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Background Limited data from small series have suggested that brain metastases from biliary tract cancers (BrM-BTC) affect ≤2% of patients with BTC. We sought to review our experience with patients with BrM-BTC and to identify associations of tumor-related molecular alterations with outcomes. Materials and Methods A retrospective review of patients with BTC seen at a tertiary referral center from 2005 to 2021 was performed; patients with BrM-BTC were identified, and clinical and molecular data were collected. Results Twenty-one of 823 patients with BTC (2.6%) developed BrM. For patients with BrM-BTC, median follow-up time was 27.9 months after primary BTC diagnosis and 3.1 months after BrM diagnosis. Median time from primary diagnosis to diagnosis of BrM was 14.4 [range, 1.1-66.0] months. Median overall survival (OS) from primary diagnosis was 31.5 [2.9-99.8] months and median OS from BrM diagnosis was 4.2 [0.2-33.8] months. Patients who underwent BrM-directed therapy trended toward longer OS following BrM diagnosis than patients receiving supportive care only (median 6.5 vs 0.8 months, P = .060). The BrM-BTC cohort was enriched for BRAF (30%), PIK3CA (25%), and GNAS (20%) mutations. patients with BrM-BTC with BRAF mutations trended toward longer OS following BrM diagnosis (median 13.1 vs 4.2 months, P = .131). Conclusion This is the largest series of patients with BrM-BTC to date and provides molecular characterization of this rare subgroup of patients with BTC. Patients with BrM-BTC may be more likely to have BRAF mutations. With advances in targeted therapy for patients with BTC with actionable mutations, continued examination of shifting patterns of failure, with emphasis on BrM, is warranted.

The value of individual variable contributions to post-hepatectomy length of stay (LOS) are difficult to quantify within bundled care pathways.Poisson regression and marginal effects models for prolonged post-hepatectomy LOS (25% median) included Kawaguchi-Gayet (KG) complexity, perioperative variables, and pathways (minimally-invasive = MIS; low-intermediate-risk = KGI/II; high-risk = KGIII; combination).Median LOS was 2, 4, 5, and 5 days for MIS, KGI/II, KGIII and combination pathways (N = 978). Poisson regression identified age, intraoperative fluids, delayed diet tolerance, and combination cases as associated with increased LOS (p 0.01). Marginal effects analysis demonstrated the following added probability of longer LOS: each year of age 0.03x, 250 mL intraoperative fluids 0.06x, each operative hour 0.2x, additional day before diet tolerance 0.4x, combination cases 0.7x. MIS was associated with 1.2x increased probability of shorter LOS.Optimizing intraoperative fluids, operative time, and postoperative diet, while favoring MIS approach when feasible, may maximize effects of post-hepatectomy care pathways to reduce LOS.

Background Enhanced Recovery After Surgery (ERAS) has been widely applied in liver surgery since the publication of the first ERAS guidelines in 2016. The aim of the present article was to update the ERAS guidelines in liver surgery using a modified Delphi method based on a systematic review of the literature. Methods A systematic literature review was performed using MEDLINE/PubMed, Embase, and the Cochrane Library. A modified Delphi method including 15 international experts was used. Consensus was judged to be reached when >80% of the experts agreed on the recommended items. Recommendations were based on the Grading of Recommendations, Assessment, Development and Evaluations system. Results A total of 7541 manuscripts were screened, and 240 articles were finally included. Twenty-five recommendation items were elaborated. All of them obtained consensus (>80% agreement) after 3 Delphi rounds. Nine items (36%) had a high level of evidence and 16 (64%) a strong recommendation grade. Compared to the first ERAS guidelines published, 3 novel items were introduced: prehabilitation in high-risk patients, preoperative biliary drainage in cholestatic liver, and preoperative smoking and alcohol cessation at least 4 weeks before hepatectomy. Conclusions These guidelines based on the best available evidence allow standardization of the perioperative management of patients undergoing liver surgery. Specific studies on hepatectomy in cirrhotic patients following an ERAS program are still needed.

