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Background Financial toxicity is a growing problem in oncology, but no prior studies have prospectively measured the financial impact of cancer treatment in a diverse national cohort of newly diagnosed cancer patients. S1417CD was the first cooperative group-led multicenter prospective cohort study to evaluate financial hardship in metastatic colorectal cancer (mCRC) patients. Methods Patients aged 18 years or older within 120 days of mCRC diagnosis completed quarterly questionnaires for 12 months. We estimated the cumulative incidence of major financial hardship (MFH), defined as 1 or more of increased debt, new loans from family and/or friends, selling or refinancing home, or 20% or more income decline. We evaluated the association between patient characteristics and MFH using multivariate cox regression and the association between MFH and quality of life using linear regression. Results A total of 380 patients (median age = 59.9 years) were enrolled; 77.7% were White, 98.0% insured, and 56.5% had annual income of $50 000 or less. Cumulative incidence of MFH at 12 months was 71.3% (95% confidence interval = 65.7% to 76.1%). Age, race, marital status, and income (split at $50 000 per year) were not statistically significantly associated with MFH. However, income less than $100 000 and total assets less than $100 000 were both associated with greater MFH. MFH at 3 months was associated with decreased social functioning and quality of life at 6 months. Conclusions Nearly 3 out of 4 mCRC patients experienced MFH despite access to health insurance. These findings underscore the need for clinic and policy solutions that protect cancer patients from financial harm.

BACKGROUND This study investigates tumor recurrence patterns and their effect on postrecurrence survival following curative-intent treatment of colorectal liver metastases (CRLM) to identify those who stand to benefit the most from adjuvant liver-directed therapy. METHODS This is a retrospective analysis of all patients that underwent liver resection and/or ablation for CRLM between 2007 and 2019. Postrecurrence survival was compared between recurrence locations. Risk factors for liver recurrence were sought. RESULTS The study included 227 patients. Majority were treated with resection (71.0%) while combination resection/ablation (18.9%) and ablation alone (11.0%), were less common. At a median follow-up of 3.0 years, recurrence was observed in 151 (66.5%) patients. Of those, liver, lung, and peritoneal recurrence were most common at 66.9%, 49.6%, and 9.2%, respectively. Median postrecurrence survival after liver, lung, and multisite recurrence was 39.6-, 68.4-, and 33.6 months, respectively. High tumor grade (p

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy projected to be the 2PDAC is classified as: a) resectable, b) borderline resectable, c) unresectable (locally advanced and metastatic). The standard of care for patients who present with resectable pancreatic adenocarcinoma is six months of adjuvant modified (m) FOLFIRINOX, gemcitabine plus capecitabine, or single agent gemcitabine. For many reasons, there has been a paradigm shift to employing neoadjuvant chemotherapy. For resectable and borderline resectable patients, we generally start with systemic therapy and reevaluate resectability with subsequent scans specifically when the tumor is located in the head or body of the pancreas. Combined chemoradiation therapy can be employed in select patients. The standard of care for metastatic PDAC is FOLFIRINOX or gemcitabine and nab-paclitaxel. Germline and somatic genomic profiling should be obtained in all patients. Patients with a germline BRCA mutation can receive upfront gemcitabine and cisplatin.Thorough understanding of molecular pathogenesis in PDAC has opened various therapeutic avenues. We remain optimistic that future treatment modalities such as targeted therapies, cellular therapies and immunotherapy will further improve survival in PDAC.

The development of novel biomarkers for cancer has exploded over the last decade with advances in novel technologies. Cholangiocarcinoma (CCA), a cancer of the bile ducts, has a dearth of strong disease and pathophysiology biomarkers, making early detection and prognostication a difficult task.In this comprehensive review, we discuss the spectrum of biomarkers for CCA diagnosis and prognostication. We elaborate on novel biomarker discovery through a comprehensive multi-omics approach. We also cover, how certain biomarkers may also serve as unique and potent targets for therapeutic development.Despite the relatively poor diagnostic and prognostic performance of existing biomarkers for CCA, there is a vast range of novel biomarkers with exquisite diagnostic and prognostic performance for CCA in the pipeline. Moreover, these biomarkers may serve as potential targets for precision medicine. Existing strategies to target unique biomolecular classes are discussed, within the context of an overall 'omics' focused profiling strategy. Omics profiling will simultaneously allow for enhanced biomarker development and identification of unique subtypes of cholangiocarcinoma and how they are influenced by an individual's unique context. In this manner, patient management strategy and clinical trial design can be optimized to the individual.

155 Background: Lorigerlimab (MGD019) is an investigational, bispecific Fc-bearing (IgG4) DART molecule designed to enhance CTLA-4 blockade on dual expressing, tumor infiltrating lymphocytes, while maintaining maximal PD-1 blockade on PD-1 expressing cells. Lorigerlimab has approximate dose proportional PK across 1–10 mg/kg IV dosing Q3W, with sustained PD-1 receptor occupancy evident at doses ≥1 mg/kg Q3W. MGD019-01 is a global first-in-human dose finding and activity estimating study of lorigerlimab in advanced solid tumors (AST). Methods: The exp phase of MGD019-01 evaluates single agent safety, PK, and antitumor effects of lorigerlimab at the recommended dose for exp of 6 mg/kg IV Q3W in 4 tumor specific cohorts. Confirmed responses were noted in each cohort. Preliminary results of the mCRPC cohort are reported here. Response evaluable pts received ≥1 dose and had ≥1 postbaseline imaging evaluation. Measurable lesions were evaluated per RECIST v1.1 and skeletal metastases assessed by bone scan. Prostate specific antigen (PSA) response was defined as a ≥50% (PSA50) or ≥90% (PSA90) PSA decline from baseline with confirmation ≥3 weeks later. Expression of proliferation marker, Ki67, and inducible costimulator (ICOS) by peripheral T cells was assessed by flow cytometry. Results: At data cutoff (9/10/22), 127 pts with AST received ≥1 dose of lorigerlimab 6 mg/kg. Median exposure was 10 weeks (range, 0.1, 94.4) with median of 4 infusions. 6 pts remain on therapy; 36 discontinued for PD (n=13), AEs (n=17), or patient/physician decision (n=6). Treatment related adverse events (TRAE) occurred in 109/127 (85.8%) pts. TRAEs occurring in ≥15% of pts were fatigue, pruritus, hypothyroidism, pyrexia. Rates of grade ≥3 TRAEs and immune-related AEs were 32.3% and 7.9%, respectively. AEs leading to drug discontinuation occurred in 22.8% of pts. There were no fatal AEs related to lorigerlimab. In the mCRPC exp cohort (n=42), pts had a median of 2 prior lines of therapy for CRPC, >80% received prior ART or taxanes; 88% had visceral (liver, 26%; lung, 26%) or nodal disease and 95% had bone metastases. 42 pts were PSA response evaluable; 35 were RECIST evaluable. ORR was 25.7% (9/35; 9 confirmed PRs). Median duration of response was 16.1 weeks (range 6–25+ weeks). 5 responders remain on study, 4 discontinued for unrelated fatal AEs: COVID-19 (2) cardiac arrest (1) C. difficile infection (1). Confirmed PSA50 and PSA90 response rates were 28.6% (12/42) and 21.4% (9/42), respectively. Increased frequencies of Ki67+ and ICOS+ T cells were observed on day 8 posttreatment compared to pretherapy per the flow cytometry analyses from 35 pts. Conclusions: Lorigerlimab demonstrates a manageable safety profile with evidence of encouraging and durable antitumor activity in a chemotherapy refractory mCRPC population. Randomized evaluation of lorigerlimab in mCRPC is warranted. Clinical trial information: NCT03761017 .

