VHL: Trends and Insight into a Multi-Modality, Interdisciplinary Approach for Management of Central Nervous System Hemangioblastoma.

Von Hippel-Lindau (VHL) is a multi-system disease which results in significant morbidity from central nervous system (CNS) involvement as well as ocular, renal and neuro-endocrine effects. Haemangioblastomas of the CNS present a number of challenges. The natural history of these lesions is varied, as is the size and location within the CNS. Whilst surgery is considered the mainstay of treatment and best chance at curing these lesions, this is also often associated with significant risks due to the anatomical location of these lesions, most commonly the posterior fossa and spinal cord.We review the literature and describe our experience across two separate European VHL referral centres. Alternative treatment options and combined modalities are increasingly being used in the context of managing CNS haemangioblastomas. We analyse the increasing use of stereotactic radiosurgery and the evolution of medical treatments as potential future adjuncts to surgery. The availability of multiple modalities in our armamentarium is essential in tailoring a personalised treatment approach to these patients. Owing to the multi-systemic nature of the disease, in our experience, managing the care of patients with VHL is best delivered using an interdisciplinary approach utilising multiple specialties and adopting an individually tailored holistic approach.

A Systematic Review of the Factors Associated with Post-Traumatic Growth in Parents Following Admission of Their Child to the Intensive Care Unit.

This systematic review aims to identify the demographic, clinical and psychological factors associated with post-traumatic growth (PTG) in parents following their child's admission to the intensive care unit (ICU). Papers published up to September 2021 were identified following a search of electronic databases (PubMed, Medline, Web of Science, PsycINFO, CINAHL, PTSDpubs and EMBASE). Studies were included if they involved a sample of parents whose children were previously admitted to ICU and reported correlational data. 1777 papers were reviewed. Fourteen studies were eligible for inclusion; four were deemed to be of good methodological quality, two were poor, and the remaining eight studies were fair. Factors associated with PTG were identified. Mothers, and parents of older children, experienced greater PTG. Parents who perceived their child's illness as more severe had greater PTG. Strong associations were uncovered between PTG and post-traumatic stress, psychological well-being and coping. PTG is commonly experienced by this population. Psychological factors are more commonly associated with PTG in comparison with demographic and clinical factors, suggesting that parents' subjective ICU experience may be greater associated with PTG than the objective reality.

Doctor-Patient Communication in an Outpatient Setting

Aim To evaluate doctor patient communication within gynaecological oncology services in Ireland. Methods An anonymous and confidential 20 question survey was designed by the patient advocacy group ISGOPPI and distributed in three gynaecological oncology outpatient clinics in tertiary referral centres. Results A total of 84 patients completed the survey in the 3 Dublin hospitals. Doctors surveyed ranged from senior house officer to consultant level. Overall women were very satisfied with the communication they had received from their doctor. 85% felt that they the doctor listened to them and took their opinion into account. 84% of patients felt that the doctor's body language was appropriate throughout the consultation. One of the main issues for women surveyed was waiting times. 33% of women waited over an hour to see their doctor and over 30% of women did not receive contact details of the clinical nurse specialist. Conclusion Overall our study shows that patients in gynae-oncology clinics are satisfied with the communication from their doctors. The main issues for patients were waiting times and contact details for follow up questions.

Triage of LSIL/ASC-US with p16/Ki-67 dual staining and human papillomavirus testing: a 2-year prospective study.

