Calcineurin Inhibitor in NEuRoloGically deceased donors to decrease kidney delayed graft function study: study protocol of the CINERGY Pilot randomised controlled trial.

INTRODUCTION: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk. METHODS AND ANALYSIS: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation. ETHICS AND DISSEMINATION: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309). TRIAL REGISTRATION NUMBER: NCT05148715.

Long-term survivors after curative-intent resection for intrahepatic cholangiocarcinoma.

OBJECTIVES: The objective of the current study was to characterize prognostic factors related to long-term recurrence-free survival after curative-intent resection of intrahepatic cholangiocarcinoma (ICC). METHODS: Data on patients who underwent curative-intent resection for ICC between 2000 and 2020 were collected from an international multi-institutional database. Prognostic factors were investigated among patients who recurred within 5 years versus long-term survivors who survived more than 5 years with no recurrence. RESULTS: Among 635 patients who underwent curative-intent resection for ICC, 104 (16.4%) patients were long-term survivors with no recurrence beyond 5 years after surgery. Patients who survived for more than 5 years with no recurrence were more likely to have less aggressive tumor features, as well as have undergone an R0 resection versus patients who recurred within 5 years after resection. On multivariable analysis, tumor size (>5 cm) (HR: 1.535, 95% CI: 1.254-1.879), satellite lesions (HR: 1.253, 95% CI: 1.003-1.564), and lymph node metastasis (HR: 1.733, 95% CI: 1.349-2.227) were independently associated with recurrence within 5 years. Patients who recurred beyond 5 years (n = 23), 2-5 years (n = 60), and within 2 years (n = 471) had an incrementally worse post-recurrence survival (PRS, 28.0 vs. 20.0 vs. 12.0 months, p = 0.032). Among patients with N0 status, tumor size (>5 cm) (HR: 1.612, 95% CI: 1.087-2.390) and perineural invasion (PNI) (HR: 1.562,95% CI: 1.081-2.255) were risk factors associated with recurrence. Among patients with N1 disease, only a minority (5/128, 3.9%) of patients survived with no recurrence to 5 years. CONCLUSION: Roughly 1 in 6 patients survived for more than 5 years with no recurrence following curative-intent resection of ICC. Among N0 patients, tumor recurrence was associated with tumor size and PNI. Only a small subset of N1 patients experienced long-term survival.

Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.

Developing therapies for the activated B-cell like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) remains an area of unmet medical need. A subset of ABC DLBCL tumors is driven by activating mutations in myeloid differentiation primary response protein 88 (MYD88), which lead to constitutive activation of interleukin-1 receptor associated kinase 4 (IRAK4) and cellular proliferation. IRAK4 signaling is driven by its catalytic and scaffolding functions, necessitating complete removal of this protein and its escape mechanisms for complete therapeutic suppression. Herein, we describe the identification and characterization of a dual-functioning molecule, KT-413 and show it efficiently degrades IRAK4 and the transcription factors Ikaros and Aiolos. KT-413 achieves concurrent degradation of these proteins by functioning as both a heterobifunctional degrader and a molecular glue. Based on the demonstrated activity and safety of KT-413 in preclinical studies, a phase 1 clinical trial in B-cell lymphomas, including MYD88 mutant ABC DLBCL, is currently underway.

Impact of postoperative pancreatic fistula on outcomes in pancreatoduodenectomy: a comprehensive analysis of American College of Surgeons National Surgical Quality Improvement Program data.

