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Background Cancer-associated fibroblasts (CAFs) are considered to play a fundamental role in pancreatic ductal adenocarcinoma (PDAC) progression and chemoresistance. Patient-derived organoids have demonstrated great potential as tumor avatars for drug response prediction in PDAC, yet they disregard the influence of stromal components on chemosensitivity. Methods We established direct three-dimensional (3D) co-cultures of primary PDAC organoids and patient-matched CAFs to investigate the effect of the fibroblastic compartment on sensitivity to gemcitabine, 5-fluorouracil and paclitaxel treatments using an image-based drug assay. Single-cell RNA sequencing was performed for three organoid/CAF pairs in mono- and co-culture to uncover transcriptional changes induced by tumor-stroma interaction. Results Upon co-culture with CAFs, we observed increased proliferation and reduced chemotherapy-induced cell death of PDAC organoids. Single-cell RNA sequencing data evidenced induction of a pro-inflammatory phenotype in CAFs in co-cultures. Organoids showed increased expression of genes associated with epithelial-to-mesenchymal transition (EMT) in co-cultures and several potential receptor-ligand interactions related to EMT were identified, supporting a key role of CAF-driven induction of EMT in PDAC chemoresistance. Conclusions Our results demonstrate the potential of personalized PDAC co-cultures models not only for drug response profiling but also for unraveling the molecular mechanisms involved in the chemoresistance-supporting role of the tumor stroma.

AbstractObjectiveTo evaluate the accuracy of the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) to screen for major depression among people with physical health problems.DesignSystematic review and individual participant data meta-analysis.Data sourcesMedline, Medline In-Process and Other Non-Indexed Citations, PsycInfo, and Web of Science (from inception to 25 October 2018).Review methodsEligible datasets included HADS-D scores and major depression status based on a validated diagnostic interview. Primary study data and study level data extracted from primary reports were combined. For HADS-D cut-off thresholds of 5-15, a bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, in studies that used semi-structured diagnostic interviews (eg, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders), fully structured interviews (eg, Composite International Diagnostic Interview), and the Mini International Neuropsychiatric Interview. One stage meta-regression was used to examine whether accuracy was associated with reference standard categories and the characteristics of participants. Sensitivity analyses were done to assess whether including published results from studies that did not provide raw data influenced the results.ResultsIndividual participant data were obtained from 101 of 168 eligible studies (60%; 25 574 participants (72% of eligible participants), 2549 with major depression). Combined sensitivity and specificity was maximised at a cut-off value of seven or higher for semi-structured interviews, fully structured interviews, and the Mini International Neuropsychiatric Interview. Among studies with a semi-structured interview (57 studies, 10 664 participants, 1048 with major depression), sensitivity and specificity were 0.82 (95% confidence interval 0.76 to 0.87) and 0.78 (0.74 to 0.81) for a cut-off value of seven or higher, 0.74 (0.68 to 0.79) and 0.84 (0.81 to 0.87) for a cut-off value of eight or higher, and 0.44 (0.38 to 0.51) and 0.95 (0.93 to 0.96) for a cut-off value of 11 or higher. Accuracy was similar across reference standards and subgroups and when published results from studies that did not contribute data were included.ConclusionsWhen screening for major depression, a HADS-D cut-off value of seven or higher maximised combined sensitivity and specificity. A cut-off value of eight or higher generated similar combined sensitivity and specificity but was less sensitive and more specific. To identify medically ill patients with depression with the HADS-D, lower cut-off values could be used to avoid false negatives and higher cut-off values to reduce false positives and identify people with higher symptom levels.Trial registrationPROSPERO CRD42015016761.

Constant-minute-volume and constant-bolus devices serve as two different means of portable oxygen conservation. A prospective randomised crossover study was conducted in COPD GOLD IV patients to investigate the effect of these two devices on dyspnea, oxygenation and 6-minute walking test (6MWT) distance. The primary endpoint was the final operating level required (operating level range 1-5 for both devices) by either device to meet the success criteria for mobile oxygen therapy, as outlined in the British Thoracic Society guidelines (SpO ≥90% throughout 6MWT; ≥10% increase in walking distance from baseline; improvement in BORG of at least 1 point from baseline). Twenty-five patients were enrolled in the study and randomly assigned to one of two sequences involving the use of each type of portable oxygen conservation device. 14 female, 67.9 years (±7.8); FEV1: 27.3%pred. (±8.4); PaO at rest without oxygen: 50.3mmHg (±5.9). For both systems, 24/25 patients (96%) were successfully recruited. The mean operating-level difference when success criteria were met was -0.58 in favor of the constant bolus device (95% CI: -0.88 to -0.28, <0.001). Secondary endpoints (walking distance, respiratory rate and BORG dyspnea) showed no statistically significant or clinically relevant differences. An algorithm created especially for this study showed a high success rate in terms of titration for the required operating level. Both portable oxygen-conserving devices met the success criteria in 96% of patients in the 6MWT when they were titrated to the correct level. The constant-bolus device required a significantly lower operating level to achieve the success criteria, hereby reducing energy consumption. Individual titration of the respective device is recommended, which can be facilitated by the novel titration algorithm described here.

