Image intensifier-guided transperineal prostate biopsy for patients without a rectum: novel technique.

INTRODUCTION: It is challenging to perform prostate biopsy in men with suspicion of prostate malignancy without a rectum to facilitate prostate biopsy. Nevertheless, such patients are presenting at an earlier stage, due to increased PSA testing in association with improved MRI imaging. We describe a novel technique for prostate biopsy in two such cases. TECHNIQUE: The patient is under General Anaesthesia and in lithotomy position. The patient is catheterised and a measured volume of contrast is inserted to the catheter balloon. By using anatomical surface landmarks, placing traction on the catheter to bring the balloon to the level of the bladder neck and using fluoroscopy, the distance to the apical prostate was estimated. This facilitates image intensifier guided trans-perineal prostate biopsy. OUTCOMES: A 67-year-old patient, with a history of panproctocolectomy for ulcerative colitis, presented with increasing PSA and a suspicious prostate on MP-MRI. The prostate couldn't be visualised on transperineal ultrasound and the patient was offered transperineal biopsy using image intensifier guidance. Several biopsy cores were taken and prostate cancer was diagnosed. The second patient was a 68-year-old who presented similarly, but with a history of panproctocolectomy for Crohn's disease. Using the above technique, biopsies were taken with low-risk prostate cancer diagnosed. Subsequently, due to rising PSA levels, a repeat set of prostate biopsies was taken 13 months later in an identical manner, upstaging his disease. There were no post-operative complications after any of the procedures. CONCLUSION: We review the literature and discuss several techniques available to sample the prostate in this patient cohort. We conclude that we have identified a safe and effective technique, which utilises commonly available equipment, to biopsy the prostate in the post proctectomy patient.

Assessing color cues of development, breeding status and reproductive condition in captive golden lion tamarins (Leontopithecus rosalia).

Color signals play an important role in intraspecific communication and are well studied in catarrhine primates, which exhibit uniform trichromatic vision that is well suited to detecting such signals. Platyrrhine primates exhibit polymorphic color vision with different individuals possessing different color vision types in most species. Intriguingly, some platyrrhine species exhibit bare faces, which are convergent with those of catarrhines. However, putative functions of bare-faced color signals in platyrrhines remain largely unexplored. We measured facial skin color of five captive golden lion tamarins (Leontopithecus rosalia) using color-calibrated digital photography and modeled these colors to the visual systems of the species. Our results show that facial coloration is different between infant and older adults and varies across reproductive condition, but not between breeding and nonbreeding adults. While preliminary, our study suggests that facial coloration may be involved in sociosexual signaling in golden lion tamarins, and provides intriguing evidence that we hope might stimulate more studies of bare-faced signaling in platyrrhines.

Phase 1 and preclinical profiling of ESM-HDAC391, a myeloid-targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia.

AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS: This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS: ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.

Structure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'.

Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a 'molecular budget' medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular size and H-bond donor count) were monitored through straightforward and intuitive use of atom count and distribution. The balance between structure-based design and an awareness of the physicochemical properties of the compounds synthesised enabled the rapid identification of a potent molecule with good oral pharmacokinetic (PK) characteristics by making fewer, higher quality compounds. The resulting candidate quality molecule was validated in a mechanistic cellular assay and a rodent secondary immunisation model.

Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762.

The bromodomain and extraterminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be accomplished. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma by using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong antiproliferative effect in vitro and in vivo. This is associated with contrasting effects on oncogenic MYC and HEXIM1, an inhibitor of the transcriptional activator P-TEFb. I-BET151 causes transcriptional repression of MYC and MYC-dependent programs by abrogating recruitment to the chromatin of the P-TEFb component CDK9 in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, preclinical studies show that I-BET762 has a favorable pharmacologic profile as an oral agent and that it inhibits myeloma cell proliferation, resulting in survival advantage in a systemic myeloma xenograft model. These data provide a strong rationale for extending the clinical testing of the novel antimyeloma agent I-BET762 and reveal insights into biologic pathways required for myeloma cell proliferation.

