Introduction to Symposium: Homophobia in the Halls of Justice: Sexual Orientation Bias and its Implications Within the Legal System

The gay moment is unavoidable. -Andrew Kopkind Gay activist, journalist and political commentator Andrew Kopkind made this profound observation at a critical moment in the queer rights movement, in the midst of the March on Washington, pride rallies, queer organizing and the ever strengthening movement to address the AIDS crisis within the queer community. The moment, however, meant different things to participants in the movement. Over the years, the queer or sexual liberation movement transformed itself into a much more equality-based movement with the most energy focused on securing recognition of gay marriage and equal access to the military. As such, and even with the constantly increasing strength and visibility of the mainstream gay rights movement, many queer issues and queer people remain marginalized, avoided or excluded. One such issue is the impact of sexual orientation bias in the legal system. Today\u27s long overdue discussion comes after the court reforms of the 1970s and after the courts, at the insistence of the American Bar Association, began to examine gender and race bias in the courts in the late 1980s and early 1990s. Despite an apparent willingness to revamp and reconstruct the courts and judicial system, in some regards, to fit our more inclusive society, there is still incredible reluctance to probe for bias based on an individual\u27s either real or perceived sexual orientation. If Andrew Kopkind were alive today, he might agree with the statement that we are at an important gay moment, but he might also question whether or not it is unavoidable. The public, still reeling from the misdeeds of public officials and betrayals of trust by important institutions like corporations, the government and religious institutions, are reluctant to examine deficits in our justice system. Is our legal system accountable, or for that matter, fair? Do we need to craft an inquiry into fairness or accountability that will give information about the experiences of lesbian, gay, bisexual, intersexual and transgendered persons? It is understandable then when one thinks about how specific individuals within certain categories (race, sexual identity, gender and class) might experience the criminal justice system, there may not be popular support for inquiry or critique. This is precisely why the decision to publish the presentations and papers from the symposium, Homophobia in the Halls of Justice: Sexual Orientation Bias and its Implications Within the Legal System, is such an important first step. This decision is necessary in order to transform an important moment into an unavoidable one

Time to endoscopic intervention in patients with upper gastrointestinal patients can be improved with pathway provision

BACKGROUND:Patients with upper gastrointestinal malignancy often require admission to hospital with dysphagia or jaundice requiring therapeutic endoscopy. Endoscopic intervention is often effective permitting rapid discharge. An efficient service would permit rapid discharge for patients who are often at the end of life. We noted that a majority of patients in hospital under the gastroenterological oncology were admitted with symptoms requiring therapeutic endoscopy. METHODS: We conducted an audit cycle of the inpatient days before and after pathway implementation. A wait of 1 day was set as acceptable for patients with bleeding as defined by NICE guidance and we set an arbitrary standard of 2 days for patients without bleeding but requiring therapeutic endoscopy. Between the audit cycles, a pathway was built to accommodate these patients. RESULTS: Inpatient waits improved from a median of 3 days to 1 day. There was no difference in outcome between those presenting with bleeding and other symptoms or any difference in patients requiring different procedures. CONCLUSIONS: Waiting times for endoscopy can be improved with the introduction of a targeted pathway of cancer patients. Further issues including cost, quality of life and nutrition require further intervention

A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study

BACKGROUND: Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC. METHODS: Eligible patients were ≥ 18 years, had histologically or cytologically-confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0-2, and adequate major organ function. Patients may have had prior surgery, radiotherapy or adjuvant chemotherapy, but no prior CisGem and no prior chemotherapy for locally advanced or metastatic disease. Patients received cisplatin 25 mg/m(2) plus gemcitabine 1000 mg/m(2) intravenously on days 1 and 8 of a 21-day cycle. Selumetinib capsules were taken daily. Patients received up to 8 cycles of CisGem and could receive selumetinib until disease progression. A dose de-escalation scheme was used to determine the recommended dose of selumetinib. The first dose level was 75 mg bd. Patients were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment. RESULTS: Thirteen patients were recruited, of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable patients received the starting dose of selumetinib 75 mg bd and one patient experienced a DLT (cardiac chest pain). The median number of days selumetinib was taken (adjusted for the number of days of dose interruptions) was 171.5 (IQR: 75.5 to 344). Two patients remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of selumetinib in cycle 1. Eight patients were evaluable for objective response (RECIST v1.1): 3 had a partial response and 5 stable disease. The median PFS was 6.4 months (IQR 5.2 to 13.7). Toxicities related to selumetinib were mostly related to oedema and rash, grade 1-2 and manageable. Pharmacokinetic analysis showed that the AUC(0-t), AUC(0-∞) and Cmax of selumetinib increased by 12, 11 and 30 % respectively when it was administered with CisGem, while Cmax for the N-desmethyl metabolite of selumetinib decreased by 40 %. There was no evidence that the time of Cmax for selumetinib or N-desmethyl metabolite of selumetinib were different when selumetinib was administered alone or with CisGem. CONCLUSION: The recommended dose of selumetinib when combined with CisGem was 75 mg bd. Translational studies are underway to identify biomarkers that may predict outcome (ClinicalTrials.gov identifier: NCT01242605 July 6(th) 2010)

Multimodal Treatment in Metastatic Colorectal Cancer (mCRC) Improves Outcomes—The University College London Hospital (UCLH) Experience

