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Biliary tract cancers demonstrate profound therapeutic resistance, and broadly effective therapies for refractory disease are lacking. We conducted a single-arm, second-line phase II trial combining DKN-01, a humanized monoclonal antibody targeting Dickkopf-1 (DKK-1), and nivolumab to treat patients with advanced biliary tract cancer (NCT04057365). No objective responses were seen. To identify mechanisms of treatment failure, we analyzed paired pre-treatment and on-treatment biopsies using scRNA-seq and constructed a detailed molecular classification of malignant and immune cells. We annotated five biliary tract cancer malignant cell states: classical, basal, mesenchymal, neural-like, and endothelial-like. Neural-like and endothelial-like states, which drive therapeutic resistance in other cancers, have not previously been described in BTC. Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials., Competing Interests: MP has served as a consultant for Third Rock Ventures. LP has served as a consultant for Astellas. DGD has received research funding support from Bayer, Bristol-Myers Squibb, Exelixis and Surface Oncology. NH holds equity in and advises Danger Bio/Related Sciences, is on the scientific advisory board of Repertoire Immune Medicines and CytoReason, owns equity in and has licensed patents to BioNTech and receives research funding from Bristol Myers Squibb and Calico Life Sciences. DTT has received consulting fees from ROME Therapeutics, Sonata Therapeutics, Leica Biosystems Imaging, PanTher Therapeutics, and abrdn. DTT is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. DTT is on the advisory board with equity for ImproveBio, Inc. DTT has received honorariums from Astellas, AstraZeneca, Moderna, and Ikena Oncology that are not related to this work. DTT receives research support from ACD-Biotechne, AVA LifeScience GmbH, Incyte Pharmaceuticals, Sanofi, and Astellas which was not used in this work. DTT’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. AM has served a consultant/advisory role for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, ManaT Bio, Flare Therapeutics, venBio Partners, BioNTech, Rheos Medicines and Checkmate Pharmaceuticals, is currently a part-time Entrepreneur in Residence at Third Rock Ventures, is an equity holder in ManaT Bio, Asher Biotherapeutics and Abata Therapeutics, and has received research funding support from Bristol-Myers Squibb. AM’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. All other authors have nothing to disclose.

Objective: The aim of this study was to evaluate the incidence of radiotherapy (RT)-related lymphopenia, its predictors, and association with survival in unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated-RT (HF-RT)., Methods: Retrospective analysis of 96 patients with unresectable ICC who underwent HF-RT (median 58.05 Gy in 15 fractions) between 2009 and 2022 was performed. Absolute lymphocyte count (ALC) nadir within 12 weeks of RT was analyzed. Primary variable of interest was severe lymphopenia, defined as Grade 3+ (ALC <0.5 k/μL) per CTCAE v5.0. Primary outcome of interest was overall survival (OS) from RT., Results: Median follow-up was 16 months. Fifty-two percent of patients had chemotherapy pre-RT, 23% during RT, and 40% post-RT. Pre-RT, median ALC was 1.1 k/μL and 5% had severe lymphopenia. Post-RT, 68% developed RT-related severe lymphopenia. Patients who developed severe lymphopenia had a significantly lower pre-RT ALC (median 1.1 vs. 1.5 k/μL, P =0.01) and larger target tumor volume (median 125 vs. 62 cm 3 , P =0.02). In our multivariable Cox model, severe lymphopenia was associated with a 1.7-fold increased risk of death ( P =0.04); 1-year OS rates were 63% vs 77% ( P =0.03). Receipt of photon versus proton-based RT (OR=3.50, P =0.02), higher mean liver dose (OR=1.19, P <0.01), and longer RT duration (OR=1.49, P =0.02) predicted severe lymphopenia., Conclusions: HF-RT-related lymphopenia is an independent prognostic factor for survival in patients with unresectable ICC. Patients with lower baseline ALC and larger tumor volume may be at increased risk, and use of proton therapy, minimizing mean liver dose, and avoiding treatment breaks may reduce RT-related lymphopenia., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate the safety and efficacy of neoadjuvant therapy (NAT), followed by surgical resection in patients with pancreatic ductal adenocarcinoma (PDAC) aged ≥75 years., Background: Whether administration of NAT, followed by surgical resection in elderly patients with PDAC is safe and effective is unknown., Methods: The present study is a three-part comparison of older (≥75 years) versus younger (<75 years) patients in different settings throughout the continuum of PDAC care. The first analysis was a comparison of older versus younger consecutive patients with nonmetastatic PDAC who were initiated on FOLFIRINOX. The second was a comparison of older versus younger patients who underwent NAT, followed by surgical resection, and the third and final analysis was a comparison of older patients who underwent either NAT, followed by surgical resection versus upfront surgical resection. Postoperative complications, overall survival (OS), and time to recurrence (TTR) were compared. Propensity score matching (PSM) analysis was performed to adjust for potential confounders., Results: In the first analysis, a lower proportion of older patients (n = 40) were able to complete the intended neoadjuvant FOLFIRINOX (8) cycles compared with younger patients (n = 214; 65.0% vs 81.4%, P = 0.021). However, older patients were just as likely to undergo surgical exploration as younger patients (77.5% vs 78.5%, P = 0.89), as well as surgical resection (57.5% vs 55.6%, P = 0.70). In the second analysis, PSM was conducted to compare older (n = 54) versus younger patients (n = 54) who underwent NAT, followed by surgical resection. There were no significant differences in postoperative complications between the matched groups. While there was a significant difference in OS between older and younger patients (median OS: 16.43 vs 30.83 months, P = 0.002), importantly, there was no significant difference in TTR (median: 7.65 vs 11.83 months, P = 0.215). In the third analysis, older patients who underwent NAT, followed by surgical resection (n = 48) were compared with similar older patients who underwent upfront surgical resection (n = 48). After PSM, there was a significant difference in OS (median OS: 15.78 months vs 11.51 months, P = 0.037), as well as TTR (median TTR: 8.81 vs 7.10 months, P = 0.046) representing an association with improved outcomes that favored the neoadjuvant approach among older patients alone., Conclusions: This comprehensive three-part study showed that administration of NAT, followed by surgical resection, seems to be safe and effective among patients ≥75 years of age. An aggressive approach should be offered to older adults undergoing multimodal treatment of PDAC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Patient-reported outcomes (PROs), such as quality of life (QOL) and symptoms, are often associated with clinical outcomes in patients with cancer. In practice, oncologists use serum tumor markers (TMs) (ie, carcinoembryonic antigen [CEA] and carbohydrate antigen 19-9 [CA 19-9]) and imaging to monitor clinical outcomes in patients with gastrointestinal cancer., Objective: To examine associations of 1-month changes in PROs and TMs with treatment response and survival among patients with gastrointestinal cancer., Design, Setting, and Participants: This cohort study enrolled patients at Massachusetts General Hospital Cancer Center with at least 1 month follow-up from May 2019 to December 2020. Included patients were beginning first-line systemic therapy, aged 18 years or older, and had been diagnosed with metastatic pancreaticobiliary, colorectal, or gastroesophageal cancer. Data analyses took place from January 2021 to January 2022., Intervention: PROs were collected, including QOL (Functional Assessment of Cancer Therapy General [FACT-G]), physical symptoms (Edmonton Symptom Assessment System [ESAS]), and psychological symptoms (Patient Health Questionnaire-4 [PHQ4] total, PHQ4-depression, and PHQ4-anxiety), as well as TMs (CEA and CA 19-9), at the time of chemotherapy initiation and 1 month later., Main Outcomes and Measures: Associations of 1-month changes in PROs and TMs with treatment response (clinical benefit vs disease progression) at first scan, progression-free survival (PFS), and overall survival (OS), adjusted for baseline values using regression models., Results: This study included 159 patients, with 134 patients (84.3%) evaluable for analysis. Patients had a median (range) age of 64.0 (28.0-84.0) years and 86 (64.2%) were male. One-month PRO changes (FACT-G: OR, 1.07; 95% CI, 1.03-1.11; P = .001; ESAS-total: OR, 0.97; 95% CI, 0.94-1.00; P = .02; ESAS-physical: OR, 0.96; 95% CI, 0.92-1.00; P = .03; PHQ4-depression: OR, 0.67; 95% CI, 0.49-0.92; P = .01) were significantly associated with treatment response, but PHQ4-total or TMs were not. Changes in FACT-G (HR, 0.97; 95% CI, 0.95-0.99; P = .003), ESAS-total (HR, 1.03; 95% CI, 1.01-1.05; P = .004), ESAS-physical (HR, 1.03; 95% CI, 1.00-1.05; P = .02), PHQ4-depression (HR, 1.22; 95% CI, 1.01-1.48; P = .04), and CEA (HR, 1.00; 95% CI, 1.001-1.004; P = .001) were associated with PFS, but changes in PHQ4-total or TMs were not. Changes in ESAS-total (HR, 1.03, 95% CI, 1.01-1.06; P = .006) and ESAS-physical (HR, 1.04, 95% CI, 1.01-1.06; P = .015) were associated with OS, but changes in TMs were not associated with OS., Conclusions and Relevance: These findings suggest that 1-month changes in PROs can be associated with treatment response and survival in patients with advanced gastrointestinal cancer. Notably, 1-month changes in TMs were not consistently associated with these outcomes. These findings highlight the potential for monitoring early changes in PROs to associate with clinical outcomes while underscoring the need to address the QOL and symptom concerns of patients with advanced cancer.

