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During fall 2020 in rural Pierce County, Washington, school districts and the county health department offered weekly rapid antigen screening to students and staff. Asymptomatic screening identified 42.5% of confirmed cases from the population. Parents reported it was a positive experience for their children. The program supported decisions to return to in-person learning, but screening ended because of resource and technical limitations. When planning in-school screening, stakeholder engagement and resource sustainability are important factors to consider. (Am J Public Health. 2022;112(8):1134–1137. https://doi.org/10.2105/AJPH.2022.306875 )

Initial dose adjustment is recommended for patients with known UGT1A1∗28 homozygosity for both conventional irinotecan and liposomal irinotecan (nal-IRI). A recent population pharmacokinetic (PK) study showed that Asian patients had a lower prevalence of UGT1A1∗28 homozygosity but a significantly higher maximum blood concentration of SN-38 (SN-38 Cmax) and a higher incidence of grade ≥3 neutropenia after nal-IRI administration than Caucasian patients. The current study investigated the association of UGT1A1 polymorphisms, including the Asian prevalent UGT1A1∗6, PK and toxicities of nal-IRI-based therapy in the Asian population.A total of 162 patients with nal-IRI-based therapy and available UGT1A1∗6 and UGT1A1∗28 genotyping were included, with 82 Asian patients from six previous phase I or II studies of nal-IRI (cohort 1) and another 80 patients with nal-IRI + 5-fluorouracil/leucovorin every 2 weeks as real-world practice in a single institute in Taiwan (cohort 2).The frequency of UGT1A1∗6 or UGT1A1∗28 homozygosity/compound heterozygosity was 9.3%, with UGT1A1∗6/∗6 in 2.5%, UGT1A1∗28/∗28 in 1.9% and UGT1A1∗6/∗28 in 4.9%. Among the 53 patients in cohort 1 with available PK data, all 7 patients with homozygosity/compound heterozygosity harbored UGT1A1∗6 and had a significantly higher level of median dose-normalized area under the concentration-time curve (AUC) and Cmax of SN-38 than those with single heterozygosity/wild type. Of the entire study population, the incidence of grade ≥3 neutropenia and diarrhea was significantly higher in patients with homozygosity/compound heterozygosity than in those with single heterozygosity/wild type, 73.3% versus 38.1% (P = 0.012, Fisher's exact test) and 33.3% versus 9.5% (P = 0.018, Fisher's exact test), respectively.The results suggest that the recommendation of a lower starting dose of nal-IRI for patients with UGT1A1∗28 homozygosity should be extended to include patients with UGT1A1∗6 homozygosity/compound heterozygosity.

This study aims to explore the biological roles of long non-coding RNA (lncRNA) ZNF281 and KLF15 in regulating cervical carcinoma progression.Differential expressions of ZNF281 in 58 collected cervical carcinoma and normal tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between ZNF281 and clinicopathologic characteristics in cervical carcinoma patients was analyzed. By generating ZNF281 knockdown model in HeLa and SiHa cells through the transfection of shZNF281, migratory ability changes were examined via transwell and wound healing assay. The role of ZNF281 in in vivo tumorgenicity of cervical carcinoma was examined by implanting xenografted cancers in nude mice. The downstream target of ZNF281 and their interaction were assessed by bioinformatics tool and Dual-Luciferase reporter assay, respectively. Finally, co-regulations of ZNF281 and KLF15 on cervical carcinoma progression were elucidated.ZNF281 was upregulated in cervical carcinoma tissues and cell lines. It was correlated to TNM staging, and incidences of lymphatic metastasis and distant metastasis in cervical carcinoma patients, while it was unrelated to age and tumor size. The knockdown of ZNF281 effectively attenuated migratory ability in HeLa and SiHa cells. Besides, knockdown of ZNF281 also reduced tumorigenicity of cervical carcinoma in nude mice. KLF15 was the downstream gene binding ZNF281, and they were negatively correlated to each other in cervical carcinoma tissues. Notably, KLF15 was responsible for ZNF281-induced regulation on cervical carcinoma migration.LncRNA ZNF281 is upregulated in cervical carcinoma samples, and it is correlated to lymphatic metastasis, distant metastasis, and poor prognosis in cervical carcinoma patients. By targeting KLF15, ZNF281 triggers migratory potential in cervical carcinoma. We believed that ZNF281 is a promising biomarker for cervical carcinoma.

