Circulating immune-related proteins associated with immune checkpoint inhibitor efficacy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Most patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383) showed a clinical benefit (CB) rate of 37% and a response rate of 14% in patients with metastatic PDAC receiving stereotactic radiation therapy and nivolumab with or without ipilimumab. Translational studies were initiated to characterize the patients who would benefit from this treatment. Here, we evaluated the association between treatment outcome and 92 circulating immuno-oncology-related proteins in patients from the CheckPAC trial. MATERIALS AND METHODS: The study included 78 patients with chemoresistant metastatic PDAC treated with nivolumab ± ipilimumab combined with radiotherapy. Proteins were measured in serum samples collected at baseline and on treatment with the use of the Olink Target 96 Immuno-Oncology panel. A cohort of 234 patients with metastatic PDAC treated with first-line chemotherapy were also included. RESULTS: High levels of Fas ligand (FASLG) and galectin 1 (Gal-1) and low levels of C-C motif chemokine 4 were associated with CB. High FASLG and Gal-1 were associated with longer progression-free survival in univariable analysis. In the multivariable Cox regression analysis, the association was significant for Gal-1 (P < 0.001) but not significant for FASLG (P = 0.06). A focused unsupervised hierarchal clustering analysis, including T-cell activation and immune checkpoint-related proteins, identified clusters of patients with higher CB rate and higher tumor expression of leukocyte or T-cell markers (CD3, CD45, granzyme B). Thirty-six proteins increased significantly during immunotherapy. Several proteins (including FASLG, checkpoint proteins, and immune activation markers) increased independently of response during immunotherapy but did not increase in the cohort of patients treated with chemotherapy. CONCLUSIONS: Circulating levels of immune-related proteins like FASLG and Gal-1 might be used to predict the efficacy of checkpoint inhibitors in patients with metastatic PDAC.

Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children's Oncology Group Report.

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.

Multiomics in the central Arctic Ocean for benchmarking biodiversity change.

Multiomics approaches need to be applied in the central Arctic Ocean to benchmark biodiversity change and to identify novel species and their genes. As part of MOSAiC, EcoOmics will therefore be essential for conservation and sustainable bioprospecting in one of the least explored ecosystems on Earth.

Genomic landscape of treatment refractory metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a complex and heterogeneous disease with few standard and targeted treatment options. Next-generation sequencing of tumor tissue was performed to identify cancer driver mutations to discover possible personalized treatment options, as targeted treatment possibilities are limited for this patient population. Results of genomic sequencing in patients with treatment-refractory mCRC are described in this retrospective analysis. MATERIAL AND METHODS: Clinico-pathological characteristics and genomic sequence results of consecutive patients with refractory mCRC, referred to the Experimental Cancer Therapy Unit (ECTU) at Department of Oncology, Herlev & Gentofte Hospital in the period from 1 October 2015 to 14 December 2018 were reviewed in this retrospective analysis. Tumor tissue from the patients was analyzed by next-generation sequencing using the Oncomine Comprehensive primer panel to detect actionable variants of cancer driver mutations and microsatellite instability status. From August 2018 tumor mutational burden was also analyzed. RESULTS: A total of 80 patients with treatment-refractory mCRC and in a fairly good performance were referred to the ECTU during this period. Genomic sequencing of tumor tissue was performed for all 80 patients and a cancer driver mutation was identified in 90% (n = 72) of the patients. A total of 31.3% (n = 25) of the patients received therapy either as targetable therapy outside an available trial (n = 2), FDA approved therapy (n = 2), or treatment in phase 1 or 2 trials, independent of the genomic signature 26.3% (n = 21). CONCLUSION: Most mCRC patients refractory to standard anti-neoplastic therapies, presented with a cancer driver mutation, however, only a few of these mutations gave rise to matched therapies as only 2.5% of the patients from this period received targeted therapy.

Postoperative and long-term survival in relation to life-expectancy after pancreatic surgery in elderly patients (cohort study).