LBA661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (Wainberg et al. Eur J Cancer 2021;151:14–24; NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Herein, we present results from NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel + gemcitabine as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated metastatic PDAC were randomized (1:1) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence or absence of liver metastases. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when ≥ 543 events were observed using a stratified log-rank test with an overall 1-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were well balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. The median OS was 11.1 months in the NALIFIROX arm as compared with 9.2 months in the Gem+NabP arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); PFS was also significantly improved (7.4 months vs 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001). Grade 3/4 treatment-emergent adverse events (TEAEs) with ≥ 10% frequency in patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in treatment-naïve patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. Funding: Funded by Ipsen. Clinical trial information: NCT04083235 .[Table: see text]

5 Background: A growing body of evidence supports the utility of circulating tumor DNA (ctDNA) as a useful biomarker for detecting molecular residual disease (MRD) in colorectal cancer (CRC). Immediately after surgery or during adjuvant therapy, high levels of cell-free DNA (cfDNA) from normal tissue may limit the detection of tumor-derived ctDNA. The optimal timing of blood collection for reliable MRD detection after surgery or adjuvant therapy remains unclear. Methods: In this retrospective, U.S.-based, multi-institutional study, data from commercial ctDNA testing in 16,347 patients with stage I-III CRC were analyzed. Complete clinical data were available for 417 patients with 2,538 plasma samples collected between 6/2019 and 4/2022. The median follow-up for relapsed and non-relapsed patients was 730 and 615 days, respectively. A personalized, tumor-informed multiplex PCR-based next-generation sequencing assay (Signatera) was used to quantify ctDNA prior to surgery and postoperatively in a longitudinal manner. We analyzed the kinetics of total cfDNA and compared it with the ctDNA MRD positivity rates at various time points after surgery. Results: Among all patients, cfDNA levels were higher immediately after surgery (0-2 weeks) and gradually declined during the subsequent 2-8 weeks (p6 months post-operatively and subsequent to any adjuvant therapy) was significantly associated with worse recurrence-free survival as compared to ctDNA negative patients (MRD: HR 14.1, 95% CI: 5.8-34; p

668 Background: We investigated the impact of distance traveled to a tertiary care center for treatment in the management and outcomes of patients with pancreatic adenocarcinoma (PDAC). Methods: Patients treated for operable PDAC at a single institution from 2010-2019 were retrospectively reviewed. Data was collected on demographics, tumor characteristics, social determinants of health, diagnostic/staging work-up, surgical details, and outcomes. Patients were divided into three groups based on distance from our institution: Group A, 11-50 miles, or Group C, > 50 miles. The primary outcome was two-year survival. Results: There were 314 patients included. The mean age was 67.6+10.5 years. Patients farther from the hospital were less likely to undergo CT with contrast (Group B 97.1% versus Group C 89.0%, p = 0.02) and more likely to get MRCP (Group A 17.0% versus Group C 36.3%, p = 0.01) for staging. Distance was also associated with increased time to first encounter with medical or surgical oncology (Group A 6 days versus Group C 9 days, p = 0.02) and treatment initiation (Group A 22 days versus Group C 28 days, p < 0.001). There were no differences in postoperative complications, length of stay, discharge disposition, or follow-up. Two-year survival was better in Group A than Group B (54.1% versus 35.5%, p = 0.04). There was no difference in five-year survival. In the multivariable model for two-year survival, no patient or tumor characteristics were significant. Conclusions: In this PDAC population, patients living farther from a tertiary cancer center had worse two-year postoperative survival. Prospective studies in this area are needed.

Cancer immunotherapy has seen tremendous strides in the past 15 years, with the introduction of several novel immunotherapeutic agents. Nevertheless, as clinical practice has shown, significant challenges remain with a considerable number of patients responding sub-optimally to available therapeutic options. Research has demonstrated the important immunoregulatory role of the tumor microenvironment (TME), with the potential to either hinder or promote an effective anti-tumor immune response. As such, scientific efforts have focused on investigating novel candidate immunomodulatory agents with the potential to alter the TME toward a more immunopotentiating composition.Herein, we discuss the novel investigational toll-like receptor 9 agonist tilsotolimod currently undergoing phase II and III clinical trials for advanced refractory cancer, highlighting its mode of action, efficacy, tolerability, and potential future applications in the treatment of cancer. To this effect, we conducted an exhaustive Web of Science and PubMed search to evaluate available research on tilsotolimod as of August 2021.With encouraging early clinical results demonstrating extensive TME immunomodulation and abscopal effects on distant tumor lesions, tilsotolimod has emerged as a potential candidate immunomodulatory agent with the possibility to augment currently available immunotherapy and provide novel avenues of treatment for patients with advanced refectory cancer.

INTRODUCTION: PDAC is a lethal malignancy with a clear unmet need; almost all patients fail 1(st), 2(nd), and 3(rd) line multi-agent cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) has been identified as a key signaling node enhancing tumor survival and drug resistance in PDAC, hence it is considered a promising therapeutic target. AREAS COVERED: We comprehensively reviewed the evidence from preclinical and phase I and II clinical trials, based on the authors’clinical experience and a pubmed, Chochrane library, Embase, and Google Scholar search everolimus + pancreatic cancer. EXPERT OPINION: Everolimus has not demonstrated efficacy in PDAC; however, an mTOR inhibitor in combination with stroma-targeted therapies may be a promising area to explore in clinical trials.

Although major innovations in treatment are advancing, cancer persists as one of the leading causes of mortality. With the rising incidence of cancer and as we treat them, patients incur short term and long-term toxicities of current traditional therapies, including chemotherapy. This imposes a significant physical, emotional, and financial burden among patients, which affects their quality of life. Tumor-Treating Fields (TTFields) is a novel innovative new treatment modality that utilizes alternating electric fields at specific intermediate frequencies to diminish tumor growth by inhibiting mitosis and thus proliferation of malignant cells. The distinguishing feature of this new treatment modality is that it is noninvasive and tolerable. In fact, TTFields is currently FDA approved for the treatment of glioblastoma multiforme (GBM) as well as malignant pleural mesothelioma (MPM). Recently, TTFields have also been found to affect immunogenic cell death resulting in stronger anti-neoplastic effects. In this review, we discuss the mechanism of action of TTFields, the plethora of clinical trials being conducted in patients with GBM, pancreatic adenocarcinoma, ovarian cancer, non-small-cell-lung-cancer (NSCLC), brain metastasis from NSCLC, and MPM and toxicity profile.