Objective: Incremental hemodialysis (HD) is a strategy utilized to gradually intensify dialysis among patients with incident end-stage renal disease. However, there are scarce data about which patients’ clinic status changes by increasing treatment frequency. Methods: We retrospectively examined statistically de-identified data from 569 patients who successfully transitioned from twice- to thrice-weekly HD (2007–2011) and compared the differences in monthly-averaged values of hemodynamic and laboratory indices during the 3 months before and after the transition with the values at 1 month prior to transition serving as the reference. Results: At 3 months after transitioning from twice- to thrice-weekly HD, ultrafiltration volume decreased by 0.5 (95% CI 0.3–0.6) L/session among 189 patients (33%) with weekly interdialytic weight gain (IDWG) ≥5.4 kg/week, and increased by 0.4 (95% CI 0.3–0.5) L/session among 186 patients (33%) with weekly IDWG Discussion: In conclusion, patients who increased HD frequency from twice to thrice weekly treatment experienced increased weekly IDWG and better pre-HD SBP control with lower post-HD body weight.

Background Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated. Patients and methods Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. Results Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0–78.2) with nivolumab plus SOX and 76.5% (50.1–93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8–NR) and 10.6 months (5.6–12.5), respectively. Conclusion Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX. Clinicaltrials.gov ID NCT02746796.

Native kidney biopsies are high-risk for bleeding complications due to the vascularity of the kidney and the inability to compress the biopsy site within a deep retroperitoneal location. Recommended parameters to minimize bleeding risk include a platelet count above 100 x 109 /L, hemoglobin above 10 g/dL, systolic blood pressure

Hemodialysis catheters are associated with higher risks of complications compared to arteriovenous fistulas and grafts. Some common complications of dialysis catheters include infection, thrombus formation, central venous stenosis, and mechanical dysfunction. Rarely, catheters can become firmly adhered to a vessel wall. Catheter adhesion is a serious complication that can impact the delivery of safe and effective dialysis to affected patients. Adherent catheters commonly present insidiously with no overt diagnostic signs and symptoms or antecedent catheter malfunction. Prognosis is variable, but can be potentially fatal depending on the severity of adhesion, and sequelae of complications. There are no standardized methods of therapy and treatment strategies are anecdotally reported by interventional radiology, vascular, and cardiothoracic surgery. We hereby describe a case of hemodialysis catheter that has become firmly embedded within the superior vena cava wall. We review the available literature on the epidemiology, risk factors, long-term sequelae, and known management strategies of adherent catheters. The development of preventative measures will be of great importance given serious complications and limited treatment options. Clinical awareness and understanding of this rare condition is imperative to the prevention and management of adherent catheters.

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection. Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Enterprises can integrate business processes and information of across departments and can exhibit real-time information to decision maker by using an enterprise resource planning (ERP) system. The implementation of a commercial ERP system often has high consulting fees, software cost and risk for small-medium enterprises (SMEs). Fortunately, open source ERP systems can be considered as an alternative solution for SMEs subject to limited funds and human resources. This study presented several proposed business processes, an implemented scenario case and several management dashboards and reports by using the Odoo 9th community edition ERP system with business intelligence tool for a studied SME (manufacturer). Implementation results shown that the business scenario provided from Odoo ERP system can be applied to the studied manufacturer. To enhance the benefits of Odoo ERP system, there are several concerns should be considered, such as localization of application modules and training of professional consultants with practical skill for Odoo ERP system. Furthermore, Odoo ERP system with less expensive, flexibility, full control and efficiency can be considered as an alternative teaching system to ERP courses and undergraduate students' topics in Universities for improving students' practical ERP skill.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in 2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treatment of HCC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with intermediate and advanced/relapsed HCC representing the oncology societies of Taiwan (TOS), China (CSCO), India (ISMPO) Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Singapore (SSO). The voting was based on scientific evidence, and was independent of the current treatment practices, the drug availability and reimbursement situations in the individual participating Asian countries.

