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e16259 Background: Colloid carcinoma (CC) of the pancreas is a rare histopathological subtype of ductal adenocarcinoma (PDAC), with poorly defined prognostic factors and therapeutic outcomes. The aim of this study is to characterize the clinicopathological features and evaluate the overall survival (OS) and prognostic factors of patients with pancreatic CC using National Cancer Database (NCDB). Methods: Patients diagnosed with CC of the pancreas and PDAC between 2004 and 2016 were identified from the NCDB using ICD-O-3 morphology (8480/3 for CC and 8140/3 for PDAC) and topography codes (C25). Univariate and multivariable analyses were conducted and Kaplan-Meier analysis and Cox proportional hazards models were used to perform OS analysis. Results: A total of 56,846 patients met the inclusion criteria for the final analysis. Of the total population included, 2,430 patients (4.3%) had CC and 54,416 patients (95.7%) had PDAC. For both, CC and PDAC, there was a male preponderance (52.0%, 52.5%), Caucasians (85.1%, 84%), occurrence above the age of 70 (39.2%, 38.2%), and the most common primary site was the head of the pancreas (50.5%, 53%). For CC, the percentage of pathologic stage III colloid pancreas cancer appeared the lowest (3.5%, 85 patients), compared to stage I (16.7%), stage II (37.8%), and stage IV (42.1%). While in PDAC, the percentage of pathologic stage I (5.94%) and stage III (4.44%) patients was lower than stage II (37.21%) and IV (52.41%). CC and PDAC more frequently presented with < 5cm tumor, at academic or research cancer centers, and diagnosed between 2009 and 2013 compared to 2004–2008 ( p< 0.001). For both CC and PDAC, the majority underwent surgical resection (58%, 53%), systemic chemotherapy (57.8%, 63%) and did not receive radiotherapy (78.8%, 77.6%). A positive surgical margin on pathologic evaluation was associated with worse outcomes for CC and PDAC in both univariate and multivariate analysis (HR 1.61; 1.56–1.66; p< 0.001 and HR 1.43; 1.38–1.48, p< 0.001). CC had a better 1-year overall survival (OS) in all stages compared to PDAC (p < 0.001). In multivariate analysis, mucinous carcinoma histology, female sex, diagnosis between 2004 and 2009, well/moderately differentiated histology, chemotherapy, age at diagnosis less than 60, radiation therapy after surgery, and local surgical procedure of primary site and pancreatectomy (p < 0.001) were associated with better OS compared to PDAC. Colloid histology was associated with better 1-year overall survival (OS) in all stages compared to PDAC (p < 0.001). Conclusions: Colloid carcinoma of pancreas is associated with a better overall survival as compared to pancreatic ductal adenocarcinoma. This is the largest study to address the clinical features and outcomes of colloid carcinoma of pancreas.

e16085 Background: Treatment of localized esophageal, gastroesophageal junction (GEJ), and stomach cancer is neoadjuvant therapy with either chemoradiation or chemotherapy followed by surgery. Treatment for T1b-2 stage disease is not well evaluated and this stage is underrepresented in prospective studies. The aim of this study is to evaluate survival outcomes among the three treatment modalities (neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiation (NACRT), and upfront surgery (US)) in this population using the National Cancer Database (NCDB). Methods: Patients (pts) with clinical stage T1b-2N0 and any pathological stage (excluding metastatic) adenocarcinoma of the esophagus, GEJ, and stomach treated with neoadjuvant therapy or upfront surgery, with or without adjuvant chemotherapy (AC), were identified between 2004 and 2015 in the NCDB. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazard models were used to identify the association between the three treatment modalities and overall survival (OS). Results: A total of 2260 pts were analyzed. The median follow-up was 66.6 months. The median age was 67 years. Most pts were White (86%) and male (77%). 1018 (45%) had moderately-differentiated grade, while 946 (42%) had poorly-differentiated/undifferentiated grade. The most common site of disease was the lower third of esophagus (34.1%). 161 pts (7%) received NACT, of whom 45 pts received AC; 537 pts (24%) received NACRT, of whom 40 pts received AC. 1562 pts (69%) underwent US, of whom 146 pts received AC. US with AC was associated with the best survival, followed by NACT with AC; median OS was 90.1 and 86.8 months for surgery with AC and NACT with AC, respectively. NACRT was associated with the worst survival (39.5 and 40.2 months with and without AC, respectively). The 5-year OS rates were 59.8%, 58.5%, 52.1%, 44.9%, 37.3%, and 37.8%, for US, NACT, and NACRT, with and without AC, respectively. The rate of tumor upstaging was highest in the NACT group, followed by the NACRT group, and lowest in the US group. Postsurgically, 62 (39%) and 48 (30%) pts in the NACT group and 198 (37%) and 161 (30%) pts in the NACRT group had upstaging in their T and N stages, respectively, compared to 214 (13%) and 326 (21%) pts in the US group. For the 1107 pts who also had pathological T1b-2N0 stage disease following US, no difference in survival was observed with or without AC. Conclusions: Upfront surgery with adjuvant chemotherapy and perioperative chemotherapy are associated with the best survival compared to preoperative radiotherapy. This is the largest study to address the best approach for the treatment of T1b-2 stage disease.