Dynamic sentinel lymph node biopsy for penile cancer: a comparison between 1- and 2-day protocols.

OBJECTIVE: To determine the outcome of clinically negative node (cN0) patients with penile cancer undergoing dynamic sentinel node biopsy (DSNB), comparing the results of a 1- and 2-day protocol that can be used as a minimal invasive procedure for staging of penile cancer. PATIENTS AND METHODS: This is a retrospective analysis of 151 cN0 patients who underwent DSNB from 2008 to 2013 for newly diagnosed penile cancer. Data were analysed per groin and separated into groups according to the protocol followed. The comparison of the two protocols involved the number of nodes excised, γ-counts, false-negative rates (FNR), and complication rates (Clavien-Dindo grading system). RESULTS: In all, 280 groins from 151 patients underwent DSNB after a negative ultrasound ± fine-needle aspiration cytology. The 1-day protocol was performed in 65 groins and the 2-day protocol in 215. Statistically significantly more nodes were harvested with the 1-day protocol (1.92/groin) compared with the 2-day protocol (1.60/groin). The FNRs were 0%, 6.8% and 5.1%, for the 1-day protocol, 2-day protocol, and overall, respectively. Morbidity of the DSNB was 21.4% for all groins, and 26.2% and 20.1% for the 1-day and 2-day protocols, respectively. Most of the complications were of Clavien-Dindo Grade 1-2. CONCLUSIONS: DSNB is safe for staging patients with penile cancer. There is a trend towards a 1-day protocol having a lower FNR than a 2-day protocol, albeit at the expense of a slightly higher complication rate.

The discovery of quinoline based single-ligand human H1 and H3 receptor antagonists.

A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.

Patient-Reported Experience of Modified Transperineal Template Guided Saturation Biopsy Under General Anaesthesia and without Prophylactic Catheterisation.

UNLABELLED: Results of patient feedback questionnaire following transperineal template guided saturation biopsy (TPSB) without prophylactic catheterisation. INTRODUCTION AND OBJECTIVE: TPSB is increasingly utilised in the diagnosis and characterisation of prostate cancer. However, there is little data on patient experience after undergoing this procedure. We circulated a questionnaire to 511 consecutive patients from July 2007 to December 2014 and now analyse the responses. MATERIALS AND METHODS: The mean age for the cohort was 64 (range 43-82). A mean of 28 biopsy cores (range 13-43) were taken under general anaesthesia (GA), as day case procedure. Patients received diclofenac 100 mg suppository on completion of the procedure. The questionnaire explored symptoms at 1 h, 1, 3 and 7 days postoperatively. RESULTS: There were 301 responses (59%). Following TPSB, 38% initially experienced rectal bleeding, falling significantly to 3% on day 7 (p < 0.001) and it was not a serious condition in all cases. A majority reported haematuria at 1 h but persisting at 1 week in over one quarter (p < 0.001). Nevertheless, although initially often dark, none had other than pale pink by the end of the reporting period. In contrast, the incidence of haematospermia increased over 7 days, rising significantly to 38% by this stage (p < 0.001). Several patients commented that the procedure was more tolerable than their previous conventional TRUS biopsy and 20 (6.6%) with voiding difficulty required catheterisation. In all, 23% patients felt pain, and out of these 23% only 5% required minor analgesia at day 7. CONCLUSION: TPSB under GA without prophylactic catheterisation is well tolerated, carrying acceptable postoperative symptom rates. Interestingly, a significant proportion of patients ejaculate within 7 days, which again suggests good tolerance to the procedure. Patients should be provided with this data preoperatively when they are considering TPSB.

The treatment of penile carcinoma in situ (CIS) within a UK supra-regional network.