BACKGROUND: An evaluation of the outcome after pancreatic surgery with focus on post-operative and late survival in elderly patients was performed. METHODS: The study included 1.556 patients from a single HBP unit operated from 1. January 2010 to 31. December 2019. Patients were divided into two cohorts, < 75 years (n = 1.296) and ≥75 years (n = 260). Post-operative outcome was evaluated in all patients and late outcome in patients with adenocarcinoma in the pancreas (n = 765) and the duodenum (n = 117). The follow-up of patients with benign disease and adenocarcinoma was 57.95 (12.1-132.7) and 39.85 (12.0-131.7) months, respectively. RESULTS: Length of hospital-stay and surgical complications were not significantly different in the two cohorts, but in-hospital death was 1.1% (<75 years) and 3.5% (≥75 years) (p = 0.008). The median overall survival of adenocarcinoma was 29.7 (<75 years) and 24.3 months (≥75 years) (p = 0.3228) with a one, two, and five-years survival of 74.5%, 56.6% and 28.6% vs. 73.6%, 51.1%, and 25.5%. Median time to relapse (46.2% of patients <75 years and 40.5% of patients ≥75 years) was 9 (1 - 51) and 8 (1 - 78) months (p = 0.534), respectively. Adjuvant chemotherapy did not have impact on the survival of the old cohort. Patients who died during the observation period had lost 94% (<75 years) and 87% (≥75 years) of expected remnant life. Estimated years lost in the old cohort was 4.2 in males and 4.9 in females (p = 0.025). CONCLUSION: Elderly patients may undergo pancreatic surgery with a low mortality and for adenocarcinoma with an acceptable long-term survival.

Metagenome Sequencing to Explore Phylogenomics of Terrestrial Cyanobacteria.

Cyanobacteria are ubiquitous microorganisms with crucial ecosystem functions, yet most knowledge of their biology relates to aquatic taxa. We have constructed metagenomes for 50 taxonomically well-characterized terrestrial cyanobacterial cultures. These data will support phylogenomic studies of evolutionary relationships and gene content among these unique algae and their aquatic relatives.

Percutaneous coronary intervention in patients hospitalized for non-ST-elevation myocardial infarction and the risk of postdischarge ischemic stroke at 6-month, 1-year, and 3-year follow-ups.

Percutaneous coronary intervention (PCI) is suggested for treating patients with non-ST-elevation myocardial infarction (NSTEMI) to reduce adverse cardiovascular events. However, the short- and long-term effects of PCI on the risk of postdischarge ischemic stroke (IS) in patients hospitalized for NSTEMI remain unclear. This study investigated the association of PCI on the risk of postdischarge IS in patients hospitalized for NSTEMI at different period follow-ups. A population-based cohort study was conducted using data from Taiwan's National Health Insurance Research Database. Propensity score matching (PSM) was used to select 6079 pairs of the patients with NSTEMI treated invasively by PCI (received PCI during hospitalization) and initial conservative strategy (did not receive PCI during hospitalization) with similar baseline characteristics for evaluation. After adjustment for patients' clinical variables and the duration of dual antiplatelet therapy, PCI was associated with a decreased risk of postdischarge IS at 6-month, 1-year, and 3-year follow-ups [adjusted hazard ratio (aHR) = 0.41, 95% confidence interval (CI) = 0.26-0.67, p < 0.001; aHR = 0.61, 95% CI 0.43-0.86, p = 0.004; and aHR = 0.69, 95% CI 0.54-0.89, p = 0.005respectively]. In the patients who had a CHA2DS2-VASc score of ≥2, PCI was also associated with a decreased risk of postdischarge IS at 6-month, 1-year, and 3-year follow-ups (aHR = 0.54, 95% CI 0.36-0.83, p = 0.005; aHR = 0.72, 95% CI 0.52-1.00, p = 0.048; and aHR =0.73, 95% CI 0.58-0.91, p = 0.005, respectively). These findings suggested that PCI might reduce the risk of postdischarge IS in patients hospitalized for NSTEMI.

Thrombotic Ringed Polytetrafluoroethylene Graft With Infection After Living-Donor Liver Transplantation.

