Improving power in PSA response analyses of metastatic castration-resistant prostate cancer trials.

BACKGROUND: To determine how much an augmented analysis approach could improve the efficiency of prostate-specific antigen (PSA) response analyses in clinical practice. PSA response rates are commonly used outcome measures in metastatic castration-resistant prostate cancer (mCRPC) trial reports. PSA response is evaluated by comparing continuous PSA data (e.g., change from baseline) to a threshold (e.g., 50% reduction). Consequently, information in the continuous data is discarded. Recent papers have proposed an augmented approach that retains the conventional response rate, but employs the continuous data to improve precision of estimation. METHODS: A literature review identified published prostate cancer trials that included a waterfall plot of continuous PSA data. This continuous data was extracted to enable the conventional and augmented approaches to be compared. RESULTS: Sixty-four articles, reporting results for 78 mCRPC treatment arms, were re-analysed. The median efficiency gain from using the augmented analysis, in terms of the implied increase to the sample size of the original study, was 103.2% (IQR [89.8,190.9%]). CONCLUSIONS: Augmented PSA response analysis requires no additional data to be collected and can be performed easily using available software. It improves precision of estimation to a degree that is equivalent to a substantial sample size increase. The implication of this work is that prostate cancer trials using PSA response as a primary endpoint could be delivered with fewer participants and, therefore, more rapidly with reduced cost.

Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer. METHODS: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing. FINDINGS: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort. INTERPRETATION: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice. FUNDING: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.

Differentiated thyroid cancer mortality by disease stage in northern England.

OBJECTIVE: Mortality from thyroid cancer is reported to be higher in the UK compared with several other European countries, though UK data on mortality by disease stage have not been published. The aim of this study was to ascertain disease-specific mortality by stage in our centre. DESIGN, PATIENTS AND MEASUREMENTS: This was a cohort study of all patients presenting to a single centre. Four hundred and twenty patients treated between 2000 and 2010 were identified. The medical records and causes of deaths were reviewed and analysed. RESULTS: Overall disease-specific mortality at 5 and 10 years was 1.4% and 5.8%, respectively. The observed mortality was 58 against 66.3 expected deaths (CI 43.8-75.4) thus yielding an age-standardized mortality rate of 0.87. There were no deaths due to thyroid cancer in patients with stage I disease at 5 or 10 years. The 10-year disease-specific mortality rose with stage (stage II 3.1%, stage III 28.6%, stage IV 30%). CONCLUSIONS: Thyroid cancer mortality of patients treated at our centre was lower than the official national UK registry and most European figures.

Gracilis Flap Reconstruction After Proctocolectomy for Malignancy and Inflammatory Bowel Disease.

BACKGROUND: Gracilis flap reconstruction (GFR) following abdominoperineal resection (APR) or proctocolectomy (PC) can reduce pelvic wound complications but has not been adequately assessed in the setting of immunosuppression, fistulous disease, and neoadjuvant chemoradiation. METHODS: Patients undergoing APR/PC with GFR were retrospectively analyzed with regard to perioperative characteristics, and morbidity was assessed. RESULTS: Patients underwent GFR for rectal cancer (n = 28), anal cancer (n = 3), inflammatory bowel disease (n = 13), or benign fistulizing disease (n = 1). 22.2% were chronically immunosuppressed, and 66.7% underwent preoperative chemoradiation. Twenty (44.4%) patients had minor wound complications, all treated nonoperatively. Nine patients had major complications with 4 patients requiring reoperation. The 4 threatened flaps were unilateral, and all were salvaged. Donor site morbidity was minimal. Patients with major complications were older (56 vs. 71 years, P = .030), and less likely to have pelvic drains (P = .018). CONCLUSION: In high-risk perineal wounds, GFR offers durable reconstruction with acceptably low morbidity.

Using the AR-V7 biomarker to determine treatment in metastatic castrate resistant prostate cancer, a feasibility randomised control trial, conclusions from the VARIANT trial [version 2; peer review: 2 approved].