OBJECTIVES: To review outcomes of the treatment of carcinoma in situ (CIS) of the penis at a large supra-regional penile cancer network, where centralisation has permitted greater experience with treatment outcomes, and suggest treatment strategies. PATIENTS AND METHODS: The network penile cancer database, which details presentation, treatment and complications was analysed from 2003 to 2010, identifying patients with CIS, with a minimum follow-up of 2 years, looking at treatments administered and outcomes. RESULTS: In all, 57 patients with mean (range) age of 61 (34-91) years were identified. In all, 18 were treated by circumcision only, 20 by circumcision and local excision (LE) and 19 by circumcision and 5-flurouracil (5-FU). The mean (range) follow-up was 3.5 (2-8) years. Of those treated by circumcision none subsequently developed CIS on the glans. For those who underwent circumcision + LE, five of 20 (25%) developed recurrence requiring further treatment. Of those treated by circumcision + 5-FU, 14/19 (73.7%) completely responded. Of the five incomplete responders, two had focal invasive malignancy at repeat biopsy. One incomplete responder underwent glansectomy and four grafting. No complete responders relapsed. Complications of 5-FU included significant inflammatory response in seven (36.8%), with two requiring hospital admission and one neo-phimosis (5.3%). CONCLUSION: This study suggests that patients undergoing circumcision for isolated CIS and complete responders to 5-FU may require only short-term follow-up, as recurrence is unlikely, whereas longer follow up is required for all other patients. However, numbers in this study are small and larger studies are needed to support this. An incomplete response to 5-FU dictates immediate re-biopsy, as it carries a significant chance of previously undetected invasive disease.

Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors.

Bromodomain-containing proteins bind acetylated lysine residues on histone tails and are involved in the recruitment of additional factors that mediate histone modifications and enable transcription. A compound, I-BET-762, that inhibits binding of an acetylated histone peptide to proteins of the bromodomain and extra-terminal domain (BET) family, was previously shown to suppress the production of proinflammatory proteins by macrophages and block acute inflammation in mice. Here, we investigated the effect of short-term treatment with I-BET-762 on T-cell function. Treatment of naïve CD4(+) T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. Gene expression analysis revealed up-regulated expression of several antiinflammatory gene products, including IL-10, Lag3, and Egr2, and down-regulated expression of several proinflammatory cytokines including GM-CSF and IL-17. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-infiltrating T cells. These effects were mimicked by an inhibitor of c-myc function, implicating reduced expression of c-myc and GM-CSF as one avenue by which I-BET-762 suppresses the inflammatory functions of T cells. Our study demonstrates that inhibiting the functions of BET-family proteins during early T-cell differentiation causes long-lasting suppression of the proinflammatory functions of Th1 cells.

Should centralized histopathological review in penile cancer be the global standard?

OBJECTIVE: To assess the role of centralized pathological review in penile cancer management. MATERIALS AND METHODS: Newly diagnosed squamous cell carcinomas (SCC) of the penis, including squamous cell carcinoma in situ (CIS), from biopsy specimens were referred from 15 centres to the regional supra-network multidisciplinary team (Sn-MDT) between 1 January 2008 and 30 March 2011. Biopsy histology reports and slides from the respective referring hospitals were reviewed by the Sn-MDT pathologists. The biopsy specimens' histological type, grade and stage reported by the Sn-MDT pathologist were compared with those given in the referring hospital pathology report, as well as with definitive surgery histology. Any changes in histological diagnosis were sub-divided into critical changes (i.e. those that could alter management) and non-critical changes (i.e. those that would not affect management). RESULTS: A total of 155 cases of squamous cell carcinoma or CIS of the penis were referred from 15 different centres in North-West England. After review by the Sn-MDT, the histological diagnosis was changed in 31% of cases and this difference was statistically significant. A total of 60.4% of the changes were deemed to be critical changes that resulted in a significant change in management. When comparing the biopsy histology reported by the Sn-MDT with the final histology from the definitive surgical specimens, a good correlation was generally found. CONCLUSIONS: In the present study a significant proportion of penile cancer histology reports were revised after review by the Sn-MDT. Many of these changes altered patient management. The present study shows that accurate pathological diagnosis plays a crucial role in determining the correct treatment and maximizing the potential for good clinical outcomes in penile cancer. In the case of histopathology, centralization has increased exposure to penile cancer and thereby increased diagnostic accuracy, and should therefore be considered the 'gold standard'.

Transperineal template-guided saturation biopsy using a modified technique: outcome of 270 cases requiring repeat prostate biopsy.