Purpose: Portal vein and superior mesenteric vein thrombosis (PVT/SMVT) are potentially morbid complications of radiation dose-escalated local therapy for pancreatic cancer. We retrospectively reviewed records for patients treated with and without intraoperative radiation (IORT) to identify risk factors for PVT/SMVT., Methods: Ninety-six patients with locally advanced or borderline resectable pancreatic adenocarcinoma received neoadjuvant therapy followed by surgical exploration from 2009 to 2014. Patients at risk for close or positive surgical margins received IORT boost to a biologically effective dose (BED10) > 100. Prognostic factors for PVT/SMVT were evaluated using competing risks regression., Results: Median follow-up was 79 months for surviving patients. Fifty-six patients (58%) received IORT. Twenty-nine patients (30%) developed PVT/SMVT at a median time of 18 months. On univariate competing risks regression, operative blood loss and venous repair with a vascular interposition graft, but not IORT dose escalation or diabetes history, were significantly associated with PVT/SMVT. The development of thrombosis in the absence of recurrence was significantly associated with a longstanding diabetes history, post-neoadjuvant treatment CA19-9, and operative blood loss. All 4 patients who underwent both IORT and vascular repair with a graft developed PVT/SMVT. PVT/SMVT in the absence of recurrence is not associated with significantly worsened overall survival but led to frequent medical interventions., Conclusions: Approximately 30% of patients who underwent neoadjuvant chemoradiation for PDAC developed PVT/SMVT a median of 18 months following surgery. This was significantly associated with venous reconstruction with vascular grafts, but not with escalating radiation dose. PVT/SMVT in the absence of recurrence was associated with significant morbidity., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: FOLFIRINOX is increasingly used in the management of pancreatic ductal adenocarcinoma (PDAC). However, neoadjuvant therapy is associated with toxicity, possible disease progression, and biopsy-related and biliary complications that may preclude operative exploration. Data on the true attrition rate outside of clinical trials or resected surgical series are lacking., Study Design: Patients with nonmetastatic PDAC who initiated FOLFIRINOX from 2015 to 2020 were identified from our institution's pharmacy records. Multivariable regression and Cox proportional hazard models were used for adjusted analyses of categorical and survival outcomes, respectively., Results: Of 254 patients who initiated first-line neoadjuvant FOLFIRINOX, 199 (78.3%) underwent exploration, and 54 (21.3%) did not complete their chemotherapy cycles due to poor tolerability (46.3%), poor response (31.5%), or disease progression (14.8%), among other causes (7.4%). A total of 109 (42.9%) patients experienced grade 3/4 FOLFIRINOX-related toxicity, of whom 73 (28.7%) and 100 (39.4%) required an emergency department visit or inpatient admission, respectively. Finally, not undergoing surgical exploration was associated with impaired overall survival (hazard ratio 7.0; 95% CI 3.8 to 12.8; p < 0.001). Independent predictors of not undergoing exploration were remote history of chemotherapy receipt (odds ratio [OR] 0.06; p = 0.02), inability to complete FOLFIRINOX cycles (OR 0.2, p = 0.003), increase in ECOG score (OR 0.2, p < 0.001), and being single or divorced (OR 0.3, p = 0.018)., Conclusions: Among 254 patients with nonmetastatic PDAC initiated on FOLFIRINOX, of whom 52% were locally advanced, a total of 199 (78.3%) were explored, 142 (71.4%) underwent successful resection, and 129 (90.8%) were resected with negative margins. Despite 109 (42.9)% of patients experiencing significant toxicity, most patients could be managed through treatment-related complications to complete planned neoadjuvant chemotherapy and undergo planned surgical exploration., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF V600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAF V600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431., (© 2023. The Author(s).)

Objective: The objective of this study was to characterize the patterns of first recurrence after curative-intent resection for pancreatic adenocarcinoma (PDAC)., Summary of Background Data: We evaluated the first site of recurrence after neoadjuvant treatment as locoregional (LR) or distant metastasis (DM). To validate our findings, we evaluated the pattern from 2 phase II clinical trials evaluating neoadjuvant chemotherapy (NAC) in PDAC., Methods: We identified site of first recurrence from a retrospective cohort of patients from 2011 to 2017 treated with NAC followed by chemoradiation and then an operation or an operation first followed by adjuvant therapy, and 2 separate prospective cohorts of patients derived from 2 phase II clinical trials evaluating patients treated with NAC in borderline-resectable and locally advanced PDAC., Results: In the retrospective cohorts, 160 out of 285 patients (56.1%) recurred after a median disease-free survival (mDFS) of 17.2 months. The pattern of recurrence was DM in 81.9% of patients, versus LR in 11.1%. This pattern was consistent in patients treated with upfront resection and adjuvant chemotherapy (DM 83.0%, LR 16.9%) regardless of margin-involvement (DM 80.1%, LR 19.4%). The use of NAC did not alter pattern of recurrence; 81.7% had DM and 18.3% had LR. This pattern also remained consistent regardless of margin-involvement (DM 94.1%, LR 5.9%). In the Phase II borderline-resectable trial (NCI# 01591733) cohort of 32 patients, the mDFS was 34.2 months. Pattern of recurrence remained predominantly DM (88.9%) versus LR (11.1%). In the Phase II locally-advanced trial (NCI# 01821729) cohort of 34 patients, the mDFS was 30.7 months. Although there was a higher rate of local recurrence in this cohort, pattern of first recurrence remained predominantly DM (66.6%) versus LR (33.3%) and remained consistent independent of margin-status., Conclusions: The pattern of recurrence in PDAC is predominantly DM rather than LR, and is consistent regardless of the use of NAC and margin involvement., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: We sought to determine the feasibility of delivering a Supportive Oncology Care at Home intervention among patients with pancreatic cancer., Methods: We prospectively enrolled patients with pancreatic cancer from a parent trial of neoadjuvant fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX). The intervention entailed (1) remote monitoring of patient-reported symptoms, vital signs, and body weight; (2) a hospital-at-home care model; and (3) structured communication with the oncology team. We defined the intervention as feasible if ≥ 60% of patients enrolled in the study and ≥ 60% completed the daily assessments within the first 2-weeks of enrollment. We determined rates of treatment delays, urgent clinic visits, emergency department visits, and hospitalizations among those who did (n = 20) and did not (n = 24) receive Supportive Oncology Care at Home from the parent trial., Results: From January 2019 to September 2020, we enrolled 80.8% (21/26) of potentially eligible patients. One patient became ineligible following consent because of moving out of state, resulting in 20 participants (median age = 67 years). In the first 2 weeks of enrollment, 65.0% of participants completed all daily assessments. Overall, patients reported 96.1% of daily symptoms, 96.1% of daily vital signs, and 92.5% of weekly body weights. Patients receiving the intervention had lower rates of treatment delays (55.0% v 75.0%), urgent clinic visits (10.0% v 25.0%), and emergency department visits/hospitalizations (45.0% v 62.5%) compared with those not receiving the intervention from the same parent trial., Conclusion: Findings demonstrate the feasibility and acceptability of a Supportive Oncology Care at Home intervention. Future work will investigate the efficacy of this intervention for decreasing health care use and improving patient outcomes., Competing Interests: Ryan D. NippThis author is an Associate Editor for JCO Oncology Practice. Journal policy recused the author from having any role in the peer review of this manuscript. Colin D. WeekesHonoraria: Celgene, Lilly, BayerConsulting or Advisory Role: Celgene, Merrimack, IpsenResearch Funding: Celgene, Genentech/Roche, AstraZeneca, Dicephera Pharmaceuticals Inc, Novartis, Actuate Therapeutics Eric J. RoelandConsulting or Advisory Role: Napo Pharmaceuticals, AIM Specialty Health, Helsinn Therapeutics, Byomass, Veloxis, PRA Health, Actimed Therapeutics, Takeda, MeterHealthExpert Testimony: Regents of the University of California Aparna R. ParikhStock and Other Ownership Interests: C2i genomicsConsulting or Advisory Role: Lilly, Natera, Checkmate Pharmaceuticals, Pfizer, Roche/Genentech, Inivata, Biofidelity, Guardant HealthResearch Funding: Plexxikon (Inst), Bristol Myers Squibb (Inst), Genentech (Inst), Guardant Health (Inst), Array BioPharma (Inst), Lilly (Inst), Novartis Pharmaceuticals UK Ltd (Inst), PureTech (Inst), PMV Pharma, Mirati Therapeutics (Inst), Daiichi Sankyo (Inst) Jennifer Y. WoHonoraria: PERResearch Funding: Genentech/Roche (Inst)Travel, Accommodations, Expenses: Lynx Group Melissa Hennessey SmithEmployment: Medically HomeStock and Other Ownership Interests: Medically HomeResearch Funding: Medically HomeTravel, Accommodations, Expenses: Medically Home Patricia M.C. BrownEmployment: Medically HomeStock and Other Ownership Interests: Medically Home Group IncConsulting or Advisory Role: AllscriiptsResearch Funding: Medically Home Group IncTravel, Accommodations, Expenses: Medically Home Group Eliza ShulmanEmployment: Medically HomeLeadership: Medically HomeStock and Other Ownership Interests: Medically Home Alec C. KimmelmanStock and Other Ownership Interests: Vescor Therapeutics, Rafael PharmaceuticalsConsulting or Advisory Role: Vescor Therapeutics, AbbVie, DecipheraPatents, Royalties, Other Intellectual Property: Inventor on patents pertaining to Kras-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach and the autophagic control of iron metabolism, and targeting alanine transport in pancreatic cancer David TingLeadership: PanTher TherapeuticsStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioConsulting or Advisory Role: ROME Therapeutics, Millipore, Foundation Medicine, Pfizer, NanoString Technologies, Tekla Capital Management, Ikena OncologyResearch Funding: ACD Biotechne (Inst), PureTech (Inst), Ribon Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: Patent licensed to Rome Therapeutics by my Institution (Inst); patent license to PanTher Therapeutics (Inst), patent license to TellBio Inc (Inst) Theodore S. HongStock and Other Ownership Interests: PanTher TherapeuticsConsulting or Advisory Role: Merck, Synthetic Biologics, Novocure, Syndax, Boston ScientificResearch Funding: Taiho Pharmaceutical (Inst), AstraZeneca (Inst), IntraOp (Inst), Tesaro (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst) Joseph A. GreerResearch Funding: NCCN/AstraZeneca (Inst), Gaido Health/BCG Digital Ventures (Inst), Blue Note Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: Royalties from Springer Publishing Company for the edited book, The Massachusetts General Hospital Handbook of Behavioral Medicine. David P. RyanStock and Other Ownership Interests: MPM Capital, Acworth Pharmaceuticals, Thrive Earlier Detection Corp, Exact SciencesHonoraria: UpToDate, Research to PracticeConsulting or Advisory Role: MPM Capital, Oncorus, Gritstone Bio, Maverick Therapeutics, TCR2 Therapeutics, Twentyeight-Seven Therapeutics, Innocrin PharmaResearch Funding: Stand up to Cancer (Inst)Patents, Royalties, Other Intellectual Property: McGraw Hill Chapter Royalties, Johns Hopkins University PressExpert Testimony: Boehringer IngelheimOther Relationship: TCR2 Therapeutics Areej El-JawahriConsulting or Advisory Role: AIM Specialty Health, Novartis, GlaxoSmithKline, IncyteNo other potential conflicts of interest were reported.

