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Genomic studies have demonstrated a high level of intra-tumoral heterogeneity in prostate cancer. There is strong evidence suggesting that individual tumor foci can arise as genetically distinct, clonally independent lesions. However, recent studies have also demonstrated that adjacent Gleason pattern (GP) 3 and GP4 lesions can originate from the same clone but follow divergent genetic and morphologic evolution. The clonal relationship of adjacent GP3 and GP5 lesions has thus far not been investigated. Here we analyzed a cohort of 14 cases-11 biopsy and 3 radical prostatectomy specimens-with a Gleason score of 3 + 5 = 8 or 5 + 3 = 8 present in the same biopsy or in a single dominant tumor nodule at radical prostatectomy. Clonal and subclonal relationships between GP3 and GP5 lesions were assessed using genetically validated immunohistochemical assays for ERG, PTEN, and P53. 9/14 (64%) cases showed ERG reactivity in both GP3 and GP5 lesions. Only 1/14 (7%) cases showed a discordant pattern with ERG staining present only in GP3. PTEN expression was lost in 2/14 (14%) cases with perfect concordance between GP5 and GP3. P53 nuclear reactivity was present in 1/14 (7%) case in both GP5 and GP3. This study provides first evidence that the majority of adjacent GP3 and GP5 lesions share driver alterations and are clonally related. In addition, we observed a lower-than-expected rate of PTEN loss in GP5 in the context of Gleason score 3 + 5 = 8 or 5 + 3 = 8 tumors.

Background: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. Methods: an automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression. Conclusions: the current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression. Lay Summary: B7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials., National Institutes of Health; National Cancer Institute Prostate Specialized Centers Research Excellence; Congressionally Directed Medical Research Programs Prostate Cancer Research Program (CDMRP- PCRP) Health Disparity Research Awards; Young Investigator Award and Congressionally Directed Medical Research Programs

The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median = 27) than those with germline ATM or CHEK2 mutations (median = 16.5 [p = 0.029] and 9 [p

Objective To compare the safety and efficacy of 10% sinecatechins (Veregen® ) ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). Design A Phase II double-blind randomised control trial. Setting A tertiary gynaecological oncology referral centre. Population All women diagnosed with primary and recurrent uVIN. Methods Eligible patients were randomised 1:1 to receive either sinecatechins or placebo ointment (applied three times daily for 16 weeks) and were followed up at 2, 4, 8, 16, 32 and 52 weeks. Main outcome measures The primary outcome measure, recorded at 16 and 32 weeks, was histological response (HR). Secondary outcome measures included clinical (CR) response, toxicity, quality of life and pain scores. Results There was no observed difference in HR between the two arms. However, of the 26 patients who were randomised, all 13 patients who received sinecatechins showed either complete (n = 5) or partial (n = 8) CR, when best CR was evaluated. In placebo group, three patients had complete CR, two had partial CR, six had stable disease and two were lost to follow up. Patients in the sinecatechins group showed a statistically significant improvement in best observed CR as compared with the placebo group (P = 0.002). There was no difference in toxicity reported in either group. Conclusion Although we did not observe a difference in HR between the two treatment arms, we found that 10% sinecatechins application is safe and shows promise in inducing clinical resolution of uVIN lesions and symptom improvement, thus warranting further investigation in a larger multicentre study. Tweetable abstract A randomised control study indicating that sinecatechins ointment may be a novel treatment for uVIN.

AIMS Prostatic intraepithelial neoplasia-like (PIN-like) ductal carcinoma is a rare tumour characterised by often cystically dilated glands architecturally resembling high-grade PIN, but lacking basal cells. These tumours are frequently accompanied by grade group 1 acinar cancer and behave relatively indolently. In contrast, conventional ductal adenocarcinoma of the prostate is an aggressive variant comparable to grade group 4 acinar cancer. Here, we used targeted next-generation sequencing to molecularly profile PIN-like ductal carcinoma cases at radical prostatectomy. METHODS AND RESULTS Five PIN-like ductal carcinoma samples at radical prostatectomy with sufficient tumour tissue available were analysed for genomic alterations by targeted next-generation sequencing using the Johns Hopkins University (JHU) solid tumour panel. DNA was captured using SureSelect for 640 genes and sequenced on the Illumina HiSeq platform. Three of five (60%) of the PIN-like ductal carcinomas showed activating mutations in the RAS/RAF pathways, which are extraordinarily rare in conventional primary prostate carcinoma (

BACKGROUND Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P

BACKGROUND: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear. METHODS: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival. RESULTS: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery. CONCLUSIONS: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).

