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Purpose: There is lack of consensus regarding the minimum arterial pulse pressure required for confirming permanent cessation of circulation for death determination by circulatory criteria in organ donors. We assessed direct and indirect evidence supporting whether one should use an arterial pulse pressure of 0 mm Hg vs more than 0 (5, 10, 20, 40) mm Hg to confirm permanent cessation of circulation., Source: We conducted this systematic review as part of a larger project to develop a clinical practice guideline for death determination by circulatory or neurologic criteria. We systematically searched Ovid MEDLINE, Ovid Embase, Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library, and Web of Science for articles published from inception until August 2021. We included all types of peer-reviewed original research publications related to arterial pulse pressure as monitored by an indwelling arterial pressure transducer around circulatory arrest or determination of death with either direct context-specific (organ donation) or indirect (outside of organ donation context) data., Principal Findings: A total of 3,289 abstracts were identified and screened for eligibility. Fourteen studies were included; three from personal libraries. Five studies were of sufficient quality for inclusion in the evidence profile for the clinical practice guideline. One study measured cessation of cortical scalp electroencephalogram (EEG) activity after withdrawal of life-sustaining measures and showed that EEG activity fell below 2 μV when the pulse pressure reached 8 mm Hg. This indirect evidence suggests there is a possibility of persistent cerebral activity at arterial pulse pressures > 5 mm Hg., Conclusion: Indirect evidence suggests that clinicians may incorrectly diagnose death by circulatory criteria if they apply any arterial pulse pressure threshold of greater than 5 mm Hg. Moreover, there is insufficient evidence to determine that any pulse pressure threshold greater than 0 and less than 5 can safely determine circulatory death., Study Registration: PROSPERO (CRD42021275763); first submitted 28 August 2021., (© 2023. The Author(s).)

Background: The prognostic role of tumor burden score (TBS) relative to albumin-bilirubin (ALBI) grade among patients undergoing curative-intent resection of ICC has not been examined., Methods: We identified patients who underwent curative-intent resection for ICC between 1990 and 2017 from a multi-institutional database. Multivariable analysis was performed to assess the effect of TBS relative to ALBI grade on both short- and long-term outcomes., Results: Among 724 patients, 360 (49.7%) patients had low TBS and low ALBI grade, 142 (19.6%) patients had low TBS and high ALBI grade, 138 (19.1%) patients had high TBS and low ALBI grade, and 84 patients (11.6%) had high TBS and high ALBI grade. Decreased tumor burden was associated with better long-term outcomes among patients with both low (5-year OS; low TBS vs. high TBS: 52.4% vs 21.4%; p < 0.001) and high ALBI grade (5-year OS; low TBS vs. high TBS: 40.7% vs 12.0%; p < 0.001). On multivariable analysis, higher ALBI grade was associated with greater odds of an extended hospital LOS (> 10 days) (OR 2.80, 95%CI 1.62-4.82; p < 0.001), perioperative transfusion (OR 2.04, 95%CI 1.25-3.36; p = 0.005), 90-day mortality (OR 2.56, 95%CI 1.12-5.81; p = 0.025), as well as a major complication (OR 1.99, 95%CI 1.13-3.49; p = 0.016) among patients with similar tumor burden. Of note, patients with high TBS and high ALBI grade had markedly worse overall survival compared with patients who had low TBS and low ALBI grade disease (HR 2.27; 95%CI 1.44-3.59; p < 0.001). Importantly, high TBS and high ALBI grade were strongly associated with both early recurrence (88.1%%) and 5-year risk of death (96.4%)., Conclusion: Both TBS (i.e., tumor morphology) and ALBI grade (i.e., hepatic function reserve) were strong predictors of outcomes among patients undergoing ICC resection. There was an interplay between TBS and ALBI grade relative to patient prognosis after hepatic resection of ICC with high ALBI grade predicting worse outcomes among ICC patients with different TBS., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: We sought to investigate whether the unique lateral patterns of lymphatic drainage impacted lymphadenectomy (LND), lymph node metastasis (LNM), and long-term survival of patients after curative hemi-hepatectomy for left- versus right-sided intrahepatic cholangiocarcinoma (ICC)., Methods: Data on patients who underwent curative hemi-hepatectomy for left- or right-sided ICC were collected from 15 high-volume centers worldwide, as well as from the Surveillance, Epidemiology, and End Results (SEER) registry. Primary outcomes included overall survival (OS) and disease-free survival (DFS)., Results: Among 697 patients identified from the multi-institutional database, patients who underwent hemi-hepatectomy for left-sided ICC (n = 363, 52.1%) were more likely to have an increased number of LND versus patients with right-sided ICC (n = 334, 47.9%) (median, left 5 versus right 3, p = 0.012), although the frequency (left 66.4% versus right 63.8%, p = 0.469) and station (beyond station no. 12, left 25.3% versus right 21.1%, p = 0.293) were similar. Consequently, left-sided ICC was associated with higher incidence of LNM (left 33.3% versus right 25.7%, p = 0.036), whereas the station and number of LNM were not different (both p > 0.1). There was no difference in OS (median, left 34.9 versus right 29.6 months, p = 0.130) or DFS (median, left 14.5 versus right 15.2 months, p = 0.771) among patients who underwent hemi-hepatectomy for left- versus right-sided ICC, which were also verified in the SEER dataset. LNM beyond station no. 12 was associated with even worse long-term survival versus LNM within station no. 12 among patients with either left- or right-sided ICC after curative-intent resection (all p < 0.05)., Conclusions: The unique lateral patterns of lymphatic drainage were closely related to utilization of LND, as well as LNM of left- versus right-sided ICC., (© 2022. Society of Surgical Oncology.)

Introduction: While generally associated with poor prognosis, intrahepatic cholangiocarcinoma (ICC) can have a heterogeneous presentation and natural history. We sought to identify specific ICC subtypes that may be associated with varied long-term outcomes and patterns of recurrence after liver resection., Methods: Patients who underwent curative-intent resection for ICC from 2000 to 2020 were identified from a multi-institutional database. Hierarchical cluster analysis characterized three ICC subtypes based on morphology (i.e., tumor burden score [TBS]) and biology (i.e., preoperative neutrophil-to-lymphocyte ratio [NLR] and CA19-9 levels)., Results: Among 598 patients, the cluster analysis identified three ICC subtypes: Common (n = 300, 50.2%) (median, TBS: 4.5; NLR: 2.4; CA19-9: 38.0 U/mL); Proliferative (n = 246, 41.1%) (median, TBS: 8.8; NLR: 2.9; CA19-9: 71.2 U/mL); Inflammatory (n = 52, 8.7%) (median, TBS: 5.4; NLR: 12.6; CA19-9: 26.7 U/mL). Median overall survival (OS) (Common: 72.0 months; Proliferative: 31.4 months; Inflammatory: 22.9 months) and recurrence-free survival (RFS) (Common: 21.5 months; Proliferative: 11.9 months; Inflammatory: 9.0 months) varied considerably among the different ICC subtypes (all p < 0.001). Even though patients with Inflammatory ICC had more favorable T-(T1/T2, Common: 84.4%; Proliferative: 80.6%; Inflammatory: 86.5%) and N-(N0, Common: 14.0%; Proliferative: 20.7%; Inflammatory: 26.9%) disease, the Inflammatory subtype was associated with a higher incidence of intra- and extrahepatic recurrence (Common: 15.8%; Proliferative: 24.2%; Inflammatory: 28.6%) (all p = 0.01)., Conclusions: Cluster analysis identified three distinct subtypes of ICC based on TBS, NLR, and CA19-9. ICC subtype was associated with RFS and OS and predicted worse outcomes among patients. Despite more favorable T- and N-disease, the Inflammatory ICC subtype was associated with worse outcomes ICC subtype should be considered in the prognostic stratification of patients., (© 2022. Society of Surgical Oncology.)

Purpose: To investigate recurrence patterns after surgery for intrahepatic cholangiocarcinoma (ICC) relative to lymph node status, tumor extension, tumor burden score (TBS), and adjuvant chemotherapy., Methods: Patients who underwent curative-intent resection for ICC from 1990 to 2020 were enrolled from a multi-institutional database. The hazard function was applied to plot the hazard rates over time, with further stratification by T and N AJCC 8th edition categories, TBS, and adjuvant chemotherapy., Results: A total of 1192 patients underwent curative-intent resection for ICC and 59.9% experienced recurrence. Overall, the peak of recurrence occurred at 6.6 months. Among patients with negative lymph nodes, the T4-category had a higher peak rate of recurrence (0.1199 at 10.2 months) compared with other T-categories, while high TBS had an earlier peak of recurrence (4.2 months) compared with lower TBS. Among patients with N1 disease, T2-T4 categories had multipeak patterns of recurrence with higher hazard rates during the first 3 years after surgery in comparison with T1-category, while patients with high TBS had an earlier (4.0 months) and higher hazard peak rate compared with lower TBS groups. The administration of adjuvant chemotherapy was associated with delayed hazard rates of recurrence for N1 (4 months) and NX (6 months) categories., Discussion: The novel application of the hazard function to assess hazard rates and timing patterns of recurrence following resection for ICC demonstrated that recurrence varied based on T- and N-categories, as well as TBS. Hazard function-based recurrence data may be helpful to tailor counseling, surveillance, and adjuvant therapy recommendations., (© 2022. Society of Surgical Oncology.)