Objectives: Neuroendocrine tumors (NETs) are characterized by their expression of vascular endothelial growth factor (VEGF). This trial investigated the activity of Ziv-aflibercept, a recombinant protein that binds to and inhibits the activity of VEGF, in patients with advanced NETs (NCT01782443)., Methods: A single-arm, phase II trial enrolling patients with advanced, progressive extrapancreatic NET. Patients were treated with Ziv-aflibercept 4 mg/kg intravenously on day 1 and 15 of a 28-day cycle; the starting dose was reduced to 2 mg/kg on days 1 and 15 of a 28-day cycle because of hypertension-related events. The primary end point was progression-free survival., Results: The trial enrolled 19 patients (13 male:6 female). Patients received a median of 7 cycles (range, 1-18 cycles). The median progression free survival was 11.8 months (95% confidence interval, 3.2-16.1 months), and the median overall survival was 36.4 months (95% confidence interval, 16.1-not reached). Best responses by Response Evaluation Criteria in Solid Tumors 1.1 are as follows: 1 (5%) partial response, 13 (68%) stable disease, 2 (10%) with progressive disease, and 3 (15%) unevaluable. Hypertension occurred in 18 patients (95%), including grade 3-4 hypertension in 12 patients (63%)., Conclusions: Although the progression free survival is similar to other VEGF inhibitors in NET, toxicity may preclude further investigation., Competing Interests: K.P. received a 1-time consulting/scientific advisory board fee from Lantheus (2/2022) and Helsinn/QED (5/2021). P.C.E. is/has been a consultant for and has received honoraria from ALX oncology, Arcus Bioscience, Astellas, AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, Chimeric Therapeutics, Celgene, Coherus, Daiichi-Sankyo, Five Prime, Ideaya, Istari, Legend, Lily, Loxo, Merck, Novartis, Ono, Servier, Taiho, Takeda, Turning Point Therapeutics, Xencor, and Zymeworks. C.S.F. is employed by Roche and Genentech. J.A.C. has received consulting fees from Advanced Accelerator Applications, Crinetics, Ipsen, Lexicon, and Novartis (spouse has consulted for Bayer and Pfizer), has received royalties from UpToDate, and has stock in Merck. The rest of the authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Altered RNA expression of repetitive sequences and retrotransposition are frequently seen in colorectal cancer, implicating a functional importance of repeat activity in cancer progression. We show the nucleoside reverse transcriptase inhibitor 3TC targets activities of these repeat elements in colorectal cancer preclinical models with a preferential effect in p53-mutant cell lines linked with direct binding of p53 to repeat elements. We translate these findings to a human phase II trial of single-agent 3TC treatment in metastatic colorectal cancer with demonstration of clinical benefit in 9 of 32 patients. Analysis of 3TC effects on colorectal cancer tumorspheres demonstrates accumulation of immunogenic RNA:DNA hybrids linked with induction of interferon response genes and DNA damage response. Epigenetic and DNA-damaging agents induce repeat RNAs and have enhanced cytotoxicity with 3TC. These findings identify a vulnerability in colorectal cancer by targeting the viral mimicry of repeat elements., Significance: Colorectal cancers express abundant repeat elements that have a viral-like life cycle that can be therapeutically targeted with nucleoside reverse transcriptase inhibitors (NRTI) commonly used for viral diseases. NRTIs induce DNA damage and interferon response that provide a new anticancer therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1397., (©2022 American Association for Cancer Research.)

Objectives: There are individual variations in neo-adjuvant chemoradiation therapy (nCRT) in patients with locally advanced rectal cancer (LARC). No reliable modality currently exists that can predict the efficacy of nCRT. The purpose of this study is to assess if CT-based fractal dimension and filtration-histogram texture analysis can predict therapeutic response to nCRT in patients with LARC., Methods: In this retrospective study, 215 patients (average age: 57 years (18-87 years)) who received nCRT for LARC between June 2005 and December 2016 and underwent a staging diagnostic portal venous phase CT were identified. The patients were randomly divided into two datasets: a training set (n = 170), and a validation set (n = 45). Tumor heterogeneity was assessed on the CT images using fractal dimension (FD) and filtration-histogram texture analysis. In the training set, the patients with pCR and non-pCR were compared in univariate analysis. Logistic regression analysis was applied to identify the predictive value of efficacy of nCRT and receiver operating characteristic analysis determined optimal cutoff value. Subsequently, the most significant parameter was assessed in the validation set., Results: Out of the 215 patients evaluated, pCR was reached in 20.9% (n = 45/215) patients. In the training set, 7 out of 37 texture parameters showed significant difference comparing between the pCR and non-pCR groups and logistic multivariable regression analysis incorporating clinical and 7 texture parameters showed that only FD was associated with pCR (p = 0.001). The area under the curve of FD was 0.76. In the validation set, we applied FD for predicting pCR and sensitivity, specificity, and accuracy were 60%, 89%, and 82%, respectively., Conclusion: FD on pretreatment CT is a promising parameter for predicting pCR to nCRT in patients with LARC and could be used to help make treatment decisions., Key Points: • Fractal dimension analysis on pretreatment CT was associated with response to neo-adjuvant chemoradiation in patients with locally advanced rectal cancer. • Fractal dimension is a promising biomarker for predicting pCR to nCRT and may potentially select patients for individualized therapy., (© 2021. European Society of Radiology.)

Background: The optimal timing of chemoradiotherapy (CRT) for patients with localized gastric cancer remains unclear. This study aimed to compare the survival outcomes between neoadjuvant and postoperative CRT for patients with gastric and gastroesophageal junction (GEJ) cancer., Methods: This retrospective study analyzed 152 patients with gastric (42%) or GEJ (58%) adenocarcinoma who underwent definitive surgical resection and received either neoadjuvant or postoperative CRT between 2005 and 2017 at the authors' institution. The primary end point of the study was overall survival (OS)., Results: The median follow-up period was 37.5 months. Neoadjuvant CRT was performed for 102 patients (67%) and postoperative CRT for 50 patients (33%). The patients who received neoadjuvant CRT were more likely to be male and to have a GEJ tumor, positive lymph nodes, and a higher clinical stage. The median radiotherapy (RT) dose was 50.4 Gy for neoadjuvant RT and 45.0 Gy for postoperative RT (p < 0.001). The neoadjuvant CRT group had a pathologic complete response (pCR) rate of 26% and a greater rate of R0 resection than the postoperative CRT group (95% vs. 76%; p = 0.002). Neoadjuvant versus postoperative CRT was associated with a lower rate of any grade 3+ toxicity (10% vs. 54%; p < 0.001). The multivariable analysis of OS showed lower hazards of death to be independently associated neoadjuvant versus postoperative CRT (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.36-0.91; p = 0.020) and R0 resection (HR 0.50; 95% CI 0.27-0.90; p = 0.021)., Conclusions: Neoadjuvant CRT was associated with a longer OS, a higher rate of R0 resection, and a lower treatment-related toxicity than postoperative CRT. The findings suggest that neoadjuvant CRT is superior to postoperative CRT in the treatment of gastric and GEJ cancer., (© 2021. Society of Surgical Oncology.)