We designed a prospective feasibility study to assess the 5x-multiplier (5x) calculation (eg, 3 pills in last 24 hours × 5 = 15) to standardize discharge opioid prescriptions compared to usual care.Faculty-based surgical teams volunteered for either 5x or usual care arms. Patients undergoing inpatient (≥ 48 hours) surgery and discharged by surgical teams were included. The primary end point was discharge oral morphine equivalents. Secondary end points were opioid-free discharges and 30-day refill rates.Median last 24-hour oral morphine equivalents was similar between arms (7.5 mg 5x vs 10 mg usual care, P = .830). Median discharge oral morphine equivalents were less in the 5x arm (50 mg 5x vs 75 mg usual care, P .001). Opioid-free discharges included 33.5% 5x vs 18.0% usual care arm patients (P .001). Thirty-day refill rates were similar (15.3% 5x vs 16.5% usual care, P = .742).The 5x-multiplier was associated with reduced opioid prescriptions without increased refills and can be feasibly implemented across a diverse surgical practice.

Precision surgery for colorectal liver metastases (CRLM) includes optimal selection of both the patient and surgery. Initial attempts of using clinical risk scores to identify patients for whom technically feasible surgery is oncologically futile failed. Since then, patient selection for single-stage hepatectomy followed three distinct approaches, all of which incorporated biomarkers. The

As minimally invasive surgery (MIS) approaches to biliary tract cancers become more commonplace, understanding the adequacy of their oncologic performance is key.The National Cancer Database 2010-2016 was queried for patients who underwent hepatectomy for intrahepatic cholangiocarcinoma (IHC) and T1b or more advanced gallbladder cancer (GBC). Patients were grouped by approach: open (OA), laparoscopic (LA), and robotic (RA). Margin status, rate of lymph node (LN) dissection, and yield of LN dissection were evaluated.This cohort of 8612 patients, including 4034 patients with IHC (OA: 3281, LA: 675, RA: 78) and 4578 patients with GBC (OA: 1893, LA: 2588, RA: 97), MIS was used 40% of the time. R0 resection was achieved in 82% OA, 84% LA, and 91% RA, p = 0.004. Rate of LN dissection was 53% (OA: 60%, LA: 42%, RA: 51%, p 0.001). Among patients who underwent lymphadenectomy, 6 + LN were retrieved less commonly with a LA (OA: 27%, LA: 20%, and RA: 30%, p 0.001). High-volume MIS hepatectomy centers were more likely to perform a lymphadenectomy (odds ratio [OR]: 1.41) and a sampling of 6 + LN (OR: 1.18).Regardless of approach, lymphadenectomy is underperformed nationwide for biliary tract tumors, particularly with LA. As the use of MIS grows for the treatment of biliary tract cancers, scrutiny of oncologic outcomes is required.

Micrometastases, defined as microscopic cancer cells spatially separated from the macroscopically evident metastasis, are identified in 24% to 56% of resected colorectal liver metastases (CLMs). Somatic gene mutations have emerged as independent prognostic factors in CLM. This study aimed to determine the prognostic impact and risk factors for the presence of micrometastases, including somatic gene mutations.Prospective evaluation for micrometastases was performed at 2 centers in the US and France from 2015 to 2019. CLM specimens were cut radially from the tumor margin to surrounding grossly normal liver for a distance of 2 cm. Depending on CLM size, 3 to 8 specimens per patient were submitted for microscopic analysis. Somatic gene mutations were detected by next-generation sequencing.Among 140 patients undergoing CLM resection in the US (n = 84) and France (n = 56), 36 (26%) patients were found to have micrometastases. Five-year overall and recurrence-free survival rates with micrometastases were 39% and 0%, respectively, compared with 61% and 20% without micrometastases (both p0.05). In multivariable analyses, the presence of micrometastases was an independent risk factor for worse overall survival (hazard ratio 2.88, 95% CI 1.46 to 5.70, p = 0.002) and recurrence-free survival (hazard ratio 1.56, 95% CI 1.01 to 2.41, p = 0.046). In binary logistic regression analysis, RAS/TP53 co-mutation was found to significantly increase the risk of micrometastases (odds ratio 2.77, 95% CI 1.15 to 6.71, p = 0.024).Micrometastases are associated with significantly worse survival after CLM resection. RAS/TP53 co-mutation correlated with increased risk of micrometastases. Further studies are needed to determine strategies to eradicate micrometastases.

