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The accurate diagnosis and classification of gliomas are essential for appropriate treatment planning and prognosis prediction. This study aimed to investigate the molecular diagnostics of IDH‐wildtype diffuse astrocytic gliomas and identify potential genetic variants that could differentiate glioblastoma (GBM) from lower‐grade gliomas when DNA methylation analysis is not feasible. In total, 479 H3‐and IDH‐wildtype diffuse astrocytic gliomas were included in this study. All the cases were diagnosed according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. Panel sequencing data were collected, and clinicopathological information was retrieved from medical records. Genetic alterations and histological findings were analyzed to determine their diagnostic utility and prognostic implications. Out of 479 cases, 439 (91.6%) were diagnosed with GBM, including 28 cases that were molecularly diagnosed as GBM. However, 40 (8.4%) cases could not be classified according to the 2021 WHO classification and were diagnosed as lower‐grade diffuse astrocytic glioma, IDH‐wildtype, not elsewhere classified (LGNEC). In addition to the three genetic alterations included in the diagnostic criteria of GBM, PTEN and EGFR mutations were found to be enriched in GBM. Patients harboring mTOR pathway mutations demonstrated a more favorable prognosis and often exhibited morphology resembling subependymal giant cell astrocytoma, along with a high tumor mutational burden. Among patients with mTOR pathway mutations, those lacking molecular diagnostic features of GBM exhibited outstanding survival outcomes, even in the presence of grade 4 histology. Integration of molecular features enhanced the diagnostic accuracy of IDH‐wildtype gliomas. Some molecular alterations enriched in GBM offer valuable insights for molecular diagnosis and glioma classification. Furthermore, high‐grade diffuse astrocytic gliomas featuring mTOR pathway mutations in the absence of molecular diagnostic features of GBM could represent more favorable tumor types distinct from GBM. [ABSTRACT FROM AUTHOR]

Background: There is still little knowledge about the outcomes of laparoscopic liver resection (LLR) for multiple hepatocellular carcinomas (HCC). The aim of this study was to assess the short‐ and long‐ term outcomes of LLR versus open liver resection (OLR) for patients with multiple HCC within and beyond the Milan criteria, and in both BCLC‐A and ‐B stage. Methods: Data regarding all consecutive patients undergoing liver resection for multiple HCC were retrospectively collected from Asian (South Korean) and European (Italian) referral HPB centers. The cases were propensity‐score matched for age, BMI, center, extent of the resection, postero‐superior location of the lesion, underlying liver condition, BCLB staging and the Milan criteria. Results: A total of 203 patients were included in the study: 27% of patients had undergone hemi‐hepatectomy, 26.6% atypical resections, 20.6% sectionectomy and 16.2% segmentectomy. After PSM two cohorts of 57 patients were obtained, with no significant differences in all preoperative characteristics. The length of hospital stay was significantly lower after LLR (median 7 vs. 9 days, p <.01), with no statistically significant differences in estimated blood loss, operation time, transfusions, postoperative bile leak, ascites, severe complications and R1 resection rates. After a median follow‐up of 61 (±7) months, there were no significant differences between OLR and LLR in both median OS (69 vs. 59 months, p =.74, respectively) and median DFS (12 vs. 10 months, p =.48, respectively). Conclusion: LLR for multiple HCC can be safe and effective in selected cases and is able to shorten median hospital stay without affecting perioperative and long‐term oncological outcomes. [ABSTRACT FROM AUTHOR]

This article investigates the nature of tensions "on the ground" between the internal and external stakeholders of arts organizations in terms of performance measurement. Based on the qualitative analysis of 19 interviews, the performance measurement practices of two different‐sized arts organizations highlight internal and external stakeholders' contrasting perspectives on a number of measurement dimensions. In endeavoring to understand tensions between internal and external stakeholders, the article highlights the main differences which result from seemingly opposed ways of knowing. Internal stakeholders tend more to reflect "phronesis," based on value‐rationality, while external stakeholders are more inclined to technical ("techne"), or analytical ("episteme") knowledge based on instrumental rationality. Nevertheless, there is some evidence of positive engagement between internal and external stakeholders. The article argues that in order to mitigate tensions, internal and external stakeholders should aim for culturally embedded understanding through evaluation‐focused dialogue. In providing both theoretical contributions to nonprofit literature and managerial implications, the article offers an original perspective that challenges existing practice and calls for greater understanding of conflicting interests when different stakeholders are involved in performance measurement. [ABSTRACT FROM AUTHOR]

Axis formation and related spatial patterning are initiated by symmetry breaking during development. A geometrically confined culture of human pluripotent stem cells (hPSCs) mimics symmetry breaking and cell patterning. Using this, polarized spinal cord organoids (pSCOs) with a self‐organized dorsoventral (DV) organization are generated. The application of caudalization signals promoted regionalized cell differentiation along the radial axis and protrusion morphogenesis in confined hPSC colonies. These detached colonies grew into extended spinal cord‐like organoids, which established self‐ordered DV patterning along the long axis through the spontaneous expression of polarized DV patterning morphogens. The proportions of dorsal/ventral domains in the pSCOs can be controlled by the changes in the initial size of micropatterns, which altered the ratio of center‐edge cells in 2D. In mature pSCOs, highly synchronized neural activity is separately detected in the dorsal and ventral side, indicating functional as well as structural patterning established in the organoids. This study provides a simple and precisely controllable method to generate spatially ordered organoids for the understanding of the biological principles of cell patterning and axis formation during neural development. [ABSTRACT FROM AUTHOR]