Background: The aim of this study was to develop a predictive model to identify individuals most likely to derive overall survival (OS) benefit from adjuvant chemotherapy (AC) after hepatic resection of intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent hepatic resection of ICC between 1990 and 2020 were identified from a multi-institutional database. Factors associated with worse OS were identified and incorporated into an online predictive model to identify patients most likely to benefit from AC., Results: Among 726 patients, 189 (26.0%) individuals received AC. Factors associated with OS on multivariable analysis included CA19-9 (Hazard Ratio [HR]1.17, 95%CI 1.04-1.31), tumor burden score (HR1.09, 95%CI 1.04-1.15), T-category (T2/3/4, HR1.73, 95%CI 1.73-2.64), nodal disease (N1, HR3.80, 95%CI 2.02-7.15), tumor grade (HR1.88, 95%CI 1.00-3.55), and morphological subtype (HR2.19, 95%CI 1.08-4.46). A weighted predictive score was devised and made available online (https://yutaka-endo.shinyapps.io/ICCrisk&#95;model&#95;for&#95;AC/). Receipt of AC was associated with a survival benefit among patients at high/medium-risk (high: no AC, 0% vs. AC, 20.6%; medium: no AC, 36.4% vs. 40.8%; both p < 0.05) but not low-risk (low: no AC, 65.1% vs. AC, 65.1%; p = 0.73) tumors., Conclusion: An online predictive model based on tumor characteristics may help identify which patients may benefit the most from AC following resection of ICC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: In April 2019, the Human Organ and Tissue Donation Act (HOTDA) in Nova Scotia was modified to incorporate a deemed consent model. In this study, we sought to understand intensive care unit (ICU) and emergency department (ED) nurses' knowledge of and confidence around organ donation and transplantation, experiences with organ donors and recipients, attitudes toward organ donation and deemed consent, and perceived opportunities and barriers to a deemed consent approach in view of the legislative change., Methods: We sent an electronic, self-administered survey to all ICU and ED nurses in Nova Scotia. The survey queried respondents on their knowledge of, experience with, and attitudes around organ donation and HOTDA, and opportunities and barriers to the implementation of HOTDA in clinical practice. Survey results were analyzed using descriptive statistics., Results: One-hundred and ninety-four nurses responded to the survey. Nearly all (98%) supported organ donation, with 86% having signed an organ donor card to donate organs and/or tissues after death. A considerable majority (89%) also supported the new legislation. Nevertheless, a minority of respondents (13%) believed that deemed consent legislation would be considered a violation of the general principles of freedom and autonomy. The three most identified topics for ongoing training were coordination of the donation process (70%), clinical management of donors (70%), and family issues in decision-making (70%)., Conclusion: Intensive care unit and ED nurses had positive attitudes toward organ donation, including deemed consent model. The findings should inform educational initiatives in Nova Scotia and beyond to optimize organ donation processes and outcomes., (© 2022. Canadian Anesthesiologists' Society.)

Objectives: To characterize the prognostic implication of jaundice and preoperative biliary drainage on postoperative outcomes among patients with gallbladder cancer (GBC) undergoing surgical resection., Methods: Patients who underwent surgical resection of GBC identified from a multicenter database between January 2000 and December 2019 were retrospectively analyzed. Data on clinical and pathological details, as well as short- and long-term overall survival (OS), were obtained and compared among patients with and without preoperative jaundice and biliary drainage., Results: Among 449 patients with GBC, median and 1-, 3-, and 5-year OS were 17.4 months, 63.7%, 28.4%, and 22.1%, respectively. Patients who presented with preoperative jaundice (n = 100, 22.3%) were more likely to have advanced disease, a lower incidence of R0 resection (29.0% vs. 69.1%, p < 0.001), as well as a higher incidence of postoperative liver failure (4% vs. 0, p = 0.002), and worse long-term survival versus patients without jaundice (median OS, 10.4 vs. 27.1 months, p < 0.001). Preoperative biliary drainage was performed for the majority of jaundiced patients (77.0%) and was associated with decreased risk of postoperative liver failure (1.3% vs. 13.0%, p = 0.041); preoperative biliary drainage failed to improve long-term survival (median OS, 10.2 months vs. 12.0 months, p = 0.679). On multivariable analysis, R0 resection (17.5 vs. 7.6 months, p < 0.001) and adjuvant therapy (15.6 vs. 6.6 months, p = 0.027) were associated with improved long-term survival among jaundiced patients., Conclusions: While preoperative biliary drainage of jaundiced GBC patients decreased the risk of postoperative liver failure, it did not impact long-term outcomes. Rather, preoperative jaundice was associated with a lower chance at R0 resection and worse long-term survival., (© 2022. The Society for Surgery of the Alimentary Tract.)

Na V 1.7 is an actively pursued, genetically validated, target for pain. Recently reported quinolinone sulfonamide inhibitors displayed promising selectivity profiles as well as efficacy in preclinical pain models; however, concerns about off-target liabilities associated with this series resulted in an effort to reduce the lipophilicity of these compounds. Successful prosecution of this strategy was challenging due to the opposing requirement for lipophilic inhibitors for Na V 1.7 potency and in vivo clearance (CL). Deconstruction of the heterocyclic core of the quinolinone series and utilization of an intramolecular hydrogen bond to mimic the requisite pharmacophore enabled the introduction of polarity without adversely impacting CL. Ultimately, this strategy led to the identification of compound 29, which demonstrated favorable ADME and was efficacious in pre-clinical models of pain., (Published by Elsevier Ltd.)