Pathogenic mutations in homologous recombination (HR) DNA repair genes may be associated with increased tumor mutational burden and numbers of tumor-infiltrating lymphocytes (TIL). Though HR-deficient prostate tumors have been anecdotally associated with improved responses to immunotherapy, it is unclear whether HR mutations or HR deficiency (HRD) scores predict for increased T-cell densities in this cancer. We evaluated 17 primary prostate tumors from patients with pathogenic germline BRCA2 mutations (gBRCA2) and 21 primary prostate tumors from patients with pathogenic germline ATM (gATM) mutations, which were compared to 19 control tumors lacking HR gene mutations, as well as the TCGA prostate cancer cohort. HRD score was estimated by targeted sequencing (gBRCA2 and gATM) or by SNP microarray (TCGA). Tumor-associated T-cell densities were assessed using validated automated digital image analysis of CD8 and FOXP3 immunostaining (gBRCA2 or gATM) or by methylCIBERSORT (TCGA). CD8 + and FOXP3 + T-cell densities were significantly correlated with each other in gBRCA2 and gATM cases. There was no significant difference between CD8 + or FOXP3 + TIL densities in gBRCA2 or gATM cases compared to controls. In the TCGA cohort, HRD score was associated with predicted CD8 + and FOXP3 + TILs. Associations were also seen for HRD score and TIL density among the germline-mutated cases. In contrast to mismatch repair-deficient primary prostate tumors, cancers from germline BRCA2 or ATM mutation carriers do not appear to be associated with elevated TIL density. However, measures of genomic scarring, such as HRD score, may be associated with increased tumor-infiltrating T-cells.

Summary The makeup of the tumor immune microenvironment may be associated with tumor somatic genomic alterations and plays a key role in tumor progression and response to immunotherapy. We examined the association of tumor-infiltrating T-cell density with TP53 status in surgically treated primary prostate cancer using 3 independent tissue microarray sets, including one set of tumors from grade-matched patients of European American or African American ancestry (n = 391), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and a set of tumors with primary Gleason pattern 5 (n = 77). The presence of TP53 missense mutation, indicated by p53 nuclear accumulation using a genetically validated assay, was significantly associated with increased CD3+ T-cell density (median, 341 versus 231 CD3+ T cells/mm2; P = .004) in the matched European American and African American ancestry patient sets. The same association was present in patients of both ancestries when analyzed separately, despite the fact that p53 nuclear accumulation was less frequent among African American compared with European American tumors (7% versus 3%, P = .2). The validation cohorts of intermediate/high-risk and primary Gleason pattern 5 patients corroborated the association of increased CD3+ T-cell density with presence of p53 nuclear accumulation. In a pooled analysis of all sets, adjusting for clinicopathological variables, CD3+ and CD8+, but not FOXP3+, T-cell densities remained significantly higher in tumors with p53 nuclear accumulation compared with those without. TP53 mutation is associated with higher tumor-infiltrating T-cell density, which may be relevant in future clinical trials of immunotherapy in prostate cancer.

Aims Prostatic adenocarcinomas with focal pleomorphic giant-cell features constitute a rare tumour subtype with abysmal clinical outcomes. More than one-third of patients with this histology die within a year of the initial diagnosis of prostate cancer. We aimed to perform molecular profiling of these tumors to identify potential therapeutic targets. Methods and results Here, we performed next-generation sequencing with a highly validated targeted panel (UW-OncoPlex) on somatic tumour DNA extracted from eight cases of prostatic adenocarcinoma with focal pleomorphic giant-cell features, including cases with and without prior treatment for prostate cancer. We found that DNA damage repair mutations are common in this rare subset of prostate tumours, with two of eight having bi-allelic pathogenic mutations in homologous DNA repair genes (including BRCA2 and NBN) and two of eight having bi-allelic pathogenic mutations in mismatch repair genes (including MSH2 and MLH1). Conclusion These data are consistent with emerging data showing that DNA repair alterations are enriched among castration-resistant prostate cancer and aggressive subsets of primary tumours. Given that these patients are potential candidates for poly(ADP-ribose) polymerase inhibitor and/or immune checkpoint blockade, and have a poor prognosis with standard therapy, we recommend that tumour and germline DNA sequencing with or without mismatch repair protein immunohistochemistry be considered for all prostatic adenocarcinomas with focal pleomorphic giant-cell features.

Objectives As we move toward human papillomavirus (HPV) only as the preferred cervical cancer screening method, we performed a retrospective analysis of Black and White women with negative cytology (Papanicolaou negative [PAPneg]) and positive high-risk HPV (hrHPV) (HPVpos) results and determined follow-up. Methods We searched our pathology data system for patients with PAPneg/HPVpos results (2017-2019). Follow-up data were reviewed (39 months), and a comparison among race was performed. Results In total, 1,728 patients were identified (Black, 53%; White, 47%). Twenty-nine percent of the patients had no follow-up with no difference among the races. HPV 16 was more common among Whites (P Conclusions Follow-up of women with PAPneg/HPVpos remains a challenge. There was no disparity in follow-up when cohorts were compared. However, Black women had higher numbers of high-grade intraepithelial lesions on endocervical curettage.

The quality of information and efficiency in the practice and care environments are important aspects of nursing care. The use of a reliable and valid scale can monitor the quality of handover and provide information for continuous improvement of practice. This study aims to describe the perception of nurses, on the domains of quality of information, efficiency, interaction and support and patient involvement.A cross-sectional descriptive study was conducted among 450 nurses from 37 wards in Hospital Kuala Lumpur. Nurses on shift duty were recruited by convenience sampling from the Medical, Surgery, ObstetricsGynaecology, Orthopaedic and Paediatric wards. Using a validated questionnaire (Handover Evaluation Scale), nurses self-rated their perceptions using a 7-point scale and provided open-ended responses to the strengths and challenges that they faced. Descriptive and inferential analyses were done while open-ended questions were summarised based on key themes.A total of 414 nurses completed the survey (92.0% response rate). Nurses had an overall mean (SD) perception score of 5.01 (SD 0.56). They perceived good interaction and support during handover and on the quality of information that they received, with mean scores of 5.54 (SD 0.79) and 5.19 (SD 0.69), respectively. There was an association between the departments where the nurses worked and their overall perceptions on nursing handover (p0.001). Interruptions being the most common theme emerged from the open-ended section.Despite having substantial interaction and support amongst nurses, opportunities for improvements were noted. Improvements in the quality of handover information and reducing interruptions should be the main emphases as these were perceived to be essential in the current handover practices by nurses.

