YAP-TEAD inhibition is associated with upregulation of an androgen receptor mediated transcription program providing therapeutic escape.

Cholangiocarcinoma (CCA) is a highly aggressive form of liver cancer and is an increasing cause of cancer-related death worldwide. Despite its increasing incidence globally and alarming mortality, treatment options for CCA have largely remained unchanged, stressing the importance of developing new effective therapies. YAP activation is common in CCA, and its major transcriptional signaling partners are the TEAD proteins. CA3 is a small-molecule YAP-TEAD disrupter discovered utilizing a TEAD reporter assay. Utilizing CCA, gastric cancer cell lines, and patient-derived xenograft models (PDX), we demonstrate that CA3 is effective in inducing cell death and delaying tumor growth in both FGFR2 fusion and wild-type models. CA3 was associated with on-target decreases in YAP-TEAD target gene expression, TEAD reporter activity, and overall TEAD levels. Hippo pathway signaling was not altered as there was no change in YAP phosphorylation status in the cells exposed to CA3. RNA sequencing of gastric cancer and CCA models demonstrated upregulation of an androgen receptor-mediated transcriptional program following exposure to CA3 in five unique models tested. Consistent with this upstream regulator analysis, CA3 exposure in CCA cells was associated with increased AR protein levels, and combinatorial therapy with CA3 and androgen receptor blockade was associated with increased cancer cell death. CA3 behaves functionally as a YAP-TEAD disrupter in the models tested and demonstrated therapeutic efficacy. Exposure to CA3 was associated with compensatory androgen receptor signaling and dual inhibition improved the therapeutic effect.

Outcomes of Visceral Arterial Interposition Graft Reconstruction for Locally Advanced Pancreatic Cancer.

OBJECTIVE: The aim of this study is to determine perioperative outcomes and the patency of interposition conduits for visceral arterial reconstruction in this setting. SUMMARY BACKGROUND DATA: Visceral arterial encasement in locally advanced pancreatic cancer was historically a contraindication for surgery. With modern effective neoadjuvant strategies, our recent experience has made advanced vascular resection and reconstruction feasible in selected patients. METHODS: A retrospective review was performed of patients undergoing pancreatic tumor resection with en bloc arterial resection and interposition revascularization between 6/2002-10/2022. Endpoints included graft patency, vascular-related complications, reinterventions, morbidity, and mortality. RESULTS: Visceral arterial reconstruction with interposition grafting was performed in 111 patients undergoing en bloc arterial resections for pancreatic cancer. Graft types included autologous arterial conduits (n=66, 58 superficial femoral artery (SFA) and 8 splenic artery), cryopreserved arterial allografts (n=24), autologous saphenous veins (n=12), synthetic conduits (n=8), and composite autologous artery and synthetic (n=1). Perioperative 90-day mortality decreased significantly over time to 5% in the last six years. Vascular complications related to arterial reconstruction occurred in 11% (n=12) and included pseudoaneurysm (n=6), graft thrombus (n=2), stenosis requiring reintervention (n=2), hepatic failure (n=1), and hepatic and intestinal ischemia (n=1). Nine (8%) patients underwent vascular-related reinterventions. After median follow-up of 17-months, primary patency was 81% for the entire cohort and was highest in the SFA group (95%). The donor limb/harvest site complication rate was 8% with 100% primary patency. CONCLUSION: Visceral arterial resection with interposition reconstruction for locally advanced pancreatic cancer can be performed with acceptable vascular morbidity and durable patency. Autologous SFA was the most suitable conduit for reconstructions in our experience, with highest primary patency.

Gastrointestinal histoplasmosis with small intestinal perforation: 20-year experience.