Silencing of tumor suppressor and DNA repair genes through methylation plays a role in cancer development, growth and response to therapy in colorectal and pancreatic cancers. Heat shock protein 90 (HSP90) regulates transcription of DNA methyltransferase enzymes (DNMT). In addition, DNMTs are client proteins of HSP90. The aim of this study is to evaluate the effects of HSP90 inhibition on DNA methylation in colorectal and pancreatic cancer cell lines. Our data shows that inhibition of HSP90 using ganetespib resulted in downregulation of mRNA and protein expression of DNMT1, DNMT3A, and DNMT3B in HT-29 and MIA PaCa-2 cell lines. This in turn was associated with a drop in the fraction of methylated cytosine residues and re-expression of silenced genes including MLH-1, P16 and SPARC. These effects were validated in HT-29 tumors implanted subcutaneously in mice following in vivo administration of ganetespib. This work demonstrates the effectiveness of ganetespib, an HSP90 inhibitor in modulating DNA methylation through downregulation of DNMT expression.

AIMS Heart failure (HF) is a multi-organ, pro-inflammatory syndrome that impairs bone metabolism. Pro-inflammatory cytokines and bone catabolism enhance periodontal disease, a local inflammatory, bacteria-induced disease that causes bone loss and periodontal soft tissue destruction. METHODS AND RESULTS Medical and dental examinations were performed on patients with HF (n = 39), following heart transplantation (post-HTx, n = 38) and controls (n = 32). Blood, saliva, and gingival crevicular fluid were analysed for bone metabolism and inflammation markers. HF average New York Heart Association classification was III. Average time since HTx was 1414 days. Pro-inflammatory tumour necrosis factor-alpha was higher in HF and HTx as compared with controls (P

Colorectal cancer (CRC) is a heterogeneous disease for which the treatment backbone has primarily been cytotoxic chemotherapy. With better understanding of the involved molecular mechanisms, it is now known that there are a number of epigenetic and genetic events, which are involved in CRC pathogenesis. Specific biomarkers have been identified which can be used to determine the clinical outcome of patients beyond tumor staging and predict for treatment efficacy. Molecular testing is now routinely performed to select for patients that will benefit the most from targeted agents and immunotherapy. In addition to KRAS, NRAS, and BRAF mutation (MT), analysis of DNA mismatch repair (MMR) status, tumor infiltrating lymphocytes, and checkpoint protein expression may be helpful to determine whether patients are eligible for certain therapies. The focus of this article is to discuss present and upcoming biomarkers for immunotherapy in CRC.

