Neoadjuvant therapy leads to objective response in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy and has a poor prognosis. Surgical resection is the standard of care for patients with resectable disease, representing 30-40% of cases. Increasingly, neoadjuvant systemic therapy is being utilized in patients due to high-risk anatomic or biologic considerations. However, data on the clinical effect of this approach are limited. We performed a cohort study to evaluate the effect of neoadjuvant therapy in patients with oncologically high-risk iCCA. METHODS: iCCA patients (n = 181) between the years 2014-2020 were reviewed for clinical, histopathologic, treatment, and outcome-related data. Tumor regression grade was scored per CAP criteria for gastrointestinal carcinomas. RESULTS: 47 iCCA patients received neoadjuvant therapy and 72 did not. Neoadjuvant treatment led to objective response and tumor regression by CAP score. After adjustment for age, clinical stage, and tumor size, the outcomes of patients who had neoadjuvant therapy followed by surgery were not significantly different from those patients who had surgery first. DISCUSSION: In conclusion, neoadjuvant therapy in iCCA facilitated surgical care. The progression-free and overall survival for surgical patients with and without neoadjuvant therapy were not significantly different suggesting this approach needs further exploration as an effective treatment paradigm.

WITHDRAWN: Neoadjuvant therapy leads to objective response in intrahepatic cholangiocarcinoma.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.hpb.2024.04.011. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Systematic Review of Procedural Skill Simulation in Health Care in Low- and Middle-Income Countries.

ABSTRACT: Low- and middle-income countries (LMICs) have adopted procedural skill simulation, with researchers increasingly investigating simulation efforts in resource-strained settings. We aim to summarize the current state of procedural skill simulation research in LMICs focusing on methodology, clinical area, types of outcomes and cost, cost-effectiveness, and overall sustainability. We performed a comprehensive literature review of original articles that assessed procedural skill simulation from database inception until April 2022.From 5371 screened articles, 262 were included in this review. All included studies were in English. Most studies were observational cohort studies (72.9%) and focused on obstetrics and neonatal medicine (32.4%). Most measured outcome was the process of task performance (56.5%). Several studies mentioned cost (38.9%) or sustainability (29.8%). However, few articles included actual monetary cost information (11.1%); only 1 article assessed cost-effectiveness. Based on our review, future research of procedural skill simulation in LMICS should focus on more rigorous research, cost assessments, and on less studied areas.

LCK inhibition downregulates YAP activity and is therapeutic in patient-derived models of cholangiocarcinoma.

BACKGROUND & AIMS: There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, Yes-associated protein (YAP), is oncogenic in CCA, but has historically been difficult to target therapeutically. Recently, we described a novel role for the LCK proto-oncogene, Src family tyrosine kinase (LCK) in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK is a viable therapeutic target in CCA via regulation of YAP activity. METHODS: A novel tyrosine kinase inhibitor with relative selectivity for LCK, NTRC 0652-0, was pharmacodynamically profiled in vitro and in CCA cells. A panel of eight CCA patient-derived organoids were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft models bearing fibroblast growth factor receptor 2 (FGFR2)-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. RESULTS: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in CCA cells. LCK inhibition with NTRC 0652-0 led to decreased tyrosine phosphorylation, nuclear localization, and co-transcriptional activity of YAP, and resulted in apoptotic cell death in CCA cell lines. A subset of tested patient-derived organoids demonstrated sensitivity to NTRC 0652-0. CCAs with FGFR2 fusions were identified as a potentially susceptible and clinically relevant genetic subset. In patient-derived xenograft models of FGFR2 fusion-positive CCA, daily oral treatment with NTRC 0652-0 resulted in stable plasma and tumor drug levels, acceptable toxicity, decreased YAP tyrosine phosphorylation, and significantly decreased tumor growth. CONCLUSIONS: A novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell lines, and patient-derived organoid and xenograft models. IMPACT AND IMPLICATIONS: Although aberrant YAP activation is frequently seen in CCA, YAP targeted therapies are not yet clinically available. Herein we show that a novel LCK-selective tyrosine kinase inhibitor (NTRC 0652-0) effectively inhibits YAP tyrosine phosphorylation and cotranscriptional activity and is well tolerated and cytotoxic in multiple preclinical models. The data suggest this approach may be effective in CCA with YAP dependence or FGFR2 fusions, and these findings warrant further investigation in phase I clinical trials.

SHP2 inhibition enhances Yes-associated protein-mediated liver regeneration in murine partial hepatectomy models.

Disrupted liver regeneration following hepatectomy represents an "undruggable" clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional coactivator that is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent mechanism of YAP activation mediated by downregulation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11, also known as SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. The effects of NSC-87877 were lost in mice with hepatocyte-specific Yap/Taz deletion, and this demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury after hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.

Post-injury outcomes of children with behavioral health disorders.

BACKGROUND: The impact of Behavioral Health Disorders (BHDs) on pediatric injury is poorly understood. We investigated the relationship between BHDs and outcomes following pediatric trauma. METHODS: We analyzed injured children (age 5-15) from 2014 to 2016 using the Pediatric Trauma Quality Improvement Program. The primary outcome was in-hospital mortality. Univariable and multivariable analyses compared children with and without a comorbid BHD. RESULTS: Of 69,305 injured children, 3,448 (5%) had a BHD. These 3,448 children had a median of 1 [IQR: 1, 1] BHD diagnosis: ADHD (n = 2491), major psychiatric disorder (n = 1037), drug use disorder (n = 250), and alcohol use disorder (n = 29). A higher proportion of injured children with BHDs suffered intentional and penetrating injury. Firearm injuries were more common for BHD patients (3% vs 1%, p<0.001). Children with BHDs were more likely to have an ISS>25 compared to children without (5% vs 3%, p<0.001). While median LOS was longer for BHD patients (2 [1, 3] vs 2 [1, 4], p<0.001), mortality was similar (1% vs 1%, p = 0.76) and complications were less frequent (7% vs 8%, p = 0.002). BHD was associated with lower risk of mortality (OR 0.45, 95%CI [0.30, 0.69]) after controlling for age, sex, race, trauma type, and injury intent and severity. CONCLUSION: Children with BHDs experienced lower in-hospital mortality risk after traumatic injury despite more severe injury upon presentation. Intentional and penetrating injuries are particularly concerning, and future work should assess prevention efforts in this vulnerable group.