Purpose: The purpose of this study was to present the successful management and outcomes in a series of 6 cases of culture-positive nontuberculous mycobacterial keratitis after clear corneal incision phacoemulsification surgery., Methods: This is a case series of 6 consecutive eyes that presented at the Cornea Division at an academic institution, diagnosed with culture-positive nontuberculous mycobacterial keratitis after phacoemulsification surgery., Results: Six eyes of 5 patients were included. The mean interval from cataract surgery to presentation was 7.7 weeks. All cases presented with intrastromal abscesses adjacent to corneal incisions, and 2 had scleral extension of the infection. Isolated organisms were Mycobacterium abscessus (n = 4), Mycobacterium chelonae (n = 1), and Mycobacterium mucogenicum (n = 1). All cases were treated with topical amikacin 8 mg/mL for 10.5 weeks on average. All cases received either oral clarithromycin at 500 mg twice-daily dosage or oral azithromycin at 500 mg daily. Two patients with scleral abscesses underwent surgical debridement with amniotic membrane grafts. All 6 eyes achieved infection resolution and good visual recovery, with the final visual acuity ranging from 20/20 to 20/60. None of the patients experienced recurrence of infection., Conclusions: Prompt medical treatment with combined topical and oral therapy can lead to infection resolution and favorable visual recovery. Early surgical intervention can ensure good outcomes in cases of scleral extension., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The physiology of dying after withdrawal of life-sustaining measures (WLSM) is not well described in children. This lack of knowledge makes predicting the duration of the dying process difficult. For families, not knowing this process's duration interferes with planning of rituals related to dying, travel for distant relatives and emotional strain during the wait for death. Time-to-death also impacts end-of-life care and determines whether a child will be eligible for donation after circulatory determination of death. This scoping review will summarise the current literature about what is known about the dying process in children after WLSM in paediatric intensive care units (PICUs)., Methods and Analysis: This review will use Joanna Briggs Institute methodology for scoping reviews. Databases searched will include Ovid MEDLINE, Ovid Embase, Cochrane Central Register of Controlled Trials via EBM Reviews Ovid, Ovid PsycINFO, CINAHL and Web of Science. Literature reporting on the physiology of dying process after WLSM, or tools that predict time of death in children after WLSM among children aged 0-18 years in PICUs worldwide will be considered. Literature describing the impact of prediction or timing of death after WLSM on families, healthcare workers and the organ donation process will also be included. Quantitative and qualitative studies will be evaluated. Two independent reviewers will screen references by title and abstract, and then by full text, and complete data extraction and analysis., Ethics and Dissemination: The review uses published data and does not require ethics review. Review results will be published in a peer-reviewed scientific journal., Competing Interests: Competing interests: LH is a paid research consultant for Canadian Blood Services., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Prospective evaluation of 2 clinical-molecular models in patients with unknown pathology who underwent endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for a cystic lesion of the pancreas., Summary of Background Data: Preoperative prediction of histologic subtype (mucinous vs nonmucinous) and grade of dysplasia in patients with pancreatic cystic neoplasms is challenging. Our group has previously published 2 clinical-molecular nomograms for intraductal papillary mucinous neoplasms (IPMN) that incorporated both clinical/radiographic features and cyst fluid protein markers (sFASL, CA72-4, MMP9, IL-4)., Methods: This multiinstitutional study enrolled patients who underwent EUS-FNA for a cystic lesion of the pancreas. Treatment recommendations regarding resection were based on standard clinical, radiographic, and endoscopic features. Predicted probabilities of high-risk IPMN (high-grade dysplasia/invasive cancer) were calculated using the previously developed clinical-molecular nomograms., Results: Cyst fluid was obtained from 100 patients who underwent diagnostic EUS-FNA. Within this group there were 35 patients who underwent resection, and 65 were monitored radiographically. Within the group that underwent resection, 26 had low-risk IPMN or benign non-IPMN lesions, and 9 had high-risk IPMN. Within the surveillance group, no patient progressed to resection or developed cancer after a median follow-up of 12months (range: 0.5-38). Using the clinical/radiographic nomogram alone, 2 out of 9 patients with high-risk IPMN had a predicted probability >0.5. In the clinical-molecular models, 6 of 9 patients in model 1, and 6 of 9 in model 2, had scores >0.5., Conclusions: This prospective study of patients with unknown cyst pathology further demonstrates the importance of cyst fluid protein analysis in the preoperative identification of patients with high-risk IPMN. Longer follow-up is necessary to determine if this model will be useful in clinical practice., Competing Interests: The authors report no conflicts of interest, (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Delayed bleeding after pancreaticoduodenectomy (PD) is a life-threatening complication. However, the optimal management remains unclear. We summarize our experience of the management of delayed bleeding after PD and define the outcomes associated with different types of management., Methods: All patients who underwent a PD between January 1987 and June 2020 at Johns Hopkins University were retrospectively reviewed. Delayed bleeding was defined as bleeding on or after postoperative day 5 following PD. Incidence, outcomes, and trends were reported., Results: Among the 6201 patients that underwent PD, delayed bleeding occurred in 130 (2.1%) at a median of 12 days (IQR: 9, 24) postoperation. The pattern of bleeding was classified as intraluminal (51.5%), extraluminal (40.8%), and mixed (7.7%). A clinically relevant postoperative pancreatic fistula and an intraabdominal abscess preceded the delayed bleeding in 43.1% and 31.5% of cases, respectively. Arterial pseudoaneurysm or bleeding from peripancreatic vessels was the most common reason (54.6%) with the gastroduodenal artery being the most common source (18.5%). Endoscopy, angiography, and reoperation were performed as a first-line approach in 35.4%, 52.3%, and 6.2% of patients, respectively. The overall mortality was 16.2% and decreased over the study period (p < 0.01)., Conclusions: Delayed bleeding following PD remains a life-threatening complication. The most common location of delayed bleeding is from the gastroduodenal artery. Angiography with embolization should be the initial approach for urgent bleeding with surgical re-exploration reserved for unstable patients or failed control of bleeding after interventional angiography or endoscopy., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Introduction: Evidence suggests the presence of deficiencies in the quality of care provided to up to half of all paediatric trauma patients in Canada, the USA and Australia. Lack of adherence to evidence-based recommendations may be driven by lack of knowledge of clinical practice guidelines (CPGs), heterogeneity in recommendations or concerns about their quality. We aim to systematically review CPG recommendations for paediatric injury care and appraise their quality., Methods and Analysis: We will identify CPG recommendations through a comprehensive search strategy including Medical Literature Analysis and Retrieval System Online, Excerpta Medica dataBASE, Cochrane library, Web of Science, ClinicalTrials and websites of organisations publishing recommendations on paediatric injury care. We will consider CPGs including at least one recommendation targeting paediatric injury populations on any diagnostic or therapeutic intervention from the acute phase of care with any comparator developed in high-income countries in the last 15 years (January 2007 to a maximum of 6 months prior to submission). Pairs of reviewers will independently screen titles, abstracts and full text of eligible articles, extract data and evaluate the quality of CPGs and their recommendations using Appraisal of Guidelines Research and Evaluation (AGREE) II and AGREE Recommendations Excellence instruments, respectively. We will synthesise evidence on recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision framework and present results within a recommendations matrix., Ethics and Dissemination: Ethics approval is not a requirement as this study is based on available published data. The results of this systematic review will be published in a peer-reviewed journal, presented at international scientific meetings and distributed to healthcare providers., Prospero Registration Number: International Prospective Register of Systematic Reviews (CRD42021226934)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Stereotactic body radiation therapy (SBRT) for patients with borderline resectable and locally advanced pancreatic adenocarcinoma (BRPC/LAPC) remains controversial. Herein, we report on surgical, pathologic, and survival outcomes in BRPC/LAPC patients treated at a high-volume institution with induction chemotherapy (CTX) followed by 5-fraction SBRT., Methods: BRPC/LAPC patients treated between 2016 and 2019 were retrospectively reviewed. Surgical and pathological outcomes were descriptively characterized. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox proportional hazard regression. Locoregional failure and distant failure were analyzed with Fine-Gray competing risk model., Results: Of 155 patients, 91 (59%) had LAPC and 64 (41%) had BRPC. Almost all were treated with induction multi-agent CTX with either FOLFIRINOX (75%) or gemcitabine and nab-paclitaxel (24%) for a median duration of 4.0 months (1-18 months). All received SBRT to a median dose of 33 Gy. Among 64 BRPC patients, 50 (78%) underwent resection, of whom 48 (96%) achieved margin-negative (R0) resection. Among 91 LAPC patients, 57 (63%) underwent resection, of whom 50 (88%) achieved R0 resection. Despite the high R0 rate, 33% of patients experienced locoregional failure, which was a component of 44% of all failures. After SBRT, median OS and PFS were 18.7 and 7.7 months, respectively. After SBRT, 1- and 2-year OS probabilities were 70% and 45%, whereas, from diagnosis, they were 93% and 51%., Conclusions: Although a high proportion of BRPC/LAPC patients treated with induction multi-agent CTX followed by SBRT successfully achieved R0 resection, locoregional failure remained common, highlighting the need to continue to optimize radiation delivery in this context., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The prognostic impact of tumor necrosis among patients undergoing resection for intrahepatic cholangiocarcinoma (ICC) remains ill-defined., Methods: Patients who underwent curative-intent resection for ICC between 2000 and 2017 were identified using a multi-institutional database. The association of pathologic tumor necrosis with overall survival (OS) and recurrence-free survival (RFS) was examined., Results: Among 757 patients who underwent resection for ICC, tumor necrosis was present in 384 (50.7%) patients (no necrosis: n = 373, 49.3%; <50% necrosis: n = 291, 38.4%; ≥50% necrosis: n = 93, 12.3%). Tumor necrosis was associated with worse OS (5-year OS: no necrosis 39.3% vs. <50% necrosis 34.7% and ≥50% necrosis 24.0%; p = 0.03) and RFS (5-year RFS: no necrosis 25.7% vs. <50% necrosis 13.9% and ≥50% necrosis 18.8%; p < 0.001). After stratifying by T stage, tumor necrosis was able to further stratify prognosis among patients with T1a ICC (5-year RFS: T1a and no necrosis 46.7% vs. T1a and necrosis 36.1%; p = 0.02), and T1b ICC (5-year RFS: T1b and no necrosis 31.1% vs. T1b and necrosis 11.2%; p = 0.006), but was not associated with outcomes among patients with more advanced T2-T3 disease. Patients with T1a ICC and tumor necrosis had similar 5-year RFS as individuals with T1b ICC and no tumor necrosis (36.1% vs. 31.1%; p = 0.66)., Conclusion: Tumor necrosis was associated with worse prognosis among patients with T1 ICC. Tumor necrosis for T1 ICC should be considered as an important factor to further stratify outcomes of patients with early T-stage ICC., (© 2022. Society of Surgical Oncology.)

Objectives: To determine the prognostic implication of the number and station of LNM, and the minimal number of LNs needed for evaluation to accurately stage patients with intrahepatic cholangiocarcinoma (ICC)., Background: Impact of the number and station of LNM on long-term survival, and the minimal number of LNs needed for accurate staging of ICC patients remain poorly defined., Methods: Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide. External validation was performed using the SEER registry. Primary outcomes included overall (OS), disease-specific, and recurrence-free survival., Results: Among 603 patients who underwent curative-intent resection, median and 5-year OS were 30.6 months and 30.4%. Patients with 1 or 2 LNM had comparable worse OS versus patients with no nodal disease (median OS, 1 LNM 18.0, 2 LNM 20.0 vs no LNM 45.0 months, both P < 0.001), yet better OS versus patients with 3 or more LNM (median OS, 1-2 LNM 19.8 vs ≥3 LNM 16.0 months, P < 0.01). On multivariable analysis, a proposed new nodal staging with N1 (1-2 LNM) (Ref. N0, HR 2.40, P < 0.001) and N2 (≥3 LNM) [Ref. N0, hazard ratio (HR) 3.85, P < 0.001] categories were independently associated with incrementally worse OS. Patients with no nodal metastasis, 1-2 LNM and ≥3 LNM also had an increasingly worse disease-specific survival, and recurrence-free survival (both P < 0.05). Total number of LNs examined ≥6 had the greatest discriminatory power relative to OS among patients with 1-2 LNM, and patients with ≥3 LNM in both the multi-institutional (area under the curve 0.780) and SEER database (area under the curve 0.820) (n = 1036). Among patients who underwent an adequate regional lymphadenectomy (total number of LNs examined ≥6), LNM beyond the HDL was associated with worse OS versus LNM within the HDL only (median OS, 14.0 vs 24.0 months, HR 2.41, P = 0.003)., Conclusion: Standard lymphadenectomy of at least 6 LNs is strongly recommended and should include examination beyond station 12 to have the greatest chance of accurate staging. The proposed new nodal staging of N0, N1, and N2 should be considered to stratify outcomes among patients after curative-intent resection of ICC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC), but most patients are not candidates for resection and most resected HCCs eventually recur. Until recently, neoadjuvant systemic therapy for HCC has been limited by a lack of effective systemic agents. Here, in a single arm phase 1b study, we evaluated the feasibility of neoadjuvant cabozantinib and nivolumab in patients with HCC including patients outside of traditional resection criteria (NCT03299946). Of 15 patients enrolled, 12 (80%) underwent successful margin negative resection, and 5/12 (42%) patients had major pathologic responses. In-depth biospecimen profiling demonstrated an enrichment in T effector cells, as well as tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders as compared to non-responders, indicating an orchestrated B-cell contribution to antitumor immunity in HCC., Competing Interests: Competing Interests The remaining authors declare no competing interests.