BACKGROUND: Pancreatoduodenectomy (PD) is a major surgical procedure associated with significant risks, particularly postoperative pancreatic fistula (POPF). Studies have highlighted the importance of certain risk factors for POPF, which are crucial for surgical decision-making and the management of high-risk patients undergoing PD. This study aimed to assess the surgical outcomes of patients undergoing PD who met the International Study Group of Pancreatic Surgery - Class D (ISGPS-D) criteria. METHODS: This study analyzed American College of Surgeons National Surgical Quality Improvement Program data (2014-2021) for patients undergoing ISGPS-D PD, classified as having a soft pancreatic texture and a pancreatic duct of ≤3 mm. This study focused on mortality rates and the correlation between several factors and POPF (ISGPS grade B/C). RESULTS: From 5964 patients who underwent PD and met the ISGPS-D criteria, the 30-day mortality rate was 1.98%. Males had a higher incidence of POPF than females (57.42% vs 47.35%, respectively; P < .001). Patients with POPF experienced significantly higher rates of major postoperative complications (Clavien-Dindo grade ≥ IIIa), including thrombosis, pneumonia, sepsis, delayed gastric emptying, wound disruption, infections, and acute renal failure. There was a marked increase in the 30-day readmission and mortality rates in patients with POPF (30.0% vs 17.6% and 3.2% vs 1.4%, respectively; all P < .001). Multivariate analysis highlighted female sex as a protective factor against mortality (odds ratio [OR], 0.47; P < .001) and extended hospital stay (>10 days) as a predictor of increased mortality risk (OR, 2.37; P < .001). CONCLUSION: This study underscored the significant association between POPF and increased postoperative morbidity and mortality rates. Future efforts should concentrate on refining surgical techniques and improving preoperative assessments to mitigate the risks associated with POPF in patients undergoing PD.

Access to and Health Outcomes of Pediatric Solid Organ Transplantation for Indigenous Children in 4 Settler-colonial Countries: A Scoping Review.

Solid organ transplantation (SOT) is considered the optimal treatment for children with end-stage organ failure; however, increased efforts are needed to understand the gap surrounding equitable access to and health outcomes of SOT for Indigenous children. This scoping review summarizes the literature on the characteristics of access to and health outcomes of pediatric SOT among Indigenous children in the settler-colonial states of Canada, Aotearoa New Zealand, Australia, and the United States. A search was performed on MEDLINE, EMBASE, PsycINFO, and CINAHL for studies matching preestablished eligibility criteria from inception to November 2021. A preliminary gray literature search was also conducted. Twenty-four studies published between 1996 and 2021 were included. Studies addressed Indigenous pediatric populations within the United States (n = 7), Canada (n = 6), Aotearoa New Zealand (n = 5), Australia (n = 5), and Aotearoa New Zealand and Australia combined (n = 1). Findings showed that Indigenous children experienced longer time on dialysis, lower rates of preemptive and living donor kidney transplantation, and disparities in patient and graft outcomes after kidney transplantation. There were mixed findings about access to liver transplantation for Indigenous children and comparable findings for graft and patient outcomes after liver transplantation. Social determinants of health, such as geographic remoteness, lack of living donors, and traditional spiritual beliefs, may affect SOT access and outcomes for Indigenous children. Evidence gaps emphasize the need for action-based initiatives within SOT that prioritize research with and for Indigenous pediatric populations. Future research should include community-engaged methodologies, situated within local community contexts, to inform culturally safe care for Indigenous children.

Minorities Face Delays to Pancreatic Cancer Treatment Regardless of Diagnosis Setting.

INTRODUCTION: Our analysis was designed to characterize the demographics and disparities between the diagnosis of pancreas cancer during emergency presentation (EP) and the outpatient setting (OP) and to see the impact of our institutions pancreatic multidisciplinary clinic (PMDC) on these disparities. METHODS: Institutional review board-approved retrospective review of our institutional cancer registry and PMDC databases identified patients diagnosed/treated for pancreatic ductal adenocarcinoma between 2014 and 2022. Chi-square tests were used for categorical variables, and one-way ANOVA with a Bonferroni correction was used for continuous variables. Statistical significance was set at p < 0.05. RESULTS: A total of 286 patients met inclusion criteria. Eighty-nine patients (31.1%) were underrepresented minorities (URM). Fifty-seven (64.0%) URMs presented during an EP versus 100 (50.8%) non-URMs (p = 0.037). Forty-one (46.1%) URMs were reviewed at PMDC versus 71 (36.0%) non-URMs (p = 0.10). No differences in clinical and pathologic stage between the cohorts (p = 0.28) were present. URMs took 22 days longer on average to receive treatment (66.5 days vs. 44.8 days, p = 0.003) in the EP cohort and 18 days longer in OP cohort (58.0 days vs. 40.5 days, p < 0.001) compared with non-URMs. Pancreatic Multidisciplinary Clinic enrollment in EP cohort eliminated the difference in time to treatment between cohorts (48.3 days vs. 37.0 days; p = 0.151). RESULTS: Underrepresented minorities were more likely to be diagnosed via EP and showed delayed times to treatment compared with non-URM counterparts. Our PMDC alleviated some of these observed disparities. Future studies are required to elucidate the specific factors that resulted in these findings and to identify solutions.