OBJECTIVES: To determine the incidence of prostate cancer (PCa), and pathological grade and location of PCa, using a modified transperineal template-guided saturation biopsy (TTSB). To compare the acute urinary retention (AUR) rate found using modified TTSB with that of published reports. PATIENTS AND METHODS: A total of 270 consecutive patients with persistent clinical suspicion of PCa, despite a median (range) of 2 (1-6) sets of negative transrectal ultrasonography-guided biopsies, were enrolled and prospectively studied. All underwent modified TTSB avoiding the peri-urethral area at the base of the prostate under general anaesthesia. Statistical analysis was performed using binary logistic regression to determine the prebiopsy predictors of PCa and AUR. RESULTS: The median (range) patient age was 64 (43-85) years, with a median (range) prostate-specific antigen (PSA) of 10 (1-114) ng/mL and median (range) prostate volume of 45 (17-106) mL. A mean (range) of 28 (16-43) cores were taken at modified TTSB. Prostate cancer was diagnosed in 54.8% (Gleason scores 6 in 27.7%, 7 in 43.2%, 8-10 in 29.1% of patients). The anterior third only was involved in 21%, the middle third in 6.8% and the posterior third in 8.7% of positive cases, although in 75% of positive cases there was some anterior involvement. Comparing uniquely anterior tumours with the 15.5% found uniquely in either the middle or posterior thirds, there was no significant difference between number of positive cores (2 vs 1, P = 0.091), maximum percentage core involvement (30 vs 17.5%, P = 0.315) and maximum tumour length (3.5 vs 2 mm, P = 0.092). Fourteen patients (5.2%) developed AUR. On multivariate analysis, PSA density (PSAD) and pre-TTSB PSA predicted PCa diagnosis, whilst prostate volume, prebiopsy PSA and PSAD predicted AUR. CONCLUSIONS: Modified TTSB has a high cancer yield, especially in the anterior region, in patients with previously negative histology but onward suspicion of PCa. The modified TTSB technique provides a low risk of AUR without compromising cancer yield.

A coprological survey of parasites in white-faced capuchins (Cebus capucinus) from Sector Santa Rosa, ACG, Costa Rica.

Neotropical primate parasitology has been dominated by studies of howler monkeys (Alouatta spp.), whereas the literature on the parasites of other platyrrhines is relatively sparse. We analysed the faeces of white-faced capuchins (Cebus capucinus) in a Costa Rican tropical dry forest and recovered 8 parasite taxa (Filariopsis barretoi,Giardia duodenalis, Strongyloides sp., Prosthenorchis sp., a spirurid nematode, a subulurid nematode, a strongylid nematode and a cestode). F. barretoi and Strongyloides sp. were the most prevalent parasites and were recovered from 84 and 76% of the sampled individuals, respectively. Individual capuchins were infected with an average of 1.89 parasite species. Capuchins host a diverse suite of parasites belonging to several taxonomic groups (Nematoda, Cestoda, Acanthocephala, Protozoa) and including species with direct and indirect life cycles. Many capuchin parasites are transmitted through the consumption of invertebrate intermediate hosts making diet a critical component of capuchin-parasite ecology. This study represents the most intensive parasitological survey of wild capuchin monkeys to date.

Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer.