Background: Although multidisciplinary treatments including the use of adjuvant therapy (AT) have been adopted for biliary tract cancers, patients with distal cholangiocarcinoma (DCC) can still experience recurrence. We sought to characterize the incidence and predictors of early recurrence (ER) that occurred within 12 months following surgery for DCC., Patients and Methods: Patients who underwent resection for DCC between 2000 and 2015 were identified from the US multi-institutional database. Cox regression analysis was used to identify clinicopathological factors to develop an ER risk score, and the predictive model was validated in an external dataset., Results: Among 245 patients included in the analysis, 67 patients (27.3%) developed ER. No difference was noted in ER rates between patients who did and did not receive AT (28.7% vs. 25.0%, p = 0.55). Multivariable analysis revealed that neutrophil-to-lymphocyte ratio (NLR), peak total bilirubin (T-Bil), major vascular resection (MVR), lymphovascular invasion, and R1 surgical margin status were associated with a higher ER risk. A DIstal Cholangiocarcinoma Early Recurrence Score was developed according to each factor available prior to surgery [NLR > 9.0 (2 points); peak T-bil > 1.5 mg/dL (1 points); MVR (2 points)]. Cumulative ER rates incrementally increased among patients who were low (0 points; 10.6%), intermediate (1-2 points; 26.8%), or high (3-5 points; 57.6%) risk (p < 0.001) in the training dataset, as well as in the validation dataset [low (0 points); 3.4%, intermediate (1-2 points); 32.7%, or high risk (3-5 points); 55.6% (p < 0.001)]., Conclusions: Among patients undergoing resection for DCC, 1 in 4 patients experienced an ER. Alternative treatment strategies such as neoadjuvant chemotherapy may be considered especially among individuals deemed to be at high risk for ER.

Background: The objective of the current study was to develop a model to predict the likelihood of occult lymph node metastasis (LNM) prior to resection of intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent hepatectomy for ICC between 2000 and 2017 were identified using a multi-institutional database. A novel model incorporating clinical and preoperative imaging data was developed to predict LNM., Results: Among 980 patients who underwent resection of ICC, 190 (19.4%) individuals had at least one LNM identified on final pathology. An enhanced imaging model incorporating clinical and imaging data was developed to predict LNM ( https://k-sahara.shinyapps.io/ICC&#95;imaging/ ). The performance of the enhanced imaging model was very good in the training data set (c-index 0.702), as well as the validation data set with bootstrapping resamples (c-index 0.701) and outperformed the preoperative imaging alone (c-index 0.660). The novel model predicted both 5-year overall survival (OS) (low risk 48.4% vs. high risk 18.4%) and 5-year disease-specific survival (DSS) (low risk 51.9% vs. high risk 25.2%, both p < 0.001). When applied among Nx patients, 5-year OS and DSS of low-risk Nx patients was comparable with that of N0 patients, while high-risk Nx patients had similar outcomes to N1 patients (p > 0.05)., Conclusion: This tool may represent an opportunity to stratify prognosis of Nx patients and can help inform clinical decision-making prior to resection of ICC.

Background: We report our experience utilizing liver donors with HCV Viremia (RNA+) for HCV-negative recipients (HCV D+R-) at a Veterans Affairs (VA) transplant center., Methods: In 2018, we introduced an informed consent process for HCV D+R- liver transplants., Results: Eight HCV D+R- liver transplants (LT) were performed. Median time from listing to LT was 189 days (range 41-511). Median MELD at LT was 23.5 (median MELD at LT of 31 for center). All recipients developed HCV viremia after transplant. Median time to DAA initiation was 10 days after viremia (range 3-25). After transplant, the DAAs used were Mavyret in five recipients and Epclusa in three, all for 12 weeks. All eight patients completed DAA therapy and achieved negative HCV RNA by end of therapy (ETR) and seven reached sustained virologic response (SVR) by 12 weeks after end of therapy. One patient died from chronic ischemic encephalopathy after ETR, before SVR., Conclusions: HCV D+R- is a practical strategy to expand the pool of donor organs. It shortened waiting time, allowing patients to receive transplants at lower MELD scores. VA liver transplant programs have provided universal and timely access to post-transplant HCV DAA therapy after donor-derived infection., (© 2020 Wiley Periodicals LLC.)

Introduction: While tumor burden (TB) has been associated with outcomes among patients with hepatocellular carcinoma, the role of overall TB in intrahepatic cholangiocarcinoma (ICC) remains poorly defined., Methods: Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified from a multi-institutional database. The impact of TB on overall (OS) and disease-free survival (DFS) was evaluated in the multi-institutional database and validated externally., Results: Among 1101 patients who underwent curative-intent resection of ICC, 624 (56.7%) had low TB, 346 (31.4%) medium TB, and 131 (11.9%) high TB. OS incrementally worsened with higher TB (5-year OS; low TB: 48.3% vs medium TB: 29.8% vs high TB: 17.3%, p < 0.001). Similarly, patients with low TB had better DFS compared with medium and high TB patients (5-year DFS: 38.3% vs 18.7% vs 6.9%, p < 0.001). On multivariable analysis, TB was independently associated with OS (medium TB: HR = 1.40, 95% CI 1.14-1.71; high TB: HR = 1.89, 95% CI 1.46-2.45) and DFS (medium TB, HR = 1.61, 95% CI 1.33-1.96; high TB: HR = 2.03, 95% CI 1.56-2.64). Survival analysis revealed an excellent prognostic discrimination using the TB among the external validation cohort (3-year OS; low TB: 44.8%, medium TB: 29.3%; high TB: 23.3%, p = 0.03; 3-year DFS: low TB: 32.7%, medium TB: 10.7%; high TB: 0%, p < 0.001). While neoadjuvant chemotherapy was not associated with survival across the TB groups, receipt of adjuvant chemotherapy was associated with increased survival among patients with high TB (5-year OS: 24.4% vs 13.4%, p = 0.02)., Conclusion: Overall TB dictated prognosis among patients with resectable ICC. TB may be used as a tool to help guide post-resection treatment strategies.

Background: To develop a scoring system to identify the subset of patients who may benefit the most from adjuvant chemotherapy following curative-intent resection for incidental gallbladder cancer (IGBC)., Methods: A novel scoring system was utilized to stratify patients relative to overall survival (OS), as well as potential benefit from adjuvant chemotherapy following curative resection for IGBC., Results: Among 266 patients with IGBC, a total of 99 (37.2%) patients received adjuvant chemotherapy. Five risk factors were used to develop an integer-based score to predict OS. Risk of death at 5-years incrementally increased among patients in the low (n = 42, 69.0%), medium (n = 64, 56.3%) and high-risk groups (n = 40, 30.0%) (median OS, 99.4 vs. 33.5 vs. 15.6 months, all p < .001). Use of adjuvant chemotherapy did not provide a survival benefit among patients in the low-risk group (median survival, 99.4 vs. 60.7 months, p = .56). In contrast, utilization of adjuvant chemotherapy was associated with an improvement in survival among medium- (median survival, 21.7 vs. 59.5 months, p = .04) and high-risk patients (median survival, 11.6 vs. 20.1 months, p = .01)., Conclusions: While low-risk patients did not benefit from adjuvant chemotherapy, individuals with medium or high-risk scores had an improved survival with the utilization of adjuvant chemotherapy., (© 2021 Wiley Periodicals LLC.)