Pre-Mortem Interventions for the Purpose of Organ Donation: Legal Approaches to Consent.

The administration of Pre-Mortem Interventions (PMIs) to preserve the opportunity to donate, to assess the eligibility to donate, or to optimize the outcomes of donation and transplantation are controversial as they offer no direct medical benefit and include at least the possibility of harm to the still-living patient. In this article, we describe the legal analysis surrounding consent to PMIs, drawing on existing legal commentary and identifying key legal problems. We provide an overview of the approaches in several jurisdictions that have chosen to explicitly address PMIs within codified law. We then provide, as an example, a detailed exploration of how PMIs are likely to be addressed in one jurisdiction where general medical consent law applies because there is no specific legislation addressing PMIs - the province of Ontario in Canada.

Navigating Post-Traumatic Osteoporosis: A Comprehensive Review of Epidemiology, Pathophysiology, Diagnosis, Treatment, and Future Directions.

Post-traumatic osteoporosis (PTO) presents a significant challenge in clinical practice, characterized by demineralization and decreased skeletal integrity following severe traumatic injuries. This literature review manuscript addresses the knowledge gaps surrounding PTO, encompassing its epidemiology, pathophysiology, risk factors, diagnosis, treatment, prognosis, and future directions. This review emphasizes the complexity of the etiology of PTO, highlighting the dysregulation of biomineralization processes, inflammatory cytokine involvement, hormonal imbalances, glucocorticoid effects, vitamin D deficiency, and disuse osteoporosis. Moreover, it underscores the importance of multidisciplinary approaches for risk mitigation and advocates for improved diagnostic strategies to differentiate PTO from other musculoskeletal pathologies. This manuscript discusses various treatment modalities, including pharmacotherapy, dietary management, and physical rehabilitation, while also acknowledging the limited evidence on their long-term effectiveness and outcomes in PTO patients. Future directions in research are outlined, emphasizing the need for a deeper understanding of the molecular mechanisms underlying PTO and the evaluation of treatment strategies' efficacy. Overall, this review provides a comprehensive overview of PTO and highlights avenues for future investigation to enhance clinical management and patient outcomes.

Beliefs of physician directors on the management of devastating brain injuries at the Canadian emergency department and intensive care unit interface: a national site-level survey.

PURPOSE: Insufficient evidence-based recommendations to guide care for patients with devastating brain injuries (DBIs) leave patients vulnerable to inconsistent practice at the emergency department (ED) and intensive care unit (ICU) interface. We sought to characterize the beliefs of Canadian emergency medicine (EM) and critical care medicine (CCM) physician site directors regarding current management practices for patients with DBI. METHODS: We conducted a cross-sectional survey of EM and CCM physician directors of adult EDs and ICUs across Canada (December 2022 to March 2023). Our primary outcome was the proportion of respondents who manage (or consult on) patients with DBI in the ED. We conducted subgroup analyses to compare beliefs of EM and CCM physicians. RESULTS: Of 303 eligible respondents, we received 98 (32%) completed surveys (EM physician directors, 46; CCM physician directors, 52). Most physician directors reported participating in the decision to withdraw life-sustaining measures (WLSM) for patients with DBI in the ED (80%, n = 78), but 63% of these (n = 62) said this was infrequent. Physician directors reported that existing neuroprognostication methods are rarely sufficient to support WLSM in the ED (49%, n = 48) and believed that an ICU stay is required to improve confidence (99%, n = 97). Most (96%, n = 94) felt that providing caregiver visitation time prior to WLSM was a valid reason for ICU admission. CONCLUSION: In our survey of Canadian EM and CCM physician directors, 80% participated in WLSM in the ED for patients with DBI. Despite this, most supported ICU admission to optimize neuroprognostication and patient-centred end-of-life care, including organ donation.