Postmortem studies show gastrointestinal tract involvement in as many as 70% of patients affected by disseminated histoplasmosis. Although gastrointestinal involvement is common in disseminated disease, the presentation of small intestinal perforation is exceedingly rare with few reported cases in the literature. Herein we present our institutional case series. The aim of the study is to describe small intestinal perforation in gastrointestinal histoplasmosis with attention to management and outcomes. This is a retrospective single-institution review of patients ≥ 18 years of age treated for small intestinal perforation due to gastrointestinal histoplasmosis. A prospectively maintained institutional database was searched from 2002 to 2022. Data obtained included demographics, comorbidities, treatment course, and outcomes. Five patients with a mean age of 54 years (range 25-72) were identified. Pertinent underlying comorbid conditions included Crohn's disease, psoriatic arthritis, rheumatoid arthritis, and solid organ transplantation. All patients were on chronic immunosuppressive medication(s) with the most common being tumor necrosis factors alpha inhibitors and corticosteroids. Four had a clinical diagnosis of perforation based on physical examination and imaging. All patients underwent segmental resection(s) of the small intestine and received medical treatment with intravenous amphotericin B and eventual transition to an oral antifungal. No patients experienced complications related to surgery. The limitations of the study include nonrandomized retrospective review, single-institution experience, and small patient sample size. Although rare, histoplasmosis should be considered in the differential of patients on chronic immunosuppressive therapy who present with gastrointestinal symptoms concerning perforation, especially from endemic areas. Small intestinal perforation due to gastrointestinal histoplasmosis can be successfully treated with resection and antifungal therapy.

In vivo label-free optical signatures of chemotherapy response in human pancreatic ductal adenocarcinoma patient-derived xenografts.

Pancreatic cancer is a devastating disease often detected at later stages, necessitating swift and effective chemotherapy treatment. However, chemoresistance is common and its mechanisms are poorly understood. Here, label-free multi-modal nonlinear optical microscopy was applied to study microstructural and functional features of pancreatic tumors in vivo to monitor inter- and intra-tumor heterogeneity and treatment response. Patient-derived xenografts with human pancreatic ductal adenocarcinoma were implanted into mice and characterized over five weeks of intraperitoneal chemotherapy (FIRINOX or Gem/NabP) with known responsiveness/resistance. Resistant and responsive tumors exhibited a similar initial metabolic response, but by week 5 the resistant tumor deviated significantly from the responsive tumor, indicating that a representative response may take up to five weeks to appear. This biphasic metabolic response in a chemoresistant tumor reveals the possibility of intra-tumor spatiotemporal heterogeneity of drug responsiveness. These results, though limited by small sample size, suggest the possibility for further work characterizing chemoresistance mechanisms using nonlinear optical microscopy.

Oncologic Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Highly Selected Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Peritoneal metastases (PM) from pancreatic ductal adenocarcinoma (PDAC) are currently treated with palliative systemic chemotherapy alone, with unsatisfactory results. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may provide an oncologic benefit for highly selected patients. PATIENTS AND METHODS: Patients with PDAC and isolated PM who completed ≥ 6 months of systemic chemotherapy with objective response between 2017 and 2022 were retrospectively reviewed. All patients met the inclusion/exclusion criteria as per our previously published PDAC CRS/HIPEC protocol. Patients who underwent CRS/HIPEC were compared with matched patients who underwent systemic therapy alone. Overall survival (OS) from diagnosis of PM and progression-free survival (PFS) from CRS/HIPEC was evaluated. RESULTS: In total, 61 patients met the inclusion criteria: 38 underwent systemic therapy alone and 23 CRS/HIPEC. There were no differences in baseline prognostic factors, including age, sex, tumor size, tumor location, anatomic resectability, or serum cancer antigen (CA) 19-9 (p > 0.05). Median OS from PM diagnosis in patients who underwent systemic therapy alone was 19 months with 1, 2, and 3 year OS of 81%, 31%, and 8%, respectively. In contrast, median OS from PM diagnosis in patients who underwent CRS/HIPEC was 41 months with improved 1, 2, and 3 year OS of 91%, 66%, and 59%, respectively (p = 0.002). In the 21 patients who achieved complete cytoreduction (CC-0), no adjuvant therapy was administered and the median PFS was 17 months. CONCLUSIONS: CRS/HIPEC in highly selected patients with PDAC and PM results in promising oncologic outcomes that are unlikely to be achieved with systemic chemotherapy alone. Further investigation is warranted and ongoing (NCT04858009).

Therapeutic Efficacy of Temsirolimus in a Patient-derived Model of Metastatic Fibrolamellar Hepatocellular Carcinoma.