Research that involves both neuroscience and art often attempts to explain the aesthetic experience of ‘beauty’ in visual art, and to define the function of art in neural terms; less has been written concerning the neural correlates of poetry reading. It is suggested that there are existing areas of study in neuroscience that may help elucidate how we enjoy literature beyond pure neuroaesthetics, such as research in creative problem-solving, knowledge-based pleasure, and music. This essay endeavours to bring together insights from both neuroscience and literature to shed light on how and why we take pleasure in interpreting T.S. Eliot's ‘The Love Song of J. Alfred Prufrock’. It is proposed that the pleasures of reading ‘Prufrock’ are ultimately associated with the ways in which the reader's expectations are confirmed or challenged. While the conclusions of this paper are intentionally constrained to a single poem, they are potentially generalisable.

The incidence of colorectal cancer (CRC) in young adults is increasing. Minority populations with CRC are known to have worse survival outcomes. The aim of this study is to evaluate adults under age 50 years with CRC by race and ethnicity.Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariable testing was done to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used for association between patient characteristics and survival.A total of 83,449 patients between 18 and 50 years of age were identified. Median age was 45 years (SD ± 6), with male preponderance (53.9%). 72% were non-Hispanic Whites (NHW), Blacks (AA) were 15.1% and Hispanics (who did not identify as Blacks) were 8.3% of the study population. Distribution across stages IIV was 15.6%, 22.4%, 33.9% and 27% consecutively. 41.8% of NHW and 28.4% of AA had rectal cancers (p 0.001). Despite equally receiving standard of care (SOC) as per national guidelines, AA had significantly lower 5-year survival rates (58.8%) compared to Hispanics (64.8%) and NHW (66.9%; HR 1.42; 1.38-1.46; p 0.001). Furthermore, NHW (HR 0.85; 0.81-0.88; p 0.001) and Hispanics (HR 0.75; 0.70-0.79; p 0.001) were more likely to benefit from chemotherapy compared to AA. SOC utilization was associated with improved survival across all racial groups, especially in AA (HR 0.64; 0.60-0.69; p 0.001).Despite comparable rates of SOC utilization, AA young adults had worse survival outcomes compared to other races. More colon (compared to rectal) cancers in AA may have contributed to their worse outcomes.

Pancreatic cancer (PDAC) with localized stage includes resectable (RPC), borderline resectable (BRPC), or locally advanced unresectable (LAPC). Standard of care for RPC is adjuvant chemotherapy. There are no prospective randomized trials for best treatment of BRPC and LAPC. We evaluate the impact of induction chemotherapy on localized PDAC.Charts of PDAC patients treated at Emory University between 2009 and 2016 were reviewed. The primary end point was overall survival (OS).A total of 409 localized PDACs were identified. Resectability was prospectively determined at a multidisciplinary tumor conference. Median age was 67 years (range, 30-92 years), 49% were male, 66% were white, 171 had RPC, 131 had BRPC, and 107 had LAPC. Median OSs for RPC, BRPC, and LAPC were 19.5, 16.1, and 12.7 months, respectively. Type of chemotherapy and age were predictors of OS. Induction chemotherapy was used in 106 with BRPC (81%) and 74 with RPC (56.5%); patients with BRPC who received combination chemotherapy and resection had a median OS of 31.5 compared with 19.5 months in patients with RPC (P = 0.0049). Patients with LAPC had a median OS of 12.7 months.In patients with BRPC who undergo resection after induction treatment, the OS was significantly better than in patients with RPC. Neoadjuvant treatment should be considered for all localized PDACs.

There are variations in the use of adjuvant chemotherapy (AC) in stage II colon cancer (CRC). We sought to determine which patients received chemotherapy, what factors were associated with receipt of AC, and how this impacted overall survival.Using the National Cancer Database, patients with stage II CRC who underwent surgical resection were selected; patients who received radiation or neoadjuvant chemotherapy were excluded. High-risk features (HRFs) were defined as pathological tumor stage IV, positive surgical margins, and perineural or lymphovascular invasion. Multivariable and subgroup analysis with eight subgroups stratified in the presence of HRFs, age, and the Charlson-Deyo score was performed.Of 77,739 patients identified with stage II CRC, 18.3% received AC. Younger, healthier patients with HRFs had the highest chemotherapy receipt rate (46.7%), whereas patients without HRFs, ≥ 75 y, and with the Charlson-Deyo score of 2+ had the lowest rate (2.1%). Community cancer centers were more likely to initiate AC (odds ratio = 1.24 P 0.01) especially among healthy HRF-negative patients and younger patients. No significant racial differences in AC use were observed. AC was associated with improved overall survival in subgroups with HRFs (hazard ratio [HR]: 0.81 P 0.001; HR: 0.75 P 0.001; HR: 0.65 P = 0.03; HR: 0.55, P 0.001) but not in patients without HRFs.AC receipt rates differed depending on patient age and type of institution delivering care. AC was associated with survival benefits only in patients with HRFs regardless of age. These findings are clinically relevant to inform appropriate use of AC in stage II CRC.