Background: The minimum duration of pulselessness required before organ donation after circulatory determination of death has not been well studied., Methods: We conducted a prospective observational study of the incidence and timing of resumption of cardiac electrical and pulsatile activity in adults who died after planned withdrawal of life-sustaining measures in 20 intensive care units in three countries. Patients were intended to be monitored for 30 minutes after determination of death. Clinicians at the bedside reported resumption of cardiac activity prospectively. Continuous blood-pressure and electrocardiographic (ECG) waveforms were recorded and reviewed retrospectively to confirm bedside observations and to determine whether there were additional instances of resumption of cardiac activity., Results: A total of 1999 patients were screened, and 631 were included in the study. Clinically reported resumption of cardiac activity, respiratory movement, or both that was confirmed by waveform analysis occurred in 5 patients (1%). Retrospective analysis of ECG and blood-pressure waveforms from 480 patients identified 67 instances (14%) with resumption of cardiac activity after a period of pulselessness, including the 5 reported by bedside clinicians. The longest duration after pulselessness before resumption of cardiac activity was 4 minutes 20 seconds. The last QRS complex coincided with the last arterial pulse in 19% of the patients., Conclusions: After withdrawal of life-sustaining measures, transient resumption of at least one cycle of cardiac activity after pulselessness occurred in 14% of patients according to retrospective analysis of waveforms; only 1% of such resumptions were identified at the bedside. These events occurred within 4 minutes 20 seconds after a period of pulselessness. (Funded by the Canadian Institutes for Health Research and others.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: The optimal time interval to define early recurrence (ER) among patients who underwent resection of gallbladder cancer (GBC) is not well defined. We sought to develop and validate a novel GBC recurrence risk (GBRR) score to predict ER among patients undergoing resection for GBC., Patients and Methods: Patients who underwent curative-intent resection for GBC between 2000 and 2018 were identified from the US Extrahepatic Biliary Malignancy Consortium database. A minimum p value approach in the log-rank test was used to define the optimal cutoff for ER. A risk stratification model was developed to predict ER based on relevant clinicopathological factors and was externally validated., Results: Among 309 patients, 103 patients (33.3%) had a recurrence at a median follow-up period of 15.1 months. The optimal cutoff for ER was defined at 12 months (p = 3.04 × 10 -18 ). On multivariable analysis, T3/T4 disease (HR: 2.80; 95% CI 1.58-5.11) and poor tumor differentiation (HR: 1.91; 95% CI 1.11-3.25) were associated with greater hazards of ER. The GBRR score was developed using β-coefficients of variables in the final model, and patients were classified into three distinct groups relative to the risk for ER (12-month RFS; low risk: 88.4%, intermediate risk: 77.9%, high risk: 37.0%, p < 0.001). The external validation demonstrated good model generalizability with good calibration (n = 102: 12-month RFS; low risk: 94.2%, intermediate risk: 59.8%, high risk: 42.0%, p < 0.001). The GBRR score is available online at https://ktsahara.shinyapps.io/GBC&#95;earlyrec/ ., Conclusions: A novel online calculator was developed to help clinicians predict the probability of ER after curative-intent resection for GBC. The proposed web-based tool may help in the optimization of surveillance intervals and the counselling of patients about their prognosis.

Introduction: Patients with intrahepatic cholangiocarcinoma (ICC) generally have a poor prognosis, yet there can be heterogeneity in the patterns of presentation and associated outcomes. We sought to identify clusters of ICC patients based on preoperative characteristics that may have distinct outcomes based on differing patterns of presentation., Methods: Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified using a multi-institutional database. A cluster analysis was performed based on preoperative variables to identify distinct patterns of presentation. A classification tree was built to prospectively assign patients into cluster assignments., Results: Among 826 patients with ICC, three distinct presentation patterns were noted. Specifically, Cluster 1 (common ICC, 58.9%) consisted of individuals who had a small-size ICC (median 4.6 cm) and median carbohydrate antigen (CA) 19-9 and neutrophil-to-lymphocyte ratio (NLR) levels of 40.3 UI/mL and 2.6, respectively; Cluster 2 (proliferative ICC, 34.9%) consisted of patients who had larger-size tumors (median 9.0 cm), higher CA19-9 levels (median 72.0 UI/mL), and similar NLR (median 2.7); Cluster 3 (inflammatory ICC, 6.2%) comprised of patients with a medium-size ICC (median 6.2 cm), the lowest range of CA19-9 (median 26.2 UI/mL), yet the highest NLR (median 13.5) (all p < 0.05). Median OS worsened incrementally among the three different clusters {Cluster 1 vs. 2 vs. 3; 60.4 months (95% confidence interval [CI] 43.0-77.8) vs. 27.2 months (95% CI 19.9-34.4) vs. 13.3 months (95% CI 7.2-19.3); p < 0.001}. The classification tree used to assign patients into different clusters had an excellent agreement with actual cluster assignment (κ = 0.93, 95% CI 0.90-0.96)., Conclusion: Machine learning analysis identified three distinct prognostic clusters based solely on preoperative characteristics among patients with ICC. Characterizing preoperative patient heterogeneity with machine learning tools can help physicians with preoperative selection and risk stratification of patients with ICC.

Background: The objective of this study was to examine whether the systemic immune inflammation index (SII) was associated with prognosis among patients following resection of intrahepatic cholangiocarcinoma (ICC)., Methods: The impact of SII on overall (OS) and cancer-specific survival (CSS) following resection of ICC was assessed. The performance of the final multivariable models that incorporated inflammatory markers (i.e. neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR] and SII [platelets∗NLR]) was assessed using the Harrell's concordance index., Results: Patients with high SII had worse 5-year OS (37.7% vs 46.6%, p < 0.001) and CSS (46.1% vs 50.1%, p < 0.001) compared with patients with low SII. An elevated SII (HR = 1.70, 95% CI 1.23-2.34) and NLR (HR = 1.58, 95% CI 1.10-2.27) independently predicted worse OS, whereas high PLR (HR = 1.17, 95% CI 0.85-1.60) was no longer associated with prognosis. Only SII remained an independent predictor of CSS (HR = 1.55, 95% CI 1.09-2.21). The SII multivariable model outperformed models that incorporated PLR and NLR relative to OS (c-index; 0.696 vs 0.689 vs 0.692) and CSS (c-index; 0.697 vs 0.689 vs 0.690)., Conclusion: SII independently predicted OS and CSS among patients with resectable ICC. SII may be a better predictor of outcomes compared with other markers of inflammatory response among patients with resectable ICC., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: To assess conditional survival (CS) according to recurrence status, as well as conditional disease-free survival (cDFS) among patients with intrahepatic cholangiocarcinoma (ICC)., Methods: CS and cDFS were evaluated among ICC patients who underwent curative-intent resection for ICC by using a multi-institutional database. Five-year CS (CS5) at "x" years was calculated separately for patients who did and did not experience recurrence. The cDFS3 at "x" years was defined as the chance to be disease-free for an additional 3 years after not having experienced a recurrence for "x" years postoperatively., Results: Among 1221 patients, median OS was 36.8 months. While estimated actuarial OS decreased over time, CS5 increased as patients survived over longer periods of time and reached 93.9% at 4 years among 139 patients who did not experience a recurrence. Among the 725 (59.4%) patients who did experience a tumor recurrence, CS5 decreased to 17.7% the first postoperative year; however, CS5 subsequently increased to 79.7% for 81 patients who had survived 4 years after surgery. While actuarial DFS decreased from 54.6% at 1 year to 28.2% at 5 years, estimated cDFS3 following liver resection increased over time. Of note, patients with known risk factors for recurrence had even more marked improvements in cDFS3 over subsequent years versus patients without risk factors for recurrence., Conclusion: CS and cDFS changed over time according to the presence of disease-specific risk factors, as well as the presence of recurrence.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide with a minority of patients being diagnosed early enough for curative-intent interventions. We report the first use of preoperative cabozantinib plus nivolumab to successfully downstage what presented as unresectable HCC as part of an ongoing phase 1b study. Preoperative treatment with cabozantinib and nivolumab led to >99% reduction in alpha-fetoprotein, -37.3% radiographic reduction by RECIST 1.1 and a near complete pathologic response (80% to 100% necrosis). An integrated immunological analysis was performed on the post-treatment surgical tumor sample and matched pre-treatment and post-treatment peripheral blood samples with high-dimensional imaging and cytometry techniques. Bayesian non-negative matrix factorization (CoGAPS, Coordinated Gene Activity in Pattern Sets) and self-organizing map (FlowSOM) algorithms were used to distinguish changes in functional markers across cellular neighborhoods in the single cell data sets. Brisk immunological infiltration into the tumor microenvironment was observed in non-random, organized cellular neighborhoods. Systemically, combination therapy led to marked promotion of effector cytotoxic T cells and effector memory helper T cells. Natural killer cells also increased with therapy. The patient remains without disease recurrence and with a normal alpha-fetoprotein approximately 2 years from presentation. Our study provides proof-of-concept that borderline resectable or locally advanced HCC warrants consideration of downstaging with effective neoadjuvant systemic therapy for subsequent curative resection., Competing Interests: Competing interests: WH is a co-inventor of patents with potential for receiving royalties from Rodeo Therapeutics unrelated to the current study. MY reports receiving a commercial research grant from Bristol Myers Squibb, Exelixis, and Merck & Co and is a consultant/advisory board member for Eisai and Exelixis. EJF is a consultant for Champions Oncology. EMJ reports receiving a commercial research grant from Bristol Myers Squibb, Aduro Biotech, and Amgen, has ownership interest (including stock, patents, and so on) in Aduro Biotech, and is a consultant/advisory board member for CStone, Dragonfly, Genocea, and Adaptive Biotechnologies., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We assessed the feasibility and safety of placing a radiopaque hydrogel in the pancreaticoduodenal groove via endoscopic ultrasound guidance in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC)., Methods and Materials: Hydrogel injections were done at time of fiducial placement to form blebs in the pancreaticoduodenal groove. Patients subsequently underwent simulation computed tomography (sim-CT) followed by hypofractionated stereotactic body radiotherapy (SBRT; 33 Gy in 5 fractions). Four to 8 weeks after SBRT, patients underwent CT re-evaluation for surgical candidacy and assessment of hydrogel location and size. Hydrogel placement was considered successful if identified in the pancreaticoduodenal groove on sim-CT scan. Stability was evaluated using equivalence testing analyses, with a null hypothesis of the presence of a ≥20% mean percentage change in volume and ≥2 mm change in the median and mean interbleb surface distance with a P value <.05 required to reject the null hypothesis and conclude equivalence. For patients undergoing pancreaticoduodenectomy, hydrogel sites were histologically examined for location and local inflammatory reactions., Results: Hydrogel placement was successful in 6 of the 6 evaluable patients. The average changes in median and mean interbleb distances were -0.43 mm and -0.35 mm, respectively, with P < .05. The average change in volume from sim-CT to post-SBRT CT was -1.0%, with P < .05. One patient experienced grade 3 nausea after fiducial/hydrogel placement, with no other adverse events to date., Conclusions: These data demonstrate feasibility and safety of injecting a hydrogel marker in the pancreaticoduodenal groove in patients with BR/LAPC and set the stage for a follow-up clinical trial to place hydrogel as a spacer between the pancreatic tumor and dose-limiting, radiosensitive duodenum., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objectives: To establish and externally validate a novel nomogram to predict recurrence of patients undergoing curative liver resection for neuroendocrine liver metastasis (NELM)., Methods: A total of 279 patients who underwent curative liver resection for NELM identified from an international multicenter database were utilized to develop a nomogram to predict recurrence; 98 cases from two different institutions were used to externally validate the nomogram., Results: Among 279 patients in the development cohort, median age was 57 years, and 50.5% were male. On multivariate analysis, primary tumor location (pancreatic vs nonpancreatic, HR 2.1, p = 0.004), tumor grade (Ref. well, moderate HR 1.9, p = 0.022; poor HR 1.6, p = 0.238), lymph node metastasis (positive vs negative, HR 2.6, p = 0.002), and extent of resection (major vs parenchymal-sparing resection, HR 0.3, p = 0.001) were independently associated with recurrence-free survival. The beta coefficients from the final multivariable model were utilized to develop a nomogram. The nomogram demonstrated good ability to predict risk of recurrence (training cohort, C-index 0.754; validation cohort, C-index 0.748). The calibrated nomogram predicted recurrence-free survival that closely corresponded to actual recurrence. Decision curve analysis demonstrated that the nomogram had a good net benefit for most of the threshold probabilities, especially between 20 and 60%, in both development and validation cohorts., Conclusions: The externally validated novel nomogram predicted 3- and 5-year recurrence-free survival among patients with NELM. Prediction of individual recurrence risk may help guide personalized estimates of prognosis, as well as surveillance protocols and consideration of adjuvant therapies.

