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Increasing evidence suggests that many of the effector CD8+ T cells reactivated (‘rejuvenated”) by immunotherapy come from outside the tumor, derived from a circulating pool of “stem-like” memory or “precursor-exhausted” (TPEX) cells. These cells have been characterized in mice, but, despite their importance, circulating counterparts in humans have not yet been identified for study. We hypothesized that immunotherapy designed to enhance immunogenic antigen-presentation during chemotherapy might produce extensive reactivation of these precursor T cells. While the antigen-presentation step occurs in tissues, homing of the rejuvenated T cells to the tumor is via the circulation; thus, we hypothesized that they would be visible in blood. Informative patients were selected from two ongoing clinical trials of children with brain tumors treated with the IDO-inhibitor drug indoximod: a Phase 2 trial (NCT04049669) of indoximod plus chemotherapy; and a Phase 1 trial (NCT05106296) of indoximod, chemotherapy and the BTK-inhibitor ibrutinib, which synergistically destabilizes IDO (Immunity 54:2354-2371, 2021). Patient selection criteria included either (i) massive clonal expansion of activated CD8+ T cells on therapy (expanded clones reaching 16-25% of total CD8+ T cells); or (ii) complete radiographic tumor response (CR) on treatment; or (iii) both. Longitudinal blood samples (4-10 samples per patient) were obtained over a period of 6-24 months and analyzed by single-cell RNA-sequencing (scRNA-seq) with paired single-cell T cell receptor sequencing (scTCR-seq). TCR clonotypes of interest were identified based on robust clonal expansion on-treatment; then each clonotype was traced back through earlier samples to the pre-treatment baseline, or the earliest sample in which that clone could be detected. Clones were pooled, subjected to UMAP clustering, and differential gene-expression and trajectory analysis performed. At earliest appearance, each clonotype was enriched for a phenotype dominated by early transcription factors TCF7 and IKZF2 (Helios). These cells expressed little PDCD1 (PD-1) but showed a “hybrid” combination of genes associated with immaturity/arrest (BACH2, DUSP2, LTB, IL7R, CD160) and effector/memory (NKG7, GZMK, GZMA). Within each responding clone, this “precursor” phenotype could be observed to progressively transition into a mature cytotoxic/effector phenotype (PRF1, GZMB, GZMH, FGFBP2, KLRB1, IFNG). Trajectory analysis of this maturation sequence allowed us to analyze key gene-regulatory networks and transcription factor profiles at each stage. To our knowledge, this is the first study in humans to identify this key stem-like precursor population in circulation, allowing us to sequentially follow the molecular changes in these cells during rejuvenation. Citation Format: Theodore S. Johnson, Rafal Pacholczyk, Zuzana Berrong, Chenbin Huang, Eugene P. Kennedy, Eric Ring, Ramses F. Sadek, Sarthak Satpathy, Beena E. Thomas, Tobey J. MacDonald, Manoj Bhasin, David H. Munn. Indoximod or ibrutinib/indoximod based clinical chemo-immunotherapy drives conversion of extra-tumoral circulating stem-like precursor CD8+ T cells into clonally expanded, rejuvenated effector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB200.

Objectives To compare the efficacy and safety of algenpantucel-L (HAPa; IND# 12311) immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). Summary background data To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. Methods A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. Results Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (IQR) overall survival was 14.9 (12.2-17.8) months in the standard group (N=158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) (hazard ratio [HR] 1.02, 95% CI 0.66-1.58; P = 0.98). Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% CI 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). Conclusions Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. Trial registration ClinicalTrials.gov Identifier: NCT01836432.

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Importance Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial. Objective To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane. Design, setting, and participants This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020. Interventions A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. Main outcomes and measures The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and β = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis. Results Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms. Conclusions and relevance This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. Trial registration ClinicalTrials.gov Identifier: NCT01792050.

Background: Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in hematologic malignancies but limited success in solid tumors. GCC19CART, the first clinical candidate from the CoupledCAR ® solid tumor platform, targets guanylate cyclase-C (GCC) which is expressed in colorectal cancers. A Phase 1 investigator-initiated dose escalation trial is underway in China for patients with relapsed or refractory metastatic colorectal cancer. Data presented here are from a single participating institution. Methods: Subjects with relapsed or refractory metastatic colorectal cancer are screened for GCC expression, with 70% to 80% of subjects expected to demonstrate GCC per historical data. Subjects undergo leukapheresis, a single dose of lymphodepleting chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 300mg/m2) 3 days prior to infusion, and then administration of a single infusion of GCC19CART at one of three doses of 1x10 6, 2x10 6, or 3x10 6 cells/kg. Endpoints are safety and preliminary evidence of efficacy as determined by CT or PET/CT per RECIST1.1 or PERCIST 1.0. Results: 5 subjects have been enrolled to dose level 1 (1x10 6 cells/kg) and 5 subjects have been enrolled to dose level 2 (2x10 6 cells/kg) and have a 1-month post-infusion imaging study available for review. The most common adverse events were cytokine release syndrome (CRS) in 10/10 subjects (Grade 1 9/10 (90%) or Grade 2 1/10 (10%)) and diarrhea in 10/10 subjects (Grade 1 3/10 (30%) Grade 2 1/10 (10%) Grade 3 6/10 (60%)). Neurotoxicity was observed in 1/10 (10%) subjects at Grade 4 and resolved with corticosteroids. The combined overall response rate (ORR) for both dose levels was 50% (5/10). For dose level 1, the overall response rate (ORR) per RECIST 1.1 was 40% (2/5). Two subjects demonstrated a partial response (PR) while an additional subject had partial metabolic response (PMR) on PET/CT with stable disease (SD) per RECIST 1.1. For dose level 2, The ORR per RECIST 1.1 was 60% (3/5). 3 subjects demonstrated a PR (2 at month 1, 1 at month 3 after being SD at month 1) and an additional subject had PMR on PET/CT with SD per RECIST 1.1. Conclusions: GCC19CART demonstrated meaningful clinical activity and an acceptable safety profile in relapsed or refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented. A United States based Phase 1 trial of GCC19CART is anticipated for early 2022. Disclosures Pu: Innovative Cellular Therapeutics: Current Employment. Zhu: Innovative Cellular Therapeutics: Current Employment. Huang: https://www.accme.org/accreditation-rules/standards-for-integrity-independence-accredited-ce/eligibility: Current Employment. Tang: Innovative Cellular Therapeutics: Current Employment. Jia: Innovative Cellular Therapeutics: Current Employment. Chen: Innovative Cellular Therapeutics: Current Employment. Kennedy: Innovative Cellular Therapeutics: Current Employment. Wu: Innovative Cellular Therapeutics: Current Employment. Xiao: Innovative Cellular Therapeutics: Current Employment.