Despite recent advances, treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) progressing after next-generation hormonal agents (NHAs) are limited and provide only modest survival benefit. Thus, an unmet need remains for mCRPC patients after treatment with targeted endocrine therapy or NHA therapy. Pembrolizumab, a humanized monoclonal antibody for PD-1, has been found to have activity as monotherapy in patients with mCRPC and as combination therapy in a Phase Ib/II study with docetaxel and prednisone/prednisolone for patients previously treated with enzalutamide or abiraterone acetate. The aim of the randomized, double-blind, Phase III KEYNOTE-921 study is to evaluate the efficacy and safety of pembrolizumab plus docetaxel in patients with mCRPC who were previously treated with an NHA. Clinical trial registration: NCT03834506 ( ClinicalTrials.gov )

Background: Leukemia inhibitory factor (LIF) is an immunosuppressive cytokine linked to tumor growth and metastasis. LIF overexpression correlates with poor prognosis and chemoresistance in multiple tumor types including PDAC. Preclinical data show that LIF promotes an immunosuppressive tumor microenvironment, hindering cytotoxic CD8+ T cell recruitment; low T cell infiltration also correlates with mortality in patients with PDAC. Preclinical studies show LIF-blocking antibodies sensitize tumors to PD-1/PD-L1 inhibition, inhibit epithelial-mesenchymal transition, and prolong survival in combination with CT. In patients with PDAC, higher LIF levels correlate with more aggressive pathology, elevated CA19-9 (a PDAC biomarker), and lower response and survival rates. AZD0171 (formerly MSC-1), a first-in-class, humanized, IgG1 monoclonal antibody, binds specifically and potently to LIF, preventing downstream signaling. In a phase 1 dose escalation study (NCT03490669), AZD0171 monotherapy had manageable safety and led to stable disease (SD) in 34.2% of patients with advanced solid tumors across all dose levels. AZD0171 + CT may improve survival outcomes vs CT alone. Based on preclinical data, AZD0171 may function to stimulate antitumor immune response, and combination with the PD-L1 inhibitor durvalumab could prolong that response and overcome peripheral tolerance in patients with metastatic PDAC. Methods: This is a phase 2, open-label, single-arm, multicenter study of AZD0171 + durvalumab and CT in treatment-naive patients with metastatic PDAC (NCT04999969). Eligible patients must have an ECOG performance status 0 or 1, a Gustave Roussy Immune Score 0 or 1, ≥1 measurable target lesion per RECIST v1.1, and confirmed presence of tumoral CD8+ T cells. Patients with central nervous system metastasis, history of leptomeningeal disease or cord compression, a thromboembolic event ≤3 months prior to study treatment, unresolved grade ≥2 toxicities from prior therapy, or a sensitizing mutation or tumor characteristic for which there is a preferred treatment, are excluded. As PDAC is poorly immune infiltrated, a novel clinical trial assay will be used to select for patients who have existing resident CD8+ T cells and may therefore be more likely to respond. About 115 patients will receive intravenous AZD0171, durvalumab and CT until disease progression or unacceptable toxicity. The primary endpoints are safety and overall survival (OS) rate at 12 months. Secondary endpoints include objective response rate, disease control rate (confirmed response or SD ≥16 weeks), duration of response, median progression-free survival (PFS), PFS rate at 4 months, median OS, pharmacokinetics, pharmacodynamics (changes in serum CA19-9 level and tumor CD8+ T cell infiltration) and immunogenicity. The trial is currently recruiting. Citation Format: Grainne O'Kane, Teresa Macarulla, Fiyinfolu Balogun, Antoine Hollebecque, Matthew J. Reilley, Sreenivasa R. Chandana, Jim Eyles, Oluwaseun Ojo, Philip Overend, Douglas C. Palmer, Nadia Luheshi, Mayukh Das, Antoine Italiano, Joan Seoane. A phase 2 trial of first-line AZD0171 + durvalumab and chemotherapy (CT) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and CD8+ T cell infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT126.

Fibroblast growth factor receptors (FGFR 1-4) are a highly conserved family of receptor tyrosine kinases, involved in several physiological processes. Genetic aberrations of FGFRs and their ligands, fibroblast growth factors (FGFs) are involved in several pathological processes including cancer. The FGF-FGFR axis has emerged as a treatment target in oncology. Because these aberrations drive cancer progression, the development of FGFR targeted therapies have been accelerated.In this comprehensive review, we evaluate molecular pathology and targeted therapies to FGFRs. We reviewed the evidence for safety and efficacy from preclinical and clinical studies (phase I-III) of FGFR targeted therapies. We also discuss potential challenges in bringing these targeted therapies from bench to bedside and the potential opportunities.Despite the challenges of the clinical development of FGFR targeted therapies, two FGFR small-molecule inhibitors, namely Erdafitinib and Pemigatinib, are FDA approved for urothelial cancer and cholangiocarcinoma, respectively. Understanding and detection of FGFR genomic aberrations, protein overexpression and the development of isoform-specific inhibitors are factors in the clinical success of these therapies. An enhanced understanding of patient selection based on a gene signatures or biomarkers is key to success of FGFR targeted therapies.

517 Background: Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death, with a recurrence rate of 85% after curative surgery and a 5-year survival rate of 10%. Serum biomarkers like CA 19-9 lack sensitivity and specificity (10% of patients fail to produce CA 19-9), and are poor indicators of molecular residual disease (MRD). Circulating tumor DNA (ctDNA) detection allows for MRD identification months ahead of radiological findings, and may assess molecular response and patient outcomes. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA in a prospective clinical cohort of patients. Serial time points were collected for unresectable, borderline resectable, and resectable subsets of patients to monitor ctDNA levels in response to treatment (see Table). Results: 93 patients were included, with a median age of 67.3 yrs and 45% female. 285 timepoints were analyzed for ctDNA presence, with each patient having between 1 and 7 timepoints (median 3 timepoints per patient). 46 patients had one or more samples positive for ctDNA, resulting in an anytime ctDNA positivity rate of 49.5%. Anytime positivity correlated with the stage of disease (p

438 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy and treatment beyond first-line platinum doublet remains largely investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells less sensitive to T cell-mediated lysis, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent anti-PD-1 antibody in BTC provide a rationale for combination chemoimmunotherapy. We conducted a multi-center, phase Ib/II, single-arm study to investigate the role of liposomal-irinotecan, 5FU and LV in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC after progression or intolerance of first-line systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. The limited phase Ib portion evaluated 10 pts to determine the recommended phase 2 dose (RP2D) based on the probability of dose-limiting toxicity (DLT) rate 2 over 46 hrs, LV 400 mg/m2, liposomal-irinotecan 70 mg/m2 at dose level 0 along with nivolumab 240 mg every 2 wks for up to 2 yrs in absence of disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS) rate with an alternative and null hypothesis of 5.0 mo and 2.9 mo (two-sided alpha 0.05, power 80%), respectively. Secondary endpoints included best overall response rate (ORR) per immune related (ir)RECIST, median overall survival (OS), 75th percentile estimates of PFS and OS, and safety. Exploratory objectives include biomarker analysis using include targeted panel exome/transcriptome and immune cell subsets in tissue. Results: 30 eligible pts (60% men, 83% Caucasian) including 10 pts in phase Ib and 20 pts in phase II with a median age of 63.5 yrs (range 36-75) were enrolled across 4 US sites between June 2019 and July 2021. In phase Ib, one pt experienced DLT (grade 3 enterocolitis); RP2D was confirmed at dose level 0. All 30 pts were included in study reported outcomes with a median follow-up time of 10.7 mo. Median PFS was 4.2 mo (95% CI, 1.9-10.2) and failed to reject the null hypothesis. Median OS was 7.5 mo (95% CI, 5.8-21.4). The 75th percentile estimates for PFS and OS are 10.2 mo (95% CI, 5.4-NE) and 21.4 mo (95% CI, 7.8-21.4). ORR estimates and toxicity data are pending and will be presented at the meeting. Conclusions: The observed median PFS is insufficient to reject the null hypothesis. The 75th percentile estimates for PFS and OS are suggestive of prolonged benefit with chemoimmunotherapy in a small fraction of patients with BTC. Clinical trial information: NCT03785873.