OBJECTIVES: • To evaluate changes in bone mineral density (BMD), body composition, muscle strength and health-related quality of life (HRQL) during bicalutamide (150 mg) monotherapy in osteoporotic patients with non-metastatic locally advanced prostate cancer. Osteoporosis is prevalent in men presenting with prostate cancer and also a common side effect of treatment with luteinizing hormone-releasing hormone agonists, which are associated with decreased BMD and loss of lean body mass and suppress testosterone, unlike bicalutamide, which results in an increase in serum testosterone and oestrogen levels. PATIENTS AND METHODS: • Forty-two men with non-metastatic locally advanced prostate cancer and osteoporosis (T-score ≤-2.5) were treated with bicalutamide (150 mg) monotherapy. BMD was measured at baseline and 1 year. HRQL was assessed 3-monthly using the RAND 36-Item Health Survey and University of California Los Angeles Prostate Cancer Index questionnaires. Bone turnover markers, liver function tests, prostate-specific antigen, testosterone, oestradiol and haemoglobin were measured at baseline, at 3 weeks and 3-monthly thereafter. Arm anthropometry and dynamometry assessed fat mass, skeletal muscle mass and quadriceps strength. RESULTS: • BMD was maintained (+2.1% lumbar spine, +1.2% total hip and +1.1% forearm). Prostate-specific antigen decreased by 88% at 3 months. Testosterone and oestradiol had increased at 1 year by 58% and 42%, respectively. No increase in bone turnover markers was seen over 1 year. Quadriceps muscle strength was maintained. General and prostate cancer-specific HRQL were maintained throughout the study, with no significant reductions in physical or sexual function. Adverse events included breast pain and gynaecomastia. CONCLUSIONS: • Bicalutamide preserves BMD, muscle strength and HRQL in osteoporotic men with non-metastatic locally advanced prostate cancer. It provides an alternative to medical castration for well informed men at high fracture risk and those wishing to retain physical and sexual activity, with luteinizing hormone-releasing hormone agonists being reserved for those failing to respond or relapsing.

Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.

Frequency of zoledronic acid to prevent further bone loss in osteoporotic patients undergoing androgen deprivation therapy for prostate cancer.

OBJECTIVE: To evaluate the efficacy of zoledronic acid (ZA) in osteoporotic patients with prostate cancer receiving either luteinizing hormone-releasing hormone agonists (LHRHA, which accelerate bone loss) or bicalutamide (which preserves bone mineral density, BMD) as androgen-deprivation therapy is the mainstay of treatment for advanced prostate cancer, and many patients are osteoporotic at presentation, with others becoming so on treatment. PATIENTS AND METHODS: Fifty-eight osteoporotic men with non-metastatic prostate cancer were followed for 3 years. Patients were randomly assigned to receive either LHRHA (29) or bicalutamide (29). All received 4 mg ZA 3-monthly for 1 year. BMD was measured by dual energy X-ray absorptiometry at four times: 1 year before ZA; immediately before ZA; after five infusions; and 1 year afterwards. Bone turnover markers (BTMs) were measured at 3-monthly intervals on ZA and 1 year later. All patients had radiography of the thoracolumbar spine at baseline and after ZA. RESULTS: Patients on LHRHA showed a 4.9% decrease in BMD before ZA, a 1.6% increase after ZA and a 3.0% decrease 1 year later, compared to 2.0% increase, 7.8% increase and 1.9% decrease, respectively, in those on bicalutamide. BTMs decreased significantly after ZA. Seven patients (12%) had vertebral fractures at baseline, with none deteriorating at 1 year; two (3.5%) developed mandibular osteonecrosis. CONCLUSION: Before ZA, BMD decreased on LHRHA, but was maintained on bicalutamide. Treatment with 3-monthly ZA increased BMD and suppressed BTMs in osteoporotic patients both on LHRHA and bicalutamide, but to a greater extent in the latter. However, 1 year after the last infusion, BMD declined, suggesting that annual administration is inadequate in these patients. The optimum frequency might be related to BMD at time of bisphosphonate initiation.

Guidance for the assessment and management of prostate cancer treatment-induced bone loss. A consensus position statement from an expert group.