Purpose: Colorectal cancer (CRC) incidence in patients younger than 50 years of age, commonly defined as early-onset (EO-CRC), is rising. EO-CRC often presents with distinct clinicopathologic features. However, data on prognosis are conflicting and outcomes with modern treatment approaches for metastatic disease are still limited., Materials and Methods: We prospectively enrolled patients with metastatic CRC (mCRC) to a biobanking and clinical data collection protocol from 2014 to 2018. We grouped the cohort based on age at initial diagnosis: < 40 years, 40-49 years, and ≥ 50 years. We used regression models to examine associations among age at initial diagnosis, treatments, clinicopathologic features, and survival., Results: We identified 466 patients with mCRC (45 [10%] age < 40 years, 109 [23%] age 40-49 years, and 312 [67%] age ≥ 50 years). Patients < 40 years of age were more likely to have received multiple metastatic resections (odds ratio [OR], 3.533; P = .0066) than their older counterparts. Patients with EO-CRC were more likely to receive triplet therapy than patients > 50 years of age (age < 40 years: OR, 6.738; P = .0002; age 40-49 years: OR, 2.949; P = .0166). Patients 40-49 years of age were more likely to have received anti-EGFR therapy (OR, 2.633; P = .0016). Despite differences in care patterns, age did not predict overall survival., Conclusion: Despite patients with EO-CRC receiving more intensive treatments, survival was similar to the older counterpart. However, EO-CRC had clinical and molecular features associated with worse prognoses. Improved biologic understanding is needed to optimize clinical management of EO-CRC. The cost-benefit ratio of exposing patients with EO-CRC to more intensive treatments has to be carefully evaluated., Competing Interests: Nora K. HorickEmployment: Northwest BiotherapeuticsStock and Other Ownership Interests: Northwest BiotherapeuticsPatents, Royalties, Other Intellectual Property: An immediate family member holds patents, has patents pending, and receives royalties from a technology relating to health or medicine Lawrence S. BlaszkowskyStock and Other Ownership Interests: Pfizer Jeffrey W. ClarkResearch Funding: Pfizer David P. RyanStock and Other Ownership Interests: MPM Capital, Acworth Pharmaceuticals, Thrive Earlier Detection Corp, Exact SciencesHonoraria: UpToDate, Research to PracticeConsulting or Advisory Role: MPM Capital, Oncorus, Gritstone Oncology, Maverick Therapeutics, TCR2 Therapeutics, Twentyeight-Seven TherapeuticsResearch Funding: Stand Up To CancerPatents, Royalties, Other Intellectual Property: McGraw Hill Chapter Royalties, Johns Hopkins University PressExpert Testimony: Boehringer IngelheimOther Relationship: TCR2 Therapeutics Lipika GoyalConsulting or Advisory Role: Debiopharm Group, Alentis Therapeutics, QED Therapeutics, H3 Biomedicine, AstraZeneca, Klus Pharma, Agios, Taiho Pharmaceutical, Incyte, Sirtex Medical, Genentech, ExelixisUncompensated Relationships: Agios, Debiopharm Group, Taiho Pharmaceutical, Merck Joseph FransesStock and Other Ownership Interests: Merck, BiogenConsulting or Advisory Role: Foundation MedicineResearch Funding: Genentech/Roche Samuel J. KlempnerStock and Other Ownership Interests: TP TherapeuticsHonoraria: NateraConsulting or Advisory Role: Lilly, Boston Biomedical, Astellas Pharma, Foundation Medicine, Bristol Myers Squibb, Pieris Pharmaceuticals, Merck, Daiichi Sankyo/UCB JapanSpeakers' Bureau: Foundation MedicineResearch Funding: Leap Therapeutics, BeiGeneOther Relationship: NCCN Eric J. RoelandConsulting or Advisory Role: Napo Pharmaceuticals, AIM Specialty Health, Oragenics, BASF, Vector Oncology, Asahi Kasei, Heron, Pfizer/EMD Serono, Astellas Pharma, Helsinn TherapeuticsExpert Testimony: Regents of the University of California Colin D. WeekesHonoraria: Celgene, Merrimack, Lilly, BayerConsulting or Advisory Role: Celgene, Merrimack, IpsenResearch Funding: Millennium, Celgene, Bayer, Genentech/Roche, AbbVie, Lilly, AstraZeneca, Gilead Sciences, Ipsen, HalozymeTravel, Accommodations, Expenses: Lilly, Celgene, Bayer Theodore S. HongConsulting or Advisory Role: Merck, Synthetic Biologics, Novocure, SyndaxResearch Funding: Novartis, Taiho Pharmaceutical, AstraZeneca, IntraOp, Tesaro, Bristol Myers Squibb, Ipsen Emily E. Van SeventerEmployment: Blueprint MedicinesStock and Other Ownership Interests: Blueprint Medicines Ryan B. CorcoranStock and Other Ownership Interests: Avidity Biosciences, nRichDx, Fount Therapeutics, C4 Therapeutics, Revolution Medicines, Kinnate Biopharma, Remix Therapeutics, Erasca IncConsulting or Advisory Role: Avidity Nanomedicines, Taiho Pharmaceutical, Merrimack, Genentech, N-of-One, Astex Pharmaceuticals, Amgen, Bristol Myers Squibb, Roche, Shire, FOGPharma, Loxo, Roivant, Warp Drive Bio, Spectrum Pharmaceuticals, Symphogen, Array BioPharma, Chugai Pharma, nRichDx, Fount Therapeutics, Novartis, Shionogi, Elicio Therapeutics, C4 Therapeutics, Revolution Medicines, Zikani Therapeutics, Natera, Kinnate Biopharma, Ipsen, AbbVie, Asana Biosciences, Remix TherapeuticsResearch Funding: AstraZeneca, Sanofi, Asana Biosciences, Lilly Aparna R. ParikhConsulting or Advisory Role: PureTech, Foundation Medicine, Lilly, NateraResearch Funding: Plexxikon, Bristol Myers Squibb, Genentech, Guardant Health, Array BioPharma, Lilly, Novartis Pharmaceuticals UK Ltd, TesaroNo other potential conflicts of interest were reported.

Purpose: We performed a NCI-sponsored, prospective study of neoadjuvant FOLFIRINOX followed by chemoradiation with carboplatin/paclitaxel followed by surgery in patients with locally advanced gastric or gastroesophageal cancer., Patients and Methods: The primary objective was to determine completion rate of neoadjuvant FOLFIRINOX × 8 followed by chemoradiation. Secondary endpoints were toxicity and pathologic complete response (pCR) rate. Exploratory analysis was performed of circulating tumor DNA (ctDNA) to treatment response., Results: From October 2017 to June 2018, 25 patients were enrolled. All patients started FOLFIRINOX, 92% completed all eight planned cycles, and 88% completed chemoradiation. Twenty (80%) patients underwent surgical resection, and 7 had a pCR (35% in resected cohort, 28% intention to treat). Tumor-specific mutations were identified in 21 (84%) patients, of whom 4 and 17 patients had undetectable and detectable ctDNA at baseline, respectively. Presence of detectable post-chemoradiation ctDNA ( P = 0.004) and/or postoperative ctDNA ( P = 0.045) were associated with disease recurrence., Conclusions: Here we show neoadjuvant FOLFIRINOX followed by chemoradiation for locally advanced gastroesophageal cancer is feasible and yields a high rate of pCR. ctDNA appears to be a promising predictor of postoperative recurrence. See related commentary by Catenacci, p. 6281 ., (©2021 American Association for Cancer Research.)

The sodium-dependent taurocholate co-transporting polypeptide (NTCP)-S267F variant is known to be associated with a reduced risk of hepatitis B virus (HBV) infection and disease progression. The NTCP-S267F variant displays diminished function in mediating HBV entry, but its function in HBV infection has not been fully established in more biologically relevant models. We introduced the NTCP-S267F variant and tested infectivity by HBV in genetically edited hepatic cells. HepG2-NTCP clones with both homozygous and heterozygous variants were identified after CRISPR base editing. NTCP-S267F homozygous clones did not support HBV infection. The heterozygote clones behaved similarly to wild-type clones. We generated genetically edited human stem cells with the NTCP-S267F variant, which differentiated equally well as wild-type into hepatocyte-like cells (HLCs) expressing high levels of hepatocyte differentiation markers. We confirmed that HLCs with homozygous variant did not support HBV infection, and heterozygous variant clones were infected with HBV equally as well as the wild-type cells. In conclusion, we successfully introduced the S267F variant by CRISPR base editing into the NTCP/SLC10A gene of hepatocytes, and showed that the variant is a loss-of-function mutation. This technology of studying genetic variants and their pathogenesis in a natural context is potentially valuable for therapeutic intervention against HBV., Competing Interests: The authors declare no competing interests.

Background: Dynamic survival data based on time already survived are lacking for resected borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC) patients who received total neoadjuvant therapy (TNT) with FOLFIRINOX followed by chemoradiation. Conditional survival, i.e., the probability of surviving an additional length of time after having already survived an amount of time, offers such information. We aimed to determine actuarial and conditional overall (OS, COS) and disease-free survival (DFS, CDFS) among this cohort., Methods: Clinicopathologic data were retrospectively collected for resected BR/LA PDAC patients who received TNT (2011-2019). COS and CDFS rates were calculated for patients being event (death/recurrence)-free at multiple intervals and by recurrence status., Results: After a median follow-up of 32.1 months, the 183 patients had a median OS and DFS of 39.1 months and 16.8 months, respectively. COS and CDFS increased as a function of time already survived. The probability of surviving an additional 24 months if a patient survived 2 years post-operatively was 70%, whereas the 4-year actuarial OS was 47%. Similarly, the probability of surviving disease-free an additional 24 months after 2 years was 66%, while actuarial 48-month DFS was 27%. COS for disease-free patients increased further over time. For patients remaining disease-free 12 months post-operatively, BR vs. LA status at diagnosis, tumor ≤ 4 cm at diagnosis, and R0 resection were independent predictors of favorable additional OS and DFS., Conclusions: For resected TNT-treated BR/LA PDAC patients, the probability of surviving an additional length of time increases as a function of survival already accrued. Dynamic survival estimates may allow personalized follow-up and counseling., (© 2021. The Society for Surgery of the Alimentary Tract.)