Background Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense neoadjuvant androgen deprivation therapy (NADT) have shown lower rates of recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known. Objective To identify genomic and histologic features associated with treatment resistance at baseline. Design, setting, and participants Targeted biopsies were obtained from 37 men with intermediate- to high-risk prostate cancer before receiving 6 mo of ADT plus enzalutamide. Biopsy tissues were used for whole-exome sequencing and immunohistochemistry (IHC). Outcome measurements and statistical analysis We assessed the relationship of molecular features with final pathologic response using a cutpoint of 0.05 cm3 for residual cancer burden to compare exceptional responders to incomplete and nonresponders. We assessed intratumoral heterogeneity at the tissue and genomic level, and compared the volume of residual disease to the Shannon diversity index for each tumor. We generated multivariate models of resistance based on three molecular features and one histologic feature, with and without multiparametric magnetic resonance imaging estimates of baseline tumor volume. Results and limitations Loss of chromosome 10q (containing PTEN) and alterations to TP53 were predictive of poor response, as were the expression of nuclear ERG on IHC and the presence of intraductal carcinoma of the prostate. Patients with incompletely and nonresponding tumors harbored greater tumor diversity as estimated via phylogenetic tree reconstruction from DNA sequencing and analysis of IHC staining. Our four-factor binary model (area under the receiver operating characteristic curve [AUC] 0.89) to predict poor response correlated with greater diversity in our cohort and a validation cohort of 57 Gleason score 8–10 prostate cancers from The Cancer Genome Atlas. When baseline tumor volume was added to the model, it distinguished poor response to NADT with an AUC of 0.98. Prospective use of this model requires further retrospective validation with biopsies from additional trials. Conclusions A subset of prostate cancers exhibit greater histologic and genomic diversity at the time of diagnosis, and these localized tumors have greater fitness to resist therapy. Patient summary Some prostate cancer tumors do not respond well to a hormonal treatment called androgen deprivation therapy (ADT). We used tumor volume and four other parameters to develop a model to identify tumors that will not respond well to ADT. Treatments other than ADT should be considered for these patients.

Highlights • SARS-CoV-2 pandemic has outpaced developing diagnostic assays. • Multiple molecular assays were developed for the detection of SARS-CoV-2. • Altona, the CDC assay, and GenMark are compared., In December 2019, a novel coronavirus (SARS-CoV-2) was first isolated from Wuhan city, China and within three months, the global community was challenged with a devastating pandemic. The rapid spread of the virus challenged diagnostic laboratories to rapidly develop molecular diagnostic methods. As SARS CoV-2 assays became available for testing on existing molecular platforms, laboratories devoted unprecedented energy and resources into evaluating the analytical performance of the new tests and in some cases developed their own diagnostic assays under FDA-EUA guidance. This study compares the validation of three different molecular assays at the Johns Hopkins Molecular Virology laboratory: the RealStar® SARS-CoV-2 RT-PCR, ePlex® SARS-CoV-2, and the CDC COVID-19 RT-PCR tests. Overall, our studies indicate a comparable analytical performance of the three assays for the detection of SARS-CoV-2.

The inflammatory microenvironment plays an important role in the pathogenesis and progression of tumors and may be associated with somatic genomic alterations. We examined the association of tumor-infiltrating T-cell density with clinical-pathologic variables, tumor molecular subtype, and oncologic outcomes in surgically treated primary prostate cancer occurring in patients of European-American or African-American ancestry. We evaluated 312 primary prostate tumors, enriched for patients with African-American ancestry and high grade disease. Tissue microarrays were immunostained for CD3, CD8, and FOXP3 and were previously immunostained for ERG and PTEN using genetically validated protocols. Image analysis for quantification of T-cell density in tissue microarray tumor spots was performed. Automated quantification of T-cell densities in tumor-containing regions of tissue microarray spots and standard histologic sections were correlated (r = 0.73, p

Background The incidence of atrial fibrillation (AF) among patients undergoing left ventricular assist device (LVAD) implantation is high. However, the impact of AF on clinical outcomes has not been clarified. We reviewed our 9-year experience of continuous flow (CF) LVADs to determine the impact of preoperative AF on stroke, device thrombosis, and survival. Methods Between March 2006 and May 2015, 231 patients underwent implantation of 240 CF LVADs, 127 (52.9%) as bridge to transplantation and 113 (47.1%) as destination therapy. Effect of AF on postoperative outcomes was assessed by using Kaplan-Meier survival and Cox proportional hazard regression. Results There were 78 patients (32.5%) with preoperative AF with a mean age of 55.7 ± 11.4 years. A similar incidence of stroke was found in patients with and without AF, 12.8% versus 16.0%, respectively ( p = 0.803). Survival was similar, with 1-, 6-, 12-, and 24-month survivals of 96.2%, 91.7%, 84.5%, and 69.2%, respectively, for AF patients, versus 93.1%, 85.0%, 79.4%, and 74.1%, respectively, for non-AF patients ( p = 0.424). Preoperative AF was not a significant independent predictor of survival with the use of Cox proportional hazard regression (hazard ratio 1.08, 95% confidence interval: 0.66 to 1.76). Conclusions Preoperative AF was associated with a similar incidence of postoperative stroke, device thrombosis, and survival. On the basis of these data, it seems unnecessary to perform a left atrial appendage ligation or to alter postoperative anticoagulation in patients with AF undergoing LVAD implantation.