The genomic architecture and molecular mechanisms controlling variation in quantitative disease resistance loci are not well understood in plant species and have been barely studied in long-generation trees. Quantitative trait loci mapping and genome-wide association studies were combined to test a large single nucleotide polymorphism (SNP) set for association with quantitative and qualitative white pine blister rust resistance in sugar pine. In the absence of a chromosome-scale reference genome, a high-density consensus linkage map was generated to obtain locations for associated SNPs. Newly discovered associations for white pine blister rust quantitative disease resistance included 453 SNPs involved in wide biological functions, including genes associated with disease resistance and others involved in morphological and developmental processes. In addition, NBS-LRR pathogen recognition genes were found to be involved in quantitative disease resistance, suggesting these newly reported genes are qualitative genes with partial resistance, they are the result of defeated qualitative resistance due to avirulent races, or they have epistatic effects on qualitative disease resistance genes. This study is a step forward in our understanding of the complex genomic architecture of quantitative disease resistance in long-generation trees, and constitutes the first step towards marker-assisted disease resistance breeding in white pine species., (© 2020 Society for Experimental Biology and John Wiley & Sons Ltd.)

Importance: Although surgery offers the best chance of a potential cure for patients with localized, resectable intrahepatic cholangiocarcinoma (ICC), prognosis of patients remains dismal largely because of a high incidence of recurrence., Objective: To predict very early recurrence (VER) (ie, recurrence within 6 months after surgery) following resection for ICC in the pre- and postoperative setting., Design, Setting, and Participants: Patients who underwent curative-intent resection for ICC between May 1990 and July 2016 were identified from an international multi-institutional database. The study was conducted at The Ohio State University in collaboration with all other participating institutions. The data were analyzed in December 2019., Main Outcomes and Measures: Two logistic regression models were constructed to predict VER based on pre- and postoperative variables. The final models were used to develop an online calculator to predict VER and the tool was internally and externally validated., Results: Among 880 patients (median age, 59 years [interquartile range, 51-68 years]; 388 women [44.1%]; 428 [50.2%] white; 377 [44.3%] Asian; 27 [3.2%] black]), 196 (22.3%) developed VER. The 5-year overall survival among patients with and without VER was 8.9% vs 49.8%, respectively (P < .001). A preoperative model was able to stratify patients relative to the risk for VER: low risk (6-month recurrence-free survival [RFS], 87.7%), intermediate risk (6-month RFS, 72.3%), and high risk (6-month RFS, 49.5%) (log-rank P < .001). The postoperative model similarly identified discrete cohorts of patients based on probability for VER: low risk (6-month RFS, 90.0%), intermediate risk (6-month RFS, 73.1%), and high risk (6-month RFS, 48.5%) (log-rank, P < .001). The calibration and predictive accuracy of the pre- and postoperative models were good in the training (C index: preoperative, 0.710; postoperative, 0.722) as well as the internal (C index: preoperative, 0.715; postoperative, 0.728; bootstrapping resamples, n = 5000) and external (C index: postoperative, 0.672) validation data sets., Conclusion and Relevance: An easy-to-use online calculator was developed to help clinicians predict the chance of VER after curative-intent resection for ICC. The tool performed well on internal and external validation. This tool may help clinicians in the preoperative selection of patients for neoadjuvant therapy as well as during the postoperative period to inform surveillance strategies.

Introduction: The objective of the current study was to comprehensively assess the change of practice in hepatobiliary surgery by determining the rates and the trends of textbook outcomes (TO) among patients undergoing surgery for primary liver cancer over time., Methods: Patients undergoing curative-intent resection for primary liver malignancies, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) between 2005 and 2017 were analyzed using a large, international multi-institutional dataset. Rates of TO were assessed over time. Factors associated with achieving a TO and the impact of TO on long-term survival were examined., Results: Among 1829 patients, 944 (51.6%) and 885 (48.4%) individuals underwent curative-intent resection for HCC and ICC, respectively. Over time, patients were older, more frequently had ASA class > 2, albumin-bilirubin grade 2/3, major vascular invasion and more frequently underwent major liver resection (all p < 0.05). Overall, a total of 1126 (62.0%) patients achieved a TO. No increasing trends in TO rates were noted over the years (p trend  = 0.90). In addition, there was no increasing trend in the TO rates among patients undergoing either major (p trend  = 0.39) or minor liver resection (p trend  = 0.63) over the study period. Achieving a TO was independently associated with 26% and 37% decreased hazards of death among ICC (HR 0.74, 95%CI 0.56-0.97) and HCC patients (HR 0.63, 95%CI 0.46-0.85), respectively., Conclusion: Approximately 6 in 10 patients undergoing surgery for primary liver tumors achieved a TO. While TO rates did not increase over time, TO was associated with better long-term outcomes following liver resection for both HCC and ICC.

Background: Prolonged survival of patients after pancreaticoduodenectomy can be associated with late complications due to altered gastrointestinal anatomy. The incidence of gastric cancer is increasingly reported. We set out to examine our experience with gastric cancer as a late complication after pancreaticoduodenectomy with a focus on incidence, risk factors, and outcomes., Methods: We queried our prospectively collected institutional database for patients that developed gastric cancer after pancreaticoduodenectomy and conducted a systematic review of the literature., Results: Our database revealed 6 patients who developed gastric cancer following pancreaticoduodenectomy, presenting with a mean age of 62.2 years and an even sex distribution. All of those patients underwent pancreaticoduodenectomy for malignant indications with an average time to development of metachronous gastric cancer of 8.3 years. Four patients complained of gastrointestinal discomfort prior to diagnosis of secondary malignancy. All of these cancers were poorly differentiated and were discovered at an advanced T stage (≥ 3). Only half developed at the gastrointestinal anastomosis. Four underwent surgery with a curative intent, and 2 patients are currently alive (mean postgastrectomy survival = 25.5 months). In accordance with previous literature, biliopancreatic reflux from pancreaticoduodenectomy reconstruction, underlying genetic susceptibility, and adjuvant therapy may play a causative role in later development of gastric cancer., Conclusion: Long-term survivors after pancreaticoduodenectomy who develop nonspecific gastrointestinal complaints should be evaluated carefully for complications including gastric malignancy. This may serve as an opportunity to intervene on tumors that typically present at an advanced stage and with aggressive histology., (© 2020 The Authors.)

Background: The objective of the current study was to assess the impact of serum CA19-9 and CEA and their combination on survival among patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent curative-intent resection of ICC between 1990 and 2016 were identified using a multi-institutional database. Patients were categorized into four groups based on combinations of serum CA19-9 and CEA (low vs. high). Factors associated with 1-year mortality after hepatectomy were examined., Results: Among 588 patients, 5-year OS was considerably better among patients with low CA19-9/low CEA (54.5%) compared with low CA19-9/high CEA (14.6%), high CA19-9/low CEA (10.0%), or high CA19-9/high CEA (0%) (P < 0.001). No difference in 1-year OS existed between patients who had either high CA19-9 (high CA19-9/low CEA: 70.4%) or high CEA levels (low CA19-9/high CEA: 72.5%) (P = 0.92). Although patients with the most favorable tumor marker profile (low CA19-9/low CEA) had the best 1-year survival (87.9%), 15.1% (n = 39) still died within a year of surgery. Among patients with low CA19-9/low CEA, a high neutrophil-to-lymphocyte ratio (NLR) (odds ratio 1.09; 95% confidence interval 1.03-1.64) and large size tumor (odds ratio 3.34; 95% confidence interval 1.40-8.10) were associated with 1-year mortality (P < 0.05)., Conclusions: Patients with either a high CA19-9 and/or high CEA had poor 1-year survival. High NLR and large tumor size were associated with a greater risk of 1-year mortality among patients with favorable tumor marker profile.