RéSUMé: OBJECTIF: L'insuffisance des recommandations fondées sur des données probantes pour guider les soins aux individus atteints de lésions cérébrales dévastatrices rend ces personnes vulnérables à des pratiques incohérentes à la jonction entre le service des urgences et de l'unité de soins intensifs (USI). Nous avons cherché à caractériser les croyances des directeurs médicaux canadiens en médecine d'urgence et médecine de soins intensifs concernant les pratiques de prise en charge actuelles des personnes ayant subi une lésion cérébrale dévastatrice. MéTHODE: Nous avons réalisé un sondage transversal auprès des directeurs médicaux des urgences et des unités de soins intensifs pour adultes du Canada (décembre 2022 à mars 2023). Notre critère d'évaluation principal était la proportion de répondant·es qui prennent en charge (ou jouent un rôle de consultation auprès) des personnes atteintes de lésions cérébrales dévastatrices à l'urgence. Nous avons effectué des analyses en sous-groupes pour comparer les croyances des médecins des urgences et des soins intensifs. RéSULTATS: Sur les 303 personnes répondantes admissibles, 98 (32 %) ont répondu aux sondages (directions médicales des urgences, 46; directions médicales d'USI, 52). La plupart des directeurs médicaux ont déclaré avoir participé à la décision de retirer des traitements de maintien des fonctions vitales (TFMV) pour des patient·es atteint·es de lésions cérébrales dévastatrices à l'urgence (80 %, n = 78), mais 63 % (n = 62) ont déclaré que c'était peu fréquent. Les directions médicales ont indiqué que les méthodes de neuropronostic existantes sont rarement suffisantes pour appuyer le retrait des TMFV à l'urgence (49 %, n = 48) et croyaient qu'un séjour aux soins intensifs était nécessaire pour améliorer leur confiance en ces méthodes (99 %, n = 97). La plupart (96 %, n = 94) estimaient que le fait d'offrir du temps de visite aux personnes soignantes avant le retrait des TMFV était un motif valable d'admission aux soins intensifs. CONCLUSION: Dans le cadre de notre sondage mené auprès des directions médicales des services d'urgence et des USI au Canada, 80 % d'entre elles ont participé au retrait de TMFV à l'urgence pour des patient·es souffrant de lésions cérébrales dévastatrices. Malgré cela, la plupart d'entre elles étaient en faveur d'une admission aux soins intensifs afin d'optimiser le neuropronostic et les soins de fin de vie axés sur les patient·es, y compris le don d'organes.

Surgery for Oligometastatic Pancreatic Cancer: Defining Biologic Resectability.

Pancreatic ductal adenocarcinoma (PDAC) is most often metastatic at diagnosis. As systemic therapy continues to improve alongside advanced surgical techniques, the focus has shifted toward defining biologic, rather than technical, resectability. Several centers have reported metastasectomy for oligometastatic PDAC, yet the indications and potential benefits remain unclear. In this review, we attempt to define oligometastatic disease in PDAC and to explore the rationale for metastasectomy. We evaluate the existing evidence for metastasectomy in liver, peritoneum, and lung individually, assessing the safety and oncologic outcomes for each. Furthermore, we explore contemporary biomarkers of biological resectability in oligometastatic PDAC, including radiographic findings, biochemical markers (such as CA 19-9 and CEA), inflammatory markers (including neutrophil-to-lymphocyte ratio, C-reactive protein, and scoring indices), and liquid biopsy techniques. With careful consideration of existing data, we explore the concept of biologic resectability in guiding patient selection for metastasectomy in PDAC.

Recurrent Intrahepatic Cholangiocarcinoma: A 10-Point Score to Predict Post-Recurrence Survival and Guide Treatment of Recurrence.

