Evolution of testosterone treatment over 25 years: symptom responses, endocrine profiles and cardiovascular changes

Introduction: Testosterone treatment has evolved rapidly over the past 25 years as new, more effective and convenient methods have become available. This study reports experience with seven different methods, introduced on the market in the UK. Aim: To establish the symptom response when testosterone treatment was initiated on the basis of clinical features and symptoms of androgen deficiency, and the resulting endocrine, biochemical and physiological responses. Methods: Of 2693 patients attending the 3 Men’s Health Centers – The UK Androgen Study (UKAS), 2247 were treated. Treatments included pellet implants, oral testosterone undecanoate (Testocaps), mesterolone (Proviron), testosterone gel (Testogel), testosterone scrotal cream (Andromen) and scrotal gel (Tostran). Results: There was no correlation between initial testosterone level, initial symptom score or the success of treatment as defined by adequate resolution of symptoms. Despite the diverse endocrine patterns produced, the testosterone preparations appear equally safe over prolonged periods, with either no change or improvement of cardiovascular risk factors, especially in lowering cholesterol and diastolic blood pressure. Conclusions: It is suggested that because of excessive reliance on laboratory measures of androgens and undue safety concerns, many men who could benefit from symptom relief, improvement in related clinical conditions and given preventive medical benefits remain untreated

Evaluating variation in use of definitive therapy and risk-adjusted prostate cancer mortality in England and the USA.

OBJECTIVES: Prostate cancer mortality (PCM) in the USA is among the lowest in the world, whereas PCM in England is among the highest in Europe. This paper aims to assess the association of variation in use of definitive therapy on risk-adjusted PCM in England as compared with the USA. DESIGN: Observational study. SETTING: Cancer registry data from England and the USA. PARTICIPANTS: Men diagnosed with non-metastatic prostate cancer (PCa) in England and the USA between 2004 and 2008. OUTCOME MEASURES: Competing-risks survival analyses to estimate subhazard ratios (SHR) of PCM adjusted for age, ethnicity, year of diagnosis, Gleason score (GS) and clinical tumour (cT) stage. RESULTS: 222,163 men were eligible for inclusion. Compared with American patients, English patients were more likely to present at an older age (70-79 years: England 44.2%, USA 29.3%, p<0.001), with higher tumour stage (cT3-T4: England 25.1%, USA 8.6%, p<0.001) and higher GS (GS 8-10: England 20.7%, USA 11.2%, p<0.001). They were also less likely to receive definitive therapy (England 38%, USA 77%, p<0.001). English patients were more likely to die of PCa (SHR=1.9, 95% CI 1.7 to 2.0, p<0.001). However, this difference was no longer statistically significant when also adjusted for use of definitive therapy (SHR=1.0, 95% CI 1.0 to 1.1, p=0.3). CONCLUSIONS: Risk-adjusted PCM is significantly higher in England compared with the USA. This difference may be explained by less frequent use of definitive therapy in England

The Burden of Revision Sinonasal Surgery in the UK – Data from the Chronic Rhinosinusitis Epidemiology Study (CRES); a cross sectional study

Objectives/Hypothesis The aim of this study was to investigate the surgical revision rate in patients with Chronic Rhinosinusitis (CRS) in the UK CRS Epidemiology Study (CRES). Previous evidence from national Sinonasal Audit showed that 1459 CRS patients demonstrated a surgical revision rate 19.1% at 5 years, with highest rates seen in those with polyps (20.6%). Setting Thirty secondary care centres around the UK. Participants A total of 221 controls and 1249 patients with CRS were recruited to the study including those with polyps (CRSwNPs), without polyps (CRSsNPs) and with allergic fungal rhinosinusitis (AFRS). Interventions Self-administered questionnaire. Primary outcome measure The need for previous sinonasal surgery. Results A total of 651 patients with CRSwNPs, 553 with CRSsNPs and 45 with AFRS were included. A total of 396 (57%) of patients with CRSwNPs/AFRS reported having undergone previous endoscopic nasal polypectomy (ENP), of which 182 of the 396 (46%) reported having received more than one operation. The mean number of previous surgeries per patient in the revision group was 3.3 (range 2 to 30) and a mean duration of time of 10 years since the last procedure. The average length of time since their first operation up to inclusion in the study was 15.5 years (range 0-74). Only 27.9% of all patients reporting a prior ENP had received concurrent endoscopic sinus surgery (ESS) (n=102). For comparison, surgical rates in patients with CRSsNPs were significantly lower; 13% of cases specifically reported ESS and of those only 30% reported multiple procedures (chi-squared p < 0.001). Conclusions This study demonstrated there is a high burden of both primary and revision surgery in patients with CRS, worst in those with AFRS and least in those with CRSsNPs. The burden of revision surgery appears unchanged in the decade since the Sinonasal Audit

A Retrospective Investigation of Thiamin and Energy Intakes Following an Outbreak of Beriberi in the Gambia

In the early part of the rainy season in 1988, an outbreak of beriberi occurred in free-living adults in a relatively small area in the North Bank region of The Gambia. In 1995 we selected two compounds in a village called Chilla situated within the affected district to retrospectively examine dietary factors potentially contributing to the outbreak. There had previously been cases of beriberi in one compound (BBC) but not in the other (NBC). We measured energy and thiamin intakes for four days on six occasions during the year. We calculated energy and thiamin intakes of people living in the two compounds and foods were collected for thiamin analysis through the year. Thiamin:Energy ratios only met international recommendations in the immediate post‑harvest season when energy and thiamin intakes were highest and then fell through the year. In the rainy season when food was short and labour was heaviest, energy intakes were lower in the NBC but thiamin:energy ratios were lower in BBC. Records of rainfall in 1988 collected near the village indicated that the amount in August was twice the average. We suggest the heavy rainfall may have increased farm workload and reduced income from outside-village work activity. The lower energy intakes in the NBC may have forced adults to rest thus sparing thiamin demands and delaying onset of beriberi. In contrast, the higher energy intake of adults in the BBC may have enabled them to continue working, thus increasing demands for thiamin and inducing the earlier onset of beriberi

National Population-Based Study Comparing Treatment-Related Toxicity in Men Who Received Intensity Modulated Versus 3-Dimensional Conformal Radical Radiation Therapy for Prostate Cancer.