Background: The incidence of hepatocellular carcinoma (HCC) is increasing. Development of newer therapeutic modalities has changed the paradigm of HCC treatment in recent years. So, the aim of our study is to analyze the impact of these treatment modalities into the survival of HCC patients, based on the stage of HCC in real life practice. Methods: We analyzed the data from the SEER database: Incidence − SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2015 Sub (1973–2013 varying). Relative survival rates (RSRs) and hazard ratios (HRs) were measured for patients diagnosed with HCC between 2001 and 2013. Rates were compared between pre sorafenib [2001–2007] and post sorafenib [2008–2013] eras. Results: A total of 50,088 patients (21,435 in pre sorafenib era and 28,653 in the post-sorafenib era) were included with HCC from SEER database. The median relative survival for the entire population was 14 months with 5-year RSR of 21.20%; 11 months for those diagnosed in 2001–2007 with 5-year RSR 19.30% and 17 months for those diagnosed in 2008–2013 with 5-year RSR 22.40% (P vs . 37.00% for pre and post sorafenib era respectively; P value vs . 22.60% for pre and post sorafenib era respectively; P value Conclusions: Survival in patients with HCC has improved since 2008, which is limited to early stage HCC. Survival of advanced stage HCC patients is extremely poor and has not shown any significant improvement since the approval of sorafenib, emphasizing the need for better therapeutic options. Not receiving any surgical intervention is associated with significantly poor prognosis. Large numbers of early stage HCC patients were not able to receive surgical interventions. This can impose a significant financial burden, as these patients would progress on to the advanced stage, where treatment options are very limited and not as cost-effective. This emphasizes the need for further research to identify various barriers and the possible need for healthcare policy changes.

Introduction: Early phase clinical trials are the first clinical research step to bringing new cancer therapeutics to patients. At this stage, a new drug's safety, dosing, and scheduling profiles are established as the main endpoints. However, excellent responses due to biomarker-guided and immune checkpoint trials in early phase have resulted in direct approvals of new anti-cancer drugs. Despite doubling of the success rate of new drug approvals, many barriers exist to expeditiously bring active new drugs to the clinic. Areas covered: This review covers roles of members of the early phase program and the challenges they face in enrolling advanced cancer patients to trials. Practical solutions are provided from the perspective of the investigators, regulatory, investigational pharmacy, research nurses, clinical research coordinators, budgets, contracts, and data management. Expert opinion: We are witnessing a burgeoning era in drug development with rapid approval of efficacious drugs. This is achieved by a strong collaboration between investigators, academic institutions, pharmaceutical sponsors, scientists, Food and Drug Administration (FDA), and community practices. Herein, we discuss some of the challenges faced by early phase clinical trials programs and discuss methods of improvement.

PURPOSE To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis. PATIENTS AND METHODS Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort. RESULTS Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months. CONCLUSION 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

137 Background: Despite evidence that rising cancer care costs contribute to “financial toxicity” in cancer pts, no studies, to our knowledge, have prospectively assessed the financial impact of cancer diagnosis (dx) using both self-reported and objective financial measures. S1417CD, led by the SWOG Cancer Research Network and conducted in the NCI Community Oncology Research Program (NCORP), was the first national prospective cohort study to evaluate time-to-first evidence of major financial hardship (MFH) in pts with newly diagnosed mCRC. We present results of the primary endpoint analysis. Methods: Pts age ≥ 18 within 120 days of mCRC dx receiving systemic treatment completed surveys every 3 months (mo) for 12 mo. MFH was defined as ≥ 1 occurrence of self-reported increase in debt, new loans, selling home, refinancing home, or ≥ 20% income decline during the 12 mo study period. Cumulative incidence (CI) of MFH was estimated to account for competing risk of death. Multivariate logistic regression was used to evaluate the association between pt characteristics with development of MFH. Results: 380 pts (median age 59.9) across 126 clinic sites were enrolled. Most pts were white (78%), male (61%), and insured (98%), with annual income ≤ $50,000 (56%). Cumulative incidence of MFH at 12 mo was 71.5% (95% CI: 65.9%-76.3%), with 24.6%, 52.4%, and 61.8% at 3, 6, and 9 mo; 104 (41%) pts reported ≥ 2 elements of MFH. Age, race, marital status, employment, and annual income (≤ vs. > $50K) were not significantly associated with MFH. In a post hoc analysis, income

3587 Background: AVID200 is a rationally designed first-in-class, selective inhibitor of transforming growth factor-beta (TGF-beta) that neutralizes TGF-beta 1 & 3 with pM potency and 4,000 fold selectivity over TGF-beta 2. TGF-beta 1 & 3 signaling has been associated with immune checkpoint inhibitor resistance and immunosuppression in the tumor microenvironment while TGF-beta 2 is required for normal cardiac function and hematopoiesis. Methods: NCT03834662 (AVID200-03) is a multicenter Phase 1 study following a standard 3 + 3 dose escalation to evaluate safety and tolerability of AVID200 given IV every 3 weeks to patients (pts) with advanced solid tumors. Peripheral target engagement was assessed in blood by ELISA and a cell-based functional assay, and in skin biopsies by immunohistochemistry (IHC). Pharmacodynamic markers of TGF-beta signal modulation and immune activation were evaluated in serum using the InflammationMAP v 1.0 (Myriad RBM) and in paired tumor biopsies by IHC and Imaging Mass Cytometry. Results: Nineteen pts (ECOG 0-1, median age 63 [range 39-77], 52.6% male) received AVID200 at 3 planned dose levels of 180 (N = 7), 550 (N = 6), and 1100 mg/m2 (N = 6) (~5, 15, and 30 mg/kg). The maximum tolerated dose was not reached. Three Grade (G) 3 treatment-related adverse events (TRAEs) were reported in 2 pts (diarrhea and lipase elevation, anemia); no > G3 TRAEs were observed. Serum exposure was dose-proportional and AVID200 sequestered all active TGF-beta 1 & 3, but not beta 2, in blood across the entire dosing period at all dose levels, providing proof-of-mechanism of AVID200. SMAD2 phosphorylation in skin biopsies was detectably reduced on Day 4 at 15 and 30 mg/kg. Pro-inflammatory markers in serum were increased on Day 8 versus baseline in a dose-dependent manner. Tumor biopsies of pts treated at 15 mg/kg showed modulation of TGF-beta signaling and immune activation. A best response of RECIST stable disease > 12 weeks was observed in 2 pts: 1 with adenoid cystic carcinoma (5 mg/kg; 8.7 months); 1 with breast carcinoma (30 mg/kg; 3.1 months). Conclusions: AVID200 was safe and well tolerated at dose levels of 5-30 mg/kg, with peripheral target engagement across the entire dosing period. AVID200 led to TGF-beta target modulation and immune activation. These data provide proof-of-principle that AVID200-mediated selective and potent inhibition of TGF-beta 1 & 3 is feasible in the clinic. The AVID200 monotherapy data warrant exploration of rational combination with a PD-(L)1 inhibitor. Clinical trial information: NCT03834662 .