INTRODUCTION: Although up to 50-70% of patients with intrahepatic cholangiocarcinoma (ICC) recur following resection, data to predict post-recurrence survival (PRS) and guide treatment of recurrence are limited. METHODS: Patients who underwent resection of ICC between 2000 and 2020 were identified from an international, multi-institutional database. Data on primary disease as well as laboratory and radiologic data on recurrent disease were collected. Factors associated with PRS were examined and a novel scoring system to predict PRS (PRS score) was developed and internally validated. RESULTS: Among 986 individuals who underwent resection for ICC, 588 (59.6%) patients developed recurrence at a median follow up of 20.3 months. Among patients who experienced a recurrence, 97 (16.5%) underwent re-resection/ablation for recurrent ICC; 88 (15.0%) and 403 (68.5%) patients received intra-arterial treatment or systemic chemotherapy/supportive therapy, respectively. Patient American Society of Anesthesiologists (ASA) class > 2 (1 point), primary tumor N1/Nx status (1 point), primary R1 resection margin (1 point), primary tumor G3/G4 grade (1 point), carbohydrate antigen (CA) 19-9 > 37 UI/mL (2 points) at recurrence and carcinoembryonic antigen (CEA) > 5 ng/mL (2 points) at recurrence, as well as recurrent bilateral disease (1 point) and early recurrence (1 point) were included in the PRS score. The PRS score successfully stratified patients relative to PRS and demonstrated strong discriminatory ability (C-index 0.70, 95% confidence interval 0.68-0.72). While a PRS score of 0-3 was associated with a 3-year PRS of 62.5% following resection/ablation for recurrent ICC, a PRS score > 3 was associated with a low 3-year PRS of 35.5% (p = 0.03). CONCLUSIONS: The PRS score demonstrated strong discriminatory ability to predict PRS among patients who had developed recurrence following initial resection of ICC. The PRS score may be a useful tool to guide treatment among patients with recurrent ICC.

Factors associated with radiological misstaging of pancreatic ductal adenocarcinoma: A retrospective observational study.

PURPOSE: Accurate staging of disease is vital in determining appropriate care for patients with pancreatic ductal adenocarcinoma (PDAC). It has been shown that the quality of scans and the experience of a radiologist can impact computed tomography (CT) based assessment of disease. The aim of the current study was to evaluate the impact of the rereading of outside hospital (OH) CT by an expert radiologist and a repeat pancreatic protocol CT (PPCT) on staging of disease. METHODS: Patients evaluated at the our institute's pancreatic multidisciplinary clinic (2006 to 2014) with OH scan and repeat PPCT performed within 30 days were included. In-house radiologists staged disease using OH scans and repeat PPCT, and factors associated with misstaging were determined. RESULTS: The study included 100 patients, with a median time between OH scan and PPCT of 19 days (IQR: 13-23 days.) Stage migration was mostly accounted for by upstaging of disease (58.8 % to 83.3 %) in all comparison groups. When OH scans were rereviewed, 21.5 % of the misstaging was due to missed metastases, however, when rereads were compared to the PPCT, occult metastases accounted for the majority of misstaged patients (62.5 %). Potential factors associated with misstaging were primarily related to imaging technique. CONCLUSION: A repeat PPCT results in increased detection of metastatic disease that rereviews of OH scans may otherwise miss. Accessible insurance coverage for repeat PPCT imaging even within 30 days of an OH scan could help optimize delivery of care and alleviate burdens associated with misstaging.

Developing Guidance for Donor Intervention Randomized Controlled Trials: Initial Discussions From the Canada-United Kingdom 2022 Workshop.