OBJECTIVE: To investigate human papillomavirus (HPV) DNA testing and p16/Ki-67 staining for detecting cervical intraepithelial grade 2 or worse (CIN2+) and CIN3 in women referred to colposcopy with minor abnormal cervical cytology low-grade squamous intraepithelial lesions (LSIL) and atypical squamous cells of undermined significance (ASC-US). The clinical performance of both tests was evaluated as stand-alone tests and combined, for detection CIN2+ and CIN3 over 2 years. METHODS: ThinPrep(®) liquid-based cytology (LBC) specimens were collected from 1349 women with repeat LSIL or ASC-US. HPV DNA was performed using Hybrid Capture. Where adequate material remained (n = 471), p16/Ki-67 overexpression was assessed. Clinical performance for detection of histologically diagnosed CIN2+ and CIN3 was calculated. RESULTS: Approximately 62.2% of the population were positive for HPV DNA, and 30.4% were positive for p16/Ki-67. p16/Ki-67 showed no significant difference in positivity between LSIL and ASC-US referrals (34.3% versus 28.6%; P = 0.189). Women under 30 years had a higher rate of p16/Ki-67 compared to those over 30 years (36.0% versus 26.6%; P = 0.029). Overall HPV DNA testing produced a high sensitivity for detection of CIN3 of 95.8% compared to 79.2% for p16/Ki-67. In contrast, p16/Ki-67 expression offered a higher specificity, 75.2% versus 40.4% for detection of CIN3. Combining p16/Ki-67 with HPV DNA improved the accuracy in distinguishing between CIN3 and

Family communication in the context of pediatric epilepsy: A systematic review.

In childhood chronic illness, family communication can impact the child's and parents' psychosocial well-being. However, little is known about family communication in the context of epilepsy in childhood. The aim of this systematic review was to identify the existing evidence available on communication strategies adopted by families living with childhood epilepsy, including; the facilitators, barriers and challenges experienced by families when choosing to communicate, or not, about epilepsy; and the consequences of this communication. Papers published in the English language prior to March 2015 were identified following a search of six electronic databases: PubMed, MEDLINE, Web of Science, PsycINFO, CINAHL, and Scopus. Studies were included if they involved a sample of parents of children with epilepsy or children/young people with epilepsy (0-18years of age) and used qualitative, quantitative, or mixed methods. Following a comprehensive search and screening process, 26 studies were identified as eligible for inclusion in the review. No studies identified specific communication strategies adopted by families living with childhood epilepsy. Some studies found that talking about epilepsy with family members had positive consequences (e.g., communication as an effective coping strategy), with no negative consequences reported in any of the studies. The main barrier to communication for parents was an unwillingness to use the word "epilepsy" because of the perceived negative social connotations associated with the health condition. For children with epilepsy, barriers were as follows: parental desire to keep epilepsy a secret, parents' tendency to deny that the child had epilepsy, parental overprotection, and parents' tendency to impose greater restrictions on the child with epilepsy than on siblings without epilepsy. Future research investigating the communication strategies of families living with epilepsy is needed in order to create effective communication-based interventions for discussing epilepsy within the home.

To tell or not to tell: A systematic review of the disclosure practices of children living with epilepsy and their parents.

Disclosing an epilepsy diagnosis to others is complex due to the condition's largely invisible nature and associated stigma. Despite this, little has been documented in terms of what this process involves for children living with epilepsy (CWE) and their parents. A systematic review was conducted to examine and synthesize evidence pertaining to: (i) the disclosure practices of CWE and their parents, (ii) enablers and barriers for disclosure, (iii) the impact of disclosure practices, and (iv) the relationship between disclosure management and other variables. The electronic databases PsycINFO, PubMed, MEDLINE, CINAHL, Scopus, and Web of Science were searched systematically. Any empirical, peer-reviewed journal articles with findings reported regarding the self- or proxy-reported disclosure practices of children aged 0-18years with any type of epilepsy and/or their parents were deemed eligible for inclusion. Two review authors completed all stages of screening, data extraction, and quality assessment independently with two additional review authors resolving any discrepancies. A total of 32 articles were included in the review. Only one dated study examined disclosure as a primary focus; in the remaining studies, disclosure was a subfocus of larger studies or pertinent qualitative themes/subthemes incidentally emerged. The limited evidence suggests that: 1) CWE and parents adopt varying disclosure management strategies - from concealment to voluntary disclosure; 2) disclosure decisions are challenging for CWE and parents; 3) many barriers to disclosure exist (e.g., fear of stigmatization and rejection); 4) only a limited number of factors that enable disclosure are known (e.g., openness by others to engage with and learn about epilepsy); 5) disclosure management is significantly related to a number of variables (e.g., child/maternal perceived stigma and seizure control); and 6) there are varying outcomes for CWE and/or their parents in accordance with the adoption of specific disclosure management strategies (e.g., disclosure resulting in greater acceptance and the receipt of support or evoking anxiety/fear in others; and concealment resulting in misunderstandings, embarrassment, and stigma-coaching), but the evidence remains inconclusive in terms of which disclosure management strategy is optimal. While some preliminary work has been conducted, disclosure of epilepsy is a topic that has been largely neglected to date. This is despite the fact that disclosure is a significant source of concern for CWE and parent populations. Future studies should focus on elucidating the unique contextual factors that inform disclosure decisions in order to develop a theoretical framework that can explain the epilepsy disclosure decision-making process.

Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma.

BACKGROUND: The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy. METHODS: Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status. RESULTS: In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35-37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAF(V600K/R) versus BRAF(V600E) melanoma in univariate and multivariate analyses. CONCLUSIONS: BRAF and NRAS mutation status does not influence survival in metastatic melanoma.

Progression of KRAS mutant pancreatic adenocarcinoma during vemurafenib treatment in a patient with metastatic melanoma.

Vemurafenib is a tyrosine kinase inhibitor of BRAF that prolongs survival in patients with BRAF V600-mutant metastatic melanoma. Secondary cutaneous malignancies are a well-documented toxicity of vemurafenib, thought to be mediated by enhanced ERK signalling in BRAF wild-type, RAS-mutant cells. Vemurafenib could also promote growth of non-cutaneous secondary malignancies by a similar mechanism. We present a case of an individual who received vemurafenib for metastatic melanoma and experienced rapid growth of a pre-existing KRAS-mutant pancreatic adenocarcinoma.

The subsurface lesion in erosive tooth wear.

OBJECTIVES: This study compared the surface change on natural and polished enamel exposed to a joint mechanical and chemical wear regimen. METHODS: Human enamel samples were randomly assigned to natural (n = 30) or polished (n = 30) groups, subjected to erosion (n = 10, 0.3% citric acid, 5 min), abrasion (n = 10, 30 s), or a combination (n = 10). Wear in the form of step height was measured with a non-contact profilometer, and surface changes were inspected with SEM on selected sections. Data was normalised and underwent repeated measures MANOVA, accounting for substrate and erosive challenge as independent variables, with Bonferroni correction for significant post hoc interactions. RESULTS: After four cycles, polished samples had mean step heights of 3.08 (0.40) µm after erosion and 4.08 (0.37) µm after erosion/abrasion. For natural samples, these measurements were 1.52 (0.22) µm and 3.62 (0.39) µm, respectively. Natural surfaces displayed less wear than polished surfaces under erosion-only conditions (p<0.0001), but the difference disappeared with added abrasion. SEM revealed a shallow subsurface layer for polished surfaces and natural ones undergoing only erosion. However, natural surfaces exposed to both erosion and abrasion showed deeper subsurface changes up to 50 µm. CONCLUSION: Natural enamel, when exposed to erosion alone, showed less wear and minimal subsurface alterations. But with added abrasion, natural enamel surfaces saw increased wear and notable subsurface changes compared to polished ones. CLINICAL SIGNIFICANCE: The pronounced subsurface lesions observed on eroded/abraded natural enamel surfaces highlight how combined wear challenges may accelerate tooth tissue loss.

CTC-5: A novel digital pathology approach to characterise circulating tumour cell biodiversity.