Background: Prostate cancer is the most commonly diagnosed malignancy in the UK. Castrate resistant prostate cancer (CRPC) can be difficult to manage with response to next generation hormonal treatment variable. AR-V7 is a protein biomarker that can be used to predict response to treatment and potentially better inform management in these patients. Our aim was to establish the feasibility of conducting a definitive randomised controlled trial comparing the clinical utility of AR-V7 biomarker assay in personalising treatments for patients with metastatic CRPC within the United Kingdom (UK) National Health Service (NHS).  Due to a number of issues the trial was not completed successfully, we aim to discuss and share lessons learned herein. Methods: We conducted a randomised, open, feasibility trial, which aimed to recruit 70 adult men with metastatic CRPC within three secondary care NHS trusts in the UK to be run over an 18-month period. Participants were randomised to personalised treatment based on AR-V7 status (intervention) or standard care (control). The primary outcome was feasibility, which included: recruitment rate, retention and compliance. Additionally, a baseline prevalence of AR-V7 expression was to be estimated. Results: Fourteen participants were screened and 12 randomised with six into each arm over a nine-month period. Reliability issues with the AR-V7 assay meant prevalence was not estimated. Due to limited recruitment the study did not complete to target. Conclusions: Whilst the trial did not complete to target, we have ascertained that men with advanced cancer are willing to take part in trials utilising biomarker guided treatment. A number of issues were identified that serve as important learning points in future clinical trials.

Endothelial surface N-glycans mediate monocyte adhesion and are targets for anti-inflammatory effects of peroxisome proliferator-activated receptor γ ligands.

Endothelial-monocyte interactions are regulated by adhesion molecules and key in the development of vascular inflammatory disease. Peroxisome proliferator-activated receptor (PPAR) γ activation in endothelial cells is recognized to mediate anti-inflammatory effects that inhibit monocyte rolling and adhesion. Herein, evidence is provided for a novel mechanism for the anti-inflammatory effects of PPARγ ligand action that involves inhibition of proinflammatory cytokine-dependent up-regulation of endothelial N-glycans. TNFα treatment of human umbilical vein endothelial cells increased surface expression of high mannose/hybrid N-glycans. A role for these sugars in mediating THP-1 or primary human monocyte rolling and adhesion was indicated by competition studies in which addition of α-methylmannose, but not α-methylglucose, inhibited monocyte rolling and adhesion during flow, but not under static conditions. This result supports the notion that adhesion molecules provide scaffolds for sugar epitopes to mediate adhesion with cognate receptors. A panel of structurally distinct PPARγ agonists all decreased TNFα-dependent expression of endothelial high mannose/hybrid N-glycans. Using rosiglitazone as a model PPARγ agonist, which decreased TNFα-induced high mannose N-glycan expression, we demonstrate a role for these carbohydrate residues in THP-1 rolling and adhesion that is independent of endothelial surface adhesion molecule expression (ICAM-1 and E-selectin). Data from N-glycan processing gene arrays identified α-mannosidases (MAN1A2 and MAN1C1) as targets for down-regulation by TNFα, which was reversed by rosiglitazone, a result consistent with altered high mannose/hybrid N-glycan epitopes. Taken together we propose a novel anti-inflammatory mechanism of endothelial PPARγ activation that involves targeting protein post-translational modification of adhesion molecules, specifically N-glycosylation.

Anticipatory foresight and adaptive decision-making as a crucial characteristic for business continuity, crisis and emergency leadership.

This paper reviews some of the common challenges to high-quality decision-making at the leadership level, such as limiting decision shortcuts, analytical blind spots, failure to consider multiple perspectives or options, and reluctance to adjust decisions that are not working well. The paper also reviews some of the pertinent literature and scholarship on decision-making approaches to build a summative decision-making model of anticipatory foresight and adaptation to overcome dysfunctional decision-making mistakes. The paper proposes a new framework that focuses on the internal decision-making processes that leaders should adopt - an approach to decision-making that combines the concepts of anticipatory foresight, predictive vision, creative imagination, adaptive skill sets and adaptive flexibility. It is essential to incorporate these dimensions in how we prepare leaders, equip and train them, create processes and protocols, and ultimately how we evaluate and assess leadership performance.

Advertising Phuket's nightlife on the Internet: a case study of double binds and hegemonic masculinity in sex tourism.