Fibroblast growth factor-1 (FGF-1) promotes differentiation of human preadipocytes into mature adipocytes via modulation of a BMP and Activin Membrane-Bound Inhibitor (BAMBI)/Peroxisome proliferator-activated receptor (PPARγ)-dependent network. Here, we combined transcriptomic and functional investigations to identify novel downstream effectors aligned with complementary analyses of gene expression in human adipose tissue to explore relationships with insulin sensitivity. RNA-Seq and qRT-PCR analysis revealed significant down-regulation of carboxypeptidase A4 (CPA4) following FGF-1 treatment or induction of differentiation of human preadipocytes in a BAMBI/PPARγ-independent manner. siRNA-mediated knockdown of CPA4 resulted in enhanced differentiation of human preadipocytes. Furthermore, expression of CPA4 in subcutaneous adipose tissue correlated negatively with indices of local and systemic (liver and muscle) insulin sensitivity. These results identify CPA4 as a negative regulator of adipogenesis that is down-regulated by FGF-1 and a putative deleterious modulator of local and systemic insulin sensitivity. Further investigations are required to define the molecular mechanism(s) involved and potential therapeutic opportunities.

Summary Background & aim Western diets rich in animal protein and poor in fruit and vegetables increase the body acid load, a predictor of type 2 diabetes risk. The relationships between dietary acid load, mild metabolic acidosis and insulin resistance remain unclear. The objective of this study was to assess the association between dietary acid load, body acid/base markers and peripheral insulin resistance at baseline and following a short-term overfeeding intervention in healthy individuals. Methods In a cross-sectional study of 104 men and women, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Plasma lactate, a marker of metabolic acidosis, was assessed and acid load scores (potential renal acid load, PRAL and net endogenous acid production, NEAP) derived from diet diaries. The cohort was grouped into lean and overweight/obese and the latter further classified as insulin-sensitive (Obsen) and insulin-resistant (Obres) based on hyperinsulinemic-euglycemic clamp glucose infusion rate (GIR, top tertile vs. bottom 2 tertiles). A subset of 40 individuals participated in an overfeeding intervention (+1250 kcal/day) for 28 days and studies repeated. Results Obsen and Obres were matched for adiposity (BMI and fat mass, both P = 1). Fasting plasma lactate was higher in Obres (0.78 [0.63–1.14] mmol/L) compared with both lean (0.71 [0.44–0.90] mmol/L, P = 0.02) and Obsen (0.67 [0.56–0.79] mmol/L, P = 0.04) and not different between lean and Obsen (P = 0.9). Overfeeding was characterized by an increase in dietary acid load scores PRAL (P = 0.003) and NEAP (P = 0.05), a reduction in GIR necessary to maintain euglycemia (P = 0.03) and an increase in fasting plasma lactate (P = 0.02). The change in lactate was inversely associated with the change in GIR (r = −0.36, P = 0.03). Conclusions Mild metabolic acidosis, measured by plasma lactate, aligns with insulin resistance independent of obesity and is induced by short-term increases in energy and dietary acid load in healthy humans. Further studies are required to determine whether buffering mild metabolic acidosis improves insulin resistance and reduces diabetes risk.

Thermal conductivity is one of the primary properties for nanofluids application investigated by many researchers. However, there are other factors such as stability and density that need to be considered to reduce sedimentation, pressure drop as well as sustain the enhanced thermal physical properties of nanofluid. The purpose of this study is to investigate and analyse the stability and density of mango bark (MB) and mango leaf (ML) nanofluids as well as hybrid nanofluids between mango bark and leaf with SiO2 and TiO2. The stability of nanofluids was measured using sedimentation method. The nanofluids arranged in order of pure ML nanofluid with increasing volume concentration of 0.25%, 0.50% and 1.00% followed by MB nanofluid, ML/SiO2 nanofluid, MB/SiO2 nanofluid, ML/TiO2 nanofluid and MB/TiO2 nanofluid. The density of nanofluids was measured using KEM DA-640 density meter and calculated using mixture rule equation. The results show that the stability of the nanofluids started to show sedimentation after 1 day of storing. Mango bark nanofluids were more stable than mango leaf nanofluids. At 1% concentration, MB nanofluid has the highest density (0.9981) followed by MB/TiO2 (0.9970), ML/TiO2 (0.9964), ML (0.9963), MB/SiO2 (0.9962) and ML/SiO2 (0.9962). Density of nanofluids have small increment with volume concentration. Meanwhile, the density of nanofluids have small decrement with volume concentration using analytical calculation. The results also shows small average error of 0.17% between experiment and analytical calculation.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/ locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Background and objectives Veterans with ESKD initiate dialysis under the Veterans Health Administration (VHA), an integrated health system, or are outsourced to non-VHA providers. It is unknown whether outcomes differ according to their dialysis provider at initiation. We sought to evaluate the association between dialysis provider and mortality and hospitalization among United States veterans initiating dialysis. Design, setting, participants, & measurements Among 68,727 United States veterans who initiated dialysis in 2007–2014, we examined the association of dialysis provider (VHA versus non-VHA) at initiation with mortality and hospitalization rates in the first 12 months post-initiation. Associations were examined across adjusted models, accounting for demographics and comorbidities. Results Patients were 72±11 years, 5% were women, 24% were black, and 10% (n=7584) initiated at VHA dialysis centers. VHA dialysis center patients were younger, more likely to be black, had fewer cardiovascular comorbidities, and lower eGFR at dialysis initiation. VHA provider patients were more likely to be hospitalized in the first 12 months (adjusted incidence rate ratio, 1.10; 95% confidence interval, 1.07 to 1.14), but had lower all-cause mortality risk (adjusted hazard ratio, 0.87; 95% confidence interval, 0.83 to 0.93) in fully adjusted models. Conclusions Veteran patients initiating dialysis with a VHA dialysis provider appear to have a lower mortality risk but higher hospitalization rates than veterans initiating dialysis at non-VHA dialysis units.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme - arginine deiminase - conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results: 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials (NCT 01287585).