Metastatic progression and tumor evolution complicates the clinical management of cancer patients. Circulating tumor cell (CTC) characterization is a growing discipline that aims to elucidate tumor metastasis and evolution processes. CTCs offer the clinical potential to monitor cancer patients for therapy response, disease relapse, and screen 'at risk' groups for the onset of malignancy. However, such clinical utility is currently limited to breast, prostate, and colorectal cancer patients. Further understanding of the basic CTC biology of other malignancies is required to progress them towards clinical utility. Unfortunately, such basic clinical research is often limited by restrictive characterization methods and high-cost barrier to entry for CTC isolation and imaging infrastructure. As experimental clinical results on applications of CTC are accumulating, it is becoming clear that a two-tier system of CTC isolation and characterization is required. The first tier is to facilitate basic research into CTC characterization. This basic research then informs a second tier specialised in clinical prognostic and diagnostic testing. This study presented in this manuscript describes the development and application of a low-cost, CTC isolation and characterization pipeline; CTC-5. This approach uses an established 'isolation by size' approach (ScreenCell Cyto) and combines histochemical morphology stains and multiparametric immunofluorescence on the same isolated CTCs. This enables capture and characterization of CTCs independent of biomarker-based pre-selection and accommodates both single CTCs and clusters of CTCs. Additionally, the developed open-source software is provided to facilitate the synchronization of microscopy data from multiple sources (https://github.com/CTC5/). This enables high parameter histochemical and immunofluorescent analysis of CTCs with existing microscopy infrastructure without investment in CTC specific imaging hardware. Our approach confirmed by the number of successful tests represents a potential major advance towards highly accessible low-cost technology aiming at the basic research tier of CTC isolation and characterization. The biomarker independent approach facilitates closing the gap between malignancies with poorly, and well-defined CTC phenotypes. As is currently the case for some of the most commonly occurring breast, prostate and colorectal cancers, such advances will ultimately benefit the patient, as early detection of relapse or onset of malignancy strongly correlates with their prognosis.

Laparoscopy versus ultrasonography for the evaluation of Mullerian structures in children with complex disorders of sex development.

PURPOSE: The diagnosis of children with disorders of sex development (DSD) requires a karyotype, different biochemical and radiological investigations in the context of a multidisciplinary team. The aim of this study was to compare the diagnostic accuracy of laparoscopy (L) versus ultrasonography (US) in the assessment of children with complex DSD. METHODS: We retrospectively examined the theatre database searching for children with DSD who underwent laparoscopic surgery from 1999 to 2011. The medical and radiological records were reviewed. RESULTS: Eighteen patients were identified. Age at diagnosis ranged from birth to 14 years (mean 2.5 years). There were seven patients with 46XY dysgenetic testicular DSD (4 mosaic Turner, 3 mixed gonadal dysgenesis), seven patients with 46XY non-dysgenetic testicular DSD (4 persistent Mullerian duct syndrome, 2 complete androgen insensitivity syndrome, one unknown), two patients with ovotesticular DSD, one patient with 46XX DSD (congenital adrenal hyperplasia) and one patient with 46XY DSD complete sex reversal. Fifteen underwent ultrasonography prior to laparoscopy. Both modalities identified Mullerian structures in seven (47 %) patients, in one (7 %) patient US and L confirmed the absence of Mullerian structures, while in six (40 %) patients there was discordance, with US failing to visualize pelvic Mullerian structures. In the last patient with 46XY non-dysgenetic testicular DSD, the rectum was thought to be a dilated uterus on ultrasonography. CONCLUSIONS: Pelvic ultrasonography failed to identify Mullerian structures in 40 % of patients with complex DSD. On the contrary, laparoscopy allowed excellent visualization of pelvic structures and gonads in children with complex DSD.

The interplay of saliva, erosion and attrition on enamel and dentine.

Purpose: This investigation aimed to compare the protective role of saliva against erosion and attrition challenges. Method: Polished enamel and dentine samples (n = 160) were prepared and randomly assigned to either the saliva or saliva-free group (n = 40 enamel and n = 40 dentine/group). Within each subgroup, they were allocated to four subgroups: negative control (deionized water exposure 10 min), erosion (0.3% citric acid 10 min), attrition (120 S of 300 g force), or combined erosion/attrition (0.3% citric acid 10 min then 120 S of 300 g force). Experimental cycles were repeated three times. Data analysis was performed using SPSS. Results: The mean and standard deviation (SD) of step heights produced by the attrition and erosion/attrition groups in enamel in the saliva-free group were 5.6 µm (2.4) and 13.4 µm (2.8), respectively, while they were 2.4 µm (3.8) and 12.9 µm (3.5) in the saliva group, with no significant difference between the saliva and saliva-free groups. For dentine, the corresponding step heights were 25.2 µm (5.5) and 35.9 µm (7.9) for the saliva-free group, but 21.8 µm (5.3) and 27.3 µm (6.4) for the saliva group (p < 0.001). Conclusion: There was a trend that saliva decreased wear, but this was only statistically significant for erosion/attrition dentine wear.