One significant human rights violation in Southeast Asia is the exploitation of women through sex tourism. Such sexual exploitation occurs in Thailand because institutions are complacent and society accepts the practice. This case study, guided by the concepts of double binds and hegemonic masculinity, sought to understand if Thai culture is symbolically constructed in ways to portray Thailand as a desirable "sex tourist" destination. Websites portray Phuket as a patriarchal world where men can live their fantasies of being perfect hegemonic males because Thai bar girls are young nymphomaniacs that have no need to be talked to or understood.

Compliance in autism: Self-report in action.

Previous research indicates that autistic individuals are more likely to be bullied, and that they experience heightened anxiety and diminished self-esteem. These factors are known to predict heightened compliance, which is the tendency to agree with or carry out the requests and demands of others. This has a range of potentially serious consequences, particularly for an autistic person. This study utilised self-report (the Gudjonsson Compliance Scale) and behavioural measures of compliance (the door-in-the-face task) with 26 autistic and 26 typically developing adults. Participants also completed measures of early life bullying experiences, anxiety and self-esteem. Autistic participants were more compliant on both self-report and experimental tasks, and they reported more bullying experiences, higher anxiety and reduced self-esteem. Looking at both groups, bullying, anxiety and self-esteem were all correlated with self-reported compliance on the Gudjonsson Compliance Scale, yet only self-esteem was a unique predictor. None of these predictor variables related to behavioural compliance on the door in the face; nor did Gudjonsson Compliance Scale scores predict door-in-the-face performance, which may be better explained by situational and motivational factors. Findings have important implications for a range of real-life settings including requests made in the context of research, schools, the criminal justice system and the workplace.

Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency.

Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of prostate cancers have homologous recombination DNA (HRD) repair defects, and that such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition and platinum, has increased interest in the utilisation of these drugs against a subset of these diseases. Here in we report three patients with advanced castration-resistant PCa with HRD defects having exceptional responses to carboplatin.

Imaging in bariatric surgery: a guide to postsurgical anatomy and common complications.

OBJECTIVE: This article reviews the various bariatric surgical techniques and the associated imaging findings of normal postoperative anatomy and of common complications. CONCLUSION: Bariatric surgery is increasingly performed to control morbid obesity secondary to failed medical approaches. As a result, imaging plays an important role in postoperative evaluation and management. Practical knowledge of postsurgical anatomy allows accurate interpretation of imaging findings related to normal postsurgical anatomy and common postsurgical complications.

Relevance of poly (ADP-ribose) polymerase inhibitors in prostate cancer.

PURPOSE OF REVIEW: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved drugs for the treatment of ovarian and breast cancer and currently under investigation for the treatment of prostate cancer and other malignancies with aberrations in homologous recombination DNA repair.This review summarizes literature published during 2017 concerning the relevance of PARPi in prostate cancer and presents new evidence on mechanisms of resistance and biomarkers of response. RECENT FINDINGS: The approval of several PARPi (olaparib, rucaparib, and niraparib) has driven the focus of anticancer treatment on synthetic lethality in prostate cancer too. Despite anecdotal reports of long-term responders, most cancers become resistant to these therapies.Different mechanisms of primary and acquired resistance to PARPi have been recently investigated including loss of PARP1 expression, BRCA mutations with partial function, and acquisition of reversion restoration of function mutations. SUMMARY: Here, we discuss the importance of PARPi in metastatic castration-resistant prostate cancer and discuss the possible mechanisms of resistance.

Onlay with Adhesive Use Compared with Sublay Mesh Placement in Ventral Hernia Repair: Was Chevrel Right? An Americas Hernia Society Quality Collaborative Analysis.