Herein, we report the first case of concomitant nesidioblastosis, pancreatic neuroendocrine tumor, and intraductal papillary mucinous neoplasia. The combination is significant as each of these pathological entities is independently very rare. The patient was a 33-year-old man who presented with symptomatic hyperinsulinemic hypoglycemia and no risk factors for pancreatic disease. Abdominal imaging showed an isolated 12 mm pancreatic lesion, whilst selective arterial calcium stimulation testing demonstrated multiple territories of insulin excess. He proceeded to subtotal pancreatectomy. Histopathology revealed an endocrine microadenoma, α and β cell nesidioblastosis, and multifocal intraductal papillary mucinous neoplasia. The endocrine microadenoma and nesidioblastosis stained for insulin, suggesting both likely contributed to hypoglycemia. Glucagon immunohistochemistry was also positive, though there were no clinical features of glucagon excess. Hypoglycemia resolved postoperatively. This case and other evidence from the literature suggest that hyperplasia and neoplasia may occur sequentially in the pancreas, and that endocrine and exocrine tumorigenesis may be linked in some individuals. Further study is required to identify a unifying mechanism, and to elucidate potential ramifications in the management of patients with pancreatic neoplasms.

Context: Whereas insulin resistance and obesity coexist, some obese individuals remain insulin sensitive. Objective: We examined phenotypic and metabolic factors associated with insulin sensitivity in both muscle and liver in obese individuals. Design and Participants: Sixty-four nondiabetic obese adults (29 males) underwent hyperinsulinemic (15 and 80 mU/m2 · min)-euglycemic clamps with deuterated glucose. Top tertile subjects for glucose infusion rate during the high-dose insulin clamp were assigned Musclesen and those in the lower two tertiles were assigned Muscleres. Secondarily, top tertile subjects for endogenous glucose production suppression during the low-dose insulin clamp were deemed Liversen and the remainder Liverres. Main Outcomes Measures: Clinical and laboratory parameters and visceral, subcutaneous, liver, and pancreatic fat were compared. Results: Musclesen and Muscleres had similar body mass index and total fat (P > .16), but Musclesen had lower glycated hemoglobin (P < .001) and systolic (P = .01) and diastolic (P = .03) blood pressure (BP). Despite similar sc fat (P = 1), Musclesen had lower visceral (P < .001) and liver (P < .001) fat. Liversen had lower visceral (P < .01) and liver (P < .01) fat and C-reactive protein (P = .02) than Liverres. When subjects were grouped by both glucose infusion rate during the high-dose insulin clamp and endogenous glucose production suppression, insulin sensitivity at either muscle or liver conferred apparent protection from the adverse metabolic features that characterized subjects insulin resistant at both sites. High-density lipoprotein-cholesterol, 1-hour glucose, systolic BP, and triglycerides explained 54% of the variance in muscle insulin sensitivity. Conclusions: Obese subjects who were insulin sensitive at muscle and/or liver exhibited favorable metabolic features, including lower BP, liver and visceral adiposity. This study identifies factors associated with, and possibly contributing to, insulin sensitivity in obesity.

