamol in refractory ovarian cancer

Trimelamol is an analogue of hexamethymelamine which exhibited activity against refractory ovarian cancer in phase I clinical trial. The dose limiting toxicity was leukopenia. In a phase II study, 42 patients with recurrent, or platinum-complex resistant, advanced ovarian cancer were treated using the dose schedule 800 mg m-2 i.v. daily for 3 days. There were one complete, three partial and five minor responses, objective response rate: 9.5%. The main toxicity observed was nausea and vomiting, myelosuppression was minor. The role of Trimelamol in the treatment of ovarian cancer remains to be defined, but its activity is limited in refractory disease

Centre selection for clinical trials and the generalisability of results: a mixed methods study.

BACKGROUND: The rationale for centre selection in randomised controlled trials (RCTs) is often unclear but may have important implications for the generalisability of trial results. The aims of this study were to evaluate the factors which currently influence centre selection in RCTs and consider how generalisability considerations inform current and optimal practice. METHODS AND FINDINGS: Mixed methods approach consisting of a systematic review and meta-summary of centre selection criteria reported in RCT protocols funded by the UK National Institute of Health Research (NIHR) initiated between January 2005-January 2012; and an online survey on the topic of current and optimal centre selection, distributed to professionals in the 48 UK Clinical Trials Units and 10 NIHR Research Design Services. The survey design was informed by the systematic review and by two focus groups conducted with trialists at the Birmingham Centre for Clinical Trials. 129 trial protocols were included in the systematic review, with a total target sample size in excess of 317,000 participants. The meta-summary identified 53 unique centre selection criteria. 78 protocols (60%) provided at least one criterion for centre selection, but only 31 (24%) protocols explicitly acknowledged generalisability. This is consistent with the survey findings (n = 70), where less than a third of participants reported generalisability as a key driver of centre selection in current practice. This contrasts with trialists' views on optimal practice, where generalisability in terms of clinical practice, population characteristics and economic results were prime considerations for 60% (n = 42), 57% (n = 40) and 46% (n = 32) of respondents, respectively. CONCLUSIONS: Centres are rarely enrolled in RCTs with an explicit view to external validity, although trialists acknowledge that incorporating generalisability in centre selection should ideally be more prominent. There is a need to operationalize 'generalisability' and incorporate it at the design stage of RCTs so that results are readily transferable to 'real world' practice

Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/refractory epithelial ovarian cancer

Background: Platinum agents have shown demonstrable activity in the treatment of patients with platinum resistant, recurrent ovarian cancer when delivered in a "dose-dense" fashion. However, the development of thrombocytopenia limits the weekly administration of carboplatin to no greater than AUC 2. Paclitaxel has a well-described platelet sparing effect however its use to explicitly provide thromboprotection in the context of dose dense carboplatin has not been explored. Methods: We treated seven patients with platinum resistant ovarian cancer who had previously received paclitaxel or who had developed significant peripheral neuropathy precluding the use of further full dose weekly paclitaxel. Results: We were able to deliver carboplatin AUC 3 and paclitaxel 20 mg/m(2) with no thrombocytopenia or worsening of neuropathic side-effects, and with good activity. Conclusions: We conclude that this regimen may be feasible and active, and could be formally developed as a "platinum-focussed dose-dense scaffold" into which targeted therapies that reverse platinum resistance can be incorporated, and merits further evaluation

Non-randomised patients in a cholecystectomy trial: characteristics, procedures, and outcomes

BACKGROUND: Laparoscopic cholecystectomy is now considered the first option for gallbladder surgery. However, 20% to 30% of cholecystectomies are completed as open operations often on elderly and fragile patients. The external validity of randomised trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy has not been studied. The aim of this study is to analyse characteristics, procedures, and outcomes for all patients who underwent cholecystectomy without being included in such a trial. METHODS: Characteristics (age, sex, co-morbidity, and ASA-score), operation time, hospital stay, and mortality were compared for patients who underwent cholecystectomy outside and within a randomised controlled trial comparing mini-laparotomy and laparoscopic cholecystectomy. RESULTS: During the inclusion period 1719 patients underwent cholecystectomy. 726 patients were randomised and 724 of them completed the trial; 993 patients underwent cholecystectomy outside the trial. The non-randomised patients were older – and had more complications from gallstone disease, higher co-morbidity, and higher ASA – score when compared with trial patients. They were also more likely to undergo acute surgery and they had a longer postoperative hospital stay, with a median 3 versus 2 days (p < 0.001 for all comparisons). Standardised mortality ratio within 90 days of operation was 3.42 (mean) (95% CI 2.17 to 5.13) for non-randomised patients and 1.61 (mean) (95%CI 0.02 to 3.46) for trial patients. For non-randomised patients, operation time did not differ significantly between mini-laparotomy and open cholecystectomy in multivariate analysis. However, the operation for laparoscopic cholecystectomy lasted 20 minutes longer than open cholecystectomy. Hospital stay was significantly shorter for both mini-laparotomy and laparoscopic cholecystectomy compared to open cholecystectomy. CONCLUSION: Non-randomised patients were older and more sick than trial patients. The assignment of healthier patients to trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy limits the external validity of conclusions reached in such trials