BACKGROUND Optimal management of progressive high-grade gliomas (HGG) is not fully defined and outcomes are poor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme which converts tryptophan to kynurenines, which contribute to the immunosuppresive tumor microenvironment (TME). Targeting the TME by inhibiting IDO1 is a strategy for potential improvement in survival in HGG. METHODS A phase 1/2 trial using the IDO1 inhibitor indoximod was conducted in progressive grade 3 and 4 gliomas. The phase 1 cmponent used a 3 + 3 design escalating indoximod from 600mg po BID to 1200mg po BID in conjunction with temozolomide (150 mg/m2, 5/28 days). The phase 2 component consisted of 3 cohorts: A) indoximod+temozolomide B) indoximod+temozolomide+bevacizumab (patients already on bevacizumab) C) indoximod+temozolomide+stereotactic radiosurgery (SRS). Patients were treated until progression or toxicity. RESULTS 33.3% of patients developed indoximod TEAEs. There were no dose limiting toxicities in the phase 1 component (n=12). 1200 mg BID was established as the phase 2 dose of indoximod. In the phase 2 component (n=148) PFS6 was 74% (A), 93% (B), 70% (C). Median OS was 289 days [10.3 months](A), 159 days [5.7 months](B), 285 days [10.2 months](C). Correlative study results will be available for meeting presentation. CONCLUSIONS The IDO1 inhibitor indoximod proved safe and tolerable in conjunction with temozolomide, bevacizumab, and SRS in patients with progressive HGG. There was a trend toward better survival outcomes when indoximod was combined with temozolomide alone or temozolomide+SRS.

Summary Monocytic-lineage inflammatory Ly6c+CD103+ dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent in tumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibit the differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologic inhibition of Bruton’s tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6c+CD103+ DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumor growth. Immature Ly6c+c-kit+ precursor cells had epigenetic profiles similar to conventional DC precursors; deletion of Btk or Ido1 promoted differentiation of these cells. Mechanistically, a BTK-IDO axis inhibited a tryptophan-sensitive differentiation pathway driven by GATOR2 and mTORC1, and disruption of the GATOR2 in monocyte-lineage precursors prevented differentiation into inflammatory DCs in vivo. IDO-expressing DCs and monocytic cells were present across a range of human tumors. Thus, a BTK-IDO axis represses differentiation of inflammatory DCs during chemotherapy, with implications for targeted therapies.

Background Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal brain tumor with no available cure. Indoximod blocks the IDO (indoleamine 2,3-dioxygenase) pathway, thereby reversing IDO-mediated immune suppression in the tumor microenvironment. Methods Patients aged 3 to 21 years with treatment-naive DIPG were eligible for this phase 1b dose-confirmation study of indoximod. The treatment regimen comprised continuous oral indoximod (38.4 mg/kg/day divided twice daily) with conformal photon radiation (54 Gy in 30 fractions), followed by cycles of indoximod with temozolomide (200 mg/m2/day, days 1–5 in 28-day cycles). Results Thirteen patients (median age 9 years, range 5 to 20 years) with DIPG were treated. Median OS was 14.5 months (follow-up ranged 4.8 to 29.3 months), 12-month OS was 61.5% (8/13), and 18-month OS was 30.8% (4/13), with 1 patient remaining in follow-up at the data cutoff. This compared favorably to expected median OS of approximately 10.8 months, 12-month OS of 45.3%, and 18-month OS of 16.2% taken from published historical data from the Pediatric Brain Tumor Consortium. Two patients showed near-complete responses lasting until relapsing after 7.6 months and 13.3 months of study therapy, respectively. Many patients had increased circulating non-classical monocytes (nc-Monos, CD16+, CD14neg, CD33+, HLA-DR+) within the first 3 treatment cycles, and elevation of this early pharmacodynamic marker was predictive of subsequent OS. Patients with nc-Monos >10% (n=7) had median OS of 19 months, whereas patients with nc-Monos below 10% (n=5) had median OS of 7 months (p=0.0047). No patients stopped therapy for toxicity. The most common indoximod-attributed adverse events were thrombocytopenia, neutropenia, nausea, vomiting, dizziness, and fatigue. Conclusions Adding indoximod immunotherapy to conventional radiation and chemotherapy for front-line treatment of pediatric patients with DIPG was well-tolerated. Improved outcomes were observed in patients having evidence of pharmacodynamic response. A follow-on phase 2 study is in progress (NCT04049669).

Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression, evading immune mediated destruction. Indoximod (D-1-methyltryptophan) is a broad IDO pathway inhibitor as it has been shown to potentially interfere with multiple targets within the IDO pathway. Preclinical studies in MMTV-neu mouse models have demonstrated that combining indoximod with cytotoxic chemotherapy had a greater in-vivo anti-tumor effect than either agent alone. A phase 1 trial combining docetaxel and indoximod demonstrated safety and responses in metastatic breast cancer (mBC) patients. Based on these data a phase 2 trial evaluating indoximod in combination with taxane chemotherapy as first line therapy in patients with metastatic breast cancer was initiated. Methods: The study is a 1:1 randomized, placebo controlled, four arm phase 2 trial. The study treatment is docetaxel 75mg/m2 IV D8 plus indoximod 1200mg PO BID D1-14 every 21 days or matching placebo in study arms 1A and 2A or paclitaxel 80 mg/m2 IV weekly 3 out of 4 weeks with indoximod or matching placebo given BID Days 1-14 in arms 1B and 2B. The primary endpoint is progression free survival. Secondary endpoints include overall survival, response rate, safety, and immune response correlative assays. Patients with measurable, histologically confirmed mBC, no prior chemotherapies (hormonal therapies allowed) in the metastatic setting, ER+ or ER –, HER2 -, ECOG PS 0-1, no active CNS disease, no active autoimmune disease are eligible. Target enrollment is 154 patients. Results: At submission, 65 patients have evaluable safety data on trial. The pooled, blinded data was evaluated for any safety signals. Patient demographics include median age 58 years, 95% female, 17% African American, 25% triple-negative disease, and 82% with multiple sites of metastatic disease. 28% of patients had at least one Grade 3 or 4 adverse event. Those occurring in multiple patients include dyspnea 5%, pleural effusion 3%, non-cardiac chest pain 3%, and febrile neutropenia 3%. Most patients had at least one adverse event (86%). The most common were anemia 14%, tearing 11%, constipation 19%, diarrhea34%, nausea 44%, vomiting 22%, fatigue 48%, peripheral edema 17%, increased liver function tests 10%, lymphopenia 17%, hyperglycemia 15%, myalgia 14%, dizziness 14%, dysguesia 16%, headache 20%, peripheral neuropathy 12%, dyspnea 19%, alopecia 34%, and rash 14%, all compatible with the side effect profile of single agent taxanes. No immune specific serious advents were reported. No treatment related deaths have been reported. Conclusion: The aggregate safety data for these 65 patient are similar to what is typically observed with docetaxel and paclitaxel. No unexpected serious immune linked adverse events were reported. The trial is currently open at multiple clinical sites in the US and Europe and actively enrolling patients. Updated data will be presented. NCT01191216. Citation Format: Tang S-C, Montero A, Munn D, Link C, Vahanian N, Kennedy E, Soliman H. A phase 2 randomized trial of the IDO pathway inhibitor indoximod in combination with taxane based chemotherapy for metastatic breast cancer: Preliminary data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-09.