7010 Background: Despite evidence that rising cancer care costs are contributing to “financial toxicity” in cancer pts, no studies, to our knowledge, have prospectively assessed the financial impact of cancer diagnosis (dx) using both self-reported and objective financial measures. S1417CD, led by the SWOG Cancer Research Network and conducted in the NCI Community Oncology Research Program (NCORP), was the first national prospective cohort study to evaluate time-to-first evidence of major financial hardship (MFH) in pts with newly diagnosed mCRC. We present results of the primary endpoint analysis. Methods: Pts age ≥ 18 within 120 days of mCRC dx receiving systemic treatment completed surveys every 3 months (mo) for 12 mo. MFH was defined as ≥ 1 occurrence of self-reported increase in debt, new loans, selling home, refinancing home, or ≥ 20% income decline during the 12 mo study period. Cumulative incidence (CI) of MFH was estimated to account for competing risk of death. Additional endpoints, not reported here, included quality of life, caregiver strain, and changes in credit status over 12 mo. Results: In total, 380 pts (median age 59.9) across 126 clinic sites were enrolled, with 377 eligible and evaluable for the primary endpoint (reached 12 mo assessment, death, or MFH endpoint); complete data were available for 92% of pts as of Jan 23, 2020. Most pts were white (78%), male (61%), and insured (98%), with annual income ≤ $50,000 (56%). Cumulative incidence of MFH at 12 mo was 71.5% (95% CI: 65.9%-76.3%), with 24.6%, 52.4%, and 61.8% at 3, 6, and 9 mo. The dominant components of MFH were new debt (12-mo CI, 56.7%) and >20% decline in income (26.7%); 104 (41%) pts reported ≥ 2 elements of MFH. In a secondary analysis excluding new debt, 12 mo cumulative incidence of MFH was 42.9% (95% CI: 37.2%-48.5%), with 10.3%, 24.4%, and 31.9% at 3, 6, and 9 mo. Conclusions: In a national sample of mCRC pts on systemic tx, financial hardship, most commonly in the form of increased debt, accumulates progressively over time. Nearly 3 out of 4 pts experiencing MFH at 12 mo despite access to health insurance coverage. These findings underscore the need for clinic and policy solutions such as early financial navigation and elimination of cost sharing to protect pts from financial devastation as they continue with tx. Clinical trial information: NCI-2015-01885 . [Table: see text]

Prognosis remains dismal for pancreatic ductal adenocarcinoma (PDAC). Genomics and proteomics have depicted heterogeneity in PDAC. Collectively, this information could be useful in improving diagnosis, prognosis, modalities of therapy, treatment responses, deciphering drug resistance and new drug development.We describe major advances in the cellular and molecular subtypes based on next-generation sequencing and their predictive and prognostic value in PDAC patients. We review aberrant genes involving in defined cellular processes in PDAC. Finally, the current state of drug development with novel investigational agents targeting cell fate, cell survival, genomic instability, tumor-stroma, and immune checkpoints are discussed.Molecular techniques have revealed distinct driver mutations in PDAC. Common genes and cellular processes are dysregulated in the pathogenesis of PDAC. These cellular processes categorized by aberrant pathways include control cell fate, genome maintenance, and cell survival. Dysregulation of the tumor microenvironment promotes an intense fibrosis and immune suppression that play a major role in drug resistance. New information on tumor biology has led to the development of targeted/stromal therapies, immunotherapies or combinations with current chemotherapy in PDAC. New drug development targeting multiple hallmarks of PDAC we hope will positively impact the quality and survival of PDAC patients.

TO THE EDITOR: We would like to report 2 cases of multiple myeloma (MM) complicated by myelomatous pleural effusions (MPE). MM is a malignant transformation and proliferation of a single clone of plasma cells, which typically infiltrates the bone marrow and produces monoclonal immunoglobulins (Ig). In the United States, the annual incidence of MM is 4-5 cases per 100,000. Myeloma accounts for 1% of all cancers and slightly over 10% of all hematologic malignancies [1]. Recent advancements in treatment have resulted in significantly improved outcomes for both newly diagnosed and relapsed cases [2]. Common complications in MM are renal insufficiency, anemia, infections, skeletal involvement leading to hypercalcemia, pathologic fractures, and neurologic involvement [3]. Pleural effusions in MM are uncommon and MPEs are very rare [4].

TheKytococcusgenus formerly belonged toMicrococcus. The first report of aKytococcus schroeteriinfection was in 2002 in a patient diagnosed with endocarditis. We report a case of central line associatedKytococcus schroeteribacteremia in a patient with underlying Hairy Cell Leukemia.Kytococcus schroeteriis an emerging infection in the neutropenic population and in patients with implanted artificial tissue. It is thought to be a commensal bacterium of the skin; however, attempts to culture the bacteria remain unsuccessful. There have been a total of 5 cases (including ours) ofK. schroeteribacteremia in patients with hematologic malignancies and neutropenia and only 18 documented cases in any population. Four of the cases of bacteria in neutropenic patients have been fatal, but early detection and treatment could make a difference in clinical outcomes.

Background AVID100, a rationally designed anti-EGFR-DM1 conjugate, showed potent activity in preclinical models, including cancer cell lines resistant to approved anti-EGFR monoclonal antibodies. In addition, AVID100 showed increased toxicity on tumor cells compared to the unconjugated antibody. There was no increased AVID100-mediated toxicity on keratinocytes. Methods In the completed Phase Ia segment, 24 patients with advanced or metastatic epithelial malignancies without available standard of care therapy and likely to express EGFR were enrolled into sequential dose-escalation cohorts to assess safety, tolerability, pharmacokinetic (PK) parameters, and to identify the recommended Phase II dose (R2PD) of 2 hour infusions on an every 3 week schedule. In the ongoing Phase IIa segment, preliminary antitumor activity is being assessed in expansion cohorts of patients with high EGFR expression, including triple-negative breast cancer (TNBC) (2+ expression in ≥75% or 3+ in ≥50% of tumor cells) or either squamous cell carcinoma of the head and neck (SCCHN) or squamous non-small cell lung carcinoma (sqNSCLC) (3+ expression in ≥ 50% of tumor cells). The DAKO PharmDx assay was validated and used for screening intensity of EGFR protein expression. Results During Phase Ia, no Cycle 1 dose limiting toxicities (DLTs) were observed in Cohorts 1-6 at doses (N) of 20 (1), 40 (1), 80 (3), 120 (3), 180 (3), and 220 (6) mg/m2. In Cohort 7 (6) (270 mg/m2; ~ 7.3 mg/kg) two patients experienced Cycle 1 DLTs (G3 asymptomatic lipase elevation, G4 reversible thrombocytopenia), exceeding the maximally tolerated dose. A third patient developed G3 reversible pneumonitis. As a result, 220 mg/m2 (~6 mg/kg) was selected as the R2PD. Tumor types in greater than one patient included: colorectal (13), breast (4), and ovarian (2). Preliminary PK results at the R2PD revealed exposure exceeding preclinically predicted therapeutic levels. Cmax increased proportionally with dose, plasma half-life was ~50 hours at the R2PD, and clearance decreased with increasing doses with saturation observed between 180-270 mg/m2. Safety and tolerability were acceptable. Other treatment-related adverse events included: infusion-related reactions that were ameliorated by premedication and infusion prolongation, rash, nausea, vomiting, fatigue, headache, anorexia, mucositis, punctate keratitis, diarrhea, elevated amylase, reversible transaminase and alkaline phosphatase elevations without other evidence of hepatotoxicity, hypomagnesemia, and hypokalemia. Prolonged disease stabilization was observed in 3 of these patients not selected for EGFR overexpression (colorectal, ovarian, cervical). Conclusions AVID100 is a well-tolerated anti-EGFR-DM1 conjugate with evidence for exposure levels at or above those observed for cetuximab and ado-trastuzumab emtansine. Antitumor activity is currently being evaluated in EGFR-overexpressing patients in Phase IIa. Citation Format: Nehal Lakhani, Sreenivasa Chandana, Anthony Tolcher, Yvette Cole, Karla Rivas, Sandra Sinclair, Paul I. Nadler, Debra L. Wood, Kyri P. Papadopoulos. A Phase Ia/IIa trial of AVID100, an anti-EGFR antibody-drug conjugate [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 CT056.