BACKGROUND: The safety of the living donor in living-donor liver transplantation (LDLT) is always the first priority, meanwhile, the graft-to-recipient weight ratio (GRWR) and the anatomy of the liver allograft must also not be compromised in order to warrant tranplatation success. When it comes to the allograft of the right lobe of the liver without the middle hepatic vein (R-M), the outflow and adequate drainage for the territory of middle hepatic vein (MHV) is one critical concern. Despite publications in some high-volume transplant centers on the positive results of using expanded polytetrafluoroethylene (ePTFE) grafts to substitute those of autologous veins, complications related to the ePTFE graft have not been well discussed. METHODS: From July 2012 to June 2016, 129 adult patients who underwent living donor liver transplantation in Taipei Veterans General Hospital were analyzed. There were 3 cases of adjacent organ erosion with gas bubbles in the lumen of an ePTFE graft, including gastrointestinal (GI) tract penetration in 2 out of the first 15 cases that used the venous graft of ringed expanded polytetrafluoroethylene (rPTFE). The patient survival rate during this period was compared and radiological findings of rPTFE function and clinical signs of erosion with infection were also examined to raise the concerns of safety as well as early detection of complications of rPTFE. RESULTS: The overall 1-year patient survival rate was 90%, of which the right lobe wih MHV (R+M) group was 93.5% and the R-M group was 91.9%. For the mean of GRWR, the R+M group was 1.05 ± 0.19 and R-M group was 1.19 ± 0.27, while those who needed reconstruction with vein grafts was 0.96 ± 0.11. Among the R-M group, 24 out of 88 cases (27.3%) needed reconstruction of MHV tributaries. Of the 24 cases, 15 cases were done with rPTFE and the 1-year patient survival rate of the rPTFE group was 73%, which is significantly worse (P = .008) than the non-rPTFE (89%) and non-reconstructed (97%) groups. The mean GRWR is significantly higher (P = .001) in the non-reconstructed group (1.19 ± 0.27) than in the rPTFE (0.99 ± 0.11) and non-rPTFE (0.94 ± 0.11) groups. The venous grafts patency rate between the different graft types is no different, and there is also significance in warm ischemic time (P = .009) between the non-reconstructed (49 ± 15), rPTFE (81 ± 51), and non-rPTFE (56 ± 18) groups in the mean minutes. CONCLUSION: In cases of fever of unknown cause in patients receiving LDLT with rPTFE graft, a regular computed tomography (CT) scan with contrast and gas bubbles within the graft lumen is the best way for early detection of graft related infection and suspicious GI tract penetration. To decrease the risks of tissue reaction induced by ePTFE graft in LDLT, omentum patches or other inert agents can be introduced as a buffer between the graft and adjacent organs, especially the GI tracts. However, research in material science shall be explored to solve the problem in the future.

Comparative effect of antipsychotics on risk of self-harm among patients with schizophrenia.

OBJECTIVE: To investigate the association of different antipsychotic treatments with hospitalization due to self-harm among patients with schizophrenia. METHOD: This retrospective cohort study was based on Taiwan's universal health insurance database. Patients aged 15-45 years with a newly diagnosed schizophrenic disorder in 2001-2012 were included. The study outcome was the first hospitalization due to self-harm or undetermined injury after the diagnosis of schizophrenic disorders. The exposure status of antipsychotics was modeled as a time-dependent variable. The analyses were stratified by antipsychotic dosage based on defined daily dose (DDD). RESULTS: Among 70 380 patients with a follow-up of 500 355 person-years, 2272 self-harm hospitalization episodes were identified. Compared with none or former use, current use of several second-generation antipsychotics with a dose of one DDD or above, including amisulpride, aripiprazole, clozapine, risperidone, and sulpiride, was associated with decreased risk of self-harm hospitalization, with clozapine showing the strongest effect (adjusted rate ratio = 0.26, 95% confidence interval 0.15-0.47). CONCLUSION: The protective effect on self-harm may vary across different antipsychotics. Further studies are needed to replicate the findings.

Risk profiles of personality traits for suicidality among mood disorder patients and community controls.