Continuous-flow left ventricular assist devices (LVADs) have become the standard of care for patients with advanced heart failure. The goal of this study was to review our 9-year institutional experience.From March 2006 through May 2015, 231 patients underwent implantation of 240 CF LVADs, HeartMate II LVAD (Thoratec Corp., Pleasanton, CA; n = 205) or HVAD (HeartWare Inc., Framingham, MA; n = 35). Of these, 127 devices (52.9%) were implanted as bridge to transplantation (BTT) and 113 (47.1%) as destination therapy (DT).Mean age was 51.2 ± 11.9 years for BTT patients and 58.2 ± 11.4 years for DT patients (p0.001). There was a higher incidence of preoperative diabetes, renal insufficiency, peripheral vascular disease, and previous cardiac operation in DT patients (p0.05). Survival was higher for BTT patients, with 1-, 6-, 12-, and 24-month survivals of 91.0%, 90.0%, 88.5%, and 72.1%, respectively, versus 85.3%, 81.1%, 75.6%, and 59.0%, respectively, for DT patients (p = 0.038). Gastrointestinal bleeding was the most common complication (29.6%), followed by right ventricular failure (22.5%) and stroke (15.0%), with a similar incidence for BTT and DT patients. Preoperative liver biopsy (hazard ratio [HR] 2.27, p = 0.036), mechanical support (HR 1.82, p = 0.025), aspartate transaminase (HR 1.07, p = 0.001), and alanine aminotransferase (HR 0.95, p = 0.024) were severe independent predictors of survival in multivariate analysis.These data indicate excellent survival for BTT and DT patients on long-term LVAD support. However, for LVAD therapy to become a plausible alternative to heart transplantation, we need to further decrease the incidence of postoperative complications.

The SPINK1 molecular subtype is more common in African-American (AA) men with prostatic adenocarcinoma (PCa) than European Americans (EA). Studies have suggested that SPINK1 expression is associated with more aggressive disease. However, the size, follow-up, and racial diversity of prior patient cohorts have limited our understanding of SPINK1 expression in AA men. The objective was to determine the associations between SPINK1 subtype, race, and oncologic outcomes after radical prostatectomy (RP).A total of 186 AA and 206 EA men who underwent RP were matched according to pathologic grade. We examined SPINK1 status by immunohistochemistry on tissue microarrays using a genetically validated assay. Cox proportional hazard analyses assessed the association of SPINK1 status with oncologic outcomes in race-specific multivariate models. A second objective was to determine the correlation between CD3/CD8 T cell densities with SPINK1 status and race, using immunostaining and automated image analysis.SPINK1-positive subtype was present in 25% (45/186) of AA and 15% (30/206) of EA men (p = 0.013). There were no differences in pathologic grade, pathologic stage, biochemical recurrence (BCR)-free survival, or metastasis-free survival between SPINK1-positive and SPINK1-negative tumors in the overall cohort or by race. In multivariate analyses, SPINK1 expression was not associated with BCR (AA: HR 0.99, 95% CI 0.56-1.75, p = 0.976; EA: HR 0.88, 95% CI 0.43-1.77, p = 0.720) or metastasis (AA: HR 0.79, 95% CI 0.25-2.49, p = 0.691; EA: HR 1.55, 95% CI 0.58-4.11, p = 0.381) in either AA or EA men. There were no significant differences in surrounding CD3/CD8 lymphocyte densities between SPINK1-positive and SPINK1-negative tumors in either race.SPINK1-positive subtype is more prevalent in AA than EA men with PCa. Contrary to previous studies, we found that SPINK1 protein expression was not associated with worse pathologic or oncologic outcomes after RP in either AA men or EA men.

Mismatch repair (MMR) gene mutations are rare in prostate cancer, and their histological and clinical characteristics are largely unknown. We conducted a retrospective study to explore disease characteristics and treatment outcomes of men with metastatic prostate cancer harboring germline and/or somatic MMR mutations detected using clinical-grade genomic assays. Thirteen patients with a deleterious MMR gene mutation were identified. Median age was 64 yr, 75% had grade group 5 (Gleason sum 9 or 10), 23% had intraductal histology, 46% had metastatic disease at initial diagnosis, and 31% had visceral metastases. Most patients (46%) had MSH6 mutations, 73% demonstrated microsatellite instability, and median tumor mutational load was 18/Mb (range, 3-165 mutations/Mb). Surprisingly, responses to standard hormonal therapies were very durable (median progression-free survival [PFS] of 67 mo to initial androgen deprivation and median PFS of 26 mo to abiraterone/enzalutamide). Two of four men receiving PD-1 inhibitors achieved a ≥50% prostate-specific antigen response at 12 wk, with a median PFS duration in these four men of 9 mo. Despite aggressive clinical and pathological features, patients with MMR-mutated advanced prostate cancer appear to have particular sensitivity to hormonal therapies, as well as anecdotal responses to PD-1 inhibitors. Certain histological features (grade group 5, intraductal carcinoma) should prompt evaluation for MMR deficiency. These data are only hypothesis generating. PATIENT SUMMARY: Prostate cancers with mismatch repair gene mutations have aggressive clinical and pathological features; however, these are very sensitive to standard and novel hormonal therapies, and also demonstrate anecdotal sensitivity to PD-1 inhibitors such as pembrolizumab.