Background HCC variants are rare primary hepatic tumors. The aim of this study is to compare clinical characteristics and outcomes of HCC variants with pure HCC. Methods Patients diagnosed between 2004 and 2013 with ICD-O-3 8180/3 and 8170/3-8175/3 were identified from the National Cancer Database. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p

BACKGROUND: Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard of care approach includes curative-intent surgery, often following preoperative (neoadjuvant) radiotherapy (RT) to increase rates of tumor downstaging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. METHODS: Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT utilizing immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. RESULTS: Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger-scale clinical trials. CONCLUSIONS: This review by the NCI’s Radiation Research Program Colorectal Cancer Working Group provides an updated comprehensive examination of the continuously evolving State of the Science regarding radiosensitizer drug development in the curative treatment of CRC.

Background: Gastric squamous cell carcinoma (GSCC) and gastric adenosquamous carcinoma (GASC) comprise less than 2% of gastric cancers. The current knowledge about clinical presentation, treatment modalities and outcomes of GSCC and GASC is limited. The aim of this study is to characterize the clinicopathological features, treatment modalities, and outcomes of GSCC and GASC in comparison to gastric adenocarcinoma (GAC) in National Cancer Database (NCDB). Methods: Patients with GSCC, GASC and GAC between 2004 and 2013 were identified using ICD-O-3 histology and topography codes 8070/3, 8560/3, 8140/3 and C16.0-9. Univariate, and multivariate analysis were performed, and Kaplan-Meier curves was used to compare survival based on histological subtype. Results: A total of 61,215 patients were identified, 836 (1.4%) GSCC, 327 (0.5%) GASC, 60,052 (98.1%) GAC between 2004 and 2013, in which 77.4% was Caucasian and 68.7% was male, 46.6% of tumors were in gastric cardia and 13.7% in gastric antrum. Neoadjuvant and adjuvant chemotherapy was administered in 11.2%, 14.1%, 8.9% vs. 2.9%, 11.9%, 9.5% for GSCC, GASC, GAC. Surgery was performed in 26.0%, 54.4%, 45.2% of GSCC, GASC, GAC. Radiotherapy was administered in 48.1%, 37.6%, 31.6% of GSCC, GASC, GAC. Median overall survival was 8.9, 9.9 and 13.2 months for GSCC, GASC, GAC. On multivariate analysis squamous cell (HR =1.14; 95% CI, 1.06–1.24, P=0.001) and adenosquamous cell histology (HR =1.52; 95% CI, 1.35–1.73, P

Background Given the increasing number of available immunotherapeutic agents, more patients are presenting after failing immunotherapy in need of new treatment options. In this study, we investigated the clinical outcomes of patients treated with sequential immunotherapy. Methods We performed a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute from 2009 to 2017. We included 49 patients with an immune checkpoint inhibitor (ICI)-indicated histology. Patients were analyzed based on whether they had received prior ICI. Clinical outcomes were overall survival (OS), progression-free survival (PFS), and clinical benefit (best response of complete response, partial response, or stable disease). Univariate analysis (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazard or logistic regression model. Covariates included age, liver metastases, number of prior lines of therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). More than half of patients (n = 27, 55%) received at least one ICI prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination, and ten received multiple ICI. In MVA, ICI-naive patients had significantly longer OS (HR: 0.22, CI: 0.07–0.70, p = 0.010) and trended towards higher chance of CB (HR: 2.52, CI: 0.49–12.97, p = 0.268). Patients who received prior ICI had substantially shorter median OS (10.9 vs 24.3 months, p = 0.046) and PFS (2.8 vs. 5.1 months, p = 0.380) than ICI-naive patients per Kaplan-Meier estimation. Within the ICI-naive group, 78% (7 of 9) of patients who received prior interleukin (IL-2) or interferon gamma (IFNγ) experienced disease control for at least 6 months, compared to a disease control rate of 15% (2 of 13) in patients who had received chemotherapy, targeted therapy, or no prior treatment. Conclusions ICI-naive patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. These results should be validated in a larger study.