The early wear susceptibility of cementum, enamel and dentine in vitro.

OBJECTIVES: To assess the differential early wear susceptibility of cementum, enamel and dentine at a micron level. METHODS: Whole human molar buccal surfaces incorporating natural enamel and cementum (n = 20) confirmed by imaging (digital microscopy: Keyence, VHX-7000 Milton Keynes, UK), were mounted, scanned (profilometry: XYRIS 4000, Taicaan, Southampton, UK), and allocated to receive erosion (citric acid, pH 2.7, 30 min (n = 10)) or erosion/abrasion challenges (3 cycles of (citric acid, pH 2.7, 10 min, 60 300 g linear abrasion strokes), n=10). Samples were polished and the experiment repeated on polished enamel, and polished coronal and radicular dentine within the same tooth. Profilometric wear data were obtained using superimposition: GeoMagic (3Dsystems, Darmstadt, Germany) and subtraction: MountainsMap (DigitalSurf, Besancon, France). Data were normal. A general linear model was used to assess differences between groups and substrates. RESULTS: The mean step height (SD) for natural enamel was 8.82 µm (2.53) for erosion and 11.48 µm (2.95) for erosion/abrasion. For natural cementum, the mean step height was 6.00 µm (2.29) for erosion and 4.67 µm (1.58) for erosion/abrasion. Dentine step heights ranged from 7.20 µm (1.53) for erosion and 9.79 µm (1.01) for erosion/abrasion with no statistical differences in dentine wear. Natural cementum surfaces had the lowest wear (p<0.001). Dentine had significantly less wear than natural enamel (p<0.02). CONCLUSIONS: Cementum surfaces demonstrated the most wear resistance, followed by dentine under erosion dominant conditions in this in vitro study. Further in-vivo investigations are needed to confirm the intraoral stability of cementum. CLINICAL SIGNIFICANCE: Cementum may be the least susceptible of dental substrates to wear and dentine does not wear at a faster rate than enamel under erosive conditions. This adds to our knowledge on the development of non-carious cervical lesions and questions whether wear rates will accelerate once dentine is exposed.

Prediction of outcome of early ER+ breast cancer is improved using a biomarker panel, which includes Ki-67 and p53.

BACKGROUND: The aim of this study is to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 improves prognostication of oestrogen receptor-positive (ER+) breast cancer after breast-conserving therapy (BCT). In all, 498 patients with invasive breast cancer from a randomised trial of BCT with or without tumour bed radiation boost were assessed using IHC. METHODS: The ER+ tumours were classified as 'luminal A' (LA): ER+ and/or PR+, Ki-67 low, p53-, HER2- or 'luminal B' (LB): ER+ and/or PR+and/or Ki-67 high and/or p53+ and/or HER2+. Kaplan-Meier and Cox proportional hazards methodology were used to ascertain relationships to ispilateral breast tumour recurrence (IBTR), locoregional recurrence (LRR), distant metastasis-free survival (DMFS) and breast cancer-specific survival (BCSS). RESULTS: In all, 73 patients previously LA were re-classified as LB: a greater than four-fold increase (4.6-19.3%) compared with ER, PR, HER2 alone. In multivariate analysis, the LB signature independently predicted LRR (hazard ratio (HR) 3.612, 95% CI 1.555-8.340, P=0.003), DMFS (HR 3.023, 95% CI 1.501-6.087, P=0.002) and BCSS (HR 3.617, 95% CI 1.629-8.031, P=0.002) but not IBTR. CONCLUSION: The prognostic evaluation of ER+ breast cancer is improved using a marker panel, which includes Ki-67 and p53. This may help better define a group of poor prognosis ER+ patients with a greater probability of failure with endocrine therapy.