Intrahepatic cholangiocarcinoma (iCCA) has previously been considered a contraindication to liver transplantation (LT). However, recent series showed favorable outcomes for LT after neoadjuvant therapy. Our center developed a protocol for neoadjuvant therapy and LT for patients with locally advanced, unresectable iCCA in 2010. Patients undergoing LT were required to demonstrate disease stability for 6 months on neoadjuvant therapy with no extrahepatic disease. During the study period, 32 patients were listed for LT and 18 patients underwent LT. For transplanted patients, the median number of iCCA tumors was 2, and the median cumulative tumor diameter was 10.4 cm. Patients receiving LT had an overall survival at 1-, 3-, and 5-years of 100%, 71%, and 57%. Recurrences occurred in seven patients and were treated with systemic therapy and resection. The study population had a higher than expected proportion of patients with genetic alterations in fibroblast growth factor receptor (FGFR) and DNA damage repair pathways. These data support LT as a treatment for highly selected patients with locally advanced, unresectable iCCA. Further studies to identify criteria for LT in iCCA and factors predicting survival are warranted.

Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47–not estimable [NE]) with nivolumab and 19·53 months (2·33–NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31–2·54); median time to progression was 9·4 months (95% CI 1·47–NE) in the nivolumab group and 19·53 months (2·33–NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31–2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. Funding: Bristol Myers Squibb and the US National Institutes of Health.

Purpose:Somatic gene mutations have been increasingly recognized to impact prognosis following resection of colorectal liver metastases (CLM). We aimed to determine the impact of combinations of somatic mutations on survival in patients undergoing CLM resection.Experimental Design:We identified patients who underwent initial CLM resection during 2007–2017 and had genetic sequencing data available. Risk factors for overall survival (OS) and recurrence-free survival (RFS) were determined using Cox proportional hazards models.Results:Of 1460 patients who underwent CLM resection during the study period, 507 met the inclusion criteria. Multigene testing revealed mutation rates greater than 10% for TP53 (mutated in 70.8% of patients), APC (53.5%), RAS (50.7%), PIK3CA (15.8%), and SMAD4 (11.0%). BRAF was mutated in 2.0% of patients. BRAF, RAS, TP53, and SMAD4 mutations were significantly associated with OS, and RAS, TP53, and SMAD4 mutations were significantly associated with RFS. Coexisting mutations in RAS, TP53, and SMAD4 were associated with significantly worse OS and RFS than coexisting mutations in any 2 of these genes and mutations in 1 or none of these genes. Coexisting mutations in 2 genes conferred significantly worse OS and RFS than single mutation or no mutations. OS and RFS did not differ significantly between patients with RAS mutation and wild-type TP53 and SMAD4 and patients with wild-type RAS (P = 0.858 and 0.729, respectively).Conclusions:RAS mutation status alone is not sufficient for precisely predicting prognosis after CLM resection.

DEG and GSEA gene set analysis post vs pre treatment

Post treatment and pre treatment DEG in RFS long vs short

Purpose:Despite the prognostic importance of immune infiltrate in colorectal cancer, immunotherapy has demonstrated limited clinical activity in refractory metastatic proficient mismatch-repair (pMMR) colorectal cancer. This study explores combining anti–CTLA-4 and an anti–PD-L1 therapy in the preoperative management of resectable colorectal cancer liver metastases with the intent to improve immune responses in this disease setting.Patients and Methods:Patients with resectable colorectal cancer liver-only metastases received one dose of tremelimumab and durvalumab preoperatively followed by single-agent durvalumab postoperatively. Primary objectives were to determine feasibility and safety.Results:A total of 24 patients were enrolled between November 2016 and November 2019. Twenty-three patients received treatment [21 pMMR and 2 deficient mismatch-repair (dMMR)] and subsequently 17 (74%; 95% CI: 53%–88%) underwent surgical resection. Grade 3/4 treatment-related immune toxicity and postoperative grade 3/4 toxicity were seen in 5/23 (22%; 95% CI: 10%–44%) and 2/17 (12%; 95% CI: 2%–38%) patients. The median relapse-free survival (RFS) was 9.7 (95% CI: 8.1–17.8) months, and overall survival was 24.5 (95% CI: 16.5–28.4) months. Four patients demonstrated complete pathologic response, two dMMR patients and two POLE mutation patients. Pre- and post-tumor tissue analysis by flow cytometry, immunofluorescence, and RNA sequencing revealed similar levels of T-cell infiltration, but did demonstrate evidence of CD8+ and CD4+ activation posttreatment. An increase in B-cell transcriptome signature and B-cell density was present in posttreatment samples from patients with prolonged RFS.Conclusions:This study demonstrates the safety of neoadjuvant combination tremelimumab and durvalumab prior to colorectal cancer liver resection. Evidence for T- and B-cell activation following this therapy was seen in pMMR metastatic colorectal cancer.