Background The association of HIV and myeloma has rarely been reported in the literature. This following case discusses the presentation of acute kidney injury (AKI) in a 53-year-old lady with HIV, subsequently diagnosed with myeloma. Furthermore, we describe recovery of renal function and dialysis independence using a combination of light chain removal by dialysis with a high cut-off dialyzer and chemotherapy. Investigations Physical examination, urine, blood tests, renal biopsy, bone marrow aspirate and trephine, US scan. Diagnosis Myeloma. Management Dialysis and chemotherapy.

Objective. A limited number of studies have looked at premalignant lesions of ovaries and the results are conflicting. Our goal is to identify, histologically and by immunohistochemistry, any features that may represent premalignant changes in the ovaries. Methods. Our cases included 29 patients with unilateral ovarian cancer. These were compared to 19 controls that had unilateral benign ovarian pathology and to 39 controls with bilateral normal ovaries. Tissue sections from the contralateral normal ovary were examined. Analysis of histological features and immunohistochemical staining for the apoptosis inhibitor Bcl-2, the proliferation marker Ki-67 and the tumor suppressor gene p53 was performed. Results. Epithelial stratification, nuclear atypia, and inclusion cysts were more often seen in the cases than in the two control groups. Epithelial stratification and nuclear atypia was statistically significantly more common among the cases than the normal controls. Inclusion cysts were present in more of the cases (P = 0.017) and in higher numbers than in the normal controls. Bcl-2 overexpression was statistically more commonly seen in the cases with contralateral ovarian cancer (39%) than in the normal controls (15%), while it was present in 28% of cases with contralateral benign pathology. Conclusions. Epithelial alterations and Bcl-2 overexpression was seen in all three groups studied. However, the epithelial alterations and Bcl-2 overexpression was more commonly seen in the contralateral ovary of women with unilateral ovarian cancer. This suggests an association between these changes and ovarian cancer. Although it is tempting to label the above changes premalignant, women with the above changes are at possibly higher risk of developing ovarian cancer rather than having acquired an oncogenic change that would inevitably lead to ovarian cancer.

OBJECTIVES To describe the prevalence of atopic symptoms in children throughout the UK. METHOD A questionnaire survey of 12–14 year olds throughout England, Wales, Scotland, and the Scottish Islands using the international study of asthma and allergies in childhood (ISAAC) protocol. RESULTS A total of 27 507 (86%) children took part. Recent rhinoconjunctivitis was reported by 18.2%, with 6.2% reporting symptoms between March and September; 16.4% reported itchy flexural rash in the past 12 months. The prevalence of atopic symptoms was higher in girls and subjects born within the UK. The prevalence of severe wheeze was highest in subjects reporting perennial rhinoconjunctivitis, as opposed to summertime only symptoms. Winter rhinoconjunctivitis was associated with severe wheeze and severe flexural rash. One or more current symptoms were reported by 47.6% of all children and 4% reported all three symptoms. CONCLUSION In general, geographical variations were small but the prevalence of symptoms was significantly higher in Scotland and northern England. The study demonstrates the importance of atopic diseases both in their own right and in association with asthma.

BACKGROUND Respiratory diseases are common in childhood and may lead to chronic disease in adult life; environmental factors probably play an important part in their causation. METHODS A survey of respiratory symptoms in children aged 12–14 years was conducted throughout Great Britain as part of the International Study of Asthma and Allergies in Childhood (ISAAC). Information was obtained on certain aspects of the home environment in order to assess their importance as risk factors. RESULTS The response rate was 79.3%, and 25 393 children in 93 schools participated. In a multiple regression analysis, wheeze was reported more often in non-metropolitan areas and in association with active smoking, passive smoking, the presence of a furry pet, bottled gas, paraffin, and other unusual heating fuels; small regional differences persisted. Current smoking, previous smoking, and passive smoking accounted for 10.4%, 6.8%, and 6.5%, respectively, of wheezing in the past 12 months, and furry pets accounted for 5.0%. Cough and phlegm were associated with active and passive smoking and with the miscellaneous fuels; similar associations were found for rhinitis, but were less consistent for rhinitis occurring in spring and summer. Gas cooking showed little association with respiratory symptoms. CONCLUSIONS Passive as well as active smoking is an important cause of respiratory symptoms in adolescence. Pets seem to increase the risk of wheeze and rhinitis, and fumes from certain unusual heating fuels may have adverse effects. Home environment and geographical location have independent effects on the prevalence of respiratory symptoms.

This study documents the impact of migration, environment and caste on the blood pressure of Sikhs living in the UK and their peers in the native Punjab state of India. A sample of 449 adult Sikhs, males and females, were studied in the Punjab state, and in Southall, in the Ealing borough of London and Handsworth in Birmingham in the UK. There is minor variation in the blood pressure of members of various castes among the Sikhs living in the Punjab. The pattern in blood pressure broadly corresponds with the economic status of the individuals, with well-off groups showing higher blood pressure compared to the poorer groups. The blood pressure of migrants, though higher than that of their sedente peers, is not significantly so. Age at arrival in the UK and the length of exposure to the new environment were generally not significantly related to variation in blood pressure. There seems to be a secular shift in the blood pressure values of the native Punjabi Sikhs compared to earlier studies, possibly because of the rise in civic disturbances and social unrest in the Punjab during recent years.