Background: The current definition for postoperative pancreatic fistula (POPF) is based on the drain fluid amylase (DFA), and drains must be positioned adequately. We investigated the impact of DFA level, drain position and fluid collection after distal pancreatectomy (DP). Methods: We performed a retrospective study of 516 patients who underwent DP between June 2004 and December 2018. Patients were excluded if DP was not main procedure, DFA was not measured, postoperative computed tomography (CT) was not performed, or drains were removed before CT. Demographic and perioperative data were analyzed in 422 eligible patients. Results: Of 422 patients, 49(11.6%) had clinically relevant (CR)-POPF and 102(24.2%) had a malpositioned drain. There was no difference in CR-POPF rate between the high and low DFA groups (12.6% vs 10.7%, P = 0.649). Drain malposition was more frequently associated with symptomatic fluid collection and CR-POPF than well-positioned drains. Male sex, high body mass index, transfusion, and drain malposition were CR-POPF risk factors. In subgroup analysis, drain malposition was also an independent risk factor for CR-POPF in the low DFA group. Conclusions: After DP, the incidence of CR-POPF in the high and low DFA groups was similar and drain malposition increased the risk of CR-POPF. Thus, the ISGPS definition of POPF based on DFA levels is limited in DP, and DFA levels should be interpreted together with the drain position. [ABSTRACT FROM AUTHOR]

Background: The chemokine CXCL13 is known to influence local anti‐tumor immunity by recruiting immune cells and forming tertiary lymphoid structures (TLS). It has been hypothesized that TLS, led by the expression of CXCL13, could be a predictive or prognostic biomarker for immunotherapy. We investigated the predictive value of CXCL13 to immune checkpoint inhibitors (ICI) in lung adenocarcinoma. Methods: We constructed an exploratory dataset (n = 63) and a validation dataset (n = 57) in metastatic lung adenocarcinoma patients treated with ICI. Based on the clinical response, the difference in gene expression profile, including CXCL13, was evaluated. Results: From the exploratory dataset, CXCL13 expression was significantly upregulated in the ICI responders (p = 0.002). Survival analysis using a cut‐off value of the median expression value of CXCL13 showed prolonged progression‐free survival (PFS) (p = 0.004) and overall survival (OS) (p = 0.007). CXCL13 expression was correlated with other immune response genes, such as GZMA, CD8A, IFNG, PRF1, TLS‐related gene sets and its receptor, CXCR5. Notably, subgroup analyses based on CXCL13 expression and CD8A showed that CXCL13‐upregulated patients demonstrated comparably prolonged survival regardless of CD8A expression. In the validation dataset, CXCL13 upregulation also demonstrated a significant prolongation of both PFS (p = 0.050) and OS (p = 0.026). Conclusion: We observed that CXCL13 upregulation is correlated to better ICI response in lung adenocarcinoma. Our results support that CXCL13 could be an important chemokine in shaping the immunoactive tumor microenvironment which affects the anti‐tumor effect of ICI. [ABSTRACT FROM AUTHOR]

Background: The quality of surgical procedures are assessed by textbook outcomes (TO). Laparoscopic liver resection (LLR) is considered a standard treatment for hepatocellular carcinoma (HCC) in the anterolateral segments of the liver. The main objective of this study was to evaluate the factors affecting achievement of TO for LLR and its impact on survival. Methods: We conducted a retrospective cohort study of patients who underwent LLR for lesions located in the anterolateral segments (n = 309). Patients were divided into TO and non‐TO group. Results: A TO was achieved in 55.0% of patients (n = 170). In multivariable analysis, Model for End‐stage Liver Disease (MELD) score ≥ 10 (odds ratio[OR] 3.076; 95% confidence interval[CI] 1.134–8.342), absence of diabetes mellitus (OR: 2.325; 95% CI: 1.227–4.407) and thrombocytopenia (OR: 2.115; 95% CI: 1.134–8.342) were independently associated with not achieving TO. The 5‐year overall (82.9% vs 72.8%, P =.017) and recurrence‐free (48.8% vs 35.4%; P =.036) survival rates were significantly greater in the TO group than in the non‐TO group. Conclusion: The MELD score, thrombocytopenia, and hypoalbuminemia were independent risk factors influencing the achievement of TO. TO influences the short‐ and long‐term outcomes after LLR for HCC. [ABSTRACT FROM AUTHOR]