BACKGROUND/AIM: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumor presenting in younger patients without chronic liver disease. Up to 80-100% develop recurrent disease, necessitating additional surgery or systemic treatment. Systemic options and pre-clinical treatment studies are lacking. We previously described patient-derived xenograft (PDX) development, allowing for pre-clinical studies. Herein, we develop FLHCC PDX models and utilize these to define tumor characteristics and determine the efficacy of systemic agents. MATERIALS AND METHODS: Primary and lymph node metastatic tumor tissues were obtained at the time of FLHCC resection in two patients. Tumor lysates were screened for protein upregulation. Cell lines were generated from metastatic and primary tumor tissue. The viability of the cell lines was assessed after treatment with temsirolimus, gemcitabine/oxaliplatin, and FOLFIRINOX. Two PDX models were developed from metastatic tissue. For in vivo studies, tumor-bearing mice were treated with temsirolimus, FOLFIRINOX, and Gemcitabine/oxaliplatin. RESULTS: PDX models were successfully generated from metastatic FLHCC, which closely recapitulated the original tumor. Upregulation of mTOR was seen in metastatic tissue compared to primary tumors. Cell lines from metastatic tissue demonstrated significant sensitivity to temsirolimus. In vivo testing of PDX models demonstrated a significant response to single-agent temsirolimus with minimal toxicity. CONCLUSION: Herein, we demonstrate the feasibility of developing PDX models that closely recapitulate FLHCC. Upregulation of mTOR was seen in metastatic tissue compared to primary tissue. The efficacy of mTOR inhibition with temsirolimus treatment suggests that the upregulation of the mTOR pathway may be a significant mechanism for growth in metastatic lesions and a potential target for therapeutics.

Identification of a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma.

A major hurdle to the application of precision oncology in pancreatic cancer is the lack of molecular stratification approaches and targeted therapy for defined molecular subtypes. In this work, we sought to gain further insight and identify molecular and epigenetic signatures of the Basal-like A pancreatic ductal adenocarcinoma (PDAC) subgroup that can be applied to clinical samples for patient stratification and/or therapy monitoring. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft models to identify subtype-specific enhancer regions that were validated in patient-derived samples. In addition, complementary nascent transcription and chromatin topology (HiChIP) analyses revealed a Basal-like A subtype-specific transcribed enhancer program in PDAC characterized by enhancer RNA (eRNA) production that is associated with more frequent chromatin interactions and subtype-specific gene activation. Importantly, we successfully confirmed the validity of eRNA detection as a possible histologic approach for PDAC patient stratification by performing RNA-ISH analyses for subtype-specific eRNAs on pathologic tissue samples. Thus, this study provides proof-of-concept that subtype-specific epigenetic changes relevant for PDAC progression can be detected at a single-cell level in complex, heterogeneous, primary tumor material. IMPLICATIONS: Subtype-specific enhancer activity analysis via detection of eRNAs on a single-cell level in patient material can be used as a potential tool for treatment stratification.

An expeditious and precise method for diameter reduction of venous aneurysm causing arteriovenous fistula steal syndrome.

Clinically significant dialysis access steal syndrome occurs in 1% to 8% of patients. In the present report, we describe an innovative, hybrid option for venoplasty of a cephalic vein aneurysm using a vascular staple device in conjunction with a 6-mm, endovascular balloon placed a few centimeters distal to the brachial artery anastomosis in a 61-year-old man with stage 3 dialysis access steal syndrome secondary to overwhelming venous outflow. The patient experienced immediate postoperative symptom relief. The arteriovenous fistula was immediately accessible for dialysis, circumventing the need for a temporary dialysis catheter. The arteriovenous fistula was functional at 12 months of follow-up.

Yield of Staging Laparoscopy for Pancreatic Cancer in the Modern Era: Analysis of More than 1,000 Consecutive Patients.