This study was conducted to see whether children living in socially deprived areas were more likely than other children to be admitted to hospital for asthma, and, if so, whether their excess risk was attributable to a higher prevalence of asthma or poorer treatment. Hospital admission rates for asthma were obtained for Cardiff electoral wards and compared with the Townsend indices of deprivation. A survey of respiratory symptoms was conducted in schoolchildren; prevalence of symptoms was compared with Townsend index and asthma admission rate for the schools' catchment areas.Asthma admissions were strongly correlated with Townsend indices at all ages. The prevalence of reported asthma and various degrees of wheeze in the schools was not significantly correlated with Townsend index or hospital admission rate in the corresponding areas. The presence of a smoker in the house was strongly associated with Townsend index and admission rate; children whose houses contained a smoker were more likely than others to have wheezed in the past year and to have disturbed nights due to wheezing. There was a non-significant negative association between Townsend index and regular use of inhaled steroids.The relationship between hospital admission for asthma and social deprivation is not explained by variations in prevalence, but it may be attributable to the aggravation of symptoms by active or passive smoking, and perhaps also to differences in management.

Reducing mucosal cyclo-oxygenase-2 and prostaglandin E(2) production and suppressing intraoesophageal acid may be effective chemopreventive strategies in patients with Barrett's oesophagus.To compare the effects of aspirin and rofecoxib when administered with esomeprazole on prostaglandin E(2) production, cyclo-oxygenase-2 expression and proliferating cell nuclear antigen expression in patients with Barrett's oesophagus.This exploratory, multicentre, randomized, open-label, four-way crossover study in 45 patients with Barrett's oesophagus evaluated prostaglandin E(2) content, proliferating cell nuclear antigen expression, and cyclo-oxygenase-2 expression after 10 days of sequential treatments with: esomeprazole 40 mg twice daily plus aspirin 325 mg once daily (E40 b.d. + A325); E40 b.d. plus rofecoxib 25 mg once daily (E40 b.d. + R25); E40 b.d.; and rofecoxib 25 mg once daily (R25).Prostaglandin E(2) content reduction in Barrett's oesophagus tissue was significantly greater with E40 b.d. + A325 compared with E40 b.d. + R25, E40 b.d. or R25 (P0.05). All treatments containing E40 b.d. significantly decreased proliferating cell nuclear antigen expression from baseline (P0.05). None of the treatments significantly reduced cyclo-oxygenase-2 expression.The combined treatment of esomeprazole 40 mg b.d. and aspirin 325 mg significantly decreased mucosal prostaglandin E(2) content and all treatments containing esomeprazole significantly reduced proliferating cell nuclear antigen expression in patients with Barrett's oesophagus.

PURPOSE: To test whether differences in smoking-related lung cancer risks in blacks and whites can explain why lung cancer incidence is greater in black males than in white males but about equal in black and white females, given that a greater proportion of blacks are smokers, but smoke far fewer cigarettes per day than do whites. METHODS: A hospital-based case-control study was conducted between 1984 and 1998 that included interviews with 1,710 white male and 1,321 white female cases of histologically confirmed lung cancer, 254 black male and 163 black female cases, and 8,151 controls. Relative risks were estimated via odds ratios using logistic regression, adjusted for age, education, and body mass index. RESULTS . We confirmed prior reports that smoking prevalence is higher but overall dosage is lower among blacks. Overall ORs were similar for blacks and whites, except among the heaviest smoking males (21+ cigarettes per day or 37.5 pack–years), in whom ORs for blacks were considerably greater than for whites. Long-term benefits of cessation were similar for white and black ex-smokers. Smokers of menthol flavored cigarettes were at no greater risk for lung cancer than were smokers of unflavored brands. CONCLUSIONS . Lung cancer risks were similar for whites and blacks with similar smoking habits, except possibly for blacks who were very heavy smokers; this sub-group is unusual in the general population of African American smokers. Explanations of racial disparities in lung cancer risk may need to account for modifying factors including type of cigarette (yield, mentholation), diet, occupation, and host factors such as ability to metabolize mainstream smoke carcinogens.

Myxoid leiomyoma is an extremely rare tumor, presenting as a scrotal mass. We report a case of 60 years male, who presented with a painless scrotal mass and operated as secondary hydrocoele. This lesion should be differentiated from other myxoid tumors and tumors with myxoid degeneration.

Vitamin C is one of the key antioxidant vitamins which is abundant in the extracellular fluid lining the lung and low vitamin C intake has been associated with pulmonary dysfunction.To evaluate the evidence for the effectiveness of vitamin C in the treatment of asthma.The Cochrane Airways Review Group asthma register was searched and bibliographies of studies identified were also checked for further trials.Only randomised controlled trials were eligible for inclusion. Studies were considered for inclusion if they dealt with the treatment of asthma using vitamin C supplementation. Two independent reviewers identified potentially relevant studies using pre-defined criteria and selected studies for inclusion.Data were abstracted independently by two reviewers. Information on patients, methods, interventions, outcomes and results was extracted using standard forms.A total of 65 abstracts and titles were identified. Ten studies were selected for potential inclusion, six met the inclusion criteria. All included studies were placebo-controlled and randomised. Only three provided data in a form that permitted further analysis and none could be aggregated in a meta analysis. The individual studies produced no significant effect on any asthma outcome.At present, evidence from randomised-controlled trials is insufficient to recommend a specific role for vitamin C in the treatment of asthma. A methodologically strong and large-scale randomised controlled trial is warranted in order to address the question of the effectiveness of vitamin C in patients with asthma.