Objectives To explore the relationship between 16 symptom clusters (SCs), clinical and demographic influencing factors, and clinical outcomes over time in patients with pancreatic cancer (PC) undergoing surgical resection. Sample & setting 143 patients with stage II PC undergoing surgical resection were recruited to participate in this longitudinal, exploratory study conducted at Thomas Jefferson University Hospital, a National Cancer Institute-designated cancer center. Methods & variables Quality of life was measured preoperatively and at three, six, and nine months postoperatively. Statistical methods included simple linear and Cox proportional hazard regression. Results Preoperative pain was significantly associated with the pain-gastrointestinal SC, and preoperative worry was significantly associated with the mood SC. The strongest negative association with emotional well-being across all study time points was found with the preoperative mood SC. The insomnia-digestive problems SC and the nutritional problems SC demonstrated a trend toward poor survival. Implications for nursing Findings provide evidence that preoperative worry and pain are associated with SC severity and that SCs may have a detrimental effect on quality of life and survival in patients with PC undergoing surgical resection.

Background Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. Methods This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed. Results Patients (n = 22) received a median of 3 cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20% of patients included fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%), and were related to navoximod in two patients (9%). Navoximod was rapidly absorbed (Tmax ~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t1/2 ~ 11 h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36%) had stable disease and 10 (46%) had progressive disease. Conclusions Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed. Trial registration ClinicalTrials.gov identifier: NCT02048709.

BACKGROUND: Indoximod is an IDO pathway inhibitor with a differentiated mechanism of action directly targeting immune cells to reverse the immune suppression generated by tumors. An ongoing phase-1b/2a study (NCT02502708) using indoximod in combination with temozolomide and/or re-irradiation for children with relapsed/refractory pediatric brain tumors has established the recommended phase-2 dose (RP2D) of indoximod for this regimen and has shown this approach to be well-tolerated and feasible in these highly complex and fragile patients. Diffuse Intrinsic Pontine Glioma (DIPG) is an FDA-designated orphan disease, with no curative treatment options and dismal prognosis. The primary hypothesis is that addition of indoximod-based immunotherapy to standard-of-care radiation, followed by immuno-chemotherapy with indoximod plus temozolomide will improve objective response rates, 12-month event-free survival, and median overall survival. DESIGN/METHODS: Newly-diagnosed DIPG patients age 3 to 21 years are treated with indoximod (RP2D) in combination with conformal radiation therapy (54 Gy), followed by cyclic immune-chemotherapy using indoximod (RP2D=38.4 mg/kg/day divided BID throughout each cycle) combined with temozolomide (200 mg/m2/day, days 1-5 of each 28-day cycle). Up to 30 patients may be enrolled. RESULTS: The trial is ongoing. At this time, we have enrolled the first 6 newly-diagnosed DIPG patients. At the end of the indoximod plus radiation block, the first two patients had objective tumor response without any significant adverse events to date. Interim outcome and safety data for the first 8 months of accrual will be presented.

Background Ethanol celiac plexus neurolysis (ECPN) has been shown to be effective in reducing cancer-related pain in patients with locally advanced pancreatic and periampullary adenocarcinoma (PPA). This study examined its efficacy in patients undergoing PPA resection. Study Design There were 485 patients who participated in this prospective, randomized, double-blind placebo controlled trial. Patients were stratified by preoperative pain and disease resectability. They received either ECPN (50% ethanol) or 0.9% normal saline placebo control. The primary endpoint was short- and long-term pain and secondary endpoints included postoperative morbidity, quality of life, and overall survival. Results Data from 467 patients were analyzed. The primary endpoint, the percentage of PPA patients experiencing a worsening of pain compared with preoperative baseline for resectable patients, was not different between the ethanol and saline groups in either the resectable/pain stratum (22% vs 18%, relative risk [RR] 1.23 [0.34, 4.46]), or the resectable/no pain stratum (37% vs 34%, RR 1.10 [0.67, 1.81]). In multivariable analysis of resected pancreatic ductal adenocarcinoma (PDA) patients, there was a significant reduction in pain in the resectable/pain group, suggesting that surgical resection of the malignancy alone (independent of ECPN) decreases pain to a significant degree. Conclusions In this study, we demonstrated a significant reduction in pain after surgical resection of PPA. However, the addition of ECPN did not synergize to result in a further reduction in pain, and in fact, its effect may have been masked by surgical resection. Given this, we cannot recommend the use of ECPN to mitigate cancer-related pain in resectable PPA patients.

Background Antiplatelet therapy with aspirin is prevalent among patients presenting for operative treatment of pancreatic disorders. Operative practice has called for the cessation of aspirin 7–10 days before elective procedures because of the perceived increased risk of procedure-related bleeding. Our practice at Thomas Jefferson University has been to continue aspirin therapy throughout the perioperative period in patients undergoing elective pancreatic surgery. Study design Records for patients undergoing pancreatoduodenectomy, distal pancreatectomy, or total pancreatectomy between October 2005 and February 2012 were queried for perioperative aspirin use in this institutional research board−approved retrospective study. Statistical analyses were performed with Stata software. Results During the study period, 1,017 patients underwent pancreatic resection, of whom 289 patients (28.4%) were maintained on aspirin through the morning of the operation. Patients in the aspirin group were older than those not taking aspirin (median 69 years vs 62 years, P Conclusion This is the first study to report that aspirin therapy is not associated with increased rates of perioperative bleeding, transfusion requirement, or major procedure related complications after elective pancreatic surgery. These data suggest that continuation of aspirin is safe and that the continuation of aspirin should be considered acceptable and preferable, particularly in patients with perceived substantial medical need for treatment with antiplatelet therapy.