BACKGROUND: Donor interventions, including medications, protocols, and medical devices administered to donors, can enhance transplantable organ quality and quantity and maximize transplantation success. However, there is paucity of high-quality evidence about their effectiveness, in part because of ethical, practical, and regulatory challenges, and lack of guidance about conduct of donor intervention randomized controlled trials (RCTs). METHODS: With the vision to develop authoritative guidance for conduct of donor intervention RCTs, we convened a workshop of Canadian-United Kingdom experts in organ donation and transplantation ethics, research, and policy to identify stakeholders, explore unique challenges, and develop research agenda to inform future work in this promising field. RESULTS: Donor intervention trials should consider perspectives of broad group of stakeholders including donors, transplant recipients, and their families; researchers in donation and transplantation; research ethics boards; and healthcare providers and administrators involved in donation and transplantation. Unique challenges include (1) research ethics (living versus deceased status of the donor at the time of intervention, intervention versus outcomes assessment in different individuals, harm-benefit analysis in donors versus recipients, consent, and impact on research bystanders); (2) outcome data standardization and linkage; and (3) regulatory and governance considerations. CONCLUSIONS: Donor intervention RCTs hold potential to benefit organ transplantation outcomes but face unique research ethics, outcome data, and regulatory challenges. By developing research agenda to address these challenges, our workshop was an important first step toward developing Canada-United Kingdom guidance for donor intervention RCTs that are poised to improve the quality and availability of transplantable organs.

The complication-overall survival (CompOS) risk tool predicts risk of a severe postoperative complications relative to long-term survival among patients with primary liver cancer.

BACKGROUND: This study aimed to develop a tool based on preoperative factors to predict the risk of perioperative complications based on the Comprehensive Complication Index (CCI) and long-term survival outcomes after liver resection for primary liver cancer. METHODS: Patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) undergoing curative-intent hepatectomy between 1990 and 2020 were identified using a multi-institutional international database. RESULTS: Among 1411 patients who underwent curative-intent hepatic resection (HCC: 997, 70.7%; ICC: 414, 29.3%), median patient age was 66.0 years (IQR, 57.0-73.0), and most patients were male (n = 1001, 70.9%). In the postoperative setting, 699 patients (49.5%) experienced a complication; moreover, 112 patients (7.9%) had major complications. Although most patients had a favorable risk complication-overall survival (CompOS) profile (CCI score > 40 risk of <30% and median survival of >5 years: n = 778, 55.1%), 553 patients (39.2%) had an intermediate-risk profile, and 80 patients (5.7%) had a very unfavorable risk profile (CCI score > 40 risk of ≥30% and/or median survival of ≤1.5 years). The areas under the curve of the test and validation cohorts were 0.73 and 0.76, respectively. CONCLUSION: The CompOS risk model accurately stratified patients relative to short- and long-term risks, identifying a subset of patients at a high risk of major complications and poor overall survival.

Cardiopulmonary Resuscitation Education in United States Schools: Shortcomings and Future Directions.

Cardiopulmonary resuscitation (CPR) is a lifesaving procedure that is performed during a cardiac arrest. CPR consists of chest compressions, rescue breaths, and the usage of an automated external defibrillator (AED) based on availability. Performance of CPR can greatly increase the chances of survival by enabling the manual perfusion of vital organs in lieu of the heart's normal function. Despite extensive studies demonstrating the efficacy and necessity of CPR in an emergency, most of the public across the United States is ill-equipped and/or educated on how to perform it. While there may be other contributing factors, the lack of CPR education across schools in the United States almost certainly furthers the CPR illiteracy of the general population. Although states require some degree of CPR training, the level of education that students receive varies widely across communities and school districts, largely dictated by the available funding for training courses. Despite the lack of CPR education in the United States, studies conducted abroad have shown the efficacy of a CPR course in preparing students to respond in emergencies-lending hope to mending the current situation in the United States. In this article, we analyze legislation dictating CPR instruction and hypothesize ways in which states' Department of Education might be able to promote education and hands-on experience for students across all ages of schooling. Ultimately, we hope to highlight the importance and feasibility of preparing the next generation of citizens across the United States to respond when their name is called upon in an emergency.

Early Onset Intrahepatic Cholangiocarcinoma: Clinical Characteristics, Oncological Outcomes, and Genomic/Transcriptomic Features.