Two members of the mu class of glutathione S-transferase (GST) genes, GSTM1 and GSTM3, have polymorphic alleles which have been associated with altered levels of GST mu protein expression and may be linked to increased risk for several tobacco-related cancers. Oral cancer is a tobacco-related disease that affects African-American men at a significantly higher incidence than Caucasian men. To examine the potential role of GSTM polymorphisms in risk for oral cancer in African-Americans and Caucasians, the prevalences of the GSTM1 null and GSTM3 intron 6 polymorphisms were examined in 63 African-American and 101 Caucasian patients with histologically confirmed primary oral cancer, as well as in 133 African-American and 213 Caucasian matched control subjects. In African-Americans, the odds ratio for oral cancer associated with the GSTM1 (0/0) genotype was 3.1 [95% confidence interval (CI) = 1.1-8.5], with the association between the GSTM1 (0/0) genotype and oral cancer risk strongest in heavy smokers [i.e. > 24 pack-years; odds ratio (OR) = 5.4, 95% CI = 1.2-24]. Using the potentially most protective GSTM1 [+]/GSTM3 (B/B) genotype as the reference group, increased risk for oral cancer was observed in African-Americans with the GSTM1 [+]/GSTM3 [(A/A) + (A/B)] (OR = 2.2, 95% CI = 0.82-6.0), GSTM1 (0/0)/GSTM3 (B/B) (OR = 4.3, 95% CI = 1.1-16), and GSTM1 (0/0)/GSTM3 [(A/A) + (A/B)] (OR = 6.6, 95% CI = 1.2-38) genotypes (P < 0.01, trend test). No significant associations were observed between GSTM genotype and oral cancer risk in Caucasians. These results suggest that the GSTM1 null and GSTM3 intron 6 polymorphisms play an important role in risk for oral cancer among African-Americans and implicates the mu class of GSTs as important tobacco carcinogen detoxifying enzymes in this population.

O6-Alkylguanine DNA alkyltransferase (AGT) plays an important role in the repair of alkylating agent-induced DNA damage and protection from the carcinogenic effects of environmental agents. To examine the importance of the AGT codon 143 and codon 160 polymorphisms in risk for lung cancer and to assess the prevalence of these polymorphisms in different racial groups, we performed genotype analysis of lung cancer patients and matched controls. The prevalence of the AGT143Val allele in controls was 0.07 in Caucasians and 0.03 in African Americans. The AGT143Val allele was not detected in an unmatched Asian control cohort. The prevalence of the AGT160Arg variant allele was 0.01 in Caucasians, 0.02 in African Americans, and 0.03 in Asians. A marginally significant association was observed between the AGT codon 143 (isoleucine/valine) genotype and risk for lung cancer (odds ratio = 2.1; 95% confidence interval = 1.01-4.7). The prevalence of the AGT160Arg variant allele was similar in lung cancer cases versus matched controls. These results suggest that the AGT codon 143 polymorphism may play an important role in risk for lung cancer.

Endothelial cell damage has been put forward as an underlying factor for development of pre-eclampsia. This study was carried out to see if fibronectin, which is a marker of endothelial damage, could be used as a marker of pre-eclampsia.A longitudinal study was conducted on 100 normotensive primigravidae registered before 20 weeks of gestation. These subjects were followed until delivery and three blood samples were collected, first at registration, i.e. before 20 weeks, second around 28 weeks and third at 36 weeks or later till delivery. Fibronectin levels were assayed by ELISA and women observed for any signs of pre-eclampsia.Fourteen subjects developed pre-eclampsia. Fibronectin levels were observed to rise as pregnancy advanced but the rise was significantly higher in subjects who developed pre-eclampsia. The fibronectin levels were also significantly higher in these 14 subjects even in the first sample, i.e. before 20 weeks of gestation when compared with normotensive subjects (P0.01).Fibronectin levels could be used as an early valuable biomarker for the development of pre-eclampsia.

AIMS: To assess the possible role of hypoxia in the formation of axonal bulbs. METHODS: Study material comprised sections from 28 brains showing evidence of cerebral hypoxia with no history of head injury, four with a history of head trauma but no evidence of hypoxic change, eight with a history of head trauma and hypoxic change, and four from control brains originally described as "diffuse axonal injury." These were subjected to microwave antigen retrieval and immunohistochemistry using monoclonal antibodies to beta amyloid precursor protein (beta APP), glial fibrillary acid protein (GFAP), and CD68-PGM1. RESULTS: Positive staining for beta APP was seen in all four controls, all four cases of head injury only, seven of eight cases of head injury and hypoxic changes, and 12 of 28 cases of hypoxia without history of head injury; 22 of 25 cases who had been ventilated showed positive staining. The majority of cases showed evidence of cerebral swelling. CONCLUSIONS: Axonal bulbs staining positively for beta APP may occur in the presence of hypoxia and in the absence of head injury. The role of hypoxia, raised intracranial pressure, oedema, shift effects, and ventilatory support in the formation of axonal bulbs is discussed. The presence of axonal bulbs cannot necessarily be attributed to shearing forces alone.