BACKGROUND: The use of mesh during ventral hernia repair (VHR) is a well-accepted concept. However, the ideal location of mesh placement remains strongly debated. Although VHR with onlay mesh placement has historically been associated with a high rate of wound events, this surgical approach is technically less challenging than VHR with sublay mesh placement. The purpose of this study was to compare 30-day wound events after onlay mesh placement with adhesive fixation vs those after sublay mesh placement using the Americas Hernia Society Quality Collaborative database. STUDY DESIGN: All patients undergoing elective, open VHR with synthetic mesh placement from January 2013 through January 2016 were identified within the Americas Hernia Society Quality Collaborative. Only patients with clean wounds were included. Patients were divided into 2 groups: onlay mesh placement with the use of adhesive and sublay mesh placement. The association of mesh location with 30-day wound events was investigated using a matched analysis. RESULTS: A total of 1,854 patients met inclusion criteria; 1,761 (95.0%) underwent sublay mesh placement and 93 (5.0%) underwent onlay mesh placement with the use of adhesive. A 2:1 sublay to onlay matched analysis was performed based on factors previously shown to influence wound events after VHR. After matching, both groups had a lower mean Ventral Hernia Working Group grade and fewer associated comorbidities. There was no statistically significant difference between the sublay and onlay groups with respect to 30-day surgical site infections (2.9% vs 5.5%; p = 0.30), surgical site occurrences (15.2% vs 7.7%; p = 0.08), or surgical site occurrences requiring procedural intervention (8.2% vs 5.5%; p = 0.42). CONCLUSIONS: Ventral hernia repair with onlay mesh placement is a safe alternative to VHR with sublay mesh placement in low-risk patients. Additional studies are needed to determine the long-term mesh outcomes and recurrence rates in both of these groups.

Osteogenic protein-1 (bone morphogenic protein-7) combined with various adjuncts in the treatment of humeral diaphyseal nonunions.

A prospective study was conducted to determine the efficacy of using recombinant BMP-7 (rhOP-1) as an adjuvant in the treatment of diaphyseal humeral nonunions. Twenty-three consecutive patients with atrophic humeral diaphyseal nonunions were treated at seven separate institutions. All nonunions were fixed with either a compression plate or an intramedullary nail in conjunction with various bone grafting techniques. Recombinant OP-1 was delivered to the fracture site in a Type I collagen carrier at the time of fixation. All fractures went on to eventual union. There were no serious complications and no adverse reactions to the rhOP-I implant. Our study suggests that rhOP-1 may be a safe and effective adjuvant for the treatment of humeral diaphyseal nonunions.

Tissue Expander versus Tissue Expander and Latissimus Flap in Morbidly Obese Breast Reconstruction Patients.

BACKGROUND: Immediate postmastectomy breast reconstruction in morbidly obese patients represents a challenge because neither prosthetic nor abdominal-based options may be suitable. METHODS: This study compared a previously published cohort of immediate prosthetic reconstruction of 346 patients (511 breasts) of whom 49 patients (67 breasts) were morbidly obese (defined as a body mass index > 35) with a morbidly obese patient population whose breasts were reconstructed immediately following postmastectomy with latissimus flap and tissue expander (21 patients and 22 breasts) in the same time period. The preoperative risk factors of mastectomy such as tobacco use, diabetes, and prior radiation and the postoperative complications of mastectomy such as skin necrosis, seroma, and prosthesis loss were examined. The explantation of the tissue expander provided a defined endpoint of reconstruction failure. RESULTS: The average body mass index in the tissue expander/implant group and in the latissimus flap plus tissue expander/implant group was 40.9 and 40.1, respectively. The risk profile of diabetes and tobacco use was similar in both groups. Fifteen of the 67 breasts (22.3%) of the tissue expander/implant group and 15 of the 23 breasts (65.2%) of the latissimus flap group had received prior radiation. The prosthesis loss was 13 of 67 breasts (19.4%) that had tissue-expander-alone reconstruction and 1 of 22 (4.8%) in the latissimus group that had tissue expander reconstruction. Modification of donor-site incision and skin-island location in the latissimus group of patients can minimize scar deformity. CONCLUSION: The loss rate in immediate postmastectomy reconstruction in morbidly obese patients with latissimus flap plus tissue expander was substantially lower than the loss rate in those with breast reconstructed with tissue expander alone.

Human acellular dermis versus no acellular dermis in tissue expansion breast reconstruction.