Background: Despite notable advances in the management of metastatic colorectal cancer (mCRC) over the last two decades, treatment intent in the vast majority of patients remains palliative due to technically unresectable disease, extensive disease, or co-morbidities precluding major surgery. Up to 30% of individuals with mCRC are considered potentially suitable for primary or metastasis-directed multimodal therapy, including surgical resection, ablative techniques, or stereotactic radiotherapy (RT), with the aim of improving survival outcomes. We reviewed the potential benefits of multimodal therapy on the survival of patients with mCRC treated at the UCLH. Methods: Clinical data on baseline characteristics, multimodal treatments, and survival outcomes were retrospectively collected from all patients with mCRC receiving systemic chemotherapy between January 2013 and April 2017. Primary outcome was the impact of multimodal therapy on overall survival, compared to systemic therapy alone, and the effect of different types of multimodal therapy on survival outcome, and was assessed using the Kaplan–Meier approach. All analyses were adjusted for age, gender, and side of primary tumour. Results: One-hundred and twenty-five patients with mCRC were treated during the study period (median age: 62 years (range 19–89). The liver was the most frequent metastatic site (78%; 97/125). A total of 52% (65/125) had ≥2 lines of systemic chemotherapy. Of the 125 patients having systemic chemotherapy, 74 (59%) underwent multimodal treatment to the primary tumour or metastasis. Median overall survival (OS) was 25.7 months [95% Confidence Interval (CI) 21.5–29.0], and 3-year survival, 26%. Univariate analysis demonstrated that patients who had additional procedures (surgery/ablation/RT) were significantly less likely to die (Hazard Ratio (HR) 0.18, 95% CI 0.12–0.29, p < 0.0001) compared to those receiving systemic chemotherapy alone. Increasing number of multimodal procedures was associated with an incremental increase in survival—with median OS 28.4 m, 35.7 m, and 64.8 m, respectively, for 1, 2, or ≥3 procedures (log-rank p < 0.0001). After exclusion of those who received systemic chemotherapy only (n = 51), metastatic resections were associated with improved survival (adjusted HR 0.36, 95% CI 0.20–0.63, p < 0.0001), confirmed in multivariate analysis. Multiple single-organ procedures did not improve survival. Conclusion: Multimodal therapy for metastatic bowel cancer is associated with significant survival benefit. Resection/radical RT of the primary and resection of metastatic disease should be considered to improve survival outcomes following multidisciplinary team (MDT) discussion and individual assessment of fitness

GLI3 Repressor Controls Nephron Number via Regulation of Wnt11 and Ret in Ureteric Tip Cells

Truncating GLI3 mutations in Pallister-Hall Syndrome with renal malformation suggests a requirement for Hedgehog signaling during renal development. HH-dependent signaling increases levels of GLI transcriptional activators and decreases processing of GLI3 to a shorter transcriptional repressor. Previously, we showed that Shh-deficiency interrupts early inductive events during renal development in a manner dependent on GLI3 repressor. Here we identify a novel function for GLI3 repressor in controlling nephron number. During renal morphogenesis, HH signaling activity, assayed by expression of Ptc1-lacZ, is localized to ureteric cells of the medulla, but is undetectable in the cortex. Targeted inactivation of Smo, the HH effector, in the ureteric cell lineage causes no detectable abnormality in renal morphogenesis. The functional significance of absent HH signaling activity in cortical ureteric cells was determined by targeted deletion of Ptc1, the SMO inhibitor, in the ureteric cell lineage. Ptc1−/−UB mice demonstrate ectopic Ptc1-lacZ expression in ureteric branch tips and renal hypoplasia characterized by reduced kidney size and a paucity of mature and intermediate nephrogenic structures. Ureteric tip cells are remarkable for abnormal morphology and impaired expression of Ret and Wnt11, markers of tip cell differentiation. A finding of renal hypoplasia in Gli3−/− mice suggests a pathogenic role for reduced GLI3 repressor in the Ptc1−/−UB mice. Indeed, constitutive expression of GLI3 repressor via the Gli3Δ699 allele in Ptc1−/−UB mice restores the normal pattern of HH signaling, and expression of Ret and Wnt11 and rescued the renal phenotype. Thus, GLI3 repressor controls nephron number by regulating ureteric tip cell expression of Wnt11 and Ret

Funnel plots, performance variation and the Myocardial Infarction National Audit Project 2003–2004

BACKGROUND: Clinical governance requires health care professionals to improve standards of care and has resulted in comparison of clinical performance data. The Myocardial Infarction National Audit Project (a UK cardiology dataset) tabulates its performance. However funnel plots are the display method of choice for institutional comparison. We aimed to demonstrate that funnel plots may be derived from MINAP data and allow more meaningful interpretation of data. METHODS: We examined the attainment of National Service Framework standards for all hospitals (n = 230) and all patients (n = 99,133) in the MINAP database between 1(st )April 2003 and 31(st )March 2004. We generated funnel plots (with control limits at 3 sigma) of Door to Needle and Call to Needle thrombolysis times, and the use of aspirin, beta-blockers and statins post myocardial infarction. RESULTS: Only 87,427 patients fulfilled criteria for analysis of the use of secondary prevention drugs and 15,111 patients for analysis by Door to Needle and Call to Needle times (163 hospitals achieved the standards for Door to Needle times and 215 were within or above their control limits). One hundred and sixteen hospitals fell outside the 'within 25%' and 'more than 25%' standards for Call to Needle times, but 28 were below the lower control limits. Sixteen hospitals failed to reach the standards for aspirin usage post AMI and 24 remained below the lower control limits. Thirty hospitals were below the lower CL for beta-blocker usage and 49 outside the standard. Statin use was comparable. CONCLUSION: Funnel plots may be applied to a complex dataset and allow visual comparison of data derived from multiple health-care units. Variation is readily identified permitting units to appraise their practices so that effective quality improvement may take place

Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial

OLIVIA, a multinational phase II study, suggests that bevacizumab plus FOLFOXIRI improves outcomes, including response rates, resection rates, and progression-free survival, compared with bevacizumab plus mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cance