This study is to investigate the optimal treatment option for synchronous bilateral breast cancer (SBBC) by comparing dosimetric and radiobiological parameters of intensity‐modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans using single and dual isocenters. Twenty patients with SBBC without lymph node involvement were selected retrospectively. Four treatment plans were generated for each patient using the Eclipse treatment planning system (Varian Medical System, Palo Alto, CA, USA) following two delivery techniques with two isocenter conditions—IMRT using a single isocenter (IMRT_Iso1), VMAT using a single isocenter (VMAT_Iso1), IMRT using dual isocenters (IMRT_Iso2), and VMAT using dual isocenters (VMAT_Iso2). A dose of 42.56 Gy in 16 fractions was prescribed for the planning target volume (PTV). All plans were calculated using the Acuros XB algorithm and a photon optimizer for a 6‐MV beam of a Vital Beam linear accelerator. PTV‐related dosimetric parameters were analyzed. Further, the homogeneity index, conformity index, and conformation number were computed to evaluate plan quality. Dosimetric parameters were also measured for the organs at risk (OARs). In addition, the equivalent uniform dose corresponding to an equivalent dose related to a reference of 2 Gy per fraction, the tumor control probability, and the normal tissue complication probability were calculated based on the dose–volume histogram to investigate the radiobiological impact on PTV and OARs. IMRT_Iso1 exhibited similar target coverage and a certain degree of dosimetric improvement in OAR sparing compared to the other techniques. It also exhibited some radiobiological improvement, albeit insignificant. Although IMRT_Iso1 significantly increased monitor unit compared to VMAT_Iso1, which is the best option in terms of delivery efficiency, there was only a 22% increase in delivery time. Therefore, in conclusion, IMRT_Iso1, the complete treatment of which can be completed using a single setup, is the most effective method for treating SBBC. [ABSTRACT FROM AUTHOR]

Background: Combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA) is a rare primary hepatic neoplasm. Currently, there are no well‐structured studies that analyze the feasibility of laparoscopic liver resection in cHCC‐CCA alone. This retrospective cohort study aimed to compare the long‐term survival of laparoscopic liver resection with open liver resection in cHCC‐CCA. Methods: Patients with a postoperative pathologic report of cHCC‐CCA who underwent liver resection from August 2004 to December 2017 were included in this study. Kaplan–Meier survival analysis was performed to analyze the 3‐y disease‐free survival and 3‐y overall survival. Propensity score matching was done to reduce the influence of confounding variables. Results: A total of 145 patients were pathologically confirmed to have cHCC‐CCA, of which 10 patients were excluded due to having received palliative surgery. Of the remaining 135 patients, 43 underwent laparoscopic and 92 underwent open liver resection; propensity score matching yielded 30 patients for each group. The 3‐y overall survival was 38 (88.4%) in the laparoscopic group and 84 (91.3%) in the open group before propensity score matching (P =.678), and 25 (83.3%) and 28 (93.3%), respectively, after matching (P =.257). The 3‐y disease‐free survival was 24 (55.8%) in the laparoscopic group and 32 (34.8%) in the open group before matching (P =.040), and 17 (56.7%) and 16 (53.3%), respectively, after matching (P =.958). The hospital stay was shorter in the laparoscopic group before and after matching, while other operative outcomes were similar in both groups. Conclusion: Laparoscopic liver resection for cHCC‐CCA is technically feasible and safe, having a shorter hospital stay without compromising oncological outcomes. [ABSTRACT FROM AUTHOR]

Aims: To measure the prospective relationship between smoking trajectories from adolescence to young adulthood and mental health in later adulthood and test whether this relationship was mediated by concurrent co‐use of alcohol and marijuana. Design Longitudinal study using data drawn from rounds 1 to 18 of the National Longitudinal Survey of Youth 1997 (NLSY97), a nationally representative cohort study spanning 21 years. Setting: United States. Participants: The analytical sample included those who completed survey items about smoking behaviors on at least half the data collection opportunities in adolescence and young adulthood (n = 8570, 48.9% female, 66.2% white). Measurements Mental health in adulthood was measured using the five‐item Mental Health Inventory (MHI‐5; range = 0–100) at round 18. Seven trajectories of smoking from adolescence to young adulthood were identified by group‐based multi‐trajectory modeling, using data over 11 years from rounds 1 to 11. Findings Late‐onset moderate smokers [β = −1.95, 95% confidence interval (CI) = −3.61 to −0.29], late‐onset accelerated smokers (β = −2.53, 95% CI = −4.28 to −0.78), early‐onset heavy smokers (β = −3.72, 95% CI = −5.59 to −1.85) and early‐onset moderate smokers (β = −2.66, 95% CI = −4.48 to −0.84) showed poorer regression‐adjusted mean MHI‐5 scores in later adulthood than stable abstainers, even after controlling for baseline mental health and covariates. Whether or not a difference in MHI‐5 scores was present between quitters and stable abstainers was inconclusive. The concurrent co‐use of alcohol and marijuana in young adulthood significantly mediated the relationship between smoking trajectory and mental health. Conclusions: Continued smoking, especially early‐onset and heavy smoking from adolescence to young adulthood, appears to increase the risk of poor mental health later in mid‐adulthood, and quitting smoking in young adulthood may mitigate such risk even among early‐onset smokers. Mediation analyses underscore the role of using multiple substances in this pathway. [ABSTRACT FROM AUTHOR]