BACKGROUND: Accurate staging prior to resection of pancreatic ductal adenocarcinoma (PDAC) is imperative to avoid unnecessary operative morbidity and oncologic futility in patients with occult intra-abdominal distant metastases. We aimed to determine the diagnostic yield of staging laparoscopy (SL) and to identify factors associated with increased risk of positive laparoscopy (PL) in the modern era. STUDY DESIGN: Patients with radiographically localized PDAC who underwent SL from 2017 to 2021 were retrospectively reviewed. The yield of SL was defined as the proportion of patients with PL, including gross metastases and/or positive peritoneal cytology. Factors associated with PL were assessed using univariate analysis and multivariable logistic regression. RESULTS: Of 1,004 patients who underwent SL, 180 (18%) had PL due to gross metastases (n = 140) and/or positive cytology (n = 96). Patients who had neoadjuvant chemotherapy prior to laparoscopy had lower rates of PL (14% vs 22%, p = 0.002). When the analysis was restricted to chemo-naive patients who had concurrent peritoneal lavage performed, 95 of 419 patients (23%) had PL. In multivariable analysis, PL was associated with younger (<60) age, indeterminate extrapancreatic lesions on preoperative imaging, body/tail tumor location, larger tumor size, and elevated serum CA 19-9 (all p < 0.05). Among patients with no indeterminate extrapancreatic lesions on preoperative imaging, the rate of PL ranged from 1.6% in patients with no risk factors to 42% in young patients with large body/tail tumors and elevated serum CA 19-9. CONCLUSIONS: The rate of PL in patients with PDAC remains high in the modern era. SL with peritoneal lavage should be considered for the majority of patients prior to resection, specifically those with high-risk features, and ideally prior to neoadjuvant chemotherapy.

Mixed Acinar Neuroendocrine Carcinoma of the Pancreas: Comparative Population-Based Epidemiology of a Rare and Fatal Malignancy in The United States.

Mixed acinar neuroendocrine carcinoma of the pancreas (MANEC-P) is an extremely rare malignancy with a poor prognosis. However, epidemiological estimates of MANEC-P remain unknown. This study aimed to estimate and compare the incidence, prevalence, and cancer-specific survival (CSS) of MANEC-P in the United States (US). Patients with MANEC-P were identified through the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries databases between 2000-2017. The primary outcomes included age-adjusted incidence rate, limited-duration prevalence, and CSS. A total of 630 patients were identified for the incidence analysis and 149 for the prevalence and CSS analyses. The MANEC-P incidence rate was 0.011 per 100,000 individuals, which was the lowest among pancreatic cancer histologic subtypes. The incidence rate was significantly higher in men and Black races and peaked at 75-79 years of age. The incidence rate was the lowest in the midwestern region (0.009) and the highest in the northeastern US (0.013). The 17-year prevalence was 0.00005%, indicating that 189 patients were alive in the United States at the beginning of 2018. The median CSS of MANEC-P was estimated to be 41 (23, 69) months. In conclusion, MANEC-P is very rare, and its incidence rate has been steady in the US over the last two decades. MANEC-P has a poor prognosis and is the 5th leading cause of pancreatic cancer-related death in the US.

Cytoreduction with Hyperthermic Intraperitoneal Chemoperfusion for Pancreatic Cancer with Low-Volume Peritoneal Metastasis: Results from a Prospective Pilot Study.

INTRODUCTION: Resection of oligometastatic pancreatic ductal adenocarcinoma (PDAC) has historically been ineffective, however modern systemic chemotherapy has improved survival. Thus, re-evaluating safety and outcomes of surgical resection in selected patients with limited peritoneal metastasis (PM) warrants consideration. METHODS: From 2018 to 2021, patients with PDAC and positive cytology or limited PM without extraperitoneal metastasis and who had an objective response to ≥ 6 months of systemic chemotherapy were enrolled. Patients underwent laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin/mitomycin C. If amenable to a complete cytoreduction, patients went on to cytoreduction and HIPEC. RESULTS: Overall, 18 patients were enrolled and received a median of 14 (interquartile range [IQR] 12-17) cycles of chemotherapy; 16 (89%) patients received chemoradiation. Laparoscopic HIPEC was completed in 17 patients, with a median length of stay of 1 day, and no grade III complications or hematological toxicities were observed. All 18 patients subsequently underwent a complete cytoreduction (CC-0) along with definitive treatment of the primary tumor, with formal resection (7/18), irreversible electroporation (IRE; 10/18), or intraoperative radiation therapy (IORT; 1/18). Median PCI was 2 (IQR 0-4), median LOS was 7 days (IQR 6-8), and 7 (39%) patients were readmitted. Eight (44%) patients experienced grade 3 or higher complications, including one 30-day mortality. At a median follow-up of 16 months, the median progression-free survival was 20 months and the median overall survival was 26 months. CONCLUSION: Cytoreduction and HIPEC for selected patients with low-volume PM from PDAC is safe and feasible with favorable short-term outcomes. A phase II trial (NCT04858009) is now enrolling to further assess this multimodality approach in select patients.

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.