OBJECTIVE: To examine the associations between personality traits and suicidal ideation (SI) and attempt (SA) in mood disorder patients and community controls. METHOD: We recruited 365 bipolar, 296 major depressive disorder patients, and 315 community controls to assess their lifetime suicidality. Participants filled out self-reported personality questionnaires to collect data of personality traits, including novelty seeking (NS), harm avoidance (HA), extraversion (E), and neuroticism (N). We used logistic regression models adjusted for diagnoses to analyze combinational effects of personality traits on the risk of suicide. Additionally, radar charts display personality profiles for suicidal behaviours by groups. RESULTS: All personality traits were associated with the risk of suicidality with various effect size, except for E that showed protective effect. High N or HA had prominent and independent risk effects on SI and SA. Combinations of high N and low E, or high HA and NS were the risk personality profiles for suicidality. Higher N scores further distinguished SA from SI in mood disorder patients. CONCLUSION: Introvert personality traits showed independent risk effects on suicidality regardless of diagnosis status. Among high-risk individuals with suicidal thoughts, higher neuroticism tendency is further associated with increased risk of suicide attempt.

The Effects of Antidepressants and Quetiapine on Heart Rate Variability.

Introduction: The autonomic effects of antidepressants and quetiapine on heart rate variability (HRV) are inconsistent based on past studies. The aim of this study was to explore their influence on the HRV of psychiatric patients without psychotic symptoms. Methods: A total of 94 patients with depression, anxiety, or somatic symptoms, were recruited into this study. Based on their medication, 4 groups were identified: the no antidepressant group (n=19), the SSRI group (using sertraline or escitalopram, n=53), the other antidepressants group (using venlafaxine or mirtazapine, n=9), and the augmentation group (AG, using an antidepressant+quetiapine, n=13). The HRV of the 4 groups were compared. The correlations between HRV and the medication(s) used were clarified. Results: Among the 4 groups, the AG had the lowest HRV with its total power (TP), very low frequency power (VLF) and low frequency power (LF) of HRV being significantly different from those of the other groups. Age and using quetiapine were found to be negatively correlated with TP, VLF and LF. With this study group, the autonomic effects of antidepressants were found not to be significant. Discussion: Among psychiatric patients without psychotic symptoms, quetiapine causes an overt decrease in HRV.

A Novel Hybrid Viabahn-assisted Bypass Technique: Extra-arterial Flossing Wiring for Chronic Total Occlusion in Superficial Femoral Artery.

INTRODUCTION: A hybrid Viabahn-assisted bypass (VAB) technique is introduced for revascularizing chronic total occlusion (CTO) in superficial femoral artery (SFA) when bypass surgery is difficult or endovascular intervention fails. REPORT: This technique combines extra-arterial flossing wiring with antegrade-retrograde intervention via traditional open exposure of middle SFA and deploying a Viabahn from the proximal true lumen through the subintimal lumen and extra-arterial space, and back into distal true lumen to restore flow. It only needs a 3-5 cm incision to expose the mid-SFA without clamping or endarterectomy of the SFA. DISCUSSION: This hybrid procedure is an alternative technique to improve SFA revascularization in some difficult CTOs.

Extracorporeal membrane oxygenation as treatment for acute respiratory failure and subsequent pneumothorax caused by Pneumocystis jirovecii pneumonia in a kidney transplant recipient.

Acute respiratory failure (ARF) accompanied by pneumothorax caused by Pneumocystis jirovecii pneumonia (PJP) is often fatal. We present our experience using extracorporeal membrane oxygenation as treatment for ARF and subsequent pneumothorax caused by PJP in a kidney transplant recipient.

Inertia sensor-based guidance system for upperlimb posture correction.

Stroke rehabilitation is labor-intensive and time-consuming. To assist patients and therapists alike, we propose a wearable system that measures orientation and corrects arm posture using vibrotactile actuators. The system evaluates user posture with respect to a reference and gives feedback in the form of vibration patterns. Users correct their arm posture, one DOF at a time, by following a protocol starting from the shoulder up to the forearm. Five users evaluated the proposed system by replicating ten different postures. Experimental results demonstrated system robustness and showed that some postures were easier to mimic depending on their naturalness.