Introduction: In the NAPOLI-1 phase 3 study of patients with mPDAC who progressed following gemcitabine-based therapy (NCT01494506), nal-IRI+5-FU/LV significantly increased median overall survival (mOS) vs 5-FU/LV control (6.1 vs 4.2 months; unstratified hazard ratio [HR] 0.67 [0.49–0.92]; P = 0.012). Best response to prior therapy may influence treatment outcomes, prognosis and subsequent therapy choices. Methods: This post-hoc analysis explored outcomes in NAPOLI-1 patients based on best response to prior anticancer therapy. Treatment response groups were: complete response/partial response as prior best response (CR/PR) vs not CR/PR, and complete response/partial response/stable disease as prior best response (CR/PR/SD) vs not CR/PR/SD. Results: Prior to study entry, 55/417 patients (13%) had CR/PR on prior anticancer therapy, and 211 (51%) had CR/PR/SD. In the overall intent-to-treat (ITT) population, trends towards improved outcomes were observed in CR/PR vs not CR/PR patients (mOS 5.6 vs 4.8 months, HR = 0.73, P = 0.08; median progression-free survival [mPFS] 3.8 vs 2.4 months, HR = 0.73, P = 0.06; objective response rate [ORR] 13% vs 6%, P = 0.085). mOS, mPFS and ORR were similar in CR/PR/SD vs not CR/PR/SD patients (mOS 4.9 vs 4.9 months, HR = 0.95, P = 0.68; mPFS 2.5 vs 2.6 months, HR = 1.00, P = 0.95; ORR 7% vs 7%, P = 1.00). In the nal-IRI+5-FU/LV arm, a trend towards improved mOS, mPFS and ORR was observed in patients with CR/PR (n = 11) vs not CR/PR (n = 106) (mOS 9.3 vs 6.1 months, HR = 0.64, P = 0.34; mPFS 4.2 vs 3.0 months, HR = 0.53, P = 0.13; ORR 27% vs 15%). mOS, mPFS and ORR were similar in patients with CR/PR/SD (n = 58) vs not CR/PR/SD (n = 59) (mOS 6.2 vs 6.1 months, HR = 1.04, P = 0.88; mPFS 4.0 vs 3.3 months, HR = 1.18, P = 0.45; ORR 14% vs 19%, P = 0.62). Patients with CR/PR numerically benefited from treatment with nal IRI+5 FU/LV (n = 11) vs 5 FU/LV (n = 21) (mOS 9.3 vs 5.1 months, HR = 0.46, P = 0.14; mPFS 4.2 vs 1.4 months, HR = 0.33, P = 0.03; ORR 27% vs 0, P = 0.03). Patients with not CR/PR also benefited from treatment with nal IRI+5-FU/LV (n = 106) vs 5-FU/LV (n = 98) (mOS 6.1 vs 4.0 months, HR = 0.69, P = 0.03; mPFS 3.0 vs 1.5 months, HR = 0.58, P

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance., eLife digest After we eat, our blood sugar levels increase. To counteract this, the pancreas releases a hormone called insulin. Part of insulin’s effect is to promote the uptake of sugar from the blood into muscle and fat tissue for storage. Under certain conditions, such as obesity, this process can become defective, leading to a condition known as insulin resistance. This condition makes a number of human diseases more likely to develop, including type 2 diabetes. Working out how insulin resistance develops could therefore unveil new treatment strategies for these diseases. Mitochondria – structures that produce most of a cell’s energy supply – appear to play a role in the development of insulin resistance. Mitochondria convert nutrients such as fats and sugars into molecules called ATP that fuel the many processes required for life. However, ATP production can also generate potentially harmful intermediates often referred to as ‘reactive oxygen species’ or ‘oxidants’. Previous studies have suggested that an increase in the amount of oxidants produced in mitochondria can cause insulin resistance. Fazakerley et al. therefore set out to identify the reason for increased oxidants in mitochondria, and did so by analysing the levels of proteins and oxidants found in cells grown in the laboratory, and mouse and human tissue samples. This led them to find that concentrations of a molecule called coenzyme Q (CoQ), an essential component of mitochondria that helps to produce ATP, were lower in mitochondria from insulin-resistant fat and muscle tissue. Further experiments suggested a link between the lower levels of CoQ and the higher levels of oxidants in the mitochondria. Replenishing the mitochondria of the lab-grown cells and insulin-resistant mice with CoQ restored ‘normal’ oxidant levels and prevented the development of insulin resistance. Strategies that aim to increase mitochondria CoQ levels may therefore prevent or reverse insulin resistance. Although CoQ supplements are readily available, swallowing CoQ does not efficiently deliver CoQ to mitochondria in humans, so alternative treatment methods must be found. It is also of interest that statins, common drugs taken by millions of people around the world to lower cholesterol, also lower CoQ and have been reported to increase the risk of developing type 2 diabetes. Further research is therefore needed to investigate whether CoQ might provide the link between statins and type 2 diabetes.