Background: Pancreatoduodenectomy (PD) is the only curative therapy for distal cholangiocarcinoma (dCC). There has been no study to compare outcomes between minimally invasive pancreatoduodenectomy (MIPD) and open pancreatoduodenectomy (OPD) for dCC. The aim of the study is to compare the two operation types for dCC in terms of postoperative and oncologic outcomes. Methods: Data from 426 patients who underwent MIPD (n = 91) or OPD (n = 335) for dCC from January 2012 to December 2019 at two tertiary hospitals were retrospectively reviewed. After 1:2 propensity score matching, postoperative and oncologic outcomes were compared. Results: Minimally invasive pancreatoduodenectomy group showed more favorable results than OPD group in terms of blood loss (MIPD vs OPD, 250 [150‐400] vs 400 [200‐600], mL, P <.001), and length of hospital stay (19.8 ± 11.3 vs 26.6 ± 14.3 days, P <.001). OPD group showed more favorable results than MIPD group in terms of operation time (MIPD vs OPD, 457 ± 70 vs 398 ± 85 min, P <.001) and harvested lymph nodes (14.9 ± 7.8 vs 20.7 ± 11.5, P <.001). There was no statistical difference between the two groups in the R0 resection rate and complications. In long‐term survival analysis, there was no significant difference between the two groups. Conclusion: Minimally invasive pancreatoduodenectomy showed comparable postoperative complications and long‐term oncologic survival with OPD in the treatment of dCC. [ABSTRACT FROM AUTHOR]

Background: Laparoscopic liver resection (LLR) is considered the standard surgical approach for resecting small hepatocellular carcinomas (HCC) located in the anterolateral segments of the liver. However, few studies have compared LLR and radiofrequency ablation (RFA) in such cases. Methods: We retrospectively compared the short‐ and long‐term outcomes of 101 patients who underwent LLR and 264 patients who underwent RFA because of a newly diagnosed single, small (≤4 cm) HCC located in the anterolateral segments of the liver. By applying 1:1 propensity score matching, we matched 61 patients in both groups. Results: Although the 5‐year overall survival rates were similar (83.6% vs 84.5%; P =.913), the 5‐year disease‐free survival rate was greater in the LLR group (56.4% vs 41.8%; P =.009). In patients with an α‐fetoprotein level of ≥100 ng/mL, the 5‐year overall (100% vs 80.0%; P =.022) and disease‐free survival (76.6% vs 45.5%; P =.006) rates were greater in the LCC group. Conclusions: For patients with a single, small HCC located in the anterolateral segments of the liver, LLR was associated with similar complication and overall survival rates, but better disease‐free survival compared with RFA. LLR may be recommended for patients with higher α‐fetoprotein levels. [ABSTRACT FROM AUTHOR]

Background: To evaluate a risk‐adjusted comparison of clinically relevant postoperative pancreatic fistula POPF (CR‐POPF) following laparoscopic pancreatoduodenectomy (LPD) vs open pancreatoduodenectomy (OPD) using the fistula risk score (FRS). Methods: We retrospectively analyzed 579 patients who underwent LPD (n = 274) or OPD (n = 305) between 2012 and 2019 at two tertiary hospitals. Using the FRS, the risk was stratified into four categories; negligible, low, intermediate and high risk. Results: The median FRS was significantly higher in the LPD than in the OPD group (5.4 ± 1.2 vs 3.9 ± 1.8, P <.001). The overall incidence of CR‐POPF in the LPD vs OPD groups were 16.4% vs 17.7% (P =.187). When POPF risks were stratified by FRS, CR‐POPF following LPD vs OPD in patients with low risk (0% vs 6.3%, P =.294), intermediate risk (16.1% vs 22.9%, P =.053) and high risk (33.3% vs 27.3%, P =.577) were not significantly different. Conclusion: Despite a higher risk score in the LPD group, the CR‐POPF was similar following both procedures in the unadjusted and FRS‐risk‐adjusted comparisons. The CR‐POPF was more significantly affected by patient risk factors such as the soft pancreas and small pancreatic duct. [ABSTRACT FROM AUTHOR]

Background: To investigate whether preoperative malnutrition in patients who underwent curative pancreaticoduodenectomy (PD) in pancreatic head cancer correlated with short‐term outcomes. Methods: This study was a retrospective review of medical records from January 2004 to December 2018. Preoperative malnutrition was defined as body mass index (BMI) <18.5 kg/m2, or hypoalbuminemia with serum albumin level < 3.5 g/dL within 30 days before surgery. Results: Of the 289 eligible patients, 60 patients (20.7%) were classified as the malnutrition group. The estimated blood loss (EBL, mL) (964.1 ± 879.7 vs 597.7 ± 501.7, P =.044) and transfusion rate (51.7% vs 18.8%, P <.001) was significantly higher in the malnutrition group than no‐malnutrition group. The hospital stay (days) (20.5 ± 12.2 vs 18.1 ± 13.6, P =.05) was significantly longer in the malnutrition group. The open conversion rate (45.4% vs 6.67%, P <.001) and major complication rate (36.7% vs 21.8%, P =.032) was significantly higher in the malnutrition group. In multivariate analysis, preoperative malnutrition was found to be the predictor of postoperative complication (HR 1.971 95% confidence interval 1.071‐3.624, P =.029). Conclusion: Preoperative malnutrition in patients who underwent curative PD for pancreatic head cancer is associated with adverse short‐term outcomes. [ABSTRACT FROM AUTHOR]