BACKGROUND: Human acellular dermis has been adopted for routine use in tissue expander reconstruction. The purported benefits include higher intraoperative fill volume, facilitation of lower pole expansion, and enhanced definition of the lower pole of the breast. Recently, concerns have arisen about an increase in postoperative complications with its use. METHODS: A retrospective review was conducted of patients who had immediate postmastectomy breast reconstruction with a tissue expander from July of 2001 to July of 2011. All tissue expander reconstructions before 2005 were performed submuscularly only and all subsequent to 2005 with the use of AlloDerm (LifeCell, Branchburg, N.J.) acellular dermis. Patient demographics were collected, and complications were recorded. RESULTS: The study cohort included 346 patients and 511 immediate breast reconstructions; 232 patients and 346 breasts were reconstructed with and 114 patients and 165 breasts without acellular dermis. Age, body mass index, diabetes, and tobacco use were equivalent in the two groups. Seroma occurrence in the acellular dermis group was nearly twice (30.0 versus 15.1 percent) that of the no acellular dermis breasts, but the tissue expander loss was only slightly higher (11.6 versus 8.5 percent) and not statistically significant. Body mass index in patients who lost their tissue expander was 31 kg/m, statistically significantly higher than in those who did not. CONCLUSIONS: The presence of acellular dermis did not increase the incidence of tissue expander loss, despite a doubling of frequency of seroma. Prior radiation and use of acellular dermis did culminate in a prohibitively high loss rate of the tissue expander.

Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell PPARgamma.

The mechanisms by which isoflavones protect against inflammatory vascular disease remain unclear. Our previous observations suggest that one mechanism involves inhibition of monocyte-endothelial cell interactions in a process that is absolutely dependent on flow. The molecular mechanisms involved and the effects of structurally distinct isoflavones on this process are not known and are investigated herein. Using static and flow-dependent monocyte adhesion assays, our data show that exposure of endothelial cells to biologically relevant concentrations of isoflavones inhibits subsequent TNF-alpha induced monocyte adhesion only during flow. This inhibition involved activating endothelial PPARgamma by stimulating promoter sequences containing the PPARgamma response element by isoflavones and attenuating antiadhesive effects by siRNA targeting of PPARgamma. A comparison of structurally distinct isoflavones suggested a critical role for the A-ring. Using chlorinated derivatives of daidzein, a key structural requirement for PPARgamma agonist activity appears to be the presence of the 7-OH group and the lack of chlorine at the 6- or 8-positions in the A-ring. Collectively, these data support 1) a novel flow-dependent anti-inflammatory mechanism for PPARgamma ligands in vascular endothelial cells and 2) exemplify the current concepts of nutrients modulating disease via regulating specific cell signaling pathways.

Imaging of acute appendicitis: US as the primary imaging modality.

BACKGROUND: The investigation of the acute abdomen in infants and children has evolved during the last two decades, placing imagers at the forefront of the evaluation and diagnosis of acute right lower quadrant abdominal problems. US and CT have recently been shown to be equally accurate in the diagnosis of acute appendicitis, but not everyone agrees. OBJECTIVE: To demonstrate the efficacy of triaging patients with acute abdominal problems that suggest appendicitis with US as the primary imaging modality. MATERIALS AND METHODS: We retrospectively reviewed the prospective imaging diagnoses in 622 children who presented to our emergency room (ER) and clinics with acute abdominal symptoms suggestive of appendicitis. We documented whether US or CT was performed and noted the diagnoses made. All of the patients had plain films. In addition, all patients undergoing surgical appendectomy during this time were also documented so as not to miss any cases of appendicitis. None was missed. RESULTS: There were 622 consecutive patients in our study. Three patients, diagnosed as normal, were eventually excluded because of lack of follow-up. In all, 152 patients were evaluated clinically and with plain films only. They were not subject to surgical exploration or further imaging. None returned with appendicitis. Eighty-one patients were directly subject to laparotomy after clinical and plain film evaluation. Of these patients, 20% had a normal appendix. Of the remaining 389 patients, 386 had US and three had CT alone. Four patients had both CT and US because of an inconclusive US examination. Three patients had CT alone because of their size. In total, 137 patients were diagnosed with appendicitis with US and/or CT. Four of these patients (3%) had normal appendices. Forty-two patients (less three lost to follow-up) were diagnosed as normal, and none returned with findings of appendicitis. Nine others had conditions other than acute appendicitis. Three had surgically proven, nonrelated conditions, and of the other six, one had pancreatitis and five nonsurgical adnexal problems. In all, 201 patients were diagnosed (with US) with mesenteric adenitis-enteritis, and none returned with findings of appendicitis. CONCLUSION: We attained a high degree of diagnostic accuracy in patients presenting with findings suggestive of appendicitis using US as the primary imaging modality. Our false-positive appendectomy rate was 3%. Therefore, triage of the acute abdomen with US supported by CT when required has considerable merit, especially when considering that US is noninvasive and does not use ionizing radiation.