Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Circadian timing in the lung; a specific role for bronchiolar epithelial cells.

In addition to the core circadian oscillator, located within the suprachiasmatic nucleus, numerous peripheral tissues possess self-sustaining circadian timers. In vivo these are entrained and temporally synchronized by signals conveyed from the core oscillator. In the present study, we examine circadian timing in the lung, determine the cellular localization of core clock proteins in both mouse and human lung tissue, and establish the effects of glucocorticoids (widely used in the treatment of asthma) on the pulmonary clock. Using organotypic lung slices prepared from transgenic mPER2::Luc mice, luciferase levels, which report PER2 expression, were measured over a number of days. We demonstrate a robust circadian rhythm in the mouse lung that is responsive to glucocorticoids. Immunohistochemical techniques were used to localize specific expression of core clock proteins, and the glucocorticoid receptor, to the epithelial cells lining the bronchioles in both mouse and human lung. In the mouse, these were established to be Clara cells. Murine Clara cells retained circadian rhythmicity when grown as a pure population in culture. Furthermore, selective ablation of Clara cells resulted in the loss of circadian rhythm in lung slices, demonstrating the importance of this cell type in maintaining overall pulmonary circadian rhythmicity. In summary, we demonstrate that Clara cells are critical for maintaining coherent circadian oscillations in lung tissue. Their coexpression of the glucocorticoid receptor and core clock components establishes them as a likely interface between humoral suprachiasmatic nucleus output and circadian lung physiology.

Evidence-based pragmatic guidelines for the follow-up of testicular cancer: optimising the detection of relapse.

Testicular germ cell tumours (TGCTs) are the most common cause of cancer in men between the ages of 15 and 40 years, and, overall, the majority of patients should expect to be cured. The European Germ Cell Cancer Consensus Group has provided clear guidelines for the primary treatment of both seminoma and nonseminomatous germ cell tumours. There is, however, no international consensus on how best to follow patients after their initial management. This must promptly and reliably identify relapses without causing further harm. The standardising of follow-up would result in optimising risk-benefit ratios for individual patients, while ensuring economic use of resources. We have identified the seven common scenarios in managing seminomas and nonseminomas of the various stages and discuss the pertinent issues around relapse and follow-up. We review the available literature and present our comprehensive TGCT follow-up guidelines. Our protocols provide a pragmatic, easily accessible user-friendly basis for other centres to use or to adapt to suit their needs. Furthermore, this should enable future trials to address specific issues around follow-up giving meaningful and useful results.

Assessment of laparoscopic injuries by three methods.

OBJECTIVE: To compare laparoscopic, gross, and fluorescent assessment of laparoscopic pelvic injuries. DESIGN: Experimental prospective study. SETTING: Cleveland Clinic Foundation Animal Research Laboratory, Cleveland, Ohio. ANIMAL(S): Nonpregnant adult female pigs. INTERVENTION(S): Pelvic organs injured with laparoscopic energy sources were assessed laparoscopically, grossly, and with a fluorescent indicator and Wood's lamp. MAIN OUTCOME MEASURE(S): Three different measurements of each laparoscopic injury. RESULT(S): Assessment of injuries by laparoscopy did not differ significantly from gross assessment of injuries. In the segments of bowel and bladder that were injured with monopolar cautery, the Wood's lamp assessment of the injuries was significantly longer than the laparoscopic assessment of the injuries. CONCLUSION(S): Laparoscopic assessment of injured ureters, bowel, and bladder appear to be similar to gross assessment of these tissues. In tissue where the serosal surface is intact, the use of a fluorescent dye and a Wood's lamp provides a clear margin of the injured tissue.

Paediatric palliative care: a lack of research-based evidence.

Providing the best possible care for the child and family is paramount to health professionals working in paediatric palliative care. However, there is little research which enables practitioners to question their current practice. There are concerns about conducting research on children receiving palliative care at such a sensitive time for the child and his/her family. These concerns must be considered against the growing demand for clear standards and guidelines for practice within health care. According to the Department of Health (DoH) there is no place within the modern healthcare system for the adoption of unproven theories or outdated care (DoH, 1998). While no-one would question the dedication and care being delivered to children and their families by well-trained staff, the lack of research is a cause for concern. A group of students undertaking a degree module in paediatric palliative care identified the lack of literature and research in this area and have undertaken a review of the available literature.