Background: NLG207 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) composed of a cyclodextrin-based polymer backbone linked to camptothecin, a topoisomerase-1 inhibitor. NDCs enhance drug delivery to tumors where gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. The RP2D of CRLX101 was previously set at 15 mg/m2 Q2W in combination with 80 mg/m2 weekly paclitaxel in Phase I and reported at ESMO 2016. This abstract will include data from both the Phase Ib and the phase II expansion. Methods: In this Phase II single arm study, patients were treated with NLG207 (Q2W) and 80 mg/m2 paclitaxel (3 wks on/1 wk off) repeated q 28 days until progression or toxicity. Primary objective was overall response (CR + PR) via RECIST v1.1 in women with recurrent platinum resistant epithelial ovarian, fallopian tube or primary peritoneal cancer. Progression free survival (PFS), duration of response (DOR), and safety were also assessed. Results: Thirty patients were enrolled and all completed at least one cycle. Median age was 62 (44-76) years. 57% of patients received ≥3 prior therapies. There were 8/30 confirmed responses for an overall response rate (ORR) of 26.7% (95% CI 14.2%, 44.4%), including one complete response (CR). ORR for platinum resistant patients (n=17) was 23.5% (4/17) vs. 30.8% (4/13) for those who were platinum sensitive (n=13) to their most recent platinum regimen. Best response (including unconfirmed) for platinum resistant patients was 41.2% (7/17) including 7 PRs. Five additional platinum resistant patients achieved stable disease (SD). Median PFS (mPFS) for all study patients was 5.4 months. The mPFS was similar for both platinum resistant at 5.5 months and platinum sensitive at 5.4 months. Median DOR was 7.2 months for platinum resistant patients vs. 4.7 months for the platinum sensitive group. The most common grade 3/4 adverse events (AEs) attributed to study treatment were: decreased neutrophil count (13 patients, 43%), anemia (3 patients, 10%), hematuria (2 patients, 7%); urinary tract infection (UTI), cystitis, hypertension, and hypokalemia (all seen in 1 patient, 3%). PK data will be included in the full presentation. Conclusions: NLG207 is a potentially best-in-class topoisomerase 1 inhibitor with demonstrated antitumor activity in recurrent ovarian cancer including those who have become resistant to platinum therapy. AE profile of this combination is consistent with that seen for paclitaxel as a single agent except for cystitis, hematuria and UTI. It was well-tolerated in combination with weekly paclitaxel in heavily pre-treated patients. NLG207 warrants further investigation in combination therapy regimens for recurrent ovarian, fallopian tube or primary peritoneal cancer, particularly in platinum resistant patients. Citation Format: Linda Duska, David M. O'Malley, Carolyn Krasner, Russell J. Schilder, Cara Mathews, Kathleen Moore, Premal Thaker, Austin Miller, Christopher Purdy, A.J. Leyco, Christopher Smith, Deborah Mercier, Lucinda Tennant, Eugene Kennedy, Nicholas Vahanian, Charles Link. A Phase II study of NLG207 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT151.

590 Background: HyperAcute Renal (HAR) immunotherapy consists of two allogeneic renal cancer cell lines that have been genetically modified to express α(1,3)Gal, to which humans have an inherent pre-existing immunity. A previous report demonstrated that HAR is well tolerated in pts with mRCC (2017 GUASCO, abstract: 528). Herein, we report the efficacy of HAR immunotherapy in mRCC. Methods: Pts with refractory clear-cell mRCC were eligible for this phase 1 dose-escalation trial. Concomitant treatment (Rx) with other approved agents was permitted after initial 2 months (m) of HAR monotherapy. The trial followed a standard 3+3 design with cells injected intradermally weekly for 4 weeks then biweekly injections for 10 immunizations (150 x106cells then escalated to 300 x106cells). Co-primary objectives were safety and efficacy. Results: A total of 18 patients were enrolled (4 low dose, 14 high dose) between 06/2015 to 07/2016. Patients received a median of 1 systemic Rx prior to HAR immunotherapy, with 8 patients receiving 2 or more prior agents. IMDC risk categories at the time of initial metastatic disease were: favorable risk (33%), intermediate risk (66%), poor risk (0%). The ORR was 0% with a disease control rate of 50%. Median PFS for patients treated with HAR immunotherapy was 2.0 months (m) (range 1.7-30.3 m). For patients receiving the low dose HAR, median overall survival (OS) was 14.2 m (range 3.6-21.6 m), while median OS for high dose HAR was 25.3 m (5.8-29.3 m). At the time of data cutoff in 09/2018, 7 patients were still living. Detailed clinical data will be presented in the meeting. Conclusions: HAR immunotherapy in refractory mRCC was well tolerated and demonstrated potential efficacy for OS similar to currently approved salvage-line Rx. With a unique mechanism of action, HAR immunotherapy may be a candidate for inclusion in novel combinatorial regimens being developed in salvage therapy setting in pts with mRCC. Clinical trial information: NCT02035358.

Background Recurrence of pancreatic adenocarcinoma after pancreaticoduodenectomy (PD) can be increased in patients with pancreatic fistula (PF). The purpose of our study was to determine if a relationship exists between PF and tumor recurrence (both peritoneal and local) in patients after PD for pancreatic ductal adenocarcinoma. Study Design A single-institution, retrospective analysis of 221 patients who underwent PD from January 2001 to December 2009 was conducted. Electronic charts and medical records were queried for tumor characteristics, recurrence, and complications. Presence and grading of PF was determined using the criteria of the International Study Group on Pancreatic Fistula. Data were analyzed using chi-square and Kaplan-Meier survival statistics. Results There were 114 male and 107 female patients. Mean age was 66 years (range 35 to 91 years). The vast majority (84%) of patients had stage II disease; 143 (65%) had positive lymph nodes (median 2 positive nodes; range 1 to 17 positive nodes). Pancreatic fistula developed in 23 patients (grade A, n = 9; grade B, n = 13; grade C, n = 1; 10.2%). Peritoneal recurrence was noted in 20 patients (9%). Of the 23 patients with PF, peritoneal recurrence developed in 3 (13%). Of the 198 patients without PF, peritoneal recurrence developed in 17 (10%). Local recurrence occurred in 47 patients (21%), 5 (2%) in patients with PF and 42 (21%) in those without PF (p = NS). In Kaplan-Meier survival analysis, there was no significant difference in recurrence-free survival (p = 0.4) and overall survival (p = 0.3) for those with PF vs those without PF. Conclusions Patients with PF after PD were not found to have a significant increase in local or peritoneal recurrence. Therefore, in this analysis, postoperative PF does not appear to serve as an adverse prognostic marker.