Objective: To investigate variations in the prevalence of self reported symptoms, diagnosis, and treatment of asthma in 12–14 year old children. Design: Self completion questionnaire. Setting: Great Britain. Subjects: All pupils aged 12–14 years in a stratified cluster sample of 93 large mixed secondary schools in 1995. Main outcome measures: Self reported prevalence of symptoms, diagnosis, and treatment of asthma at four geographical levels. Results: 27 507 questionnaires were completed (85.9% response rate). The national 12 month prevalence of any wheezing, speech limiting wheeze, four or more attacks of wheeze, and frequent night waking with wheeze was 33.3% (n=9155), 8.8% (2427), 9.6% (2634), and 3.7% (1023) respectively. The prevalence of ever having had a diagnosis of asthma was 20.9% (5736). In total, 19.8% (5438/27 507) of pupils reported treatment with anti-asthma drugs in the past year, but, of pupils reporting frequent nocturnal wheeze in the past year, 33.8% (342/1012) had no diagnosis of asthma and 38.6% (395/1023) denied receiving inhaler therapy. The 12 month prevalence of wheeze was highest in Scotland (36.7%, 1633/4444), but in England and Wales there was no discernible north-south or east-west gradient. Wheeze prevalence was slightly higher in non-metropolitan areas (35.0%, 6155/17 605) than in metropolitan areas (30.3%, 3000/9902). The prevalence of self reported asthma diagnosis and inhaler use showed no discernible national, regional, north-south, or east-west geographical pattern but was higher in non-metropolitan areas. Conclusion: Prevalence of self reported symptoms, diagnosis, and treatment of asthma was high among 12–14 year olds throughout Great Britain with little geographical or urban-rural variation. Underdiagnosis and undertreatment were substantial. Key messages - We investigated the prevalence of self reported symptoms, diagnosis, and treatment of asthma in 12–14 year old children in Great Britain - A third of subjects reported wheezing in the past year, and a fifth reported ever having had a diagnosis of asthma—higher prevalences than reported previously - Prevalences of symptoms generally varied by a factor of 1.3 or less across Great Britain but, in contrast to previous reports, were significantly higher in Scotland than England and in non-metropolitan areas than metropolitan ones - Asthma may still be undiagnosed and undertreated—4% of pupils reported having had a diagnosis of asthma but were still experiencing moderate or greater disruption of their lives, while 1-3.4% reported moderate to severe symptoms but were undiagnosed and untreated -The limited geographical variation in prevalences of symptoms and diagnosis of asthma suggests that the causes of asthma are widely distributed in Great Britain and that factors which do vary geographically—such as climate, diet, and outdoor environment—are not the main determinants of prevalence.

In the past in India, a strong preference for sons made unwanted female infants susceptible to infanticide at the hands of midwives. Today, amniocentesis, which allows identification of sex in utero, has led to abortion of unwanted female fetuses. The incidence of this practice is revealed by the presence of an adverse sex ratio in many states. Amniocentesis was developed to detect genetic abnormalities, and the process is associated with the risk of miscarriage, septicemia, misinterpretation of results, and maternal death. While pregnancy may be legally terminated in India up to 12 weeks' gestation, amniocentesis takes place at 16 weeks. It is difficult, if not impossible, however, to prove that parents are guilty of female feticide. In some states, parents who can not afford amniocentesis are continuing the practice of female infanticide. The Indian government should act immediately to control female feticide. Amniocentesis should take place only within government-run institutions, and the sex of the child should never be revealed to parents. A massive educational effort will be required to modify belief that it is only sons who can make necessary offerings after the death of a parent.

Compulsory detention of an individual in hospital, because they have a notifiable disease, is controversial. Difficulties experienced by the authors in applying Sections 37 and 38 of the Public Health (Control of Disease) Act 1984 led them to conduct a postal survey of the experience of Consultants in Communicable Disease Control/Medical Officers of Environmental Health (CCDC/MOEH) currently in post in England. Out of 138 respondents (80% response rate), 48 respondents (34.8%) had dealt with ‘non-compliant’ individuals posing an infectious risk to the community. Of the 48, 13 respondents achieved compliance by threatening to use Section 37/38 and only 6 respondents resorted to using Section 37/38, equivalent to less than one use of the sections for every hundred years of CCDC/MOEH experience. In most cases the notifiable discase in question was tuberculosis. In contrast to our experience and previously reported cases, the survey suggests generally satisfactory experience of Section 37/38 amongst CCDC/MOEH currently in post. Recommended guidelines for the use of Section 37/38 are given.

A case of carcinoma cecum presented as a gluteal enterocutaneous fistula. Tumor excision provided effective palliation for nearly three years.

Five instances of urethro-venous intravasation during retrograde urethrography are reported. Four cases were of urethral strictures and one case was of urethral hemangioma. All patients had post procedural bleeding while one patient got allergic reactions, another showed chills and rigors. Anatomy of the drainage veins is described. Factors responsible for this complication and its clinical implications are discussed. It is suggested that urethro-venous intravasation should be considered a diagnostic sign of urethral inflammation.