Introduction: Patients with malignant biliary obstruction and prior biliary intervention are prone to develop acute cholangitis, a complication that can delay chemotherapy, prolong hospitalization, and decrease overall survival. We sought to evaluate clinical outcomes of malignant biliary obstruction and consequent acute cholangitis based on timing of biliary decompression. Methods: The 2010-2014 Nationwide Readmission Database was queried to identify adult (≥18 years) patients with a principal diagnosis of acute cholangitis and malignant biliary obstruction. Clinical outcomes were reported according to whether biliary decompression was performed early (≤ 24hr) or late (≥ 1-7 days). Primary outcomes were mortality at index admission and calendar year mortality. Inclusion criteria were patients with primary pancreaticobiliary or gastrointestinal cancer, all metastatic cancers, or lymphomas and malignancies of the bone marrow with biliary obstruction. Exclusion criteria were absence of biliary decompression or decompression after ≥ 7 days, and presence of gallstones, choledocholithiasis, or acute pancreatitis. A multivariate analysis was performed to identify reasons for late ERCP while a one-to-one propensity score-matched analysis was utilized for mortality at index admission and calendar-year mortality. Results: 923 patients were identified among which 538 (31.5%) underwent early and 385 (22.5%) late biliary decompression. The majority of biliary decompression was via ERCP, with significantly more among early decompression (91.1%, Table 1). Multivariate analysis revealed that weekend admission (Odds Ratio (OR) 2.32, 95% Confidence Interval (CI) 1.33, 4.03) and duodenal cancers (OR 8.69, 95% CI 1.59, 47.4) were associated with late biliary decompression. A propensity matched analysis (179 unweighted pairs; Table 2) revealed that late ERCP/non-endoscopic biliary decompression was associated with higher rates of index admission (OR 4.11,95% CI 1.29, 13.12) and calendar year mortality (Hazard ratio 2.65, 95% CI 1.29, 5.45). Conclusion: Late biliary decompression >24 hours in acute cholangitis due to malignant biliary obstruction is associated with a more than two-fold increase in both index admission and calendar year mortality. Weekend admission, a potentially reversible variable, was associated with delaying biliary decompression. With the continued increase in cancer prevalence, there is a need to optimize strategies to prevent delays in managing these emergent conditions.

Introduction: The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is a nationally recognized, publicly reported, standardized instrument used to measure patients' perceptions of their hospital experience. The aim of this study is to determine which survey instrument questions are associated with high HCAHPS scores in patients (pts) hospitalized with acute pancreatitis (AP). Methods: HCAHPS surveys were randomly administered to discharged pts with AP (n=318). The primary outcome, \"patients' satisfaction\", was judged by overall hospital rating(1-10 scale): A score of 9 or 10 was considered SATISFIED while scores less than 9 are considered NOT SATSIFIED. For the secondary outcome, \"willingness to recommend the hospital\", choosing that they would \"definitely\" recommend the hospital was considered a positive response. Binary variables were derived to represent each criteria of interest. A univariate analysis and subsequent adjustments for confounders using fitted logistic regression models were used for this analysis. Significance was determined using Holm's method with a family-wise p value =.05 Results: 299 responders [NOT SATISFIED, n=96; SATISFIED, n=203] were included in the final analyses. Groups were similar with the exception that SATISFIED responders were older (57 vs 53yr; p=.006, Table 1). Perception of adequate pain control did not impact patients' satisfaction [adjusted odd ratio (aOR)=1.07 p=.874] or willingness to recommend the hospital (aOR=1.46 p=.326). However, courtesy/respect (aOR=10.18 p=.001, 5.16 p=.007), and effective communication with nurses and doctors (aOR=4.01 p< .0002, 3.97 p< .0002), and positive facilities rating (aOR=4.01 p < .0002, 3.97 p < .002) were all positively associated with patients' satisfaction and willingness to recommend the hospital (Table 2). Conclusion: In hospitalized AP pts, perceived courtesy/respect, effective communication, facility cleanliness and quietness impacted HCAHPS score. Perception of adequate pain control had no impact on HCAHPS scores. Facility-based interventions intended to improve patients' experience should be directed to these domains to be effective. Additional studies involving larger sample size are needed to validate these findings.