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13-41%) and 20% for PDAC (five of 25; 95% CI, 7-41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19-58%) in CRC and 29% (five of 17; 95% CI, 10-56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection., Experimental Design: A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence., Results: Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only ( n = 39) or completion of adjuvant therapy ( n = 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive value (PPV), 100%; HR, 11.28 ( P < 0.0001)]. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence [HR, 1.84 ( P = 0.18); PPV = 53.9%]., Conclusions: Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection. See related commentary by Bent and Kopetz, p. 5449 ., (©2021 American Association for Cancer Research.)

Background and Aims: 17-Beta hydroxysteroid dehydrogenase 13 (HSD17B13) is genetically associated with human nonalcoholic fatty liver disease (NAFLD). Inactivating mutations in HSD17B13 protect humans from NAFLD-associated and alcohol-associated liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma, leading to clinical trials of anti-HSD17B13 therapeutic agents in humans. We aimed to study the in vivo function of HSD17B13 using a mouse model., Approach and Results: Single-cell RNA-sequencing and quantitative RT-PCR data revealed that hepatocytes are the main HSD17B13-expressing cells in mice and humans. We compared Hsd17b13 whole-body knockout (KO) mice and wild-type (WT) littermate controls fed regular chow (RC), a high-fat diet (HFD), a Western diet (WD), or the National Institute on Alcohol Abuse and Alcoholism model of alcohol exposure. HFD and WD induced significant weight gain, hepatic steatosis, and inflammation. However, there was no difference between genotypes with regard to body weight, liver weight, hepatic triglycerides (TG), histological inflammatory scores, expression of inflammation-related and fibrosis-related genes, and hepatic retinoid levels. Compared to WT, KO mice on the HFD had hepatic enrichment of most cholesterol esters, monoglycerides, and certain sphingolipid species. Extended feeding with the WD for 10 months led to extensive liver injury, fibrosis, and hepatocellular carcinoma, with no difference between genotypes. Under alcohol exposure, KO and WT mice showed similar hepatic TG and liver enzyme levels. Interestingly, chow-fed KO mice showed significantly higher body and liver weights compared to WT mice, while KO mice on obesogenic diets had a shift toward larger lipid droplets., Conclusions: Extensive evaluation of Hsd17b13 deficiency in mice under several fatty liver-inducing dietary conditions did not reproduce the protective role of HSD17B13 loss-of-function mutants in human NAFLD. Moreover, mouse Hsd17b13 deficiency induces weight gain under RC. It is crucial to understand interspecies differences prior to leveraging HSD17B13 therapies., (© 2020 by the American Association for the Study of Liver Diseases.)

Background: Patient-reported outcomes (PROs) assessing quality of life (QOL) and symptom burden correlate with clinical outcomes in patients with cancer. However, to the authors' knowledge, data regarding associations between PROs and treatment response are lacking., Methods: The authors prospectively approached consecutive patients with advanced gastrointestinal cancer who were initiating a new treatment. Prior to treatment, patients reported their QOL (Functional Assessment of Cancer Therapy-General [FACT-G], 4 subscales: Functional, Physical, Emotional, Social; higher scores indicate better QOL) and symptom burden (Edmonton Symptom Assessment System [ESAS], Patient Health Questionnaire-4 [PHQ-4]; higher scores represent greater symptoms). Regression models were used to examine associations of baseline PROs with treatment response (clinical benefit or progressive disease [PD] at time of first scan), healthcare utilization, and survival., Results: From May 2019 to April 2020, a total of 112 patients with advanced gastrointestinal cancer were enrolled. For treatment response, 64.3% had CB and 35.7% had PD. Higher baseline ESAS-Physical (odds ratio, 1.04; P = .027) and lower FACT-G Functional (odds ratio, 0.92; P = .038) scores were associated with PD. Higher ESAS-Physical (hazard ratio [HR], 1.03; P = .044) and lower FACT-G Total (HR, 0.96; P = .005), FACT-G Physical (HR, 0.89; P < .001), and FACT-G Functional (HR, 0.87; P < .001) scores were associated with a greater hospitalization risk. Lower FACT-G Total (HR, 0.96; P = .009) and FACT-G Emotional (HR, 0.86; P = .012) scores as well as higher ESAS-Total (HR, 1.03; P = .014) and ESAS-Physical (HR, 1.04; P = .032) scores were associated with worse survival., Conclusions: Baseline PROs are associated with treatment response in patients with advanced gastrointestinal cancer, namely physical symptoms and functional QOL, in addition to health care use and survival. The findings of the current study support the association between PROs and important clinical outcomes, including the novel finding of treatment response., (© 2020 American Cancer Society.)

Background: Neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC., Methods: Clinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided., Results: Two hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival., Conclusions: Neoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: This study assessed patterns of failure and rates of subsequent biliary intervention among patients with resected biliary tract cancers (BTCs) including gallbladder carcinoma (GBC) and extra- and intrahepatic cholangiocarcinoma (eCCA and iCCA) treated with adjuvant chemoradiation therapy (CRT)., Methods: In this single-institution retrospective analysis of 80 patients who had GBC (n = 29), eCCA (n = 43), or iCCA (n = 8) treated with curative-intent resection and adjuvant CRT from 2007 to 2017, the median radiation dose was 50.4 Gy (range 36-65 Gy) with concurrent 5-fluorouracil (5-FU) chemotherapy. All but two of the patients received adjuvant chemotherapy. The 2-year locoregional failure (LRF), 2-year recurrence-free survival (RFS), and 2-year overall survival (OS), and univariate predictors of LRF, RFS, and OS were calculated for the entire cohort and for a subgroup excluding patients with iCCA (n = 72). The predictors of biliary interventions also were assessed., Results: Of the 80 patients (median follow-up period, 30.5 months; median OS, 33.9 months), 54.4% had American Joint Committee on Cancer (AJCC) stage 1 or 2 disease, 57.1% were lymph node-positive, and 66.3% underwent margin-negative resection. For the entire cohort, 2-year LRF was 23.8%, 2-year RFS was  43.7%, and 2-year OS was 62.1%.  When patients with iCCA were excluded, the 2-year LRF was 22.6%, the 2-year RFS was 43.9%, and the 2-year OS was 59.2%. In the overall and subgroup univariate analyses, lymph node positivity was associated with greater LRF, whereas resection margin was not. Biliary intervention was required for 12 (63.2%) of the 19 patients with LRF versus 11 (18%) of the 61 patients without LRF (P < 0.001). Of the 12 patients with LRF who required biliary intervention, 4 died of biliary complications., Conclusions: The LRF rates remained significant despite adjuvant CRT. Lymph node positivity may be associated with increased risk of LRF. Positive margins were not associated with greater LRF, suggesting that CRT may mitigate LRF risk for this group. An association between LRF and higher rates of subsequent biliary interventions was observed, which may yield significant morbidity. Novel strategies to decrease the rates of LRF should be considered.

Background: Although treatment-related lymphopenia (TRL) is common and associated with poorer survival in multiple solid malignancies, few data exist for anal cancer. We evaluated TRL and its association with survival in patients with anal cancer treated with chemoradiation (CRT)., Materials and Methods: A retrospective analysis of 140 patients with nonmetastatic anal squamous cell carcinoma (SCC) treated with definitive CRT was performed. Total lymphocyte counts (TLC) at baseline and monthly intervals up to 12 months after initiating CRT were analyzed. Multivariable Cox regression analysis was performed to evaluate the association between overall survival (OS) and TRL, dichotomized by grade (G)4 TRL (<0.2k/μL) 2 months after initiating CRT. Kaplan-Meier and log-rank tests were used to compare OS between patients with versus without G4 TRL., Results: Median time of follow-up was 55 months. Prior to CRT, 95% of patients had a normal TLC (>1k/μL). Two months after initiating CRT, there was a median of 71% reduction in TLC from baseline and 84% of patients had TRL: 11% G1, 31% G2, 34% G3, and 8% G4. On multivariable Cox model, G4 TRL at two months was associated with a 3.7-fold increased risk of death. On log-rank test, the 5-year OS rate was 32% in the cohort with G4 TRL versus 86% in the cohort without G4 TRL., Conclusion: TRL is common and may be another prognostic marker of OS in anal cancer patients treated with CRT. The association between TRL and OS suggests an important role of the host immunity in anal cancer outcomes., Implications for Practice: This is the first detailed report demonstrating that standard chemoradiation (CRT) commonly results in treatment-related lymphopenia (TRL), which may be associated with a poorer overall survival (OS) in patients with anal squamous cell carcinoma. The association between TRL and worse OS observed in this study supports the importance of host immunity in survival among patients with anal cancer. These findings encourage larger, prospective studies to further investigate TRL, its predictors, and its relationship with survival outcomes. Furthermore, the results of this study support ongoing efforts of clinical trials to investigate the potential role of immunotherapy in anal cancer., (© 2020 AlphaMed Press.)

Subsets of esophagogastric (EG) cancers harbor genetic abnormalities, including amplification of HER2, MET, or FGFR2 or mutations in PIK3CA, EGFR, or BRAF. Ganetespib which is a novel triazolone heterocyclic inhibitor of HSP90, is a potentially biologically rational treatment strategy for advanced EG cancers with these gene amplification. This multicenter, single-arm phase 2 trial enrolled patients with histologically confirmed advanced EG cancer with progression on at least one line of systemic therapy. Patients received Ganetespib 200 mg/m2 IV on Days 1, 8, and 15 of a 28-day cycle. The primary endpoint was overall response rate (ORR). Secondary endpoints included: Progression Free Survival (PFS); to correlate the presence of HSP clients with ORR and PFS; evaluating the safety, tolerability and adverse events profile. In this study 26 eligible patients mainly: male 77%, median age 64 years were enrolled. The most common drug-related adverse events were diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and elevated ALKP (8%). The ORR of 4% reflects the single patient of 26 who had a complete response and stayed on treatment for more than seventy (70) months. Median PFS and OS was 61 days (2.0 months), 94 days (3.1 months) respectively. Ganetespib showed manageable toxicity. While the study was terminated early due to insufficient evidence of single-agent activity, the durable CR and 2 minor responses suggest that there may be a subset of EG patients who could benefit from this drug.