Cryopreservation of spermatozoa from freeze-tolerant and -intolerant anurans.

Spermatozoa of the freeze-tolerant wood frog (Rana sylvatica) were used to develop a general protocol for the frozen storage of amphibian spermatozoa. Tolerance of spermatozoa to cryoprotective agents and freezing in suspension (-80 degrees C) was determined from rates of sperm lysis and dual-fluorochrome vital dye assays. We tested the efficacy of four cryoprotectants (Me2SO, methanol, glycerol, and ethylene glycol), two supplements (fetal bovine serum or glutathione), and combinations of these cryoprotectants and supplements. Me2SO and fetal bovine serum were the most effective cryoprotectant and supplement, respectively, in reducing sperm lysis. Vital dye assays showed that viability was greatest for spermatozoa treated with both Me2SO and fetal bovine serum. Thus, this combination was used to cryopreserve spermatozoa from the freeze-intolerant anurans, Rana pipiens and Bufo americanus. Recovery of viable spermatozoa was significantly greater for R. sylvatica (mean +/- SE = 81.2 +/- 9.6%) than for R. pipiens (59.0 +/- 2.8%) and B. americanus (47.8 +/- 4.1%), perhaps owing to inherent factors promoting its freeze tolerance. Nonetheless, our results support the feasibility of using gamete cryopreservation techniques in programs aimed at the captive propagation of amphibians.

Muscle madness.

AIDS: The Bio-electrical Impedance Analysis (BIA) test is being used to follow wasting syndrome in patients with HIV infection because of its ability to determine how much muscle and fat a person has in their body. Because muscle mass is essential to supporting the immune system, suppressing viral replication, and avoiding opportunistic infections, it is important to track any changes. The test is painless and involves an electrode attached to one foot and a hand whereby an electrical current is passed through the body and its speed is measured. The faster the passage, the more muscle is present. Results of the test include a fluid assessment, body cell mass, fat mass, and a cellular health measure.^ieng

Weighty matters.

AIDS: People with HIV and AIDS need to monitor their diet and nutrition, especially considering the elevated cholesterol and triglyceride levels that can accompany protease inhibitor therapy. It is suggested that cholesterol and triglyceride levels be checked every 6 months by a doctor. Suggested levels for cholesterol and triglycerides are listed. Rather than skipping meals to lose weight, people are urged to modify their eating habits and food choices and to increase exercise. Guidelines for diet, exercise, and the use of dietary supplements are included. If weight loss needs to be avoided, despite high cholesterol and triglyceride levels, a dietician can help construct a proper menu, or a physician can prescribe medication to help lower these levels while maintaining a normal diet. Suggestions for lifestyle and nutritional changes to prevent protease paunch are outlined. Contact information is provided.^ieng

Protease inhibitors and food: how to maximize absorption into the blood.

AIDS: Food plays a crucial role with protease inhibitors, affecting both the absorption and tolerableness of the drugs. Food guidelines are provided for Crixivan, saquinavir, ritonavir, and nelfinavir. Each protease inhibitor food guideline varies; there is no general diet to be used with protease inhibitors. How to take the drug, which meals are most effective in enhancing the drug's effectiveness, and what foods to avoid are detailed. Specific examples of recommended meals and snacks are included.^ieng

Food, fitness and HIV: the connection.

AIDS: An HIV-positive diagnosis is often followed by wasting syndrome, in which chronic loss of muscle makes the patient feel progressively weaker and sicker. Exercise and eating can minimize muscle loss. Patients are advised to eat small frequent meals with high calorie and high protein foods. They should also eat at least four servings of starches, two of dairy products, and three fruits and vegetables. Exercise is important, and can reverse some of the muscle loss.^ieng

Cannabis use in a general psychiatric population.

It is known that there is an association between cannabis use and psychosis. Clinically we had thought that there were increasing numbers of patients admitted to hospital who were using cannabis and that this was affecting their illness. A study was therefore undertaken to determine the extent of cannabis use and its relationships over a one month period. The findings and their implications for junior doctors on-call are also discussed.

Rhodanese in insects.

Forty-four species of insects were assayed for the presence of rhodanese, an enzyme generally considered to be responsible for the detoxification of cyanide. Rhodanese was found to be widely distributed in both adults and larvae and was not restricted to those species which encounter exogenous cyanide through feeding on cyanogenic plants. These results indicate that cyanide detoxification is unlikely to be the primary role for rhodanese in insects.