A biobanking turning-point in the use of formalin-fixed, paraffin tumor blocks to unveil kinase signaling in melanoma (C) Quantification of the phosphosite Y187 in a patient with BRAFV600E positive tumor metastasis compared to a patient with WT-BRAF tumor metastasis for both FFPE and FFT samples. Abbreviations BRAF serine/threonine-protein kinase B-raf ERK extracellular signal-regulated kinase FFPE formalin-fixed and paraffin-embedded FFT fresh frozen tumors MEK mitogen-activated protein kinase MM malignant melanoma MS mass spectrometry PTMs posttranslational modifications Malignant melanoma (MM) is one of the most aggressive human solid tumors, and it is associated with the highest mortality of all skin cancers.1 Aberrant patterns of protein expression and posttranslational modifications (PTMs) have been linked to MM pathogenesis,2 which has promoted large-scale proteomics studies. Blue and red colors represent BP up- and downregulated in primary tumors (respectively), regardless of condition gl Since alterations in protein phosphorylation most likely reflect changes in kinase activity levels, we assess the potential of FFPE samples to explore the MM kinome. [Extracted from the article]

Matrix-assisted laser desorption ionization - mass spectrometry imaging of erlotinib reveals a limited tumor tissue distribution in a non-small-cell lung cancer mouse xenograft model GLO:F2H7/01jul21:ctm2481-fig-0002.jpg PHOTO (COLOR): 2 Erlotinib-resistant mouse xenograft model with H1299 cells and erlotinib distribution in tumor, liver, and kidney tissue. Although erlotinib still has a binding affinity to the target protein, EGFR, even in the H1299 tumor cells, the reduced distribution within in tumor tissues suggests a new mechanism of erlotinib resistance I in vivo i . H1299 tumor tissue, liver, and kidney were isolated from the xenograft mice previously treated with either vehicle ( I N i = 4) or erlotinib ( I N i = 5) (10 mg/kg) for analyzing erlotinib distribution. [Extracted from the article]

Background: LLR is widely adapted for HCC, while LLR in PS segments is still challenging. With recent improvement of techniques and accumulation of experiences, LLR in PS segments is feasible, but studies investigating the result after the modifications are lacking. Methods: In this single-center, retrospective study, 149 patients who underwent LLR for HCC located in PS segments from September 2003 to December 2016 were analyzed. The patients were divided into Group 1 (n=43) and Group 2 (n=106) who underwent LLR before and after 2012, respectively, when advanced techniques including use of intercostal trocars, Pringle maneuver, and semi-lateral position of patient were introduced. Also, these patients were compared with those who underwent open liver resection (OLR; n=124) for HCC in PS segments during the same period. Results: Mean operative time (394.7 minutes vs 331.2 minutes; P=0.013), intraoperative blood loss (1545.8 ml vs 1208.2 ml; P=0.020), and hospital stay (11.6 days vs 9.2, P<0.001) were significantly less in Group 2. Postoperative complication rate (18.6% vs 18.9%; P=0.970), open conversion rate (23% vs 17%; P=0.374), 5-year overall (79% vs 89%; P=0.607) and 5-year disease-free (52% vs 53%; P=0.657) survival rates were not significantly different between the groups. Compared to the OLR group, complication rate (40.3% vs 18.8%; P< 0.001) and hospital stay (17.6 days vs 9.7 days; P< 0.001) were significantly lower in the LLR group. Conclusion: The complexity of LLR for HCC in PS segments is being gradually overcome by the introduction of advanced techniques. [ABSTRACT FROM AUTHOR]

Approximately half of lung cancer patients (LCP) receiving chemotherapy are experiencing cancer‐related fatigue (CRF). In East Asia, herbal medicines (HMs) have been used as tonics due to their anti‐fatigue effect. This systematic review evaluated the effectiveness and safety of HMs for CRF in LCP. We comprehensively searched 12 electronic medical databases to search randomized controlled trials (RCTs) and quasi‐RCTs investigating HMs for CRF in LCP, published up to September 2019. The primary outcome was the fatigue severity. Secondary outcomes included patients' quality of life (QOL), activities of daily life (ADL), and incidence of adverse events. Cochrane's risk of bias tool assessed the methodological quality of included RCTs. The risk ratio or mean difference was estimated with 95% confidence intervals by performing a meta‐analysis. Twelve RCTs with 861 participants were included. Compared to conventional medicine alone, HM combined with conventional medicine significantly improved fatigue level, QOL, and ADL. As monotherapy, HM significantly improved ADL compared with megestrol. No serious HM‐related adverse events were reported. Limited evidence suggests that HM could be effective and safe for CRF in LCP. However, further high‐quality RCTs are needed to confirm these findings owing to the small number and low methodological quality of the included studies. [ABSTRACT FROM AUTHOR]

