A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol

Background:

The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS).

Methods:

From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan–Meier curves and log-rank test, and finally through multivariable stratified Cox''s proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance.

Results:

At study entry, the median age was 76 years (inter-quartile range: 70–80 years), the median PSA was 79 ng ml⁻¹, and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ⩾11 g dl⁻¹ decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25–0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno–thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001).

Conclusion:

Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.     

Efficacy of oral miltefosine in visceral leishmaniasis in rural West Bengal, India

Context:

Visceral leishmaniasis (VL), also known as Kala-azar (KA) is a public health problem of tropical and subtropical countries, which infects about 12 million people annually, out of which about 1.5 million are new cases. India contributes a major share of the global burden of VL. For many years leishmaniasis has been treated with pentavalent antimonials. Antimony resistance is a problem in India and in other different geographic areas of the world. Amphotericin B deoxycholate and pentamidine isethionate are effective by parenteral administration and associated with toxicities. The quest for an effective, orally administered, non-toxic and less expensive alternative resulted in the identification of miltefosine (hexadecylphosphocholine). In India, therapeutic efficacy of miltefosine in VL was assessed by many groups of scientists, mainly from Bihar and Uttar Pradesh. No such data is available from West Bengal.

Aims:

The present study was designed to observe the efficacy of miltefosine in VL in rural West Bengal.

Materials and Methods:

A total of 71 parasitologically proven VL patients participated in the study who received miltefosine in accordance with the National Vector Born Disease Control Programme (NVBDCP) of India and were followed up for the following one year.

Results:

The overall efficacy of the drug was 93% and no significant adverse side effects were observed during the study period.

Conclusions:

The study concludes that miltefosine is effective, well tolerated, and easily administrable drug in the treatment of visceral leishmaniasis at the field levels.KEY WORDS: India, visceral leishmaniasis, miltefosine     

Assessing Operative Performance in Advanced Laparoscopic Colorectal Surgery

Background  

Competent technical skills performance in complex operations is vital for satisfactory patient outcome. Assessing these skills is therefore of paramount importance. In this study we aim to develop and validate a new tool that can assess both generic and specific technical skills in advanced complex laparoscopic colorectal surgery in the operating room.     

Smaller sample sizes for phase II trials based on exact tests with actual error rates by trading-off their nominal levels of significance and power

Background:

Sample sizes for single-stage phase II clinical trials in the literature are often based on exact (binomial) tests with levels of significance (alpha (α) <5% and power >80%). This is because there is not always a sample size where α and power are exactly equal to 5% and 80%, respectively. Consequently, the opportunity to trade-off small amounts of α and power for savings in sample sizes may be lost.

Methods:

Sample-size tables are presented for single-stage phase II trials based on exact tests with actual levels of significance and power. Trade-off in small amounts of α and power allows the researcher to select from several possible designs with potentially smaller sample sizes compared with existing approaches. We provide SAS macro coding and an R function, which for a given treatment difference, allow researchers to examine all possible sample sizes for specified differences are provided.

Results:

In a single-arm study with P₀ (standard treatment)=10% and P₁ (new treatment)=20%, and specified α=5% and power=80%, the A''Hern approach yields n=78 (exact α=4.53%, power=80.81%). However, by relaxing α to 5.67% and power to 77.7%, a sample size of 65 can be used (a saving of 13 patients).

Interpretation:

The approach we describe is especially useful for trials in rare disorders, or for proof-of-concept studies, where it is important to minimise the trial duration and financial costs, particularly in single-arm cancer trials commonly associated with expensive treatment options.     

Determinants of arsenicosis patients' perception and social implications of arsenic poisoning through groundwater in Bangladesh

Adverse human health effects ranging from skin lesions to internal cancers as well as widespread social and psychological problems caused by arsenic contaminated drinking water in Bangladesh may be the biggest arsenic calamity in the world. From an arsenicosis patients survey, this paper empirically analyzes the determinants of arsenicosis patients' perception about chronic arsenic poisoning and social and psychological implications of arsenicosis. In this study, cross-sectional data were collected from the Matlab and Hajiganj Upzillas of Chandpur district which are known to be highly contaminated with arsenic in their underground water. Respondents informed that arsenic poisoning causes a wide range of social and psychological problems. Female respondents were less vulnerable in the case of social problems (p < 0.01) and more vulnerable for the psychological problems (p < 0.001) of arsenicosis than male respondents. The results based on logit analysis showed that education (p < 0.01) and household income (p < 0.05) were significantly correlated to respondents' perception about arsenicosis. The arsenicosis related special program (s) needs a clear understanding of people's perception about arsenic exposure for abating the health burden as well as social and psychological problems.     