The overall complication rate after pancreaticoduodenectomy (PD) approaches 50 %, with anastomotic failure being the most frequent cause of serious postoperative morbidity. Hepaticojejunostomy leaks (also called bile leaks) are the second most common type of leak, behind pancreaticojejunostomy leaks, yet have been the focus of only a single study as reported by Suzuki et al. (Hepatogastroenterology 50:254–257, 12). We reviewed the recent experience with bile leaks at a single, high-volume pancreatic surgery center over a six-year time period. Bile leaks were identified in 16 out of 715 patients (2.2 %). Low preoperative albumin was associated with an increased risk. Bile leaks typically manifested within the first week after surgery as bilious drainage in a surgically placed drain. Associated warning signs included fever and leukocytosis. Patients with a bile leak frequently developed other complications, including a pancreatic fistula, wound infection, delayed gastric emptying, and sepsis. The impact on perioperative outcomes was comparable to patients with a pancreatic leak. A grading system is proposed based on the International Study Group on Pancreatic Fistula model. Grade A bile leaks were classified as those managed with prolonged drainage by operatively placed drains, grade B bile leaks with percutaneous abdominal drainage, and grade C bile leaks with insertion of a percutaneous transhepatic biliary drainage. Hepaticojejunostomy leaks are rare after PD. The complication severity ranges from trivial to life threatening and is comparable overall to pancreaticojejunostomy leaks. Surgical intervention is rarely, if ever, required. With prompt and aggressive management, a full recovery can be expected.

Pancreaticoduodenectomy (PD) has a high morbidity rate. Previous work has shown that hypoalbuminemia on postoperative day 1 (POD) to be contributory to post-esophagectomy complications. We set out to determine the impact of blood urea nitrogen (BUN) and albumin on POD 1 for patients undergoing PD. We examined 446 consecutive patients who underwent PD at the Thomas Jefferson University Hospital between January 1, 2000 and December 31, 2008. Complications were graded using the Clavien scale. We examined the incidence of complications based on POD 1 albumin

Background Pancreaticoduodenectomy (PD) is a complex surgical procedure with a historically high morbidity rate. The goal of this study was to determine if the implementation of a 12-measure perioperative surgical care bundle (SCB) was successful in reducing infectious and other complications in patients undergoing PD compared with a routine preoperative preparation group (RPP). Methods In this retrospective cohort study utilizing the HPB surgery database at the Thomas Jefferson University, we analyzed clinical data from 233 consecutive PDs from October 2005 to May 2008 on patients who underwent RPP, and compared them with 233 consecutive PDs from May 2008 to May 2010 following the implementation of the SCB. The SCB was the product of multidisciplinary discussion and extensive literature review. Results The RPP group and the SCB group had similar demographic characteristics. The overall rate of postoperative morbidity was similar between groups (42.1% versus 37.8%). However, wound infections were significantly lower in the SCB group (15.0% versus 7.7%, P = 0.01).The rates of other common complications, as well as postoperative hospital length of stay, readmissions, and 30-d postoperative mortality were similar between groups. Conclusions The implementation of a SCB was followed by a significant decline in wound infection in patients undergoing PD.

Background As patients with pancreas and periampullary cancer (PPC) experience improved survival rates and longevity, the focus shifts toward living life while surviving cancer. Fatigue is the most commonly reported symptom in all cancer patients. Exercise has been found to effectively decrease fatigue levels and improve physical functioning in cancer patients. Study Design One hundred two patients with resected PPC consented to participate in this study and were randomized to either an intervention group (IG) or a usual care group (UCG). Subjects completed visual analog scales, the FACIT-Fatigue Scale and the Short Form-36v2 after surgery and again 3 to 6 months after hospital discharge. Results Patients in the IG and UCG were comparable with regard to demographics, comorbidities, cancer type and staging, type of resection, preoperative fatigue and pain levels, adjuvant therapy, and baseline walking distance. Patients in the IG had significantly improved scores on the FACIT-Fatigue Scale at study completion, improved fatigue and pain scores, as well as overall physical functioning and mental health composite scores. At study completion, participants in the IG were walking twice as far and were significantly more likely to have continued walking or another form of exercise as compared with the UCG. Using hierarchical cluster analysis, 3 mutually exclusive symptom groupings were identified in the cohort. Kaplan-Meier survival analysis did not indicate an overall survival benefit for the IG. Conclusions This is the first prospective, randomized controlled trial to report that participation in a home walking program confers a significant benefit in resected PPC patients with regard to fatigue levels, physical functioning, and health-related quality of life.

Background Completion pancreatectomy (CP) is a reoperative procedure to excise remnant pancreatic tissue after a prior pancreatic resection. In this study, we document our institution’s experience with CP for recurrent malignant disease of the pancreas, describing indications for surgery, procedures performed, and patient outcomes. Methods We performed a retrospective review of 861 patients from the pancreatic surgery database in the Department of Surgery of Thomas Jefferson University from October 2005 to December 2010 to identify all cases of CP performed for suspected malignant disease. Results Eleven patients underwent reoperative CP at our institution from 2005 to 2010. The median time interval between the initial operation and CP was 32 mo. A combination of clinical symptoms, elevated tumor markers, and imaging studies were used for diagnosis of recurrent disease. Pancreatic ductal adenocarcinoma was the most common pathology, found in six patients. The postoperative complication rate was 18% and the median postoperative hospital length of stay was 6 d. There were no 30-d readmissions and no perioperative deaths. The 1-y survival rate following CP was 71% with an overall median survival of 17.5 mo. Conclusions CP is a safe and effective option for a highly selected group of patients with suspected recurrent malignant disease of the remnant pancreas. Morbidity and mortality rates are within acceptable limits and similar to initial pancreatic resection. Eligibility depends heavily upon the absence of distant metastatic disease, technical factors for resection, and patient performance status.

The prognosis after pancreaticoduodenectomy (PD) for ampullary carcinoma (AC) is superior to that of pancreatic cancer. Decisions regarding adjuvant therapy are influenced by factors such as nodal status, stage, and grade, but the influence of these individual variables on survival is unclear.A prospective tumor registry database was queried to identify patients who underwent PD for AC at Thomas Jefferson University between Jan 1997 and Apr 2009. The study was conducted with the approval of the institutional review board. Data were collected through review of hospital and departmental charts. Overall survival (OS) was analyzed using univariate and multivariate Cox proportional hazard models. The proportional hazard assumption was verified for the overall model and individual covariates.A total of 61 patients underwent PD for AC at our institution. There were five perioperative deaths (8.2%). Mean age was 70 years (62% male). Median survival time (MST) was 50 months for all patients. Only primary tumor stage, T1/T2 versus T3/T4 (American Joint Committee on Cancer Staging, version 6), was associated with OS in univariate analyses (p = 0.003). The association of nodal status with OS was borderline-significant (p = 0.08), with the MST being 84 months for node-negative and 17 months for node-positive patients. The remaining covariates were not predictors of OS. In the multivariate analysis, only primary tumor stage (HR, 5.1; p 0.001) and age (HR, 1.04; p = 0.06), but not nodal status or adjuvant therapy, were associated with overall survival.Advanced primary tumor stage and age were associated with inferior OS after PD for AC. Adjuvant therapy did not impact survival. Patients with advanced tumor stage should be considered for clinical trials of adjuvant therapy after PD with novel compounds and optimized radiation therapy strategies.