Introduction: In NAPOLI-1 (NCT01494506), treatment with liposomal irinotecan + 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) significantly increased median overall survival (mOS) vs. 5-FU/LV (6.1 vs. 4.2 months; unstratified hazard ratio [HR]=0.67, 95% confidence interval [CI] 0.49–0.92; P = 0.012) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had progressed following gemcitabine-based therapy. We investigated the effect of metabolism and nutrition disorders (MNDs) on survival in NAPOLI-1 patients. Methods: This post-hoc analysis explored outcomes in patients with vs. without MNDs (based on MedDRA v14.1), including diabetes mellitus (DM), decreased appetite (DA; which included anorexia, poor appetite, lack of appetite, loss of appetite), hypercholesterolemia (HC), and dyslipidemia. Results: At baseline, 267/417 intent-to-treat (ITT) patients had any MND. Differences in baseline characteristics were observed in some MND subgroups vs. the ITT population: e.g. Karnofsky performance status (DA), gender and race (HC), albumin (DA, HC). Both mOS (3.6 vs. 5.3 months; HR = 1.65, 95% CI 1.25–2.18; P

Introduction: In NAPOLI-1 (NCT01494506), treatment with liposomal irinotecan + 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) significantly increased median overall survival (mOS) vs. 5-FU/LV (6.1 vs. 4.2 months; unstratified hazard ratio [HR]=0.67, 95% confidence interval [CI]:0.49–0.92; P = 0.012) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had progressed following gemcitabine-based therapy. A potential prognostic impact of primary tumor location on metastatic pancreatic cancer outcomes has been reported. We investigated the effect of primary tumor location on survival following inclusion in the NAPOLI-1 study. Methods: This post-hoc analysis explored outcomes in patients with primary tumor locations of the pancreatic head only (H only), body only (B only), tail only (T only), and multiple locations including (H_incl) and excluding (H_excl) the head. Results: Of 417 patients, 239 (57%) had a primary tumor location of H only, 54 (13%) B only, 62 (15%) T only, 17 (4%) H_incl and 30 (7%) H_excl. Karnofsky performance status was lower in patients with a primary tumor location of T only versus the intent-to-treat population. The mOS (HRs: 0.87–1.06) and median progression-free survival (mPFS) (HRs: 0.82–0.98) were similar across primary tumor location subgroups and no clear prognostic signal for OS was detected. The mOS and mPFS in patients with a primary tumor location of H only were 5.0 and 2.7 months, respectively, versus 5.4 and 2.8 months, respectively, for those with B only (mOS: HR = 1.06, 95%CI:0.75–1.50, P = 0.737; mPFS: HR = 0.98, 95%CI:0.70–1.37, P = 0.925). For patients with T only, mOS and mPFS were 4.3 and 1.7 months respectively (mOS H only vs. T only: HR = 0.89, 95%CI:0.64–1.23, P = 0.469; mPFS H only vs. T only HR = 0.89, 95%CI:0.66–1.22, P = 0.471). For patients with H_incl, mOS and mPFS were 5.7 and 2.3 months respectively, while for H_excl patients they were 4.6 and 1.4 months, respectively. For the comparison of mOS between the H only and B only+T only+H_excl subgroup (mOS=4.4, mPFS=1.7 months), HR = 0.88 (95%CI:0.69–1.11, P = 0.285) while for mPFS HR = 0.83 (95%CI:0.66–1.05, P = 0.116). For the comparison of mOS between the H only and B only+T only+H_excl+H_incl subgroup (mOS=4.6, mPFS=1.7 months), HR = 0.91 (95%CI:0.72–1.15, P = 0.421), while for mPFS HR = 0.87 (95%CI:0.70–1.09, P = 0.233). For the comparison of mOS between the H only+H_incl and B only+T only+H_excl subgroup HR = 0.87 (95%CI:0.69–1.10, P = 0.240), while for mPFS HR = 0.82 (95%CI:0.65–1.03, P = 0.084). Both mOS and mPFS were higher in patients treated with nal IRI+5 FU/LV vs. 5 FU/LV across primary tumor location subgroups (mOS: HRs: 0.39–0.88; two groups with n