Non-alcoholic steatohepatitis (NASH) represents the progressive sub-disease of non-alcoholic fatty liver disease that causes chronic liver injury initiated and sustained by steatosis and necroinflammation. The Ron receptor is a tyrosine kinase of the Met proto-oncogene family that potentially has a beneficial role in adipose and liver-specific inflammatory responses, as well as glucose and lipid metabolism. Since its discovery two decades ago, the Ron receptor has been extensively investigated for its differential roles on inflammation and cancer. Previously, we showed that Ron expression on tissue-resident macrophages limits inflammatory macrophage activation and promotes a repair phenotype, which can retard the progression of NASH in a diet-induced mouse model. However, the metabolic consequences of Ron activation have not previously been investigated. Here, we explored the effects of Ron receptor activation on major metabolic pathways that underlie the development and progression of NASH. Mice lacking apolipoprotein E (ApoE KO) and double knockout (DKO) mice that lack ApoE and Ron were maintained on a high-fat high-cholesterol diet for 18 weeks. We observed that, in DKO mice, the loss of ligand-dependent Ron signaling aggravated key pathological features in steatohepatitis, including steatosis, inflammation, oxidation stress, and hepatocyte damage. Transcriptional programs positively regulating fatty acid (FA) synthesis and uptake were upregulated in the absence of Ron receptor signaling, whereas lipid disposal pathways were downregulated. Consistent with the deregulation of lipid metabolism pathways, the DKO animals exhibited increased accumulation of FAs in the liver and decreased level of bile acids. Altogether, ligand-dependent Ron receptor activation provides protection from the deregulation of major metabolic pathways that initiate and aggravate non-alcoholic steatohepatitis.

Background: There is limited data on the efficacy of adjuvant therapy (AT) in patients with invasive intraductal papillary mucinous neoplasms of the pancreas (IPMN). This single center retrospective cohort study aims to assess the impact of AT on survival in these patients., Methods: Patients undergoing surgery for invasive IPMN between 1993 and 2018 were included in the study. We compared the clinicopathologic features and evaluated overall survival (OS) using multivariate Cox regression adjusting for adjuvant therapy, age, T and N stage, perineural and lymphovascular invasion. We also assessed survival differences between surgery alone and AT in node negative (N0) and node positive (N+) subgroups., Results: 103 patients were included in the study; 69 underwent surgery alone while 34 also received AT. Patients in the AT group were significantly younger, presented at higher T and N stages and had more perineural and lymphovascular invasion. Median OS in the surgery alone group was 134 months and 65 months in the AT group, p = 0.052. On multivariate analysis, AT was not associated with improved OS; hazard ratio (HR) = 1.03 (0.52-2.05). In N0 patients, compared to surgery alone, AT was associated with a worse median OS (65 vs 167 months, p = 0.03), whereas in N+ patients there was a non-significant improvement (50.5 vs 20.4 months, p = 0.315)., Conclusion: AT did not improve survival in the overall cohort even after multivariate analysis. N0 patients have excellent survival, and AT should probably be avoided in them, whereas it may be considered in patients with N+ disease., Competing Interests: Declaration of competing interest All the authors state that there is no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To define short-term and long-term outcomes of IORT for the management of BR/LA PDAC in the era of modern neoadjuvant therapy (NAT)., Background: In the era of neoadjuvant FOLFIRINOX, many patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC) become candidates for surgical exploration with curative intent. IORT may be used to consolidate treatment for successfully resected patients with close or positive margins or administered in unresectable patients without distant metastases., Methods: A retrospective review of 158 patients who received IORT in the setting of biopsy-proven BR/LA PDAC following NAT between 2008 and 2017 was performed. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS) of FOLFIRINOX treated patients., Results: Most patients (83%) received FOLFIRINOX, and 95% underwent consolidative chemoradiation therapy (50.4-58.8 Gy). Among FOLFIRINOX-treated patients, 86 underwent combined surgical resection with IORT (10 Gy) while 46 received IORT alone (15-20 Gy). The median PFS and OS were 21.5 and 46.7 months for patients who underwent resection with IORT and 14.7 and 23 months in the IORT alone group. Local progression occurred in 12.7% of patients after resection with IORT, and in 15% of patients who received IORT alone. Major complications occurred in 13% of patients following resection, and 5% of patients after IORT alone, including one death., Conclusion: IORT combined with surgical resection appears to be associated with improved survival and minimal morbidity in patients with positive or close margins. IORT is also associated with improved survival in patients with unresectable, non-metastatic disease.

Purpose: ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer., Experimental Design: A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response., Results: A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB ( P < 0.0001). Four-week change in tumor markers also predicted response ( P = 0.0026) and CB ( P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively ( P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001)., Conclusions: Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation., (©2020 American Association for Cancer Research.)

Objective: The aim of this study was to evaluate outcomes for patients with unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated proton or photon radiation therapy (HF-RT)., Methods: We retrospectively identified 66 patients with ICC who were treated with HF-RT from 2008 to 2018. Median age at RT was 76 years (range 30-92), including 27 patients (41%) aged ≥ 80 years. Median RT dose was 58.05 Gy (range 37.5-67.5), all delivered in 15 daily fractions. Thirty-two patients received proton RT and 34 patients received photon RT., Results: Median follow-up times from diagnosis and RT start were 21 months and 14 months, respectively. In total, five patients (7.6%) developed local failure. The 2-year outcomes were 84% local control (LC) and 58% OS. Among the 51 patients treated with definitive intent, the 2-year LC rate was 93% and the OS rate was 62%. On multivariate analysis for LC, older age was associated with a lower risk of local failure [hazard ratio (HR) 0.91; p = 0.02], while prior surgery (HR 16.5; p = 0.04) and macrovascular invasion (HR 123.93; p = 0.02) were independently associated with an increased risk of local failure. On multivariate analysis for OS, female sex (HR 0.33; p = 0.001) and prior chemotherapy (HR 0.38; p = 0.003) remained significantly associated with OS. On multivariate analysis for OS, compared with photon RT, there was a trend towards improved survival with proton RT (HR 0.50; p = 0.05). The rate of overall grade 3 + toxicity was 11%. One patient developed radiation-induced liver disease and was treated with corticosteroids., Conclusions: HF-RT yields high rates of local control and is an effective modality to optimize biliary control for unresectable/locally recurrent ICC.

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient 1-3 . Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance 4-8 . However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.

Purpose: Definitive chemoradiation with concurrent 5-fluorouracil (5-FU)/mitomycin C (MMC) is an effective treatment for localized anal cancer, but it is associated with significant acute long-term treatment-related toxicity. Pencil beam scanning proton beam (PBS-PT) radiation therapy may potentially reduce this toxicity. This is a multi-institutional pilot study evaluating the feasibility of definitive concurrent chemoradiation with PBS-PT in combination with 5-FU and MMC for carcinoma of the anal canal., Methods and Materials: Patients were enrolled on a National Cancer Institute-sponsored, prospective, multi-institutional, single-arm pilot study (NCT01858025). Key eligibility criteria included Eastern Cooperative Oncology Group 0 to 2, age ≥18 years, histologically confirmed invasive squamous cell carcinoma of the anal canal, and clinically staged T1-4, N0-3 disease. Patients were treated with PBS-PT per Radiation Therapy Oncology Group 0529 dose schema and concurrent 5-FU/MMC on day 1 and 29. The primary objective of this study was to determine feasibility of PBS-PT with concurrent 5-FU/MMC, defined as grade 3+ dermatologic toxicity less than 48% (reported grade 3+ dermatologic toxicity from Radiation Therapy Oncology Group 98-11). Secondary objectives were to determine the rates of overall grade 3+ toxicities, clinical complete response rate, and disease outcomes., Results: Between February 2014 and April 2017, we enrolled 25 patients into our study, all of whom were analyzed. Twenty-three patients (92%) completed treatment per protocol, and 2 patients died on treatment. Median time to completion of treatment was 42 days (range, 38-49). The grade 3+ radiation dermatitis rate was 24%. Median follow-up is 27 months (range, 21-50) among the 21 patients still alive. The overall rate of clinical complete response was 88%. The 2-year local failure, colostomy-free survival, progression-free survival, and overall survival are 12%, 72%, 80%, and 84%, respectively., Conclusions: In our prospective, multi-institutional pilot study of PBS-PT with concurrent 5-FU/MMC, PBS-PT was found to be feasible. A phase 2 study of proton beam radiation therapy is currently underway., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Ablative radiation therapy is increasingly being used for hepatocellular carcinoma (HCC) resulting in excellent local control rates; however, patients without evidence of disease progression often die from liver failure. The clinical benefit of proton- over photon-based radiation therapy is unclear. We therefore sought to compare clinical outcomes of proton versus photon ablative radiation therapy in patients with unresectable HCC., Methods and Materials: This is a single-institution retrospective study of patients treated during 2008 to 2017 with nonmetastatic, unresectable HCC not previously treated with liver-directed radiation therapy and who did not receive further liver-directed radiation therapy within 12 months after completion of index treatment. The primary outcome, overall survival (OS), was assessed using Cox regression. Secondary endpoints included incidence of non-classic radiation-induced liver disease (defined as increase in baseline Child-Pugh score by ≥2 points at 3 months posttreatment), assessed using logistic regression, and locoregional recurrence, assessed using Fine-Gray regression for competing risks. All outcomes were measured from radiation start date., Results: The median follow-up was 14 months. Of 133 patients with median age 68 years and 75% male, 49 (37%) were treated with proton radiation therapy. Proton radiation therapy was associated with improved OS (adjusted hazard ratio, 0.47; P = .008; 95% confidence interval [CI], 0.27-0.82). The median OS for proton and photon patients was 31 and 14 months, respectively, and the 24-month OS for proton and photon patients was 59.1% and 28.6%, respectively. Proton radiation therapy was also associated with a decreased risk of non-classic radiation-induced liver disease (odds ratio, 0.26; P = .03; 95% CI, 0.08-0.86). Development of nonclassic RILD at 3 months was associated with worse OS (adjusted hazard ratio, 3.83; P < .001; 95% CI, 2.12-6.92). There was no difference in locoregional recurrence, including local failure, between protons and photons., Conclusions: Proton radiation therapy was associated with improved survival, which may be driven by decreased incidence of posttreatment liver decompensation. Our findings support prospective investigations comparing proton versus photon ablative radiation therapy for HCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted., Objective: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer., Design, Setting, and Participants: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion., Interventions: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine., Main Outcomes and Measures: R0 resection rate., Results: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached)., Conclusions and Relevance: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%., Trial Registration: ClinicalTrials.gov identifier: NCT01821729.