Continuous ambulatory peritoneal dialysis: pharmacokinetics and clinical outcome of paclitaxel and carboplatin treatment

Purpose: Administration of chemotherapy in patients with renal failure, treated with hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) is still a challenge and literature data is scarce. Here we present a case study of a patient on CAPD, treated with weekly and three-weekly paclitaxel/ carboplatin for recurrent ovarian cancer. Experimental: During the first, second and ninth cycle of treatment, blood, urine and CAPD samples were collected for pharmacokinetic analysis of paclitaxel and total and unbound carboplatin-derived platinum. Results: Treatment was well tolerated by the patient. No excessive toxicity was observed and at the e

Interpreting and reporting ⁴⁰Ar/³⁹Ar geochronologic data

The ⁴⁰Ar/³⁹Ar dating method is among the most versatile of geochronometers, having the potential to date a broad variety of K-bearing materials spanning from the time of Earth’s formation into the historical realm. Measurements using modern noble-gas mass spectrometers are now producing ⁴⁰Ar/³⁹Ar dates with analytical uncertainties of ∼0.1%, thereby providing precise time constraints for a wide range of geologic and extraterrestrial processes. Analyses of increasingly smaller subsamples have revealed age dispersion in many materials, including some minerals used as neutron fluence monitors. Accordingly, interpretive strategies are evolving to address observed dispersion in dates from a single sample. Moreover, inferring a geologically meaningful “age” from a measured “date” or set of dates is dependent on the geological problem being addressed and the salient assumptions associated with each set of data. We highlight requirements for collateral information that will better constrain the interpretation of ⁴⁰Ar/³⁹Ar data sets, including those associated with single-crystal fusion analyses, incremental heating experiments, and in situ analyses of microsampled domains. To ensure the utility and viability of published results, we emphasize previous recommendations for reporting ⁴⁰Ar/³⁹Ar data and the related essential metadata, with the amendment that data conform to evolving standards of being findable, accessible, interoperable, and reusable (FAIR) by both humans and computers. Our examples provide guidance for the presentation and interpretation of ⁴⁰Ar/³⁹Ar dates to maximize their interdisciplinary usage, reproducibility, and longevity

Born Knowing: Tentacled Snakes Innately Predict Future Prey Behavior

Background: Aquatic tentacled snakes (Erpeton tentaculatus) can take advantage of their prey’s escape response by startling fish with their body before striking. The feint usually startles fish toward the snake’s approaching jaws. But when fish are oriented at a right angle to the jaws, the C-start escape response translates fish parallel to the snake’s head. To exploit this latter response, snakes must predict the future location of the fish. Adult snakes can make this prediction. Is it learned, or are tentacled snakes born able to predict future fish behavior? Methods and Findings: Laboratory-born, naïve snakes were investigated as they struck at fish. Trials were recorded at 250 or 500 frames per second. To prevent learning, snakes were placed in a water container with a clear transparency sheet or glass bottom. The chamber was placed over a channel in a separate aquarium with fish below. Thus snakes could see and strike at fish, without contact. The snake’s body feint elicited C-starts in the fish below the transparency sheet, allowing strike accuracy to be quantified in relationship to the C-starts. When fish were oriented at a right angle to the jaws, naïve snakes biased their strikes to the future location of the escaping fish’s head, such that the snake’s jaws and the fish’s translating head usually converged. Several different types of predictive strikes were observed. Conclusions: The results show that some predators have adapted their nervous systems to directly compensate for the future behavior of prey in a sensory realm that usually requires learning. Instead of behavior selected during their lifetime