The population of the United States is aging. Studies within the last several years have demonstrated that major abdominal operations in elderly patients can be done safely, but with increased rates of complications. We set out to determine the rates of morbidity and mortality in elderly patients undergoing gastric resection at a tertiary care university hospital. A retrospective analysis was performed of 157 consecutive gastric resections between January 1998 and July 2007. Group A (n = 99) consisted of patients < 75-years-old at surgery, whereas group B (n = 58) included patients who were ≥ 75 years of age at time of surgery. These two groups had their clinical and demographic data analyzed. Postoperative length of hospital stay, perioperative major morbidity, and in-hospital mortality were analyzed using analysis of variance, χ2, and multivariate analyses. The average age of patients in group A was 57 years, compared with 81 years in group B. We found no significant difference in the percentage of gastric resections for malignancy (group A, 49% vs group B, 62%) or emergency surgery (group A, 10% vs group B, 10%) between age groups. There was a significant increase in length of stay in the older patients (11.7 days vs 17.6 days; P = 0.032), as well as major complications (11.1% in group A vs 27.6% in group B; P = 0.008). The in-hospital mortality rates approached significance (group A, 4% vs group B, 12%; P = 0.057). Gastric resection in elderly patients carries with it longer hospital stays, higher risk of complications, and in-hospital mortality rates despite similarity in patient disease. This information is imperative to convey to the elderly patients in the preoperative period before gastric resection.

Background Successful allogeneic stem cell transplantation (HSCT) in treatment of patients (pts) with acute myeloid leukemia (AML) is dependent upon graft-versus-leukemia, suggesting that intact immune surveillance is essential for eradicating minimal residual disease. Myeloblast-induced T-cell tolerance through overexpression of indoleamine 2,3-dioxygenase (IDO) is thought to play a significant role in immune evasion through upregulation of tryptophan (Trp) catabolism and kynurenine production, resulting in a Trp-poor environment that leads to immune system suppression. Indoximod is a small-molecule inhibitor of the IDO pathway that acts directly on immune cells to reverse IDO pathway-mediated suppression. We are assessing the safety and preliminary efficacy of indoximod in combination with standard induction chemotherapy in patients (pts) with newly diagnosed AML. Methods In this open-label, multicenter, phase 1 study (NCT02835729), eligible pts with newly diagnosed AML were treated with indoximod in combination with induction chemotherapy (idarubicin 12 mg/m2/d x3 days with cytarabine 100 mg/m2/d x7 days). Using a "3+3" design, indoximod (600 mg [dose level 0], 1000 mg [dose level 1], 1200 mg [dose level 2]) was given orally every 8 hours (Q8h) starting on day 9 of induction. Regimen limiting toxicity (RLT) was defined as any ≥ grade 3 non-hematologic adverse event (AE) that was not incontrovertibly related to the underlying AML or cytarabine or idarubicin. After induction, pts received up to 4 cycles of high dose cytarabine (HiDAC) consolidation while continuing indoximod. Patients continued on maintenance indoximod for up to 6 months from completion of consolidation therapy. Indoximod was discontinued 4 weeks prior to HSCT in eligible patients and not restarted as maintenance post-HSCT. Results As of July 15, 2018, 31 pts were enrolled (median age 55 years, range 18-78; 77% male). Six patients did not proceed with study therapy due to a diagnosis of acute promyelocytic leukemia, issues with medical insurance coverage, consent withdrawal, critical illness, and intestinal myeloid sarcoma preventing oral intake. Pts who received ≥1 dose of indoximod were included in the intention-to-treat (ITT) analysis (n=25), and pts who received ≥80% of their scheduled indoximod doses were included in the per-protocol (PP) analysis (n=19). Reasons for not completing ≥80% of indoximod doses were: consent withdrawal (n=3), inability to swallow (n=2) and physician decision (n=1). Of the 19 PP patients, 16 (84%) had either unfavorable karyotype or adverse mutation profile and 3 (16%) had secondary AML (s-AML). Indoximod combined with induction chemotherapy was well tolerated; no RLT was observed. The most frequent grade ≥3 non-hematologic treatment-emergent AEs in the ITT population, regardless of attribution, were febrile neutropenia (60%), hypoxia (16%), atrial fibrillation (12%), pneumonia (12%), hypocalcemia (12%), and hypotension (12%). Among 25 ITT pts, 21 (84%) achieved a remission (CR/CRh/CRi/CRp), and 15 of 19 (79%) in the PP analysis achieved remission. Among 12 pts with measurable residual disease (MRD) available in remission, 10 (83%) had MRD Conclusions Indoximod is well tolerated in combination with standard AML induction therapy. Rates of morphologic response and of MRD-neg status are very promising. The recommended phase 2 dose (RP2D) was 1200 mg oral Q8h and a placebo-controlled randomized phase 2 study is under development. Disclosures Emadi: NewLink Genetics: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. Kennedy:NewLink Genetics: Employment, Equity Ownership. Link:NewLink Genetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munn:NewLink Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Giant splenic artery pseudoaneurysms (≥5 cm in size) are rare entities. We document the successful operative management of one of the largest splenic artery pseudoaneurysms (18 cm) ever reported as well as review the world literature on the subject. Our literature review identified 160 cases of splenic artery pseudoaneurysm in the last 43 years. These ranged in size from 0.3 to 17 cm, and of these, 18 (11%) were 5 cm or larger. The majority of patients underwent treatment, either endovascularly or with open surgery, and their outcomes were independent of presenting symptoms or size. Giant splenic artery pseudoaneurysms are uncommon, most often caused by pancreatitis, trauma, or iatrogenic etiologies and typically present with vague constitutional symptoms, or occasionally with hemorrhage. Most can be treated endovascularly, though in our case this was not possible due to the presence of celiac artery occlusion with retrograde filling of the pseudoaneurysm from superior mesenteric artery collaterals. Ultimately, we opted for an open technique, with supraceliac aortic control prior to manipulation and resection of the pseudoaneurysm. Our recommendation is that splenic artery pseudoaneurysms should be repaired when encountered, regardless of aneurysm size at presentation.

