Expression of LMO4 and outcome in pancreatic ductal adenocarcinoma

Identification of a biomarker of prognosis and response to therapy that can be assessed preoperatively would significantly improve overall outcomes for patients with pancreatic cancer. In this study, patients whose tumours exhibited high LMO4 expression had a significant survival advantage following operative resection, whereas the survival of those patients whose tumours had low or no LMO4 expression was not significantly different when resection was compared with operative biopsy alone

Climate change and epilepsy: insights from clinical and basic science studies

Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change. (C) 2021 Elsevier Inc. All rights reserved.Paroxysmal Cerebral Disorder

TRP family proteins in the lower urinary tract: translating basic science into new clinical prospective

The lower urinary tract (LUT) is densely innervated by capsaicin-sensitive primary afferent neurons, a sub set of sensory nerves, in a number of species including humans. These fibers exhibit both a sensory (afferent) function, including the regulation of the micturition reflex and the perception of pain, and an ‘efferent’ function, involved in the detrusor smooth muscle contractility and plasma protein extravasation. The discovery of specific binding sites for capsaicin, the pungent ingredient of red chilli, initiated a rush that ended up with the cloning of the ‘vanilloid receptor’, which belongs to the TRP (transient receptor potential) family. Here we reviewed the knowledge about the presumable functions of TRP family proteins in the LUT as regulators of bladder reflex activity, pain perception and cell differentiation. This review will focus on experimental evidence and promising clinical applications of targeting these proteins for the treatment of detrusor overactivity and bladder pain syndrome. As TRP receptor ligands may promote cellular death, and inhibit the growth of normal and neoplastic cells, the translation of basic science evidence into new clinical prospective for bladder and prostate cancer will be shown

HSD17B4 overexpression, an independent biomarker of poor patient outcome in prostate cancer.

Steroid hormones and their metabolising enzymes have been studied extensively for their potential role in prostate cancer, with more recent interest in the androgen/estrogen inactivating enzyme 17 beta-hydroxysteroid dehydrogenase type 4 (HSD17B4). Gene expression profiling showed HSD17B4 to be significantly overexpressed in prostate cancer compared to matched-benign epithelium. We therefore hypothesized that altered HSD17B4 expression may contribute to prostate cancer progression via altered hormone balance. In this study, HSD17B4 mRNA and protein expression were assessed by in situ hybridisation (ISH) and immunohistochemistry (IHC), respectively, in tissue arrays of prostate tissue from 172 patients treated by radical prostatectomy. Overexpression of HSD17B4 mRNA and protein was associated with prostate cancer (P < 0.0001) and multivariate Cox proportional hazards analysis, adjusted for known prognostic indicators, demonstrated HSD17B4 mRNA and high protein expression were significant independent predictors of poor patient outcome as measured by time until PSA relapse (mRNA: hazards ratio [HR] = 1.90,95% confidence interval [CI] = 1.15-3.12; P < 0.0001; and protein: HR = 2.09,95% Cl = 1.31-3.33: P = 0.0026). Here we provide strong evidence that both mRNA and protein overexpression of HSD17B4 is not only associated with the presence of prostate cancer, but is also a significant independent predictor of poor patient outcome

Margin clearance and outcome in resected pancreatic cancer

PURPOSE: Current adjuvant therapies for pancreatic cancer (PC) are inconsistently used and only modestly effective. Because a high proportion of patients who undergo resection for PC likely harbor occult metastatic disease, any adjuvant trials assessing therapies such as radiotherapy directed at locoregional disease are significantly underpowered. Stratification based on the probability (and volume) of residual locoregional disease could play an important role in the design of future clinical trials assessing adjuvant radiotherapy. PATIENTS AND METHODS: We assessed the relationships between margin involvement, the proximity to operative resection margins and outcome in a cohort of 365 patients who underwent operative resection for PC. RESULTS: Microscopic involvement of a resection margin by tumor was associated with a poor prognosis. Stratifying the minimum clearance of resection margins by 0.5-mm increments demonstrated that although median survival was no different to clear margins based on these definitions, it was not until the resection margin was clear by more than 1.5 mm that optimal long-term survival was achieved. CONCLUSION: These data demonstrate that a margin clearance of more than 1.5 mm is important for long-term survival in a subgroup of patients. More aggressive therapeutic approaches that target locoregional disease such as radiotherapy may be beneficial in patients with close surgical margins. Stratification of patients for entry onto future clinical trials based on this criterion may identify those patients who benefit from adjuvant radiotherapy