FDG-PET Predicts Neoadjuvant Therapy Response and Survival in Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.

BACKGROUND: Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively. Because metabolic imaging (FDG-PET) reveals primary tumor viability, this study aimed to evaluate our experience with preoperative FDG-PET in patients with BR/LA PDAC in predicting NAT response and survival. METHODS: We reviewed all patients with resected BR/LA PDAC who underwent NAT with FDG-PET within 60 days of resection. Pre- and post-NAT metabolic (FDG-PET) and biochemical (CA 19-9) responses were dichotomized in addition to pathologic responses. We compared post-NAT metabolic and biochemical responses as preoperative predictors of pathologic responses and recurrence-free survival (RFS) and overall survival (OS). RESULTS: We identified 202 eligible patients. Post-NAT, 58% of patients had optimization of CA 19-9 levels. Major metabolic and pathologic responses were present in 51% and 38% of patients, respectively. Median RFS and OS times were 21 and 48.7 months, respectively. Metabolic response was superior to biochemical response in predicting pathologic response (area under the curve, 0.86 vs 0.75; P<.001). Metabolic response was the only univariate preoperative predictor of OS (odds ratio, 0.25; 95% CI, 0.13-0.40), and was highly correlated (P=.001) with pathologic response as opposed to biochemical response alone. After multivariate adjustment, metabolic response was the single largest independent preoperative predictor (P<.001) for pathologic response (odds ratio, 43.2; 95% CI, 16.9-153.2), RFS (hazard ratio, 0.37; 95% CI, 0.2-0.6), and OS (hazard ratio, 0.21; 95% CI, 0.1-0.4). CONCLUSIONS: Among patients with post-NAT resected BR/LA PDAC, FDG-PET highly predicts pathologic response and survival, superior to biochemical responses alone. Given the poor ability of anatomic imaging or biochemical markers to assess NAT responses in these patients, FDG-PET is a preoperative metric of NAT efficacy, thereby allowing potential therapeutic alterations and surgical treatment decisions. We suggest that FDG-PET should be an adjunct and recommended modality during the NAT phase of care for these patients.

Patency rates of hepatic arterial resection and revascularization in locally advanced pancreatic cancer.

BACKGROUND: Arterial resection (AR) for pancreatic adenocarcinoma is increasingly considered at specialized centers. We aimed to examine the incidence, risk factors, and outcomes of hepatic artery (HA) occlusion after revascularization. METHODS: We included patients undergoing HA resection with interposition graft (IG) or primary end-to-end anastomoses (EE). Complete arterial occlusion (CAO) was defined as "early" (EO) or "late" (LO) before/after 90 days respectively. Kaplan-Meier and change-point analysis for CAO was performed. RESULTS: HA resection was performed in 108 patients, IG in 61% (66/108) and EE in 39% (42/108). An equal proportion (50%) underwent HA resection alone or in combination with celiac and/or superior mesenteric artery. CAO was identified in 18% of patients (19/108) with arterial IG least likely to occlude (p=0.019). Hepatic complications occurred in 42% (45/108) and correlated with CAO, symptomatic patients, venous resection, and postoperative portal venous patency. CAO-related operative mortality was 4.6% and significantly higher in EO vs LO (p = 0.046). Median CAO occlusion was 126 days. With change-point analysis, CAO was minimal beyond postoperative day 158. CONCLUSION: CAO can occur in up to 18% of patients and the first 5-month post-operative period is critical for surveillance. LO is associated with better outcomes compared to EO unless there is inadequate portal venous inflow.

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.

Re-resection of Microscopically Positive Margins Found on Intraoperative Frozen Section Analysis Does Not Result in a Survival Benefit in Patients Undergoing Surgery and Intraoperative Radiation Therapy for Locally Recurrent Rectal Cancer.