Background: This study characterizes the tumor-immune microenvironment in pretreatment, localized anal squamous cell carcinoma (ASCC), including two markers that have not previously been studied in ASCC: indoleamine 2,3 dioxygenase 1 (IDO1) and human leukocyte antigen (HLA) class I., Materials and Methods: Retrospective review identified 63 patients with ASCC receiving definitive chemoradiation between 2005 and 2016 with pretreatment tissue available. Immunohistochemistry was used to quantify cluster of differentiation 8 (CD8), programmed cell death protein 1, programmed death-ligand 1, HLA class I, and IDO1. Cox proportional hazards models evaluated associations between outcomes and immune markers, controlling for clinical characteristics., Results: With a median follow-up of 35 months, 3-year overall survival was 78%. The only marker found to have a robust association with outcome was tumor IDO1. In general, the percentage of tumor cells expressing IDO1 was low (median 1%, interquartile range 0%-20%); however, patients with >50% of tumor cells expressing IDO1 had significantly worse overall survival (hazard ratio [HR] 4.7, p  = .007) as well as higher local recurrence (HR 8.6, p  = .0005) and distant metastasis (HR 12.7, p  = .0002). Tumors with >50% IDO1 were also more likely to have the lowest quartile of CD8 infiltrate (<40 per high-power field, p  = .024)., Conclusion: ASCC has a diverse immune milieu. Although patients generally do well with standard therapy, IDO1 may serve as a prognostic indicator of poor outcome and could help identify a patient population that might benefit from IDO-targeted therapies., Implications for Practice: After definitive chemoradiation, patients with locally advanced anal cancer may experience significant treatment morbidity and high risk of recurrence. The goal of the current study is to identify novel prognostic factors in the tumor-immune microenvironment that predict for poor outcomes after definitive chemoradiation. This study characterizes the tumor-immune microenvironment in pre-treatment, localized anal squamous cell carcinoma (ASCC), including two markers which have not previously been studied in ASCC: indoleamine 2,3 dioxygenase 1 (IDO1) and HLA class I. With a median follow-up of 3 years, this study demonstrated that high IDO1 expression is correlated with significantly worse 3-year overall survival (88% vs. 25%). Whereas recent studies of IDO1 inhibitors have shown mixed results, this study suggests that patients with anal cancer with high IDO1 expression have dismal prognosis and may represent a patient population primed for response to targeted IDO1 inhibition., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Objective: The aim of this study was to determine (1) whether preoperative factors can predict resectability of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant FOLFIRINOX, (2) which patients might benefit from adjuvant therapy, and (3) survival differences between resected BR/LA patients who received neoadjuvant FOLFIRINOX and upfront resected patients., Background: Patients with BR/LA PDAC are often treated with FOLFIRINOX to obtain a margin-negative resection, yet selection of patients for resection remains challenging., Methods: Clinicopathologic data of PDAC patients surgically explored between 04/2011-11/2016 in a single institution were retrospectively collected., Results: Following neoadjuvant FOLFIRINOX, 141 patients were surgically explored (BR: 49%, LA: 51%) and 110 (78%) were resected. Resected patients had lower preoperative CA 19-9 levels (21 vs 40 U/mL, P = 0.03) and smaller tumors on preoperative computed tomography (CT) scan (2.3 vs 3.0 cm, P = 0.03), but no predictors of resectability were identified. Median overall survival (OS) was 34.2 months from diagnosis for all FOLFIRINOX patients and 37.7 months for resected patients. Among resected patients, preoperative CA 19-9 >100 U/mL and >8 months between diagnosis and surgery predicted a shorter postoperative disease-free survival (DFS); Charlson comorbidity index >1, preoperative CA 19-9 >100 U/mL and tumor size (>3.0 cm on CT or >2.5 cm on pathology) predicted decreased OS. DFS and OS were significantly better for BR/LA PDAC patients treated with neoadjuvant FOLFIRINOX compared with upfront resected patients (DFS: 29.1 vs 13.7, P < 0.001; OS: 37.7 vs 25.1 months from diagnosis, P = 0.01)., Conclusion: BR/LA PDAC patients with no progression on neoadjuvant FOLFIRINOX should be offered surgical exploration. Except size, traditional pathological parameters fail to predict survival among resected FOLFIRINOX patients. Resected FOLFIRINOX patients have survival that appears to be superior than that of resectable patients who go directly to surgery.

Purpose: Sorafenib is a standard first-line treatment for advanced hepatocellular carcinoma (HCC). The phase III SHARP trial showed a median time-to-progression (mTTP) of 5.5 months, overall response rate (ORR) of 2%, and median overall survival (mOS) of 10.7 months with sorafenib. FOLFOX4 has shown modest activity in advanced HCC. We evaluated the combination of sorafenib and modified (m)FOLFOX in a single-arm, multicenter phase II study., Patients and Methods: The study included Child-Pugh A patients with advanced HCC and no prior systemic therapies. Patients received sorafenib 400 mg twice a day for 2 weeks, followed by concurrent mFOLFOX [5-fluorouracil (5-FU) 1,200 mg/m 2 /day for 46 hours, leucovorin 200 mg/m 2 , and oxaliplatin 85 mg/m 2 biweekly]. The primary endpoint was mTTP with an alternative hypothesis of 7 months, and secondary endpoints included ORR, mOS, and circulating biomarkers., Results: The study enrolled 40 patients: HCV/EtOH/HBV, 43%/28%/13%; Child-Pugh A5, 70%. Notable grade 3/4 adverse events (AE) included AST/ALT elevation (28%/15%), diarrhea (13%), hyperbilirubinemia (10%), hand-foot syndrome (8%), and bleeding (8%). mTTP was 7.7 months [95% confidence interval (CI): 4.4-8.9], ORR 18%, and mOS 15.1 months (7.9-16.9). Sorafenib + mFOLFOX increased plasma PlGF, VEGF-D, sVEGFR1, IL12p70, and CAIX and CD4 + and CD8 + effector T lymphocytes and decreased plasma sVEGFR2 and s-c-KIT and regulatory T cells (Tregs). Shorter TTP was associated with high baseline sVEGFR1. Shorter TTP and OS were associated with increases in Tregs and CD56 Dim natural killer (NK) cells after sorafenib alone and plasma sMET after combination treatment (all P < 0.05)., Conclusions: Sorafenib + mFOLFOX met the prespecified endpoint with encouraging efficacy but moderate hepatotoxicity. Thus, this regimen may be effective in select patients with adequate liver reserve. Biomarker evaluations suggested a correlation between time-to-progression (TTP) and angiogenic biomarkers and circulating Tregs., (©2018 American Association for Cancer Research.)

Purpose: This study aimed to assess the safety and efficacy of administering liver reirradiation to patients with primary liver tumors or liver metastasis., Methods and Materials: A total of 49 patients (with 64 individual tumors) who received liver reirradiation at our institution between June 2008 and December 2016 were identified for retrospective review. Patients were treated to the same, different, or a combination of previously treated liver tumors for recurrent primary (53%) or metastatic (47%) disease using photons or protons. Clinical and treatment-related factors were compiled and patients were monitored for toxicity and evidence of classic or nonclassic radiation-induced liver disease. Survival was estimated with the Kaplan-Meier method and cumulative incidence of local failure (LF) was used to estimate LF using the Response Evaluation Criteria in Solid Tumors version 1.1., Results: The median age at the time of reirradiation was 72 years and the median interval between radiation courses was 9 months. At a median follow-up of 10.5 months, 36 patients (73%) had died, 9 patients (18%) were alive, and 4 patients (8%) were lost to follow-up. The median survival for the cohort was 14 months. The overall 1-year estimate of LF was 46.4%. The 1-year estimates of LF for liver metastases and hepatocellular carcinoma were 61.0% and 32.5%, respectively. The average prescription dose was similar between the reirradiation and initial courses (equivalent dose in 2 Gy fractions EQD2: 65.0 vs 64.3 Gy α/β = 10 , respectively) but the average dose to the untreated liver was lower at the time of reirradiation (EQD2: 10.5 vs 13.9 Gy α/β = 3 , respectively, P = .01). Among patients with hepatocellular carcinoma, the average normal liver dose was significantly larger for patients who exhibited a worsening of Child-Pugh score after reirradiation compared with those who did not (1210 cGy vs 759 cGy, P = .04). With regard to toxicity, 85.7% of patients experienced grade 1 to 2 toxicity, 4.1% developed grade 3, and only 2 patients (4.1%) met the criteria for radiation-induced liver disease after reirradiation., Conclusions: Liver reirradiation may be an effective and safe option for select patients; however, further prospective study is necessary to establish treatment guidelines and recommended dosing., (Copyright © 2018. Published by Elsevier Inc.)