TPS6652 Background: Few studies have assessed the financial impact of cancer diagnosis (dx) in diverse patients (pts) and caregivers (cgs) using objective and standard financial measures. S1417CD, led by the SWOG Cancer Research Network, is the first prospective cohort study assessing financial outcomes to be conducted in the NCI Community Oncology Research Program (NCORP). We present our experience with design and accrual. Methods: Pts age ≥ 18 within 120 days of mCRC dx were considered eligible and asked to identify a caregiver (cg) who could participate concurrently. The primary endpoint is incidence of treatment-related financial hardship, defined as ≥ 1 of the following: debt accrual, selling/refinancing home, ≥ 20% income decline, or borrowing money. Measures include 1) pt and cg surveys (baseline (BL), 3, 6, 9 and 12 months (mo)) assessing out-of-pocket spending, financial impacts, cg burden, and quality of life and 2) pt credit reports (BL, 6, and 12 mo). Linkage to records from TransUnion, a national credit agency, required pt social security number (SSN) and processes for batched credit report transfer via secure web portal. The accrual goal was n = 374 pts in 3 years. The study activated on Apr 1, 2016 and closed on Feb 1, 2019 after reaching its accrual goal. A total of 380 pts (median age 59.7 years) and 155 cgs enrolled (41% cg participation). Enrollment steadily increased during the study period; 56% enrolled in the last 12 mo. Credit data were not obtainable for 76 (20%) pts due to early death, lack of credit, or inability to match records. S1417CD, the first cooperative group led study assessing financial outcomes in the community setting, completed enrollment faster than anticipated. Required SSN collection was not a barrier to enrollment, which improved as sites became familiar with data security measures. Robust accrual to S1417CD demonstrates pts’ and cgs’ desire to improve understanding of financial toxicity and its solutions. Follow-up will conclude in 12 mo with results to follow. SWOG plans to launch a randomized study (S1912) assessing the impact of financial navigation on household finances, using credit data for primary endpoint assessment. Clinical Trials Registry Identifier NCI-2015-01885. Clinical trial information: NCT02728804.

� Oxaliplatin is a widely used chemotherapy agent in the treatment of colorectal cancer, in the adjuvant and palliative setting. � Polyneuropathy is a common side effect of oxaliplatin at higher doses. � Lhermitte sign is a peripheral neuropathy best characterized by an electric shock-like sensation shooting down the back into all 4 limbs when a patient’s neck is flexed. � Oxaliplatin-induced Lhermitte sign is a very rare side effect. � A 50-year-old Hispanic man with stage III colorectal cancer, who underwent chemotherapy with capecitabine and oxaliplatin, presented reporting that every time he bent his neck he had a severe shooting pain down both of his upper and lower extremities. Physical examination was significant for Lhermitte sign. Other causes of Lhermitte sign were ruled out. � The clinical symptoms and Lhermitte sign completely resolved 1 year after discontinuation of oxaliplatin chemotherapy. � The literature review indicated our case is the first report of Lhermitte sign induced by oxaliplatin in combination with capecitabine in colorectal cancer.

2594Background: We have developed a unique strategy to tactically reduce on-target platelet toxicity with APG-1252, a novel dual Bcl-2/Bcl-xL inhibitor, while maintaining strong in vivo antitumor a...

e13561Background: Incidence rates of small intestinal neuroendocrine tumors (SNETs) are increasing and has become the most common type of small intestinal cancer. SNETs often present with distant m...

Pancreatic adenocarcinoma is associated with advanced presentation and poor survival. Currently approved therapies have minimal effect on patient survival. Pancreatic adenocarcinomas have a high incidence of activated K-RAS, which may confer resistance to epidermal growth factor receptor (EGFR) inhibitors. Mixed lineage kinase-3 (MLK3) is a MAP3K that activates multiple MAPK pathways. The role of MLK3 in the pathophysiology and resistance to therapy of pancreatic adenocarcinoma has not been investigated. MLK3 is over expressed in pancreatic cancer cell lines compared to an immortalized pancreatic epithelial cell line. The requirement of MLK3 for cell proliferation and survival of pancreatic cancer cell lines, PANC-1 and MiaPaCa-2, was investigated using RNA interference (siRNA) and MLK inhibitor, K252a, alone or in conjunction with the EGFR inhibitor, Compound 56. Ablation of expression of MLK3 via siRNA-mediated gene silencing and pharmacological inhibition of MLK3 by K252a each decreased cell viability in both pancreatic cancer cell lines, with a concurrent decrease in the activation of ERK, JNK and AKT. Concomitant inhibition of EGFR and MLK3 induced apoptosis, as evidenced by increased cleavage of PARP and caspase-3. These results suggest that MLK3 plays an important role in survival and proliferation of pancreatic cancer cell lines and that inhibition of MLK3 may enhance the therapeutic efficacy of EGFR inhibitors in the treatment of pancreatic cancer.

The biological role of vitamin D outside of calcium homeostasis is still under evaluation. The ability of vitamin D to inhibit cell proliferation and induce differentiation makes it a potential modifier of neoplastic transformation. Vitamin D affects the cell cycle, apoptosis, hormone receptors, angiogenesis, and hypoxia, all of which are related to the breast cancer growth, progression and metastasis. A large percentage of the industrial-world population is deficient in vitamin D. Epidemiological evidence suggests that vitamin D deficiency increases the risk of breast cancer. Vitamin D may have synergistic, additive, or antagonistic effects when combined with other therapeutic agents against breast cancer. Vitamin D appears to depress aromatase inhibitor by acting through cytochrome P 450. This evidence along with pre-clinical and clinical studies, justify the inclusion of vitamin D in future clinical trials related to breast cancer in order to determine its efficacy as a part of the breast cancer therapeutic armament.