Background: Pancreatic ductal adenocarcinoma (PDA) is a devastating disease that killed nearly 38,000 people in the United States this past year. Objective: Treatment of PDA typically includes surgery and/or chemotherapy with gemcitabine. No reliable biomarker exists for prognosis or response to chemotherapy. Two previously proposed prognostic markers, cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), are regulated by Hu protein antigen R (HuR), an mRNA binding protein that we have previously demonstrated to be a promising predictive marker of gemcitabine response. This study was designed to evaluate the clinical utility of HuR, COX-2, and VEGF as potential prognostic and predictive biomarkers for PDA. Methods: A tissue microarray of 53 PDA specimens from patients who underwent potentially curative pancreatic resection was analyzed. HuR, COX-2, and VEGF status were correlated with clinicopathologic and survival data. We also performed ribonucleoprotein immunoprecipitation assays using an HuR antibody to assess VEGF and COX-2 mRNA binding to HuR in pancreatic cancer cells. Results: Roughly 50% (27/53) of patients had high cytoplasmic HuR expression. These patients had worse pathologic features as assessed by T staging (P = 0.005). Only cytoplasmic HuR status correlated with tumor T staging, whereas VEGF (P = 1.0) and COX-2 (P = 0.39) expression did not correlate with T staging. Additionally, HuR status was an unprecedented positive predictive marker for overall survival in patients treated with gemcitabine, pushing median survival over 45 months in the high cytoplasmic HuR expressing patient population compared with less than 23 months in the low cytoplasmic HuR expressing patient group (P = 0.033 for log-rank test and P = 0.04 in a Cox regression model) for the low versus high cytoplasmic HuR expressing group. We also validated that mRNA transcripts for both VEGF and the gemcitabine metabolizing enzyme, deoxycytidine kinase, are specifically bound by HuR in pancreatic cancer cells. Conclusions: HuR is a useful prognostic biomarker for PDA patients as indicated by its association with higher tumor T stage. Additionally, HuR status is a robust predictor of outcome for patients with resected PDA in the setting of adjuvant gemcitabine therapy. Finally, HuR binds to VEGF mRNA implying that HuR, in part, regulates VEGF expression in PDA. This study supports the notion that HuR status should be used by clinicians for the individualized treatment of PDA in the future.

Background. Mechanical bowel preparations (MBPs) are commonly administered preoperatively to patients who undergo pancreaticoduodenectomy (PD); however, their effectiveness over a clear liquid diet (CLD) preparation remains unclear. The aim of this study was to determine whether MBP offers an advantage to patients who undergo PD. Methods. In this retrospective review, we analyzed the clinical data from 100 consecutive PDs performed on patients who received preoperative MBP from March 2006 to April 2007, and we compared them with 100 consecutive patients who received a preoperative CLD from May 2007 to March 2008. Results. No differences were observed between the MBP and CLD groups in the rates of pancreatic fistula (13% vs 14%; P = 1.0), intra-abdominal abscess (11% vs 13%; P = .83), or wound infection (9% vs 8%; P = 1.0). Trends toward increased urinary tract infections (13% vs 5 %; P < .08) and Clostridium difficile infections were found in the MBP group (6% vs 1%; P = .12). The median duration of postoperative hospital stay was 7 days in each group, and the 12-month survival rates were equivalent (74% vs 75%; P = 1. 0). Conclusion. There is no clinical benefit to the administration of a preoperative MBP for patients undergoing PD.

BACKGROUND: In theory, combining immunotherapy with radiation (RT) and chemotherapy is an appealing therapeutic strategy that may offer potential synergistic benefits. The indoleamine 2,3-dioxygenase (IDO) pathway regulates inflammation and immune responses to apoptotic cells. Indoximod reverses the profound immunosuppression created by IDO in the tumor microenvironment. METHODS: 29 pediatric patients with recurrent or progressive malignant brain tumors were treated in two separate indoximod dose-escalation cohorts. Patients eligible for re-irradiation (re-RT) (17/29) were treated with conformal RT (15-54 Gy) in combination with indoximod, followed by indoximod with cyclic temozolomide (200 mg/m2/day for the first 5 days of each 28-day cycle). Patients not eligible for RT received indoximod plus cyclic temozolomide. After initial response or disease stabilization (at least 4 months), patients who showed progression were offered planned re-RT to escape lesions, surgical debulking where indicated, and cross-over to an alternative chemotherapy regimen (oral metronomic cyclophosphamide plus etoposide) while continuing indoximod immunotherapy. Time to Regimen Failure (TTRF) was used to capture time on study. RESULTS: In aggregate, 29 relapsed patients had a median PFS of 6.2 months, median time on study (TTRF) was 11.7 months, and 9/29 are continuing treatment. Patients given RT had median TTRF 13.5 months vs. 4.3 months for no RT. Patients not eligible for conventional full-dose re-RT (>50 Gy) received lower-dose RT (= all patients, radiographic responses in 3/3, and near resolution of one tumor at the end of radiotherapy. An additional patient with progressive DIPG received re-RT (27 Gy) combined with indoximod, which was tolerated well with symptomatic improvement and objective tumor reduction on post-RT MRI. CONCLUSIONS: Indoximod was well-tolerated in combination with RT and chemotherapy. TTRF compares favorably with historical controls. Lower-dose, restricted-field RT may be beneficial when combined with indoximod in relapse cases. Front-line studies have begun in a cohort of DIPG patients. Citation Format: Theodore S. Johnson, Dolly Aguilera, Ahmad Al-Basheer, Robert C. Castellino, Bree R. Eaton, Natia Esiashvili, Nicholas Foreman, Ian M. Heger, Eugene P. Kennedy, Charles J. Link, William Martin, Eric K. Ring, Ramses F. Sadek, Amy Smith, Vahanian N. Vahanian, Tobey J. MacDonald, David H. Munn. Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT004.

9512Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to prevent and evade anti-tumor immunity. Inhibitors of t...

Pancreatic fistula (PF) is a major source of morbidity following distal pancreatectomy (DP). Our aim was to identify risk factors related to PF following DP and to determine the impact of technique of transection and stump closure. We performed a retrospective review of 215 consecutive patients who underwent DP. Perioperative and postoperative data were collected and analyzed with attention to PF as defined by the International Study Group of Pancreatic Fistula. PF developed in 36 patients (16.7%); fistulas were classified as Grade A (44.4%), B (44.4%), or C (11.1%). The pancreas was transected with stapler (n = 139), cautery (n = 70), and scalpel (n = 3). PF developed in 19.8% of remnants which were stapled/oversewn and 27.7% that were stapled alone (p = 0.4). Of the 69 pancreatic remnants transected with cautery and oversewn, a fistula developed in 4.3% (p = 0.004 compared to stapled/oversewn; p = 0.006 compared to stapled/not sewn). The median length of postoperative hospital stay was significantly increased in patients who developed PF (10 vs. 6 days, p = 0.002) The method of transection and management of the pancreatic remnant plays a critical role in the formation of PF following DP. This series suggests that transection using electrocautery followed by oversewing of the pancreatic remnant has the lowest risk of PF.