Extended thromboprophylaxis post gynaecological cancer surgery; the effect of weight adjusted and fixed dose LMWH (Tinzaparin).

OBJECTIVE: Gynaecological cancer surgery is associated with high rates of venous thromboembolism (VTE) despite recommended prophylaxis. We sought to investigate the impact of extended prophylaxis with fixed dose and weight based LMWH in patients undergoing gynaecological cancer surgery. METHODS: VTE rates were recorded in patients who received LMWH prophylaxis (4500 IU Tinzaparin once daily) for the duration of hospital stay (2006-2012) (n = 610) and were compared with VTE rates in patients who underwent surgery after the introduction of extended prophylaxis (3500/4500 IU Tinzaparin for patients with BMI < 40kg/m2 and 75 IU/kg for BMI > 40 kg/m2) (2012-2017) (n = 651). Peak (4 h) anti-Xa levels in a subset of patients were also evaluated. RESULTS: 73 (5.7%) cases of VTE were recorded during 1 year of follow-up. 20 cases occurred during hospital stay. There was no significant difference in the rate of VTE between the extended prophylaxis cohort and the standard prophylaxis cohort. 23/24 patients who developed VTE in the extended prophylaxis cohort received a fixed (4500 units) dose of Tinzaparin. 63% of patients who received a fixed LMWH dose had peak anti-Xa levels below the target range (0.2-0.4 IU/ml). Peak anti-Xa was lower in patients who subsequently developed VTE compared with those who received either fixed dose (P = 0.041) and weight adjusted Tinzaparin (P = 0.0006). CONCLUSIONS: Extended prophylaxis with Tinzaparin does not significantly reduce VTE rates in gynaecological cancer patients post surgery. Peak anti-Xa levels may be suboptimal in many patients receiving a fixed LMWH dose. Further studies are required to determine whether weight adjusted doses of Tinzaparin may provide more effective prophylaxis following gynaecological cancer surgery.

The concordance between serum anti-Mullerian hormone and testosterone concentrations depends on duration of hCG stimulation in boys undergoing investigation of gonadal function.

BACKGROUND: In boys undergoing investigation of gonadal function, the relationship between a single measurement of serum anti-Mullerian hormone (AMH) and hCG stimulated serum testosterone is unclear. AIM: The aim of the study was to assess concordance between serum AMH and testosterone concentrations following hCG stimulation of two different durations. METHODS: Samples from 284 children (M : F, 154 : 130) with a median age of 8 years (10th, 90th centiles, 0.25, 14) were used to establish an AMH reference range. Clinical data were reviewed in boys undergoing investigation of gonadal function and who had an AMH measurement and a hCG stimulated (3-day or 3-week) (n = 26) testosterone. Of these 26 boys, 11 had combined genital anomalies, whereas the rest had conditions such as isolated hypospadias, undescended testes or microphallus. Normal testosterone response to hCG stimulation was defined as a level greater than 3.5 nmol at day 4 and 9.5 nmol/l at day 22. RESULTS: In the reference group, the 5th centile AMH for boys below 1 year was 215 pmol/l and between 1 and 8 years 180 pmol/l. The 95th centile for girls for these respective age groups was 30 pmol/l and 25 pmol/l. In those cases where serum testosterone concentrations were available at day 1, day 4 and day 22 of the 3 week-hCG test, five cases had a normal serum testosterone at day 4 and three cases only showed such a response by day 22. In those where serum AMH was less than 180 pmol/l, a poor testosterone response of less than 3.5 nmol was observed in approximately seven of eight (88%) cases with a 3-day hCG stimulation test or the 3-week test. An AMH of greater than 180 pmol/l was associated with a normal testosterone response at day 4 in 10 out of 15 (67%) cases and at day 22 in eight of 11 (73%) cases. However, a low serum testosterone concentration of less than 3.5 nmol after the 3-day hCG test was only associated with a likelihood of a low AMH in three of eight (37%) cases. With the 3-week hCG test, a low day 22 testosterone of 9.5 mmol/l or less was associated with a low AMH of 180 pmol/l or less in four of seven (57%) cases. CONCLUSION: In boys undergoing investigation of gonadal function, the concordance between AMH and testosterone is better at day 22 than day 4. A normal AMH may provide useful information on overall testicular function but does not exclude the need for an hCG stimulation test.