Introduction: Cardiac transplantation remains the best treatment for patients with end-stage heart disease that is refractory to medical or device therapies, however, a major challenge for heart transplantation is the persistent discrepancy between the number of patients on waiting lists and the number of available hearts. While other countries (eg, UK, Australia and Belgium) have explored and implemented alternative models of transplantation, such as cardiac donation after circulatory determination of death (DCDD) to alleviate transplantation wait times, ethical concerns have hindered implementation in some countries. This study aims to explore the attitudes and opinions of healthcare providers and the public about cardiac DCDD in order to identify and describe opportunities and challenges in ensuring that proposed cardiac DCDD procedures in Canada are consistent with Canadian values and ethical norms., Methods and Analysis: This study will include two parts that will be conducted concurrently. Part 1 is a qualitative study consisting of semi-structured interviews with Canadian healthcare providers who routinely care for organ donors and/or transplant recipients to describe their perceptions about cardiac DCDD. Part 2 is a convergent parallel mixed-methods design consisting of a series of focus groups and follow-up surveys with members of the Canadian general public to describe their perceptions about cardiac DCDD., Ethics and Dissemination: This study has been approved by the Research Ethics Board at Western University. The findings will be presented at regional and national conferences and reported in peer-reviewed publications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In a patient-centred and family-centred approach to organ donation, compassion is paramount. Recent guidelines have called for more research, interventions and approaches aimed at improving and supporting the families of critically ill patients. The objective of this study is to help translate patient-centred and family-centred care into practice in deceased organ donation., Methods and Analysis: This will be a national, qualitative study of family members of deceased organ donors in Canada. We will include family members who had been approached regarding an organ donation decision, including those who agreed and declined, at least 2 months and no later than 3 years after the patients' death. Data collection and analysis is ongoing and will continue until September 2020 to include approximately 250 participants. Family members will be identified and recruited from provincial organ donation organisation databases. Four experienced qualitative researchers will conduct telephone interviews in English or French with audio-recording for subsequent transcription. The research team will develop a codebook iteratively through this process using inductive methods, thus generating themes directly from the dataset., Ethics and Dissemination: Local research ethics boards (REB) at all participating sites across Canada have approved this protocol. The main REB involved is the Ottawa Health Science Network REB. Data collection began in August 2018. Publication of results is anticipated in 2021. Study findings will help improve healthcare provider competency in caring for potential organ donors and their families and improve organ donation consent rates. Findings will also help with the development of educational materials for a competency-based curriculum for critical care residents., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Accurate risk stratification and patient selection is necessary to identify patients who will benefit the most from surgery or be better treated with other non-surgical treatment strategies. We sought to identify which patients in the preoperative setting would likely derive the most or least benefit from resection of intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent curative-intent resection for ICC between 1990 and 2017 were identified from an international multi-institutional database. A machine-based classification and regression tree (CART) was used to generate homogeneous groups of patients relative to overall survival (OS) based on preoperative factors., Results: Among 1146 patients, CART analysis revealed tumor number and size, albumin-bilirubin (ALBI) grade and preoperative lymph node (LN) status as the strongest prognostic factors associated with OS among patients undergoing resection for ICC. In turn, four groups of patients with distinct outcomes were generated through machine learning: Group 1 (n = 228): single ICC, size ≤ 5 cm, ALBI grade I, negative preoperative LN status; Group 2 (n = 708): (1) single tumor > 5 cm, (2) single tumor ≤ 5 cm, ALBI grade 2/3, and (3) single tumor ≤ 5 cm, ALBI grade 1, metastatic/suspicious LNs; Group 3 (n = 150): 2-3 tumors; Group 4 (n = 60): ≥ 4 tumors. 5-year OS among Group 1, 2, 3, and 4 patients was 60.5%, 35.8%, 27.5%, and 3.8%, respectively (p < 0.001). Similarly, 5-year disease-free survival (DFS) among Group 1, 2, 3, and 4 patients was 47%, 27.2%, 6.8%, and 0%, respectively (p < 0.001)., Conclusions: The machine-based CART model identified distinct prognostic groups of patients with distinct outcomes based on preoperative factors. Survival decision trees may be useful as guides in preoperative patient selection and risk stratification.

Purpose: Collection and analysis of health data are crucial to achieving high-quality clinical care, research, and quality improvement. This review explores existing hospital, regional, provincial and national data platforms in Canada to identify gaps and barriers, and recommend improvements for data science., Source: The Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group undertook an environmental survey using list-identified names and keywords in PubMed and the grey literature, from the Canadian context. Findings were grouped into sections, corresponding to geography, purpose, and patient sub-group initiatives, using a narrative qualitative approach. Emerging themes, impressions, and recommendations towards improving data initiatives were generated., Principal Findings: In Canada, the Canadian Institute for Health Information Discharge Abstract Database contains high-level clinical data on every adult and child discharged from acute care facilities; however, it does not contain data from Quebec, critical care-specific severity of illness risk-adjustment scores, physiologic data, or data pertaining to medication use. Provincially mandated critical care platforms in four provinces contain more granular data, and can be used to risk adjust and link to within-province data sets; however, no inter-provincial collaborative mechanism exists. There is very limited infrastructure to collect and link biological samples from critically ill patients nationally. Comprehensive international clinical data sets may inform future Canadian initiatives., Conclusion: Clinical and biological data collection among critically ill patients in Canada is not sufficiently coordinated, and lags behind other jurisdictions. An integrated and inclusive critical care data platform is a key clinical and scientific priority in Canada.

Background: The survival benefit of lymphadenectomy among patients with gallbladder cancer (GBC) remains poorly understood., Methods: Patients who underwent resection for GBC between 2000 and 2015 were identified from a US multi-institutional database. The therapeutic index (LNM rate multiplied by 3-year overall survival [OS]) was determined to assess the survival benefit of lymphadenectomy., Results: Among 449 patients, less than half had LNM (N = 183, 40.8%). The median number of evaluated and metastatic lymph nodes (LNs) was 3 (interquartile range [IQR]: 1-6) and 1 (IQR: 0-1), respectively. 3-year OS among patients with LNM in the entire cohort was 26.8%. The therapeutic index was lower among patients with T4 (5.9) or T1 (6.0) tumors as well as carbohydrate antigen (CA19-9) ≥200 UI/mL (6.0). Of note, a therapeutic index difference ≥10 was noted relative to CA19-9 (<200: 18.7 vs ≥200: 6.0), American Joint Committee on Cancer T Stage (T1: 6.0 vs T2: 17.8 vs T4: 5.9) and number of LNs examined (1-2: 6.9 vs ≥6: 16.9). Concomitant common bile duct resection was not associated with a higher therapeutic index among patients with either T2 or T3 disease., Conclusion: Certain clinicopathological factors including T1 or T4 tumor and CA19-9 ≥200 UI/mL were associated with a low therapeutic index. Resection of six or more LNs was associated with a meaningful therapeutic index benefit among patients with LNM., (© 2020 The Authors. Journal of Surgical Oncology published by Wiley Periodicals, Inc.)

Introduction: In Canada, deceased organ donation provides over 80% of transplanted organs. At the time of death, families, friends or others assume responsibility as substitute decision-makers (SDMs) to consent to organ donation. Despite their central role in this process, little is known about what barriers, enablers and beliefs influence decision-making among SDMs. This study aims to explore the experiences and perspectives of SDMs involved in making decisions around the withdrawal of life-sustaining therapies, end-of-life care and deceased organ donation., Methods and Analysis: SDMs of 60 patients admitted to intensive care units will be enrolled for this study. Ten hospitals across five provinces in Canada in a prospective multicentre qualitative cohort study. We will conduct semistructured telephone interviews in English or French with SDMs between 6 and 8 weeks after the patient's death. Our sampling frame will stratify SDMs into three groups: SDMs who were not approached for organ donation; SDMs who were approached and consented to donate and SDMs who were approached but did not consent to donate. We will use two complementary theoretical frameworks-the Common-Sense Self-Regulation Model and the Theoretical Domains Framework- to inform our interview guide. Interview data will be analysed using deductive directed content analysis and inductive thematic analysis., Ethics and Dissemination: This study has been approved by the Centre Hospitalier de l'Université de Montréal Research Ethics Board. The findings from this study will help identify key factors affecting substitute decision-making in deceased organ donation, reasons for non-consent and barriers to achieve congruency between SDM and patient wishes. Ultimately, these data will contribute to the development and evaluation of tools and training for healthcare providers to support SDMs in making decisions about organ donation., Trial Registration Number: NCT03850847., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neuroendocrine liver metastases (NELM) are typically associated with high recurrence rates following surgical resection. Conditional disease-free survival (CDFS) estimates may be more clinically relevant compared to actuarial survival estimates., Methods: CDFS was assessed using a multi-institutional cohort of patients. Cox proportional hazards models were used to evaluate factors associated with disease-free survival (DFS). Three-year CDFS (CDFS3) estimates at "x" year after surgery were calculated as CDFS 3  = DFS(x + 3)/DFS(x)., Results: A total of 521 patients met the inclusion criteria. While actuarial 3-year DFS gradually decreased from 49% at 1 year to 39% at 5 years, CDFS 3 increased over time. CDFS 3 at 5 years was estimated as 89% vs actuarial 8-year DFS of 39% (P < .001). The probability of remaining disease-free at 5 years after resection increased as patients remained disease-free. For example, the probability of being disease-free for an additional 3 years was 66.3% and 88.8% for patients who lived 2 and 5 years, respectively. Overall, CDFS 3 in each subgroup increased postoperatively as years elapsed, however, the impact of each prognostic factor on CDFS 3 changed over time., Conclusion: CDFS of patients who underwent resection of NELM exponentially improved as patients survived additional years without recurrence. CDFS provides more accurate prognostic measures compared with traditional DFS measures., (© 2019 Wiley Periodicals, Inc.)