Pancreaticoduodenectomy is one of the most challenging procedures performed by general surgeons. Many studies have been performed looking at the technical aspects of reconstruction after pancreaticoduodenal resection. Multiple randomized trials have failed to convincingly demonstrate the superiority of any single approach or technique. Here, we illustrate our approach to reconstruction, with an emphasis on technical aspects and details. The fine points can help avoid technical errors that result in anastomotic failure.

Background RECQL is a DNA helicase involved in DNA mismatch repair. The RECQL polymorphism, 3′ untranslated region (UTR) A159C, was previously associated with overall survival of patients with resectable pancreatic adenocarcinoma treated with neoadjuvant chemoradiation. In the present study, we examined RECQL for somatic mutations and other polymorphisms and compared these findings with the outcome in patients who received adjuvant or neoadjuvant chemoradiation. We hypothesized that RECQL (i) would be mutated in cancer, (ii) would have polymorphisms linked to the 3′UTR A159C and that either or both events would affect function. We also hypothesized that (iii) these changes would be associated with survival in both cohorts of patients. Material and methods We sequenced RECQL ' s 15 exons and surrounding sequences in paired blood and tumour DNA of 39 patients. The 3′UTR A159C genotype was determined in blood DNA samples from 176 patients with resectable pancreatic adenocarcinoma treated with adjuvant (53) or neoadjuvant (123) chemoradiation. Survival was calculated using the Kaplan–Meier method, with log rank comparisons between groups. The relative impact of genotype on time to overall survival was performed using the Cox proportional hazards model. Results Somatic mutations were found in UTRs and intronic regions but not in exonic coding regions of the RECQL gene. Two single nucleotide polymorphisms (SNPs), located in introns 2 and 11, were found to be part of the same haplotype block as the RECQL A159C SNP and showed a similar association with overall survival. No short-term difference in survival between treatment strategies was found. We identified a subgroup of patients responsive to neoadjuvant therapy in which the 159 A allele conferred strikingly improved long-term survival. Discussion The RECQL 3′UTR A159C SNP is not linked with other functional SNPs within RECQL but may function as a site for regulatory molecules. The mechanism of action needs to be clarified further.

Obesity has been implicated as a risk factor for perioperative and postoperative complications. The aim of this study was to determine the impact of obesity on morbidity and mortality in patients undergoing pancreaticoduodenectomy (PD).Between January 2000 and July 2007, 262 patients underwent PD at Thomas Jefferson University Hospital, of whom 240 had complete data, including body mass index (BMI; calculated as kg/m(2)) for analysis. Data on BMI, preoperative parameters, operative details, and postoperative course were collected. Patients were categorized as obese (BMIor= 30), overweight (BMIor= 25 and30), or normal weight (BMI25). Complications were graded according to previously published scales. Other end points included length of postoperative hospital stay, blood loss, and operative duration. Analyses were performed using univariate and multivariable models.There were 103 (42.9%) normal-weight, 71 (29.6%) overweight, and 66 (27.5%) obese patients. There were 5 perioperative deaths (2.1%), with no differences across BMI categories. A significant difference in median operative duration and blood loss between obese and normal-weight patients was identified (439 versus 362.5 minutes, p = 0.0004; 650 versus 500 mL, p = 0.0139). In addition, median length of stay was significantly longer for BMI (9.5 versus 8 days, p = 0.095). Although there were no significant differences in superficial wound infections, obese patients did have an increased rate of serious complications compared with normal-weight patients (24.2% versus 13.6%, respectively; p = 0.10).Obese patients undergoing PD have a substantially increased blood loss and longer operative time but do not have a substantially increased length of postoperative hospital stay or rate of serious complications. These findings should be considered when assessing patients for operation and when counseling patients about operative risk, but they do not preclude obese individuals from undergoing definitive pancreatic operations.

An 80-year-old white man underwent pylorus-preserving pancreaticoduodenectomy after presenting with obstructive jaundice and a dilated biliary tree on cholangiopancreatography. Histologic evaluation of the specimen revealed synchronous autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis) and infiltrating ductal adenocarcinoma of the pancreas. The mixed inflammatory infiltrate centered on the pancreatic ducts was associated with acinar loss, parenchymal fibrosis, and obliterative venulitis. Immunohistochemical labeling with an antibody to IgG4 revealed greater than 50 IgG4-positive plasma cells per high power field. Although not appreciated grossly, pancreatic intraepithelial neoplasia-3 and a neurotropic infiltrating poorly differentiated adenocarcinoma of the pancreas were also present. This case highlights the importance of carefully evaluating patients with autoimmune pancreatitis to rule out an underlying neoplasm and the importance of following those who were treated nonsurgically until the disease fully resolves.

Renal cell cancer (RCC) most commonly metastasizes to the lungs, bones, liver, renal fossa, and brain, although metastases can occur elsewhere. RCC metastatic to the duodenum is especially rare, with only a small number of cases reported in the literature. Herein, we describe a case of an 86-year-old woman with a history of RCC treated by radical nephrectomy 13 years previously. The patient presented with duodenal obstruction and anemia from a solitary duodenal mass invading into the pancreas and was treated via classic pancreaticoduodenectomy. Preoperative imaging and intra-operative assessment showed no evidence of other disease. Pathology confirmed metastatic RCC without lymph node involvement. Our case report and review of the English language literature underscore the rarity of this entity and support aggressive surgical treatment in such patients.

Background Pancreaticoduodenectomy (PD) is a complex general surgical procedure originally associated with significant perioperative morbidity and mortality. Multiple studies have now shown that this operation can be performed quite safely at high-volume institutions that develop a particular expertise. Critical pathways are among the key tools used to achieve consistently excellent outcomes at these institutions. It remains to be determined if implementation of a critical pathway at an academic institution with earlier moderate experience with PD will result in performance gains and improved outcomes. This study was designed to track performance improvements brought about by the implementation of a critical pathway for complex alimentary tract surgery. Study Design Between January 1, 2004, and October 15, 2006, 135 patients underwent PD: 44 before implementation of a critical pathway on October 15, 2005, and 91 after. Perioperative and postoperative parameters were analyzed retrospectively to identify those that could be used to track performance improvement and outcomes. Results Compared with the prepathway group, the postpathway group had a significantly shorter postoperative length of stay (13 versus 7 days, p ≤ 0.0001) and operative time. Mean total hospital charges were significantly reduced, from $240,242 ± $32,490 to $126,566 ± $4,883 (p ≤ 0.0001). Conclusions Implementation of a critical pathway for a complex procedure can be demonstrated to improve short-term outcomes at an academic institution. This improvement can be quantified and tracked and has implications for better use of resources (greater operating room and hospital bed availability) and overall cost containment.