Background: EGFR tyrosine kinase inhibitors (TKIs) have shifted the treatment paradigm in advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, patients who are treated with TKIs inevitably develop acquired resistance by mechanisms that are not fully understood. The purpose of this study was to investigate the mechanism of acquired resistance after treatment with third-generation EGFR TKIs.Methods: Advanced EGFR-mutant NSCLC patients treated with olmutinib or osimertinib who underwent a rebiopsy before treatment or after progression were analyzed retrospectively. Targeted sequencing was performed on 113 specimens (77 pretreatment and 36 posttreatment, including 15 paired samples) obtained via tissue biopsy.Results: A total of 98 patients were included, 53 (54%) of whom were treated with osimertinib and 45 (46%) of whom were treated with olmutinib. Of the 36 patients with posttreatment biopsies, EGFR-dependent mechanisms, including C797S and L718Q mutations, were observed in 10 (28%) patients: 29% (5/17) in the osimertinib group and 26% (5/19) in the olmutinib group. EGFR-independent mechanisms were detected in 21 patients (21/36, 58%): 65% (11/17) in the osimertinib group and 53% (10/19) in the olmutinib group. The disappearance of EGFR T790M was detected in 14 patients (39%); of these patients, 59% (10/17) were treated with osimertinib and 21% (4/19) were treated with olmutinib. Patients who lost the T790M mutation were more inclined to show EGFR-independent pathways as a secondary resistance mechanism.Conclusion: Resistance acquired after third-generation EGFR TKIs is associated with diverse pathways; however, treatment with osimertinib is primarily associated with a loss of EGFR T790M and the subsequent emergence of EGFR-independent resistance mechanisms. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to describe a plastic scintillating plate‐based gantry‐attachable dosimetry system for pencil beam scanning proton therapy to monitor entrance proton beam fluence, and to evaluate the dosimetric characteristics of this system and its feasibility for clinical use. Methods: The dosimetry system, consisting of a plastic scintillating plate and a CMOS camera, was attached to a dedicated scanning nozzle and scintillation during proton beam irradiation was recorded. Dose distribution was calculated from the accumulated recorded frames. The dosimetric characteristics (energy dependency, dose linearity, dose rate dependency, and reproducibility) of the gantry‐attachable dosimetry system for use with therapeutic proton beams were measured, and the feasibility of this system during clinical use was evaluated by determining selected quality assurance items at our institution. Results: The scintillating plate shortened the range of the proton beam by the water‐equivalent thickness of the plate and broadened the spatial profile of the single proton spot by 11% at 70 MeV. The developed system functioned independently of the beam energy (<1.3%) and showed dose linearity, and also functioned independently of the dose rate. The feasibility of the system for clinical use was evaluated by comparing the measured quality assurance dose distribution to that of the treatment planning system. The gamma passing rate with a criterion of 3%/3 mm was 97.58%. Conclusions: This study evaluated the dosimetric characteristics of a plastic scintillating plate‐based dosimetry system for use with scanning proton beams. The ability to account for the interference of the dosimetry system on the therapeutic beam enabled offline monitoring of the entrance beam fluence of the pencil beam scanning proton therapy independent of the treatment system with high resolution and in a cost‐effective manner. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the quality of patient‐specific complicated treatment plans, including commercialized treatment planning systems (TPS) and commissioned beam data, we developed a process of quality assurance (QA) using a Monte Carlo (MC) platform. Specifically, we constructed an interface system that automatically converts treatment plan and dose matrix data in digital imaging and communications in medicine to an MC dose‐calculation engine. The clinical feasibility of the system was evaluated. Materials and Methods: A dose‐calculation engine based on GATE v8.1 was embedded in our QA system and in a parallel computing system to significantly reduce the computation time. The QA system automatically converts parameters in volumetric‐modulated arc therapy (VMAT) plans to files for dose calculation using GATE. The system then calculates dose maps. Energies of 6 MV, 10 MV, 6 MV flattening filter free (FFF), and 10 MV FFF from a TrueBeam with HD120 were modeled and commissioned. To evaluate the beam models, percentage depth dose (PDD) values, MC calculation profiles, and measured beam data were compared at various depths (Dmax, 5 cm, 10 cm, and 20 cm), field sizes, and energies. To evaluate the feasibility of the QA system for clinical use, doses measured for clinical VMAT plans using films were compared to dose maps calculated using our MC‐based QA system. Results: A LINAC QA system was analyzed by PDD and profile according to the secondary collimator and multileaf collimator (MLC). Values for MC calculations and TPS beam data obtained using CC13 ion chamber (IBA Dosimetry, Germany) were consistent within 1.0%. Clinical validation using a gamma index was performed for VMAT treatment plans using a solid water phantom and arbitrary patient data. The gamma evaluation results (with criteria of 3%/3 mm) were 98.1%, 99.1%, 99.2%, and 97.1% for energies of 6 MV, 10 MV, 6 MV FFF, and 10 MV FFF, respectively. Conclusions: We constructed an MC‐based QA system for evaluating patient treatment plans and evaluated its feasibility in clinical practice. We observed robust agreement between dose calculations from our QA system and measurements for VMAT plans. Our QA system could be useful in other clinical settings, such as small‐field SRS procedures or analyses of secondary cancer risk, for which dose calculations using TPS are difficult to verify. [ABSTRACT FROM AUTHOR]