BACKGROUND: Intraoperative frozen-section analysis provides real-time margin resection status that can guide intraoperative decisions made by the surgeon and radiation oncologist. For patients with locally recurrent rectal cancer undergoing surgery and intraoperative radiation therapy, intraoperative re-resection of positive margins to achieve negative margins is common practice. OBJECTIVE: This study aimed to assess whether re-resection of positive margins found on intraoperative frozen-section analysis improves oncologic outcomes. DESIGN: This is a retrospective cohort study. SETTINGS: This study was an analysis of a prospectively maintained multicenter database. PATIENTS: All patients who underwent surgical resection of locally recurrent rectal cancer with intraoperative radiation therapy between 2000 and 2015 were included and followed for 5 years. Three groups were compared: initial R0 resection, initial R1 converted to R0 after re-resection, and initial R1 that remained R1 after re-resection. Grossly positive margin resections (R2) were excluded. MAIN OUTCOME MEASURES: The primary outcome measures were 5-year overall survival, recurrence-free survival, and local re-recurrence. RESULTS: A total of 267 patients were analyzed (initial R0 resection, n = 94; initial R1 converted to R0 after re-resection, n = 95; initial R1 that remained R1 after re-resection, n = 78). Overall survival was 4.4 years for initial R0 resection, 2.7 years for initial R1 converted to R0 after re-resection, and 2.9 years for initial R1 that remained R1 after re-resection ( p = 0.01). Recurrence-free survival was 3.0 years for initial R0 resection and 1.8 years for both initial R1 converted to R0 after re-resection and initial R1 that remained R1 after re-resection ( p ≤ 0.01). Overall survival did not differ for patients with R1 and re-resection R1 or R0 ( p = 0.62). Recurrence-free survival and freedom from local re-recurrence did not differ between groups. LIMITATIONS: This study was limited by the heterogeneous patient population restricted to those receiving intraoperative radiation therapy. CONCLUSIONS: Re-resection of microscopically positive margins to obtain R0 status does not appear to provide a significant survival advantage or prevent local re-recurrence in patients undergoing surgery and intraoperative radiation therapy for locally recurrent rectal cancer. See Video Abstract at http://links.lww.com/DCR/B886 . LA RERESECCIN DE LOS MRGENES MICROSCPICAMENTE POSITIVOS ENCONTRADOS DE MANERA INTRAOPERATORIA MEDIANTE LA TCNICA DE CRIOSECCIN, NO DA COMO RESULTADO UN BENEFICIO DE SUPERVIVENCIA EN PACIENTES SOMETIDOS A CIRUGA Y RADIOTERAPIA INTRAOPERATORIA PARA EL CNCER RECTAL LOCALMENTE RECIDIVANTE: ANTECEDENTES:El análisis de la ténica de criosección para los margenes positivos encontrados de manera intraoperatoria proporciona el estado de la resección del margen en tiempo real que puede guiar las decisiones intraoperatorias tomadas por el cirujano y el oncólogo radioterapeuta. Para los pacientes con cáncer de recto localmente recurrente que se someten a cirugía y radioterapia intraoperatoria, la re-resección intraoperatoria de los márgenes positivos para lograr márgenes negativos es una práctica común.OBJETIVO:Evaluar si la re-resección de los márgenes positivos encontrados en el análisis de la ténica por criosecciónde manera intraoperatorios mejora los resultados oncológicos.DISEÑO:Estudio de cohorte retrospectivo.AJUSTES:Análisis de una base de datos multicéntrica mantenida de forma prospectiva.POBLACIÓN:Todos los pacientes que se sometieron a resección quirúrgica de cáncer de recto localmente recurrente con radioterapia intraoperatoria entre 2000 y 2015 fueron incluidos y seguidos durante 5 años. Se compararon tres grupos: resección inicial R0, R1 inicial convertido en R0 después de la re-resección y R1 inicial que permaneció como R1 después de la re-resección. Se excluyeron las resecciones de márgenes macroscópicamente positivos (R2).PRINCIPALES MEDIDAS DE RESULTADO:Supervivencia global a cinco años, supervivencia sin recidiva y recidiva local.RESULTADOS:Se analizaron un total de 267 pacientes (resección inicial R0 n = 94, R1 inicial convertido en R0 después de la re-resección n = 95, R1 inicial que permaneció como R1 después de la re-resección n = 78). La supervivencia global fue de 4,4 años para la resección inicial R0, 2,7 años para la R1 inicial convertida en R0 después de la re-resección y 2,9 años para la R1 inicial que permaneció como R1 después de la re-resección ( p = 0,01). La supervivencia libre de recurrencia fue de 3,0 años para la resección inicial R0 y de 1,8 años para el R1 inicial convertido en R0 después de la re-resección y el R1 inicial que permaneció como R1 después de la re-resección ( p ≤ 0,01). La supervivencia global no difirió para los pacientes con R1 y re-resección R1 o R0 ( p = 0,62). La supervivencia libre de recurrencia y la ausencia de recurrencia local no difirieron entre los grupos.LIMITACIONES:Población de pacientes heterogénea, restringida a aquellos que reciben radioterapia intraoperatoria.CONCLUSIONES:La re-resección de los márgenes microscópicamente positivos para obtener el estado R0 no parece proporcionar una ventaja de supervivencia significativa o prevenir la recurrencia local en pacientes sometidos a cirugía y radioterapia intraoperatoria para el cáncer de recto localmente recurrente. Consulte Video Resumen en http://links.lww.com/DCR/B886 . (Traducción-Dr. Daniel Guerra ).