INTRODUCTION: Data on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited. METHODS: Patients undergoing hepatectomy for ICC between 2000 and 2020 were identified by using a multi-institutional database. The association of early (≤50 years) versus typical onset (>50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS) was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases. RESULTS: Among 971 patients undergoing resection for ICC, 22.7% (n = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, p < 0.05) and DSS (36.5% vs. 48.9%, p = 0.03) compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, p = 0.002) compared with individuals with typical onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients. CONCLUSIONS: Early-onset ICC has distinct clinical and genomic/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC.

Predicting risk of recurrence after resection of stage I intrahepatic cholangiocarcinoma.

BACKGROUND: Early-stage intrahepatic cholangiocarcinoma (ICC) is often an indication of curative-intent resection. Although patients with early-stage ICC generally have a better prognosis than individuals with advanced ICC, the incidence and risk factors of recurrence after early-stage ICC remain unclear. METHODS: A multi-institutional database was used to identify patients who underwent surgery between 2000 and 2018 for ICC with pathologically confirmed stage I disease. Cox regression analysis was used to identify clinicopathological factors associated with recurrence, and an online prediction model was developed and validated. RESULTS: Of 430 patients diagnosed with stage I ICC, approximately one-half of patients (n = 221, 51.4%) experienced recurrence after curative-intent resection. Among patients with a recurrence, most (n = 188, 85.1%) experienced it within 12 months. On multivariable analysis, carcinoembryonic antigen (hazard ratio [HR], 1.011; 95% CI, 1.004-1.018), systemic immune-inflammation index (HR, 1.036; 95% CI, 1.019-1.056), no lymph nodes evaluated (HR, 1.851; 95% CI, 1.276-2.683), and tumor size (HR, 1.101; 95% CI, 1.053-1.151) were associated with greater hazards of recurrence. A predictive model that included these weighted risk factors demonstrated excellent prognostic discrimination in the test (12-month recurrence-free survival [RFS]: low risk, 80.1%; intermediate risk, 60.3%; high risk, 37.7%; P = .001) and validation (12-month RFS: low risk, 84.5%; intermediate risk, 63.5%; high risk, 47.1%; P = .036) datasets. The online predictive model was made available at https://ktsahara.shinyapps.io/stageI_icc/. CONCLUSIONS: Patients with stage I ICC without vascular invasion or lymph node metastasis had a relatively high incidence of recurrence. An online tool can risk stratify patients relative to recurrence risk to identify individuals best suited for alternative treatment approaches.

Benchmarks in Liver Resection for Intrahepatic Cholangiocarcinoma.

INTRODUCTION: Benchmarking in surgery has been proposed as a means to compare results across institutions to establish best practices. We sought to define benchmark values for hepatectomy for intrahepatic cholangiocarcinoma (ICC) across an international population. METHODS: Patients who underwent liver resection for ICC between 1990 and 2020 were identified from an international database, including 14 Eastern and Western institutions. Patients operated on at high-volume centers who had no preoperative jaundice, ASA class <3, body mass index <35 km/m2, without need for bile duct or vascular resection were chosen as the benchmark group. RESULTS: Among 1193 patients who underwent curative-intent hepatectomy for ICC, 600 (50.3%) were included in the benchmark group. Among benchmark patients, median age was 58.0 years (interquartile range [IQR] 49.0-67.0), only 28 (4.7%) patients received neoadjuvant therapy, and most patients had a minor resection (n = 499, 83.2%). Benchmark values included ≥3 lymph nodes retrieved when lymphadenectomy was performed, blood loss ≤600 mL, perioperative blood transfusion rate ≤42.9%, and operative time ≤339 min. The postoperative benchmark values included TOO achievement ≥59.3%, positive resection margin ≤27.5%, 30-day readmission ≤3.6%, Clavien-Dindo III or more complications ≤14.3%, and 90-day mortality ≤4.8%, as well as hospital stay ≤14 days. CONCLUSIONS: Benchmark cutoffs targeting short-term perioperative outcomes can help to facilitate comparisons across hospitals performing liver resection for ICC, assess inter-institutional variation, and identify the highest-performing centers to improve surgical and oncologic outcomes.