CONTEXT AND OBJECTIVE: Incidence of prostate cancer (PC) is increasing, but androgen deprivation therapy (ADT) and other therapies are substantially improving survival. In this context, careful consideration of skeletal health is required to reduce the risk of treatment-related fragility fractures and their associated morbidity and mortality. This risk is currently not well-managed. ADT causes significant loss of bone mineral density (BMD). In the metastatic setting, systemic treatments (e.g. chemotherapy, abiraterone, enzalutamide) are used alongside ADT and may require concomitant glucocorticoids. Both ADT and glucocorticoids pose significant challenges to skeletal health in a population of patients already likely to have ongoing age-related bone loss and/or comorbid conditions. Current PC guidelines lack specific recommendations for optimising bone health. This guidance presents evidence for assessment and management of bone health in this population, with specific recommendations for clinical practitioners in day-to-day PC management. METHODS: Structured meetings of key opinion leaders were integrated with a systematic literature review. Input and endorsement was sought from patients, nursing representatives and specialist societies. SUMMARY OF GUIDANCE: All men starting or continuing long-term ADT should receive lifestyle advice regarding bone health. Calcium/vitamin D supplementation should be offered if required. Fracture risk should be calculated (using the FRAX® tool), with BMD assessment included where feasible. BMD should always be assessed where fracture risk calculated using FRAX® alone is close to the intervention threshold. Intervention should be provided if indicated by local or national guidelines e.g. UK National Osteoporosis Guideline Group (NOGG) thresholds. Men requiring bone protection therapy should be further assessed (e.g. renal function), with referral to specialist centres if available and offered appropriate treatment to reduce fracture risk. Those near to, but below an intervention threshold, and patients going on to additional systemic therapies (particularly those requiring glucocorticoids), should have FRAX® (including BMD) repeated after 12-18 months. PATIENT SUMMARY: Modern treatments for prostate cancer have led to significant improvements in survival and quality of life. However, some of these treatments may lead to weakening of patient's bones with risk of fracture and it is therefore important to monitor patients' bone health and provide bone protection where needed. This paper provides specific guidance to clinical teams, based on the most recent research evidence, to ensure optimal bone health in their patients.

Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors.

BACKGROUND: Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. METHODS: This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. RESULTS: Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60-100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%-42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3-7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. CONCLUSIONS: Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.

Long-term changes in bone mineral density and predicted fracture risk in patients receiving androgen-deprivation therapy for prostate cancer, with stratification of treatment based on presenting values.

OBJECTIVE: To study the long-term effects of androgen-deprivation therapy (ADT) using luteinizing hormone-releasing hormone (LHRH) agonists or antiandrogen therapy with bicalutamide on bone mineral density (BMD) of selected groups of patients with newly diagnosed advanced prostate cancer, stratified by BMD at presentation and to predict alterations in fracture risk. PATIENTS AND METHODS: In all, 618 men with a mean (sd, range) age of 73 (7.1, 49-94) years, initiating ADT for prostate cancer were prospectively recruited and followed from October 1999 to January 2007. BMD was measured by forearm dual-energy X-ray absorptiometry (DEXA) before ADT and repeated annually. Patients with osteoporosis (T-score < or =-2.5) were commenced on bicalutamide; patients with osteopenia (T-score between -1.0 and -2.5) and normal BMD (T-score > -1.0) were commenced on an LHRH agonist. Patients with osteopenia and osteoporosis received calcium and vitamin D supplements. RESULTS: Over 7 years, 1690 DEXA scans were performed. In all, 41% of patients with newly diagnosed prostate cancer were osteoporotic, 39% were osteopenic and 20% had normal BMD. In the normal group, treated with an LHRH agonist, there were significant decreases in BMD (1 year 1.2%; 2 year 3.7%; 3 year 6.5%; 4 year 8.9%; 5 year 9.9%; 6 year 12.7%), which also occurred in the patients with osteopenia with 60% developing osteoporosis after 2 years (1 year 1.8%; 2 year 5.1%; 3 year 8.0%; 4 year 8.2%; 5 year 11.5%; 6 year 14.1%). By contrast, the osteoporotic group maintained BMD (1 year 0.5%; 2 year 0%; 3 year +1.2%; 4 year 0.5%; 5 year 1.7%; 6 year 2.2%). CONCLUSION: Patients treated with an LHRH agonist have significant and sustained decreases in BMD, whereas bicalutamide maintains BMD. We advocate routine assessment of BMD before ADT, with surveillance thereafter.

Light-fluorous safety-catch arylgermanes - exceptionally robust, photochemically activated precursors for biaryl synthesis by Pd(0) catalysed cross-coupling.

A new class of arylgermane derivative that participate efficiently in Pd(0)-catalysed cross-coupling reactions with aryl bromides following photochemical activation is described.