To understand the coordination of gene expression in the Salmonella typhimurium ilvIH-leuO-leuABCD gene cluster, we had previously identified a 72-bp AT-rich (78% A+T) DNA sequence element, AT4, which was capable of silencing transcription in a promoter nonspecific manner. LeuO protein provided in trans relieved (derepressed) AT4-mediated gene silencing (transcriptional repression), but underlying mechanisms remained unclear. In the present communication, the 72-bp DNA sequence element is further dissected into two functional elements, AT7 and AT8. LeuO binds to the 25-bp AT7, which lies closest to the leuO promoter in the AT4 DNA. After deletion of the AT7 DNA sequence responsible for LeuO binding from AT4, the remaining 47-bp AT-rich (85% A+T) DNA sequence, termed AT8, retains the full bi-directional gene-silencing activity, which is no longer relieved by LeuO. LeuO-mediated transcriptional derepression is restored when the LeuO binding site, AT7, is placed within close proximity to the gene silencer AT8. As a pair of functionally coupled transcription elements, the presence of an equal copy number of AT7 and AT8 within proximity is important for the transcription control. The characterization provides clues for future elucidation of the molecular details whereby LeuO negates the gene-silencing activity.

e15644 Background: Current limited evidence from observational studies suggest lack of survival benefit from liver transplantation (LT) for combined hepatocellular carcinoma with cholangiocarcinoma (cHCC-CC) when compared to surgical resection. This is in contrast to hepatocellular carcinoma (HCC) which has clear survival benefit with LT. We hypothesized that cHCC–CC patients have similar overall survival (OS) after LT compared to resection. Methods: Localized HCC and cHCC–CC patients treated with surgical resection versus transplant were identified in SEER Database (1973–2013). Kaplan-Meier method was used to examine survival with LT versus resection. Results: In the total period between 1973-2013, we identified 9,306 (5496 [59.06%] resection, 3810 [40.94%] transplant) patients with HCC, and 175 (107 [61.14%] resection, 68 [38.85%] transplant) patients with cHCC–CC. 3-year OS of patients undergoing LT remains significantly greater for HCC than for cHCC–CC (80.5% vs 59.9%, P < 0.01). Interesting, for period 2008-13, 3-yr OS for cHCC-CC patients undergoing LT was better than resection, although the difference was not statistically significant (66.4% vs 46.27%, p > 0.10). While there has been improved 3-year and 5-year OS from period 2002-07 to 2008-13 after LT for localized HCC patients (83.6% vs 79.4%, p < 0.002 and 76.4% vs 73.6, p < 0.01, respectively), there has been no significant improvement in 3-year or 5-year survival after for HCC-CC (66.4% vs 65.2%, p < 0.4 and 58.3% vs 55.3%, p > 0.4 respectively). Conclusions: Over the past decade, 3-yr OS of cHCC-CC with LT remains dismal and has not improved. However, LT in patients with localized cHCC–CC may have a potential survival benefit over liver resection, although clearly lower than the survival benefit of LT for HCC. Our results argue for a randomized trial for LT versus resection for localized cHCC-CC patients to obtain better understanding of survival benefit from the two surgical options.

e18097 Background: Appediceal cancers (AC) are rare, and often found on appendectomies. Adenocarcinomas represents approximately two-thirds of all AC. We performed the analysis of SEER database to understand the overall incidence and survival trends. Methods: We analyzed SEER database: Incidence - SEER 18 RegsResearch Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2015 Sub (1973-2013 varying). Cases diagnosed of AC between 1988 and 2013 were identified. Trend of incidence rate was calculated. Relative survival rates (RSR) were calculated stratified by age, gender, race, stage, histological subtypes which were divided into mucinous, non-mucinous and signet ring cell carcinoma (SRCC). We calculated survival difference for patient diagnosed before and after 2000. Results: Age adjusted incidence rate of appendiceal adenocarcinoma was 0.4 cases per 100,000 person years. Overall incidence rate increased on average 3.7% per 100,000 person years (P < 0.05). The highest increase was seen in SRCC (4.8% per 100,000 person years). Survival was worst in SRCC (5 years RSR-28.40%) compared to other types (5 year RSR- 61.0% and 52.90% for mucinous and non-mucinous carcinoma (P < 0.01). Survival significantly improved for patients diagnosed after 2000 for mucinous (5 years RSR -51.90% and 64.30%) and SRCC (5 year RSR-18.0% and 31.0%), respectively before and after 2000 in each category. No improvement in survival was found in non-mucinous carcinomas since 2000. While survival among different histological types was not different for localized disease, it was significantly better for regional or distant stages in mucinous cancers when compared to non-mucinous cancers (P < 0.01). Elderly patient ( > 65 years) showed significantly poor survival for mucinous and non-mucinous carcinomas, while there was no variation in survival based on age for SRCC. Moreover, females showed significantly poor survival (P < 0.05) compared to males for SRCC, while no variation in survival based on gender for other types. Survival was not different among different races. Conclusions: Incidence of appendiceal adenocarcinomas is increasing. The highest increase is seen in SRCC which has the worst survival. Survival from mucinous adenocarcinomas has improved significantly in last decade.

Background Autoimmune pancreatitis is a rare chronic inflammatory pancreatic disease that is increasingly being diagnosed worldwide. As a result of overlap in clinical and radiological features, it is often misdiagnosed as pancreatic cancer. We report the case of a patient with autoimmune pancreatitis that was initially misdiagnosed as pancreatic cancer. Case presentation A 31-year-old Caucasian man presented to our hospital with epigastric pain, jaundice and weight loss. His CA 19-9 level was elevated, and computed tomography and endoscopic ultrasound revealed a pancreatic head mass abutting the portal vein. Endoscopic retrograde cholangiopancreaticography showed narrowing of the biliary duct and poor visualization of the pancreatic duct. Fine-needle aspiration biopsy revealed atypical ductal epithelial cells, which raised clinical suspicion of adenocarcinoma. Because of the patient's unusual age for the onset of pancreatic cancer and the acuity of his symptoms, he was referred to a tertiary care center for further evaluation. His immunoglobulin G4 antibody level was 365 mg/dL, and repeat computed tomography showed features typical of autoimmune pancreatitis. The patient's symptoms resolved with corticosteroid therapy. Conclusion Autoimmune pancreatitis is a rare disease with an excellent response to corticosteroid therapy. Its unique histological appearance and response to corticosteroid therapy can reduce unnecessary surgical procedures. A thorough evaluation by a multidisciplinary team is important in rendering the diagnosis of autoimmune pancreatitis.

Biological complexity, inaccessible anatomical location, nonspecific symptoms, lack of a screening biomarker, advanced disease at presentation and drug resistance epitomise pancreatic ductal adenocarcinoma (PDA) as a poor-prognosis, lethal disease. Twenty-five years of research (basic, translational and clinical) have barely made strides to improve survival, mainly because of a fundamental lack of knowledge of the biological processes initiating and propagating PDA. However, isolation of pancreas cancer stem cells or progenitors, whole-genome sequencing for driver mutations, advances in functional imaging, mechanistic dissection of the desmoplastic reaction and novel targeted therapies are likely to shed light on how best to treat PDA. Here we summarise current knowledge and areas where the field is advancing, and give our opinion on the research direction the field should be focusing on to better deliver promising therapies for our patients.

To assess the role of neoadjuvant chemotherapy for locally advanced squamous head and neck cancer.Several phase III clinical trials in locally advanced squamous head and neck cancer show promising results for neoadjuvant platinum, taxane, and fluorouracil chemotherapy prior to definitive radiation or concurrent chemoradiation.Clinical trials comparing cisplatin and 5-fluorouracil with or without a taxane followed by radiation or concurrent chemoradiation show that the three-drug induction chemotherapy may improve survival particularly for unresectable tumors. Clinical trials comparing chemoradiation with and without induction three-drug chemotherapy are ongoing. Molecular and clinical considerations for using neoadjuvant chemotherapy in the treatment of locally advanced head and neck cancers are being explored.