GSI-I (Z-LLNle-CHO) inhibits γ-secretase and the proteosome to trigger cell death in precursor-B acute lymphoblastic leukemia.

Gamma secretase inhibitors (GSIs) comprise a growing class of compounds that interfere with the membrane-bound Notch signaling protein and its downstream intra-nuclear transcriptional targets. As GSI-I (Z-LLNle-CHO) is also a derivative of a widely used proteosome inhibitor MG-132, we hypothesized that this compound might be active in precursor-B acute lymphoblastic leukemia (ALL) cell lines and patient samples. We found that GSI-I treatment of precursor-B ALL blasts induced apoptotic cell death within 18-24 h. With confirmation using RNA and protein analyses, GSI-I blocked nuclear accumulation of cleaved Notch1 and Notch2, and inhibited Notch targets Hey2 and Myc. Microarray analyses of 207 children with high-risk precursor-B ALL demonstrate that Notch pathway expression is a common feature of these neoplasms. However, microarray studies also implicated additional transcriptional targets in GSI-I-dependent cell death, including genes in the unfolded protein response, nuclear factor-κB and p53 pathways. Z-LLNle-CHO blocks both γ-secretase and proteosome activity, inducing more robust cell death in precursor-B ALL cells than either proteosome-selective or γ-secretase-selective inhibitors alone. Using Z-LLNle-CHO in a nonobese diabetes/severe combined immunodeficiency (NOD/SCID) precursor-B ALL xenograft model, we found that GSI-I alone delayed or prevented engraftment of B-lymphoblasts in 50% of the animals comprising the experimental group, suggesting that this compound is worthy of additional testing.

Multiple regression models for the lower heating value of municipal solid waste in Taiwan.

A multiple regression analysis was used to develop two predictive models of lower heating value (LHV) for municipal solid waste (MSW), using 180 samples gathered from cities and counties in Taiwan during 2001-2002. These models are referred to as the original proposed model (OPM) and the simplified model (SM). The coefficients of multiple determinations for the OPM and SM were 0.983 and 0.975, respectively. To verify the feasibility of the models, a demonstration program based on sampling of MSW in Kaohsiung City was conducted. As a result, the OPM showed superior precision in terms of relative percentage deviation (RPD) and mean absolute percentage error (MAPE), when compared to the conventional models based on the proximate analysis, physical composition and ultimate analysis. The SM was derived by neglecting the three minor physical components used in the OPM. The resulting SM was less precise when compared to the OPM, but it was still acceptable, with a precision level better than the conventional models. It was concluded that the predictability of empirical models could be improved significantly through selection of the appropriate physical components and multiple regression analysis.

Correlation of gas chromatographic properties of chlorobenzenes and polychlorinated biphenyls with the occurrence of reductive dechlorination by untamed microorganisms.

To understand the dechlorination ability of chlorobenzenes (CBs) and polychlorinated biphenyls (PCBs) by untamed microorganisms under anaerobic condition and to correlate gas chromatographic properties with the occurrence of reductive dechlorination, introduction of CBs and PCBs in the culture medium inoculated with microorganisms from sludge and sediment, respectively, were performed. Three kinds of culture media preparing from sludge, river water and a synthetic medium were used in the experiments. HCB was degraded to 1,3,5-trichlorobenzene (1,3,5-TCB) and 1,3-dichlorobenzene (1,3-DCB) in both sludge medium and synthetic medium with inoculated microorganisms. Three PCB congeners including 2,3,4-, 3,4,5- and 2,3,4,5-CBp (chlorinated biphenyl) were not found to be dechlorinated in the river water medium with inoculation culture but to be dechlorinated in the synthetic medium. MNDO methodology was used to compute theoretical dechlorination reaction heats and GC-ECD techniques were used to estimate chromatographic data of CB and PCB congeners. Both CB and PCB congeners showed that dechlorination by untamed microorganisms under anaerobic mixed cultures were more likely to occur when larger amounts of energy were released and greater deltaln RRT value between the parent congener and the daughter product was observed. Deltaln RRT provided a more precise information on the singularity of PCBs ortho-dechlorination in an aspect of thermodynamic favorable rule.