Cytotoxicity of the Roots of Trillium govanianum Against Breast (MCF7), Liver (HepG2), Lung (A549) and Urinary Bladder (EJ138) Carcinoma Cells

Trillium govanianum Wall. (Melanthiaceae alt. Trilliaceae), commonly known as ‘nag chhatri’ or ‘teen patra’, is a native species of the Himalayas. It is used in various traditional medicines containing both steroids and sex hormones. In folk medicine, the rhizomes of T. govanianum are used to treat boils, dysentery, inflammation, menstrual and sexual disorders, as an antiseptic and in wound healing. With the only exception of the recent report on the isolation of a new steroidal saponin, govanoside A, together with three known steroidal compounds with antifungal property from this plant, there has been no systematic pharmacological and phytochemical work performed on T. govanianum. This paper reports, for the first time, on the cytotoxicity of the methanol extract of the roots of T. govanianum and its solid‐phase extraction (SPE) fractions against four human carcinoma cell lines: breast (MCF7), liver (HEPG2), lung (A549) and urinary bladder (EJ138), using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide cytotoxicity assay and liquid chromatography and electrospray ionization quadrupole time‐of‐flight mass spectrometry analysis of the SPE fractions. The methanol extract and all SPE fractions exhibited considerable levels of cytotoxicity against all cell lines, with the IC₅₀ values ranging between 5 and 16 µg/mL. Like other Trillium species, presence of saponins and sapogenins in the SPE fractions was evident in the liquid chromatography mass spectrometry data. Copyright © 2016 John Wiley & Sons, Ltd.     

Large cerebellopontine angle tuberculoma: a case report

Tuberculoma involving the cerebellopontine angle is very rare. Preoperative neuroradiological features of such lesions may mimic neoplastic lesions and postoperative histopathological study brings the ultimate diagnosis. Here we present a patient with a large tuberculoma at the cerebellopontine angle who had another small lesion at the right fronto-basal region and was managed by surgical excision of the cerebellopontine angle lesion along with post-surgical antitubercular therapy for 18 months. On the 14th postoperative day, the patient developed status epilepticus, left hemiplegia and left-sided complete hearing loss. Computed tomography showed right frontal oedema. Then he recovered his motor function slowly and incompletely but left-sided hearing loss remained unchanged. Magnetic resonance imaging of the brain at 18 months after surgery showed no residual lesion with right frontal cortical atrophy.     

Technical and technological skills assessment in laparoscopic surgery.

OBJECTIVES: Surgical appraisal and revalidation are key components of good surgical practice and training. Assessing technical skills in a structured manner is still not widely used. Laparoscopic surgery also requires the surgeon to be competent in technological aspects of the operation. METHODS: Checklists for generic, specific technical, and technological skills for laparoscopic cholecystectomies were constructed. Two surgeons with >12 years postgraduate surgical experience assessed each operation blindly and independently on DVD. The technological skills were assessed in the operating room. RESULTS: One hundred operations were analyzed. Eight trainees and 10 consultant surgeons were recruited. No adverse events occurred due to technical or technological skills. Mean interrater reliability was kappa=0.88, P=<0.05. Construct validity for both technical and technological skills between trainee and consultant surgeons were significant, Mann-Whitney P=<0.05. CONCLUSIONS: Our study demonstrates that technical and technological skills can be measured to assess performance of laparoscopic surgeons. This technical and technological assessment tool for laparoscopic surgery seems to have face, content, concurrent, and construct validities and could be modified and applied to any laparoscopic operation. The tool has the possibility of being used in surgical training and appraisal. We aim to modify and apply this tool to advanced laparoscopic operations.