Recent research has elucidated another mechanism for gene expression and signalling protein regulation in malignant cells. Histone deacetylases (HDACs) have been associated with silencing of tumour suppressor genes, and with other functions that promote malignant cell phenotype, such as the function of the chaperone protein heat shock protein (HSP)-90. Malignant cells overexpress some HDACs, and aberrant gene products have been shown to recruit HDACs to DNA to accomplish silencing of differentiation in other genes. Several chemical classes of small molecule inhibitors of HDAC have been synthesized, including small chain fatty acids, benzamides, hydroxamic acids and hybrid molecules. All have shown preclinical activity in vitro and/or in vivo in nanomolar to micromolar concentrations. Some have shown activity in clinical trials. One (vorinostat; suberoylanalide hydroxamic acid [SAHA]) has been approved by the US FDA for therapy of T-cell lymphomas. HDAC inhibitors show the most promising activity as single agents in haematological malignancies rather than solid tumours. Clinical trials testing combinations of HDAC inhibitors with other antineoplastic agents and with demethylating agents have shown promising results. HDAC inhibitors also seem to enhance radiation effects on malignant tissue, while potentially sparing toxicity to normal tissues. In this article, we review the rationale for development of HDAC inhibitors as therapy for malignant diseases, as well as the preclinical and clinical trial data for some HDAC inhibitors under development.

Primary malignant brain tumors account for 2 percent of all cancers in U.S. adults. The most common malignant brain tumor is glioblastoma multiforme, and patients with this type of tumor have a poor prognosis. Previous exposure to high-dose ionizing radiation is the only proven environmental risk factor for a brain tumor. Primary brain tumors are classified based on their cellular origin and histologic appearance. Typical symptoms include persistent headache, seizures, nausea, vomiting, neurocognitive symptoms, and personality changes. A tumor can be identified using brain imaging, and the diagnosis is confirmed with histopathology. Any patient with chronic, persistent headache in association with protracted nausea, vomiting, seizures, change in headache pattern, neurologic symptoms, or positional worsening should be evaluated for a brain tumor. Magnetic resonance imaging is the preferred initial imaging study. A comprehensive neurosurgical evaluation is necessary to obtain tissue for diagnosis and for possible resection of the tumor. Primary brain tumors rarely metastasize outside the central nervous system, and there is no standard staging method. Surgical resection of the tumor is the mainstay of therapy. Postoperative radiation and chemotherapy have improved survival in patients with high-grade brain tumors. Recent developments in targeted chemotherapy provide novel treatment options for patients with tumor recurrence. Primary care physicians play an important role in the perioperative and supportive treatment of patients with primary brain tumors, including palliative care and symptom control.

Salivary gland cancers are relatively rare and quite diverse. Current therapy relies on local ablation. There are few large clinical trials or randomized trials to guide treatment, especially for metastatic disease. This article reviews the epidemiology, staging, molecular characteristics, and treatment evidence for the most common types of salivary cancers and suggests potential future diagnostic and treatment directions. Progress in understanding the molecular and cell biology of salivary gland cancers may lead to the development of targeted therapies in these rare tumors. Multidisciplinary and multi-institutional collaborative studies are needed to help improve survival in salivary gland cancers.

Vitamin D deficiency, an important risk factor for osteoporosis and other chronic medical conditions, is epidemic in the United States. Uninsured women may be at an even higher risk for vitamin D deficiency than others owing to low intake of dietary and supplemental vitamin D and limited sun exposure.Our goal was to determine the prevalence of vitamin D deficiency in this vulnerable population.We enrolled 145 uninsured women at a County Free Medical Clinic in urban Michigan. Questionnaires were used to obtain information about demographics, medical history, vitamin supplementation, sunlight exposure, and dietary vitamin D intake.The 96 women who were tested for vitamin D status ranged in age from 21 to 65 years (mean 48 +/- 11), and 67% were vitamin D deficient as indicated by a 25-hydroxyvitamin D [25(OH)D)] level50 nmol/L (20 ng/mL). Non-Caucasians were 3 times more likely than Caucasians to be vitamin D deficient (P = .049). Mean dietary vitamin D intake was low (125 +/- 109 IU/d) and only 24% of the participants used any supplemental vitamin D. Participants with total vitamin D intake400 IU/day from diet and supplements were 10 times more likely to be vitamin D deficient than others (P.001).These results demonstrate a high prevalence of vitamin D deficiency in an uninsured, medically underserved female population. Uninsured women should be strongly encouraged to increase their vitamin D intake.

e18006 Background: Patient readmission within 30 days from discharge has been perceived to be an indicator of poor healthcare quality for high-cost medical conditions. Patient’s who undergo bone ma...

We studied the relationship between brain glucose metabolism patterns and objectively measured interictal epileptiform abnormalities in six children with intractable epilepsy and continuous spike-and-wave activity during slow-wave sleep. Five of the six patients showed lateralized positron emission tomographic (PET) findings, with the hemisphere showing a relative increase in glucose metabolism concordant with the presumed origin of the generalized interictal spike activity delineated by quantitative electroencephalographic (EEG) analysis. One of these five patients achieved seizure freedom following cortical resection involving the areas of unilateral multifocal hypermetabolism, and another patient has been approved for cortical resection. The results in the present study add further support to the hypothesis that the general ized spike-waves in most cases of continuous spike-and-wave activity during slow-wave sleep are the result of secondary bilateral synchrony. Resective surgery can be effective in selected patients with uncontrolled seizures associated with continuous spike-and-wave activity during slow-wave sleep provided that there is concordance between focal abnormalities on PET and EEG. ( J Child Neurol 2005;20:682—690).

The role of serotonin in prenatal and postnatal brain development is well documented in the animal literature. In earlier studies using positron emission tomography (PET) with the tracer alpha[(11)C]methyl-l-tryptophan (AMT), we reported global and focal abnormalities of serotonin synthesis in children with autism. In the present study, we measured brain serotonin synthesis in a large group of autistic children (n = 117) with AMT PET and related these neuroimaging data to handedness and language function. Cortical AMT uptake abnormalities were objectively derived from small homotopic cortical regions using a predefined cutoff asymmetry threshold (>2 S.D. of normal asymmetry). Autistic children demonstrated several patterns of abnormal cortical involvement, including right cortical, left cortical, and absence of abnormal asymmetry. Global brain values for serotonin synthesis capacity (unidirectional uptake rate constant, K-complex) values were plotted as a function of age. K-complex values of autistic children with asymmetry or no asymmetry in cortical AMT uptake followed different developmental patterns, compared to that of a control group of non-autistic children. The autism groups, defined by presence or absence and side of cortical asymmetry, differed on a measure of language as well as handedness. Autistic children with left cortical AMT decreases showed a higher prevalence of severe language impairment, whereas those with right cortical decreases showed a higher prevalence of left and mixed handedness. Global as well as focal abnormally asymmetric development in the serotonergic system could lead to miswiring of the neural circuits specifying hemispheric specialization.