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Background Advanced, unresectable biliary tract cancer (BTC) represents an area of unmet medical need due to its aggressive nature, limited treatment options, and poor prognosis. BTCs express PD-L1 and high levels of soluble PD-L1 correlate with poor prognosis in BTC patients (pts) treated with chemotherapy. PD-1/PD-L1 antagonists such as durvalumab (D; an anti–PD-L1 mAb) in combination with cytotoxic chemotherapy may contribute to a more effective antitumor immune response. Early clinical data demonstrate safety and efficacy for D as a single agent, but also in combination with chemotherapy in pts with BTC. Together, these data support the evaluation of D combined with the established chemotherapy regimen of gemcitabine (G) and cisplatin (C) for treatment of pts with previously untreated, unresectable locally advanced or metastatic BTC. Trial design TOPAZ-1 (NCT03875235) is the first large, phase III, randomized, double-blind, placebo-controlled, international study to evaluate immunotherapy + chemotherapy in pts with BTC in the first-line setting. Approximately 474 pts with previously untreated, unresectable locally advanced, recurrent or metastatic BTC will be randomized 1:1 to Arm A (D + G/C for up to 8 cycles, followed by D until progressive disease [PD]) or Arm B (placebo + G/C for up to 8 cycles, followed by placebo until PD). Pts will be stratified by disease status (initially unresectable vs recurrent) and primary tumor location. Eligibility criteria include previously untreated disease if unresectable or metastatic at initial diagnosis (and pts with recurrent disease >6 months after curative surgery or completion of adjuvant therapy), WHO/ECOG PS of 0 or 1, and no history of another primary malignancy, brain metastases or spinal cord compression. Pts with ampullary cancer or prior locoregional therapy will be excluded and major surgery must have been completed >28 days prior to the study. The primary endpoint is overall survival for Arm A vs Arm B. Secondary endpoints include progression-free survival, objective response rate, and duration of response by investigator assessment using RECSIST v1.1. Clinical trial identification NCT03875235. Editorial acknowledgement Jubilee Stewart, PhD, of PAREXEL, was funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure D. Oh: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. L. Chen: Honoraria (self), Advisory / Consultancy: AstraZeneca; Bristol-Myers Squibb; Lilly; MSD; Ono Pharmaceutical; PharmaEngine; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; TTY; Biopharm; Advisory / Consultancy: Five Prime Therapeutics; Syncore; Research grant / Funding (institution): Celgene; GlaxoSmithKline; Merck Serono; Novartis; Pfizer; Polaris; Syncore; Licensing / Royalties: anti-alpha-enolase (ENO-1) monoclonal antibody to HuniLife Technology, Taiwan. T. Okusaka: Honoraria (self), Research grant / Funding (institution): Eisai; Lilly; Novartis; Yakult Honsha; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Dainippon Sumitomo Pharma; Advisory / Consultancy: Zeria Pharmaceutical; Honoraria (self): AbbVie; AstraZeneca Japan; Bayer Yakuhin; Celgene; Chugai Pharma; EA Pharma; Fujifilm; Nobelpharma; Ono Pharmaceutical; Pfizer; Shire; Takara Bio; Teijin Pharma; Zeria Pharmaceutical. S. Chin: Full / Part-time employment: AstraZeneca. N. Rokutanda: Full / Part-time employment: AstraZeneca. H. Uchinda: Full / Part-time employment: AstraZeneca. A. Vogel: Honoraria (self): Amgen; Bayer; Bristol-Myers Squibb; Delcath Systems; Lilly; MSD; Novartis; Roche; Sanofi, Incyte, AstraZeneca; Advisory / Consultancy: Amgen; Bayer; Bristol-Myers Squibb; Delcath Systems; Lilly; MSD; Novartis; Roche; Sanofi, Incyte, AstraZeneca; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Bayer; Ipsen; Roche. J.W. Valle: Honoraria (self): Ipsen; Advisory / Consultancy: Agios; AstraZeneca; Delcath Systems; Genoscience Pharma; Incyte; Ipsen; Keocyt; Merck; Novartis; PCI Biotech; Pfizer; Pieris Pharmaceuticals; QED; Speaker Bureau / Expert testimony: Ipsen; Novartis; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Celgene; Nucana. H. Kim: Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.