Supplementary figures and supplemental methods

Supplementary Figure 3. Overall survival (OS) and recurrence-free survival (RFS) by RAS mutation status.

RFS long and short microbiome-taxa abundance

Supplementary Figure description

Supplementary Figure 1. Patient selection

Supplementary Figure 4. Overall survival (OS) by RAS, TP53, and SMAD4 mutation status in 313 patients with unresectable colorectal metastases.

Treatment related adverse events and list of antibodies used.

Supplementary Table 1. Genes and codon tested for adequate amplicons Supplementary Table 2. Multivariable hazard ratios (HRs) for OS and RFS by RAS mutation status in 507 patients Supplementary Table 3. Demographic and clinicopathologic characteristics of 313 patients with unresectable colorectal metastases.

PURPOSE KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

BACKGROUND We evaluated the associations of surgical margin status and somatic mutations with the incidence of local recurrence (LR) and oncologic outcomes in patients undergoing R0-intent (microscopically negative margin) resection of colorectal liver metastases (CLM). METHODS Patients with CLM who underwent initial R0-intent resection and analysis of tumor tissue using next-generation sequencing during 2001-2018 were analyzed. Recurrences were classified as LR (at the resection margin), other intrahepatic recurrence, or extrahepatic recurrence. Predictors and survival effect of LR were evaluated using univariate and multivariate analysis. RESULTS Of 552 patients analyzed, 415 (75%) had R0 resection (margin width ≥ 1.0 mm), and 38 (7%) had LR. LR incidence was not affected by surgical margin width. RAS/TP53 co-mutation was associated with increased risk of intrahepatic recurrence (67% vs. 49%; p 8 cycles of preoperative chemotherapy (HR, 1.98; p = 0.033), tumor viability ≥ 50% (HR, 1.55; p = 0.007), RAS/TP53 co-mutation (HR, 1.69; p = 0.001), and SMAD4 mutation (HR, 2.44; p

The past 20 years have seen advances in colorectal cancer management. We sought to determine whether survival in patients undergoing resection of colorectal liver metastases (CLM) has improved in association with three landmark advances: introduction of irinotecan- and/or oxaliplatin-containing regimens, molecular targeted therapy, and multigene alteration testing. Patients undergoing CLM resection during 1998–2014 were identified and grouped by resection year. The influence of alterations in RAS, TP53, and SMAD4 was evaluated and validated in an external cohort including patients with unresectable metastatic colorectal cancer. Of 1961 patients, 1599 met the inclusion criteria. Irinotecan- and/or oxaliplatin-containing regimens and molecular targeted therapy were used for more than 50% of patients starting in 2001 and starting in 2006, respectively, so patients were grouped as undergoing resection during 1998–2000, 2001–2005, or 2006–2014. Liver resectability indications expanded over time. The 5-year overall survival (OS) rate was significantly better in 2006–2014, vs. 2001–2005 (56.5% vs. 44.1%, P