An analysis of multiple biomarkers to better predict prostate cancer metastasis and death after radical prostatectomy

Abstract 54 Background: Identification of potentially lethal disease at the time of diagnosis with localized prostate cancer (PCa) remains a significant clinical issue despite a plethora of candidate biomarkers. This study evaluates a range of biomarkers previously associated with biochemical relapse (BR) in localized PCa to determine whether a combined expression model can improve detection of clinically significant cases. Methods: The Australian PCa Research Centre NSW has completed 23 studies of molecular biomarkers associated with BR in a well-described localized PCa cohort (n=324, median followup 16 years). 12 studies were excluded due to missing data. Each biomarker was analyzed as a marker for metastatic-free survival (MFS) and prostate cancer specific survival (PCSS) and then used to develop a prognostic model for clinical outcomes incorporating clinico-pathological factors. This model is currently being validated in an independent cohort. Results: The PCa cohort experienced 39 metastatic relapses (12%) and 23 PCa deaths (7%). Of 12 biomarkers (AR, AZPG1, C0S, Cyclin D1a, Cyclin D1b, E6AP, H3K18Ac, H3K4me2, Ki67, p53, PML, SGTA) assessed, only AZGP1 and Ki67 were associated with MFS (HR 2.9, 95% CI, 1.4-5.6; P=0.002, and HR 1.2, 95% CI, 1.0-1.4; P=0.03, respectively) and PCSS (HR 4.2, 95% CI, 1.7-10.5; P=0.002; and HR 1.2, 95% CI, 1.0-1.5; P=0.04, respectively). The combined panel of AZGP1 and Ki67 was an independent predictor of MFS (HR 1.9, 95% CI, 1.1-3.2; P=0.01), and PCSS (HR 3.3, 95% CI, 1.5-7.3; P=0.002) when modeled with known clinicopathological variables. The panel was more robust in predicting MFS and PCSS compared to the individual biomarkers alone and superior to other prognostic models (See table). Data from the validation cohort will be available for the meeting. Conclusions: Our novel signature of AZPG1 and Ki67 improves existing prognostication tools in predicting PCa metastasis and death. [Table: see text] Alison Yan Zhang, Karen Chiam, Ygal Haupt, Stephen B. Fox, Simone Birch, Wayne Tilley, Lisa Butler, Karen E. Knudsen, Christopher Cornstock, Krishan Rasiah, Judith Grogan, Kate Lynette Mahon, Tina Bianco-Miotto, Maret Bohm, Susan M. Henshall, Warick Delprado, Phillip Stricker, Lisa Horvath, James Kenc

Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer

Background and Aims: Current methods of preoperative staging and predicting outcome following pancreatectomy for pancreatic cancer (PC) are inadequate. We evaluated the utility of multiple biomarkers from distinct biologic pathways as potential predictive markers of response to pancreatectomy and patient survival. Methods: We assessed the relationship of candidate biomarkers known, or suspected, to be aberrantly expressed in PC, with disease-specific survival and response to therapy in a cohort of 601 patients. Results: Of the 17 candidate biomarkers examined, only elevated expression of S100A2 was an independent predictor of survival in both the training (n = 162) and validation sets (n = 439; hazard ratio [HR], 2.19; 95% confidence interval [CI]: 1.48–3.25; P < .0001) when assessed in a multivariate model with clinical variables. Patients with high S100A2 expressing tumors had no survival benefit with pancreatectomy compared with those with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6 months (19.4 vs 8.8 months, respectively) and a HR of 3.23 (95% CI: 2.39–4.33; P < .0001). Of significance, patients with S100A2-negative tumors had a significant survival benefit from pancreatectomy even in the presence of involved surgical margins (median, 15.7 months; P = .0007) or lymph node metastases (median, 17.4 months; P = .0002). Conclusions: S100A2 expression is a good predictor of response to pancreatectomy for PC and suggests that high S100A2 expression may be a marker of a metastatic phenotype. Prospective measurement of S100A2 expression in diagnostic biopsy samples has potential clinical utility as a predictive marker of response to pancreatectomy and other therapies that target locoregional disease