The routine use of a flumazenil infusion following percutaneous endoscopic gastrostomy placement to reduce early post-procedure mortality.

OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) insertion offers secure enteral nutrition, but there is a significant mortality associated with the procedure. We reviewed our sedation practice and the effect of yearly protocol changes to establish if the routine reversal of midazolam with a flumazenil infusion improved mortality. METHODS: Since 2003 yearly protocol changes have been introduced, including pre-assessment and sedation reversal. We retrospectively audited one-week and one-month mortality and aspiration rates. RESULTS: The average one-week mortality rate was 9.2%. The pooled death rates within the first week for patients prior to routine sedation reversal (n=522) was 10.7% and for patients who received routine reversal (n=144) was 5.4% (p=0.087). Within the first month, death rates were 26.3% prior to reversal and 21.4% in the sedation reversal group (p=0.30). CONCLUSIONS: The routine use of flumazenil infusion in appropriate patients is safe. Flumazenil infusion may have a role to play in selected patients at highest risk of aspiration. A prospective, randomised study is warranted.

A multiplanet system of super-Earths orbiting the brightest red dwarf star GJ 887.

The closet exoplanets to the Sun provide opportunities for detailed characterization of planets outside the Solar System. We report the discovery, using radial velocity measurements, of a compact multiplanet system of super-Earth exoplanets orbiting the nearby red dwarf star GJ 887. The two planets have orbital periods of 9.3 and 21.8 days. Assuming an Earth-like albedo, the equilibrium temperature of the 21.8-day planet is ~350 kelvin. The planets are interior to, but close to the inner edge of, the liquid-water habitable zone. We also detect an unconfirmed signal with a period of ~50 days, which could correspond to a third super-Earth in a more temperate orbit. Our observations show that GJ 887 has photometric variability below 500 parts per million, which is unusually quiet for a red dwarf.

BAG-1 predicts patient outcome and tamoxifen responsiveness in ER-positive invasive ductal carcinoma of the breast.

BAG-1 (bcl-2-associated athanogene) enhances oestrogen receptor (ER) function and may influence outcome and response to endocrine therapy in breast cancer. We determined relationships between BAG-1 expression, molecular phenotype, response to tamoxifen therapy and outcome in a cohort of breast cancer patients and its influence on tamoxifen sensitivity in MCF-7 breast cancer cells in vitro. Publically available gene expression data sets were analysed to identify relationships between BAG-1 mRNA expression and patient outcome. BAG-1 protein expression was assessed using immunohistochemistry in 292 patients with invasive ductal carcinoma and correlated with clinicopathological variables, therapeutic response and disease outcome. BAG-1-overexpressing MCF-7 cells were treated with antioestrogens to assess its effects on cell proliferation. Gene expression data demonstrated a consistent association between high BAG-1 mRNA and improved survival. In ER+ cancer (n=189), a high nuclear BAG-1 expression independently predicted improved outcome for local recurrence (P=0.0464), distant metastases (P=0.0435), death from breast cancer (P=0.009, hazards ratio 0.29, 95% CI: 0.114-0.735) and improved outcome in tamoxifen-treated patients (n=107; P=0.0191). BAG-1 overexpression in MCF-7 cells augmented antioestrogen-induced growth arrest. A high BAG-1 expression predicts improved patient outcome in ER+ breast carcinoma. This may reflect both a better definition of the hormone-responsive phenotype and a concurrent increased sensitivity to tamoxifen.