Objective: The aim of this work is to formulate recommendations based on global expert consensus to guide the surgical community on the safe resumption of surgical and endoscopic activities. Background: The COVID-19 pandemic has caused marked disruptions in the delivery of surgical care worldwide. A thoughtful, structured approach to resuming surgical services is necessary as the impact of COVID-19 becomes better controlled. The Coronavirus Global Surgical Collaborative sought to formulate, through rigorous scientific methodology, consensus-based recommendations in collaboration with a multidisciplinary group of international experts and policymakers. Methods: Recommendations were developed following a Delphi process. Domain topics were formulated and subsequently subdivided into questions pertinent to different aspects of surgical care in the COVID-19 crisis. Forty-four experts from 15 countries across 4 continents drafted statements based on the specific questions. Anonymous Delphi voting on the statements was performed in 2 rounds, as well as in a telepresence meeting. Results: One hundred statements were formulated across 10 domains. The statements addressed terminology, impact on procedural services, patient/staff safety, managing a backlog of surgeries, methods to restart and sustain surgical services, education, and research. Eighty-three of the statements were approved during the first round of Delphi voting, and 11 during the second round. A final telepresence meeting and discussion yielded acceptance of 5 other statements. Conclusions: The Delphi process resulted in 99 recommendations. These consensus statements provide expert guidance, based on scientific methodology, for the safe resumption of surgical activities during the COVID-19 pandemic.

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

Brian De,1,* Sweet Ping Ng,1,2,* Amy Y Liu,1 Santiago Avila,1 Randa Tao,3 Emma B Holliday,1 Zachary Brownlee,4 Ahmed Kaseb,5 Sunyoung Lee,3 Kanwal Raghav,5 Jean-Nicolas Vauthey,6 Bruce D Minsky,1 Joseph M Herman,1 Prajnan Das,1 Grace L Smith,1 Cullen M Taniguchi,1 Sunil Krishnan,7 Christopher H Crane,8 Clemens Grassberger,9 Theodore S Hong,9 Steven H Lin,1 Albert C Koong,1 Radhe Mohan,1 Eugene J Koay1 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Radiation Oncology, Austin Health, Melbourne, Victoria, Australia; 3Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA; 4Department of Radiation Oncology, Tufts Medical Center, Boston, MA, USA; 5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Radiation Oncology, Mayo Clinic Jacksonville, Jacksonville, FL, USA; 8Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 9Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Eugene J KoayMD Anderson Cancer Center, Department of Radiation Oncology, 1400 Pressler St. Unit 1422, Houston, TX, 77030, USATel + 1 713-563-2381Fax +1 713-563-2331Email EKoay@mdanderson.orgBackground: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).Patients and Methods: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan–Meier method. Univariableand multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.Results: Of 143 patients identified, the median age was 66 (range, 19– 90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13– 25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/μL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.Conclusion: Grade 3 or higherlymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.Keywords: lymphocyte count, circulating lymphocytes, splenic dose, liver dose, overall survival

While surgery is a mainstay of curative-intent treatment for patients with intrahepatic cholangiocarcinoma (IHC), the role of neoadjuvant therapy (NT) has not been well-established. We sought to describe trends in NT utilization, characterize associated factors, and evaluate association with overall survival (OS). Retrospective cohort study of 4456 surgically resected IHC patients within National Cancer Data Base (2006–2016). NT included chemotherapy alone and/or (chemo)radiation. Descriptive statistics used to describe the cohort. Multivariable hierarchical logistic regression models were used to examine factors associated with NT administration. Analyses conducted comparing OS among upfront surgery patients and NT patients using propensity matching using nearest-neighbor methodology and adjustment using inverse probability of treatment weighting (IPTW). Association between NT and risk of death evaluated using multivariable Cox shared frailty modeling. Utilization of NT did not significantly increase over time (11%-2006 to 16%-2016, trend test p = 0.07) but did increase among patients with clinical nodal involvement (cN+, 13% to 36%, p = 0.002). Factors associated with NT use include cN+ disease (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.31–2.15) and advanced clinical T stage: T2 (OR 1.65, 95% CI 1.33–2.06); T3 (OR 1.51, 95% CI 1.13–2.02). After propensity matching, NT associated with a 23% decreased risk of death relative to upfront surgery (hazard ratio [HR] 0.77, 95% CI 0.61–0.97). Findings were similar after IPTW (HR 0.83, 95% CI 0.78–0.88). NT is increasingly used for the management of IHC patients with characteristics indicating aggressive tumor biology and is associated with decreased risk of death. These data suggest need for prospective studies of NT in management of patients with potentially resectable IHC.