Background Pancreatic cancer (PC) is the 4th deadliest cancer in Europe, with more than 95% of those affected dying from the disease and is set to be the second greatest cause of death from cancer by 2020.(ECPC, European Cancer Patient Coalition) FOLFIRINOX regimen is the standard 1st-line treatment for PC patients with good performance status; however, there is still no standard of care in 2nd-line therapy for patients failed FOLFIRINOX. EndoTAG-1 is a novel formulation of cationic liposomes embedded with Paclitaxel, which specifically displays antivascular and antiangiogenic activity. By binding and internalizing at tumor endothelial cells after intravenous administration, the cytostatic and cytotoxic activities of paclitaxel are targeted to the activated tumor endothelial cells. Trial design •Patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas failed on FOLFIRINOX treatment will be screened and randomized into one of the two arms in the study (n = 218). •ArmA: EndoTAG-1 and Gemcitabine Patients will be administrated with EndoTAG-1 (22 mg/m²) twice weekly plus gemcitabine (1000 mg/m²) once weekly for 1 cycle (8 weeks), which consisting of 3 weeks of treatment and 1 week rest, followed by 3 weeks of treatment and 1 week rest. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. •ArmB: Gemcitabine Patients will be administrated with Gemcitabine (1000 mg/m²) once weekly for 1 cycle (8 weeks), which consisting of 3 weeks of treatment and 1 week rest, followed by 3 weeks of treatment and 1 week rest. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. Clinical trial identification NCT03126435, other study ID numbers:CT4006. Legal entity responsible for the study SynCore Biotechnology Co., Ltd. Funding SynCore Biotechnology Co., Ltd. Disclosure All authors have declared no conflicts of interest.

Background Local health department leaders are expected to improve the health of their populations as they "use and contribute to" the evidence base for practice, but effectively providing and utilizing data and evidence for local public health decision making has proven difficult. Purpose This study was conducted in 2011 and initiated by Washington State's public health practice–based research network to identify factors influencing local resource allocation and programmatic decisions among public health leaders facing severe funding losses. Methods Quantitative data informed sampling for the collection of interview data. Qualitative methods were used to capture diverse insights of Washington State's local public health leaders in making decisions regarding resource allocation. Results Local decision-making authority was perceived as greatly restricted by what public health activities were legally mandated and the categoric nature of funding sources, even as some leaders exercised deliberate strategic approaches. One's workforce and board of health were also influential in making decisions regarding resource allocations. Challenges were expressed regarding making use of data and research evidence for decision making. Data were analyzed in 2011–2012. Conclusions Programmatic mandates, funding restrictions, local stakeholders, and workforce capacity appear to trump factors such as research evidence and perceived community need in public health resource allocation. Study findings highlight tensions between the literature descriptions of what "should" influence decision making in local public health and the realities of practice. Advancements in practice-based research and evidence-based decision making, however, provide opportunities for strengthening the development of evidence and research translation for local decision making to maximize resources and promote effective service provision.

Background and Aim: With the rising incidence of digestive cancers in the Asia Pacific region and the advancement in diagnosis, management and palliation in these conditions, the clinical burden on oncologists is ever increasing. This Summit meeting was called to discuss the optimal management of digestive cancers and the role of Gastroenterologists Method: Experts from Asia Pacific countries in the fields of medical, oncologic, surgical and endoscopic management of cancers in the esophagus, stomach, colon/rectum and the liver reviewed the literature and their practice. 18 position statements were drafted, debated and voted. Results: It was agreed that the burden on GI cancer is increasing. More research will be warranted on chemotherapy, chemoprevention, cost-effectiveness of treatment and nutrition. Cancer management guidelines should be developed in this region when more clinical data are available. In order to improve care to patients, a multi-disciplinary team coordinated by a “cancer therapist” is proposed. This cancer therapist can be a gastroenterologist, a surgeon or any related discipline who have acquired core competence training. This training should include an attachment in a center-of-excellence in cancer management for no less than 12 months. Conclusion: The management of GI cancer should be an integrated multi-disciplinary approach and training for GI cancer therapists should be provided for.