"Answers in hours": A prospective clinical study using nanopore sequencing for bile duct cultures.

BACKGROUND: Surgical site infection is a major source of morbidity in patients undergoing pancreatic head resection and is often from organisms in intraoperative bile duct cultures. As such, many institutions use prolonged prophylactic antibiotics and tailor based on bile duct cultures. However, standard cultures take days, leaving many patients unnecessarily on prolonged antibiotics. Nanopore sequencing can provide data in hours and, thus, has the potential to improve antibiotic stewardship. The present study investigates the feasibility of nanopore sequencing in intraoperative bile samples. METHODS: Patients undergoing pancreatic head resection were included. Intra-operative bile microbial profiles were determined with standard cultures and nanopore sequencing. Antibiotic recommendations were generated, and time-to-results determined for both methods. Organism yields, resistance patterns, antibiotic recommendations, and costs were compared. RESULTS: Out of 42 patients, 22 (52%) had samples resulting in positive standard cultures. All positive standard cultures had microbes detected using nanopore sequencing. All 20 patients with negative standard cultures had negative nanopore sequencing. Nanopore sequencing detected more bacterial species compared to standard cultures (10.5 vs 4.4, p < 0.05) and more resistance genotypes (10.3 vs 2.7, p < 0.05). Antimicrobial recommendations based on nanopore sequencing provided coverage for standard cultures in 27 out of 44 (61%) samples, with broader coverage recommended by nanopore sequencing in 13 out of 27 (48%) of these samples. Nanopore sequencing results were faster (8 vs 98 hours) than standard cultures but had higher associated costs ($165 vs $38.49). CONCLUSION: Rapid microbial profiling with nanopore sequencing is feasible with broader organism and resistance profiling compared to standard cultures. Nanopore sequencing has perfect negative predictive value and can potentially improve antibiotic stewardship; thus, a randomized control trial is under development.

Neoadjuvant Chemotherapy Switch in Borderline Resectable/Locally Advanced Pancreatic Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is an integral part of preoperative treatment for patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). The identification of a chemotherapeutic regimen that is both effective and tolerable is critical for NAC to be of oncologic benefit. After initial first-line (FL) NAC, some patients have lack of response or therapeutic toxicities precluding further treatment with the same regimen; optimal decision making regarding this patient population is unclear. Chemotherapy switch (CS) may allow for a larger proportion of patients to undergo curative-intent resection after NAC. METHODS: We reviewed our surgical database for patients undergoing combinatorial NAC for BR/LA PDAC. Variant histologic exocrine carcinomas, intraductal papillary mucinous neoplasm-associated PDAC, and patients without research consent were excluded. RESULTS: Overall, 468 patients with BR/LA PDAC receiving FL chemotherapy were reviewed, of whom 70% (329/468) continued with FL chemotherapy followed by surgical resection. The remaining 30% (139/468) underwent CS, with 72% (100/139) of CS patients going on to curative-intent surgical resection. Recurrence-free survival (RFS) and overall survival (OS) were not significantly different between the resected FL and CS cohorts (30.0 vs. 19.1 months, p = 0.13, and 41.4 vs. 36.4 months, p = 0.94, respectively) and OS was significantly worse in those undergoing CS without subsequent resection (19 months, p < 0.0001). On multivariable analysis, carbohydrate antigen (CA) 19-9 and pathologic treatment responses were predictors of RFS and OS. CONCLUSION: CS in patients undergoing NAC for BR/LA pancreatic cancer does not incur oncologic detriment. The incorporation of CS into NAC treatment sequencing may allow a greater proportion of patients to proceed to curative-intent surgery.