This study examined parenting styles and culturally‐specific parenting practices of Korean immigrant mothers (N = 128) and fathers (N = 79) of children (ages 6–10) in New Zealand and the parenting predictors of child behaviour. Participants completed questionnaires on parenting styles and practices, and parental perceptions of child behaviour. Both parents indicated a high degree of devotion (Mo jeong) and involvement in care and education of their child with fathers were more likely than mothers to utilise shaming/love withdrawal and modesty encouragement. Results of regression analyses showed that there were some differences between mothers and fathers in the parenting predictors of child internalising and externalising behaviour problems and prosocial behaviour. Across the whole sample, there were contrasting relationships for authoritative parenting styles, devoted/involved parenting and modesty encouragement/shaming/non‐reasoning parenting practices with child behaviour problems. Results indicated a blend of Western and Korean parenting practices were being utilised after settling in New Zealand. [ABSTRACT FROM AUTHOR]

Subcutaneous and visceral adipose tissues show a different risk effect on metabolic disorders because they have distinct cellular properties. We isolated stem cells from the separate human adipose tissues to investigate that subcutaneous and visceral fat depots have metabolic differences. Adipose-derived stem cells (ASCs) were characterized by immunophenotype and differentiation potentials into adipogenic, osteogenic, and chondrogenic lineages. Although subcutaneous and visceral ASCs (S-ASC and V-ASC) express same surface markers (CD31−, CD34−, CD45−, CD73+, CD90+, and CD105+) and have differentiation potentials, S-ASCs had higher capacity to proliferate and to differentiate into adipogenic lineage than V-ASCs. Next, we identified that S-ASC and V-ASC were genetically distinct based on microarray analysis. Among a total of 810 genes detected in ASCs of both depots, the differentially expressed genes were involved in energy and lipid metabolism. These data show the existence of the intrinsic difference between S-ASC and V-ASC and suggest the differences of anatomically separated adipose tissue. On the basis of the differentially expressed gene profiles between S-ASC and V-ASC, we suggested significant evidence that adipose tissues originating from different anatomic regions are distinguished at the level of the undifferentiated stem cells such as mature adipocytes. V-ASCs had the upregulated clusters of genes related to lipid biosynthesis and metabolism. By contrast, S-ASCs highly expressed genes involved in DNA-dependent transcription, contributing to proliferation. We provide further insights for ASCs with the different origins to understand fat accumulation and distribution and a possibility of ASCs as a therapeutic target against metabolic disorders or cancer. [ABSTRACT FROM AUTHOR]

Purpose The foreign body reactions are comprised of macrophages and foreign body giant cells and are considered possible risk factors for recurrence in several conditions. The purpose of this study was to determine the effect of pathologically proven foreign body reactions on the recurrence of the auricular keloids. Methods This study was carried out in 76 cases in 70 patients reaching the pathologic diagnosis of auricular keloids from March 2006 to February 2012. Patients with auricular keloids were included in the study according to the following criteria: The keloid scar was caused by ear piercing and confirmed pathologically; surgical excision with primary closure was performed; and female patients who have not underwent any previous treatments. To compare any differences of recurrence rate between categorical variables (the presence/absence of foreign body reactions), Fisher's exact tests were used. All patients completed the treatment protocol with a follow-up interval of 18 months. Results Of these patients, 90.9% (69 keloids) had successful irradication of their auricular keloids, whereas 9.2% (seven keloids) had recurrences. Of the seven recurrent cases, two exhibited foreign body reactions at pathology, while five revealed no foreign body reactions (28.6% vs. 71.4%, P = 0.092). Conclusions Detection of foreign body reactions in keloid tissue may not predict recurrence in auricular keloids. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 μ m and 0.38 μ m, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 μ m), whereas it did not inhibit the other UGTs tested (IC50 > 200 μ m). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 μ m) and UGT1A9 (IC50 = 19.4 μ m). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 μ m). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

GSK5182 (4-[(Z)-1-[4-(2-dimethylaminoethyloxy)phenyl]-hydroxy-2-phenylpent-1-enyl]phenol) is a specific inverse agonist for estrogen-related receptor γ, a member of the orphan nuclear receptor family that has important functions in development and homeostasis. This study was performed to elucidate the metabolites of GSK5182 and to characterize the enzymes involved in its metabolism. Incubation of human liver microsomes with GSK5182 in the presence of NADPH resulted in the formation of three metabolites, M1, M2 and M3. M1 and M3 were identified as N-desmethyl-GSK5182 and GSK5182 N-oxide, respectively, on the basis of liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. M2 was suggested to be hydroxy-GSK5182 through interpretation of its MS/MS fragmentation pattern. In addition, the specific cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) isoforms responsible for GSK5182 oxidation to the three metabolites were identified using a combination of correlation analysis, chemical inhibition in human liver microsomes and metabolism by expressed recombinant P450 and FMO isoforms. GSK5182 N-demethylation and hydroxylation is mainly mediated by CYP3A4, whereas FMO1 and FMO3 contribute to the formation of GSK5182 N-oxide from GSK5182. The present data will be useful for understanding the pharmacokinetics and drug interactions of GSK5182 in vivo. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