Recent reports demonstrate inferior outcomes associated with primary right-sided vs left-sided colorectal tumors in patients with metastatic colorectal cancer (mCRC). We sought to describe our experience with mCRC patients on whom we have molecular data to determine whether primary tumor sidedness was an independent prognostic marker for overall survival (OS). mCRC patients with documented primary tumor sidedness who received mutational profiling between 2009 and 2014 were identified (n = 367, median follow-up 30.4 months). Mutational profiling for >150 mutations across commonly mutated cancer genes including RAS, PIK3CA, BRAF, and PTEN as well as treatment data, including receipt of a biologic agent, were collected. Univariable/multivariable models were used to analyze relationships between collected data and OS. Among 367 patients, sidedness breakdown was as follows: 234 left (64%), 133 right (36%). 56% were male, with a median age at diagnosis of 57 (range 24-89). A total of 143 patients had RAS mutations. Five-year OS was 41%, median OS was 54 months (range 1-149). Five-year OS for left- vs right-sided tumors was 46% vs 24% (P < .0001). On univariable analysis, among both RAS wildtype and mutant tumors, left-sided tumors continued to have improved OS vs right-sided tumors (HR: 0.49, 95% CI: 0.34-0.69 RAS wildtype; HR: 0.61, 95% CI: 0.40-0.95 RAS mutant). Left-sidedness was an important prognostic factor for OS among RAS wildtype patients despite treatment with or without a biologic agent (P < .05). Left-sidedness remained significant for improved OS on multivariable analysis (P < .0001). Left-sided primary tumor remained most important prognostic factor for OS, even when adjusting for mutational status and receipt of biologic agent., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: We reviewed our experience involving patients with borderline resectable or locally advanced pancreatic cancer, treated with the dose-painted (DP) boost technique to regions of vessel involvement which preclude upfront surgical resection. We evaluated patient outcomes with respect to tolerability and treatment outcomes., Materials and Methods: We retrospectively reviewed 99 patients with borderline resectable (n=25) or locally advanced pancreatic cancer (n=74) treated with DP-neoadjuvant chemoradiation from 2010 to 2015. Tumor and regional lymph nodes were prescribed 50.4 Gy and the region around the involved blood vessel was boosted to 58.8 Gy in 28 fractions. The primary outcome was acute toxicity and late duodenal toxicity. Secondary outcomes included conversion to surgical resectability, local failure, disease-free survival, and overall survival (OS). Cox proportional hazards models were performed to evaluate for predictors of survival., Results: All but 1 patient completed chemoradiation. The rates of grade 2+ and 3+ nausea were 40% and 12%, respectively. With regards to late toxicity, 5 patients developed potential RT-related grade 3+ duodenal complications including duodenal ulceration/bleeding (n=3) and duodenal stricture (n=2). With a median follow-up of 15 months, the median OS was 18.1 months. Among 99 patients in our study, 37 patients underwent surgical resection. For patients who underwent surgical resection (n=37), the median OS was 30.9 months. On multivariate analysis, only normalization of CA 19-9 post-RT was associated with improved OS., Conclusions: We found that DP-neoadjuvant chemoradiation to regions of vessel involvement is both feasible and well tolerated. In addition, we demonstrated that over one third of patients with initially deemed unresectable disease were able to undergo surgical resection after receiving neoadjuvant therapy including DP-chemoradiation.

Importance: Patients with borderline-resectable pancreatic ductal adenocarcinoma have historically poor outcomes with surgery followed by adjuvant chemotherapy. Evaluation of a total neoadjuvant approach with highly active therapy is warranted., Objective: To evaluate the margin-negative (R0) resection rate in borderline-resectable pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX (fluorouracil, irinotecan, and oxaliplatin) therapy and individualized chemoradiotherapy., Design, Setting, and Participants: A single-arm, phase 2 clinical trial was conducted at a large academic hospital with expertise in pancreatic surgery from August 3, 2012, through August 31, 2016, among 48 patients with newly diagnosed, previously untreated, localized pancreatic cancer determined to be borderline resectable by multidisciplinary review, who had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 18.0 months among the 30 patients still alive at study completion., Interventions: Patients received FOLFIRINOX for 8 cycles. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy with fluorouracil or capecitabine., Main Outcomes and Measures: The primary outcome was R0 resection rate; secondary outcomes were median progression-free survival (PFS) and median overall survival (OS)., Results: Of the 48 eligible patients, 27 were men and 21 were women, with a median age of 62 years (range, 46-74 years). Of the 43 patients who planned to receive 8 preoperative cycles of chemotherapy, 34 (79%) were able to complete all cycles. Twenty-seven patients (56%) had short-course chemoradiotherapy, while 17 patients (35%) had long-course chemoradiotherapy. R0 resection was achieved in 31 of the 48 eligible patients (65%; 95% CI, 49%-78%). Among the 32 patients who underwent resection, the R0 resection rate was 97% (n = 31). Median PFS among all eligible patients was 14.7 months (95% CI, 10.5 to not reached), with 2-year PFS of 43%; median OS was 37.7 months (95% CI, 19.4 to not reached), with 2-year OS of 56%. Among patients who underwent resection, median PFS was 48.6 months (95% CI, 14.4 to not reached) and median OS has not been reached, with a 2-year PFS of 55% and a 2-year OS of 72%., Conclusions and Relevance: Preoperative FOLFIRINOX followed by individualized chemoradiotherapy in borderline resectable pancreatic cancer results in high rates of R0 resection and prolonged median PFS and median OS, supporting ongoing phase 3 trials., Trial Registration: ClinicalTrials.gov Identifier: NCT01591733.

Objectives: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic pancreatic adenocarcinoma (PDAC) have prompted incorporation of these regimens into neoadjuvant treatment of locally advanced unresectable PDAC. Whereas some patients remain unresectable on surgical exploration, others are able to undergo resection after intensive neoadjuvant treatment. We evaluated outcomes and toxicity associated with use of intensive neoadjuvant treatment followed by intraoperative radiotherapy (IORT) in combination with resection or exploratory laparotomy., Methods: We retrospectively analyzed patients with locally advanced unresectable or borderline-resectable PDAC who received intensive neoadjuvant treatment with induction chemotherapy and chemoradiotherapy followed by exploratory laparotomy in an IORT-equipped operating suite between 2010 and 2015. Surgical outcomes and overall survival (OS) were compared., Results: Of 68 patients, 41 (60.3%) underwent resection, 18 (26.5%) had unresectable disease, and 9 (13.2%) had distant metastases. Of 41 resectable patients, 22 received IORT for close/positive resection margins on intraoperative frozen section. There was no significant difference in operative times or morbidity with addition of IORT to resection. Median OS was 26.6 months for all patients who underwent resection, 35.1 months for patients who underwent resection and IORT, and 24.5 months for patients who underwent resection alone (P=NS). Of 18 patients with unresectable disease, all but 1 received IORT, with median OS of 24.8 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative times or morbidity., Conclusions: IORT in addition to intensive neoadjuvant chemotherapy and chemoradiotherapy was not associated with increased toxicity when used with resection or exploratory laparotomy, and was associated with encouraging survival rates in patients with close/positive margins and patients with unresectable disease.

Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAF V600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo In vitro , the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome. Significance: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAF V600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417-27. ©2018 AACR. See related commentary by Janku, p. 389 See related article by Corcoran et al., p. 428 This article is highlighted in the In This Issue feature, p. 371 ., (©2018 American Association for Cancer Research.)

Neurodegeneration is a critical problem in aging populations and is characterized by severe central nervous system (CNS) inflammation. Macrophages closely regulate inflammation in the CNS and periphery by taking on different activation states. The source of inflammation in many neurodegenerative diseases has been preliminarily linked to a decrease in the CNS M2 macrophage population and a subsequent increase in M1-mediated neuroinflammation. The Recepteur D'Origine Nantais (Ron) is a receptor tyrosine kinase expressed on tissue-resident macrophages including microglia. Activation of Ron by its ligand, macrophage-stimulating protein, attenuates obesity-mediated inflammation in the periphery. An in vivo deletion of the ligand binding domain of Ron (Ron -/- ) promotes inflammatory (M1) and limits a reparative (M2) macrophage activation. However, whether or not this response influences CNS inflammation has not been determined. In this study, we demonstrate that in homeostasis Ron -/- mice developed an inflammatory CNS niche with increased tissue expression of M1-associated markers when compared to age-matched wild-type (WT) mice. Baseline metabolic analysis of CNS tissue indicates exacerbated levels of metabolic stress in Ron -/- CNS. In a disease model of multiple sclerosis, experimental autoimmune encephalomyelitis, Ron -/- mice exhibit higher disease severity when compared to WT mice associated with increased CNS tissue inflammation. In a model of diet-induced obesity (DIO), Ron -/- mice exhibit exacerbated CNS inflammation with decreased expression of the M2 marker Arginase-1 (Arg-1) and a robust increase in M1 markers compared to WT mice following 27 weeks of DIO. Collectively, these results illustrate that activation of Ron in the CNS could be a potential therapeutic approach to treating various grades of CNS inflammation underlying neurodegeneration.