Background: Tumor burden is an important factor in defining prognosis among patients with primary and secondary liver cancers. Although the eighth edition of the American Joint Committee on Cancer staging system has changed the criteria for staging patients with intrahepatic cholangiocarcinoma to better define the effect of tumor burden on prognosis, the impact of intrahepatic cholangiocarcinoma tumor burden on overall survival has not been examined using a machine-learning tool., Methods: Patients who underwent resection of intrahepatic cholangiocarcinoma at 1 of 14 participating international hospitals between 1990 and 2015 were identified. Classical survival models and the Classification and Regression Tree model were used to identify groups of patients with a homogeneous risk of death and investigate the hierarchical association between variables and overall survival., Results: Among 1,116 patients included in the analysis, tumor size was ≤5 cm in 447 (40.1%) patients and >5 cm in 669 (59.9%) patients. Although 82.9% (n = 926) of patients had a single intrahepatic cholangiocarcinoma, 9.9% (n = 110) and 7.2% (n = 80) of patients had 2 and ≥3 tumors, respectively. Patients with intrahepatic cholangiocarcinoma tumors ≤5 cm and >5 cm had a 5-year overall survival of 51.7% and 32.6%, respectively (P < 0.001). Five-year overall survival decreased from 44.6% among patients with a single intrahepatic cholangiocarcinoma to 28.1% and 14.2% among patients with 2 and ≥3 intrahepatic cholangiocarcinomas, respectively (P < 0.001). Among the combinations of tumor size and intrahepatic cholangiocarcinoma tumor number used to estimate tumor burden, logarithmic transformation of tumor size (log tumor size) and intrahepatic cholangiocarcinoma tumor number had the highest concordance index. The Classification and Regression Tree model identified 8 classes of patients with a homogeneous risk of death, illustrating the hierarchical relationship between tumor burden (log tumor size and number of intrahepatic cholangiocarcinomas) and other factors associated with prognosis., Conclusion: Intrahepatic cholangiocarcinoma tumor size and number demonstrated a strong nonlinear association with survival after resection of intrahepatic cholangiocarcinoma. A log-model Classification and Regression Tree-derived tumor burden score may be a better tool to estimate prognosis of patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Multiple tumor foci of intrahepatic cholangiocarcinoma (ICC) are often considered a contra-indication for resection. We sought to define long-term outcomes after resection of ICC in patients with multiple foci., Methods: Patients who underwent resection for ICC between 1990 and 2017 were identified from 12 major HPB centers. Outcomes of patients with solitary lesions, multiple lesions (ML), and oligometastases (OM) were compared. OM were defined as extrahepatic metastases spread to a single organ., Results: One thousand thirteen patients underwent resection of ICC. On final pathology, 185 patients (18.4%) had ML and 27 (2.7%) had OM. Median survival of patients with a solitary tumor was 43.2 months, while the median survival of patients with 2 tumors was 21.2 months; the median survival of patients with 3 or more tumors was 15.3 months (p < 0.001). Five-year survival was 43.3%, 28.0%, and 8.6%, respectively. The median survival of patients without OM was 37.8 months versus 14.9 months among patients with OM (p < 0.001); estimated 5-year survival was 39.3% and 10.6%, respectively. In multivariable analysis, the presence of two lesions was not an independent poor prognostic factor for OS (HR 1.19; 95%CI 0.90-1.57; p = 0.229). However, the presence of three or more tumors was an independent poor prognostic factor for OS (HR 1.97; 95%CI 1.48-2.64; p < 0.001)., Conclusion: Resection of multiple liver tumors for patients with ICC did not preclude 5-year survival: in particular, estimated 5-year OS for resection of two tumors was 28.0%.

Background: Despite recent enthusiasm for the use of laparoscopic liver resection, data evaluating costs associated with laparoscopic liver resections are lacking. We sought to examine the use of laparoscopic liver surgery, and investigate variations in cost among hospitals performing these procedures., Methods: A nationally representative sample of 12,560 patients who underwent a liver resection in 2012 was identified. Multivariable analyses were performed to compare outcomes associated with liver resection., Results: Among the 12,560 patients who underwent liver resection, 685 (5.4%) underwent a laparoscopic liver resection. The proportion of liver resections performed laparoscopically varied among hospitals ranging from 4.6% to 20.0%; the median volume of laparoscopic liver resections was 10 operations/year. Although laparoscopic surgery was associated with lower postoperative morbidity (aOR = 0.60, 95%CI: 0.36-0.99) and shorter lengths of stay [(LOS) aIRR = 0.83, 95%CI: 0.70-0.97], it was not associated with inpatient mortality (p = 0.971) or hospital costs (p = 0.863). Costs associated with laparoscopic liver resection varied ranging from $5,907 (95%CI: $5,140-$6,674) to $67,178 (95%CI: $66,271-$68,083). The observed variations between hospitals were due to differences in morbidity (coefficient: $20,415, 95%CI: $16,000-$24,830) and LOS (coefficient: $24,690, 95%CI: $21,688-$27,692)., Conclusions: Although laparoscopic liver resection was associated with improved short-term perioperative clinical outcomes, utilization of laparoscopic liver resection remains low., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Viral particle purification is a challenge due to the complexity of the broth, the particle size, and the need to maintain virus activity. Aqueous two-phase systems (ATPSs) are a viable alternative for the currently used and expensive downstream processes. This work investigated the purification of two non-enveloped viruses, porcine parvovirus (PPV), and human rhinovirus (HRV) at various ATPS tie lines. A polyethylene glycol (PEG) 12 kDa-citrate system at pH 7 was used to study the behavior of the partitioning on three different thermodynamic tie line lengths (TLLs). It was experimentally determined that increasing the TLL, and therefore increasing the hydrophobic and electrostatic driving forces within the ATPS, facilitated higher virus recoveries in the PEG-rich phase. A maximum of 79% recovery of infectious PPV was found at TLL 36 w/w% and tie line (TL) ratio 0.1. Increased loading of PPV was studied to observe the change in the partitioning behavior and similar trends were observed for all the TLs. Most contaminants remained in the citrate-rich phase at all the chosen TLLs, demonstrating purification of the virus from protein contaminants. Moderate DNA removal was also measured. Net neutral charged HRV was studied to demonstrate the effects of driving forces on neutrally charged viruses. HRV recovery trends remained similar to PPV on each TLL studied, but the values were lower than PPV. Recovery of viral particles in the PEG-rich phase of the PEG-citrate system utilized the difference in the surface hydrophobicity between virus and proteins and showed a direct dependence on the surface charge of each studied virus. The preferential partitioning of the relatively hydrophobic viral particles in the PEG-rich phase supports the hypothesis that both hydrophobic and electrostatic forces govern the purification of viruses in ATPS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Although lymph node metastasis (LNM) is an important prognostic indicator for patients with intrahepatic cholangiocarcinoma (ICC), the benefit and indication for lymphadenectomy remain unclear., Methods: Patients diagnosed with ICC between 1990 and 2016 were identified in the international multi-institutional dataset. To determine the survival benefit from lymphadenectomy, the therapeutic index was calculated by multiplying the frequency of LNM in a particular group of patients by the 3-year cancer-specific survival (CSS) rate of patients with LNM in that subgroup., Results: Among 471 patients who met the inclusion criteria, approximately half had LNM (n = 205, 43.5%). The median number of resected and metastatic LNs were 4 [interquartile range (IQR) 2-8] and 0 (IQR 0-1), respectively. Three-year CSS in the entire cohort was 29.9%, reflecting a therapeutic index value of 13.0. The therapeutic index was lower among patients with major vascular invasion (5.4), preoperative carcinoembryonic antigen (CEA) > 5.0 (8.2), and LNM in areas other than the hepatoduodenal ligament (5.2). Of note, a therapeutic index difference of more than 10 points was noted only when examining the number of LNs harvested [1-2 (4.1) vs. 3-6 (16.1) vs. ≥ 7 (17.8)]., Conclusion: The survival benefit derived from lymphadenectomy was poor among patients with major vascular invasion, CEA > 5.0, and LNM in areas other than the hepatoduodenal ligament. Resection of three or more LNs was associated with the highest therapeutic value among patients with LNM.