PURPOSE: To compare, in a national population-based study, severe genitourinary (GU) and gastrointestinal (GI) toxicity in patients with prostate cancer who were treated with radical intensity modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT). METHODS AND MATERIALS: Patients treated with IMRT (n=6933) or 3D-CRT (n=16,289) between January 1, 2010 and December 31, 2013 in the English National Health Service were identified using cancer registry data, the National Radiotherapy Dataset, and Hospital Episodes Statistics, the administrative database of care episodes in National Health Service hospitals. We developed a coding system that identifies severe toxicity (at least grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events scoring system) according to the presence of a procedure and a corresponding diagnostic code in patients' Hospital Episodes Statistics records after radiation therapy. A competing risks regression analysis was used to estimate hazard ratios (HRs), comparing the incidence of severe GI and GU complications after IMRT and 3D-CRT, adjusting for patient, disease, and treatment characteristics. RESULTS: The use of IMRT, as opposed to 3D-CRT, increased from 3.1% in 2010 to 64.7% in 2013. Patients who received IMRT were less likely than those receiving 3D-CRT to experience severe GI toxicity (4.9 vs 6.5 per 100 person-years; adjusted HR 0.66; 95% confidence interval 0.61-0.72) but had similar levels of GU toxicity (2.3 vs 2.4 per 100 person-years; adjusted HR 0.94; 95% confidence interval 0.84-1.06). CONCLUSIONS: Prostate cancer patients who received radical radiation therapy using IMRT were less likely to experience severe GI toxicity, and they had similar GU toxicity compared with those who received 3D-CRT. These findings in an unselected "real-world" population support the use of IMRT, but further cost-effectiveness studies are urgently required

Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR

MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA

Patient-Reported Functional Outcomes After Hypofractionated or Conventionally Fractionated Radiation for Prostate Cancer: A National Cohort Study in England.

PURPOSE: The aim of the current study was to determine patient-reported functional outcomes in men with prostate cancer (PCa) undergoing moderately hypofractionated (H-RT) or conventionally fractionated radiation therapy (C-RT) in a national cohort study. PATIENDS AND METHODS: All men diagnosed with PCa between April 2014 and September 2016 in the English National Health Service undergoing C-RT or H-RT were identified in the National Prostate Cancer Audit and mailed a questionnaire at least 18 months after diagnosis. We estimated differences in patient-reported urinary, bowel, sexual, and hormonal function-Expanded Prostate Cancer Index Composite short-form 26 domain scores on a 0 to 100 scale-and health-related quality of life-EQ-5D-5L on a 0 to 1 scale-using linear regression with adjustment for patient, tumor, and treatment-related factors in addition to GI and genitourinary baseline function, with higher scores representing better outcomes. RESULTS: Of the 17,058 men in the cohort, 77% responded: 8,432 men received C-RT (64.2%) and 4,699 H-RT (35.8%). Men in the H-RT group were older (age ≥ 70 years: 67.5% v 60.9%), fewer men had locally advanced disease (56.5% v 71.3%), were less likely to receive androgen-deprivation therapy (79.5% v 87.8%), and slightly more men had pretreatment genitourinary procedures (24.2% v 21.2%). H-RT was associated with small increases in adjusted mean Expanded Prostate Cancer Index Composite short-form 26 sexual (3.3 points; 95% CI, 2.1 to 4.5; P < .001) and hormonal function scores (3.2 points; 95% CI, 1.8 to 4.6; P < .001). These differences failed to meet established thresholds for a clinically meaningful change. There were no statistically significant differences in urinary or bowel function and quality of life. CONCLUSION: This is the first national cohort study comparing functional outcomes after H-RT and C-RT reported by patients. These real-world results further support the use of H-RT as the standard for radiation therapy in men with nonmetastatic PCa

Privileged Structure: Novel Indane Scaffolds as Potential Anticancer and Anti-Inflammatory Agents

The identification and use of “privileged structures” can increase the reliability and shorten the process in the drug discovery and drug design (a-b). Indane scaffolds occur in various natural products and they constitute the privileged structure that is ubiquitous in many biologically and pharmaceutically active molecules (c-e). Our research group has been working on the synthesis and pharmacological activity of nature identical and synthetically modified indanes and indanones for 20 years. In the current study, the molecular design is centred on elaboration of a fern derived bioactive pharmacophore. The fern is used in traditional Taiwanese medicine to treat inflammation, allergy, stomach cramps and fever (f). Using a synthetic approach we have designed a novel chemical scaffold which can be modified to inhibit angiogenesis and 5-lipoxygenase activity. The parent scaffold and a number of strategically modified derivatives were initially screened using the Zebra fish (Danio rerio) model of tumour angiogenesis (g). This screen led to the identification of two lead molecules, which were then further evaluated in in vitro cell lines and colorectal explants. Results from these experiments establish that the lead compounds affect inter-segmental vessel formation. These molecules also inhibit cell invasion and tube formation. When evaluated in ex vivo colorectal cancer explants where the molecules significantly affected angiogenic and inflammatory protein secretions. These small molecules also alter gene expression. Modification of the scaffold can inhibit 5-lipoxygenase activity. These data suggest that the new scaffold may have significant potential in the treatment of angiogenesis and inflammatory related diseases