RATIONALE Uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes are essential for the clearance of many drugs; however, altered UGT activity is a potential cause of adverse drug-drug interactions (DDI). The early detection of potential DDI is an important aspect of drug discovery that has led to the development of new screening methods for drug interactions. We developed a screening method for the simultaneous evaluation of six human liver UGT enzyme activites using in vitro cocktail incubation and tandem mass spectrometry. METHODS The two in vitro cocktail doses were developed to minimize drug interactions among substrates. The method is based on liquid chromatography/tandem mass spectrometry (LC/MS/MS). Electrospray ionization (ESI) in both positive and negative modes was used to quantify the metabolites and the diagnostic loss of the glucuronosyl moiety to form the aglycone product was estimated using the selected reaction monitoring (SRM) mode. RESULTS The method was validated by comparing inhibition data obtained from the incubation of each individual probe substrate alone with data from the cocktail method. The intra- and inter-day accuracy and precision data for the six UGT metabolites ranged from 92.2 to 100.3% and less than 15.2%, respectively. The IC50 values showed no significant differences between individual and cocktail incubations. CONCLUSIONS As a screening technique for inhibitory interactions of these six human liver UGT enzymes, this method will be useful for advancing mechanistic understanding of drug interactions. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Platinum doublets are standard first-line treatment for stage IV non-small cell lung cancer ( NSCLC) without targetable driver mutations. Oxaliplatin is more potent than cisplatin, requiring fewer DNA adducts to provide equivalent cytotoxicity. The objective of this study was to evaluate the efficacy and safety of oxaliplatin combined with docetaxel as a first-line treatment for stage IV NSCLC. Methods This was a prospective, single-center, phase II trial. Patients with chemotherapy-naive NSCLC received 60 mg/m2 docetaxel (day 1) and 70 mg/m2 oxaliplatin (day 2) every three weeks for up to six cycles. The primary endpoint was objective response rate ( ORR), and the secondary endpoints were progression-free survival ( PFS), overall survival ( OS), and safety. Treatment response was evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Results Thirty-three patients were enrolled and a response evaluation was available in 31 patients. There were 11 patients with a partial response, 15 with stable disease, and five with progressive disease. Two patients ceased further treatment after the first cycle of chemotherapy. Thus, the ORR was 33.3% in the 33 patients of the intention-to-treat population. Median PFS was 3.6 months (95% confidence interval [ CI], 2.8-4.5), and median OS was 10.9 months (95% CI, 8.2-13.6). The most common hematologic toxicity was neutropenia. Grade 3-4 neutropenia occurred in 51.5% of patients. Conclusion The results suggest that the combination of oxaliplatin and docetaxel is effective in patients with NSCLC with reasonable toxicity. [ABSTRACT FROM AUTHOR]

Tree nuts are responsible for many cases of severe food allergies. The 7S seed storage protein vicilin has been identified as a food allergen in many kinds of tree nuts. The vicilin protein consists of an N-terminal low-complexity region with antimicrobial activity and a C-terminal domain that forms a trimeric structure that belongs to the cupin superfamily. In this study, vicilin from pecan ( Carya illinoinensis) was isolated and was expressed in bacteria for the first time. The cupin structural core of the protein, residues 369-792, was purified by metal-affinity and gel-filtration chromatography to high purity. Vicilin crystals were obtained and the best crystal diffracted to 2.65 Å resolution in space group P212121. [ABSTRACT FROM AUTHOR]

This study aims to compare the early outcomes between pure laparoscopic living donor right hepatectomy (PLDRH) and open living donor right hepatectomy (ODRH) after those learning curve. Our analysis was based on 78 consecutive cases of living liver donor, who underwent right hepatectomy, of which 43 underwent ODRH and 35 PLDRH. The learning curve for each group was analyzed. Donor characteristics were comparable between the two groups. Two donors in the PLDRH required conversion to an open due to bleeding and large graft size (open conversion rate: 6.06%). The following outcomes during the study period were comparable between the two groups: operative time (P = .64); estimated blood loss (EBL; P = .86); intra‐operative transfusion (P = .57); hospital stay (P = .41); and postoperative complications (P = .51). The operative time stabilized for the ODRH group after 17 cases and for the PLDRH group after 15 cases. After the learning curve, the EBL was lower for PLDRH than ODRH (P = .04). Pure laparoscopic living donor right hepatectomy can be performed as safely as ODRH and with a lower volume of EBL once the surgeon has attained an appropriate level of learning. [ABSTRACT FROM AUTHOR]