35 Background: The combination of oxaliplatin, bolus 5-FU (b5FU), infusional 5-FU (5-FUCI), and leucovorin (LV) is the preferred first line treatment option for mCRC. This study evaluates the impact of b5FU on survival in first line therapy for mCRC patients treated with mFOLFOX6. Methods: This was a retrospective chart review of patients ≥ 18 years old with mCRC receiving palliative first line mFOLFOX6 chemotherapy with or without b5FU/ LV from January 1, 2010 through June 1, 2019 at Winship Cancer Institute, Emory University. Data collection included the following: demographics (age, race, gender), disease characteristics (tumor sidedness), microsatellite status, KRAS status, BRAF status, addition of monoclonal antibodies (bevacizumab, panitumumab), ECOG PS, grade 3/4 neutropenic events, addition of growth factors, and treatment delays. The primary endpoint was PFS. The multivariable Cox proportional hazards model for PFS and OS was performed with selected covariates of interest. Results: A total of 252 patients with mCRC met the inclusion criteria. Median follow-up time was 2.4 years. 161 patients (64%) received mFOLFOX6 with b5FU/LV and 91 patients (36%) received mFOLFOX6 with no b5FU/LV. More cycles were delivered in the b5FU group as compared to the non-b5FU group (mean, 4.8 v. 3.8 cycles, respectively; p < 0.001). There were no differences in grade 3 and 4 neutropenic events between groups. Growth factor usage was numerically higher in the bolus group though not significantly different (p = 0.06). No difference was observed in treatment delays between groups (p = 0.83). There was no statistical difference in PFS between treatment groups (1.1 years in the b5FU/LV group v. 0.8 years (95% CI, 0.6-1.0) in the no 5-FU/LV bolus group; p = 0.076). The median OS was 2.5 years in the b5FU/LV group compared to 1.8 years in the no b5FU/LV group (p = 0.012). On univariate analysis, tumor sidedness and performance status were significantly different between groups. On multivariate analysis, none of the variables were significantly different between groups. Conclusions: The omission of the b5FU/LV from mFOLFOX6 does not significantly impact PFS, toxicity or treatment delays. However, OS is significantly shorter when the b5FU/LV is omitted suggesting the clinical importance of maintaining bolus administration with 5-FUCI in the first line palliative treatment of mCRC.

125 Background: Pathologic staging in colorectal cancer (CRC) is crucial in patient management. Data regarding the impact of size/horizontal tumor extent is limited, contradictory and currently excluded from the American Joint Committee on Cancer (AJCC) staging model. However, a previously published SEER analysis showed that AJCC stages I and IIIA have similar 2- and 5- year survival rates, and worse rates for stage II. Using the largest cohort to date, we report the impact of primary tumor size on CRC survival. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2010 and 2015. Univariate and multivariate analyses were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor/patient characteristics and overall survival (OS). Results: A total of 61,145 patients were identified with a similar gender distribution (M/F:50.9%/49.1%). The mean age was 62.7years (SD+/-14.1) and 82% were non-Hispanic Whites. Majority had colon primary (82.7%) and 82.4% had microsatellite stable (MSS) disease. Distribution across stages I-IV was 20.1%, 32.1%, 34.7% and 13.2% respectively. Among the total study population, AJCC stage correlated closely with OS on multivariate analysis (HR 1.49, 2.29, 8.38 for stages II to IV compared to stage I), while the distinguishing power for tumor size was relatively mild (HR 1.19 and 1.33 for 5-10 cm and >5cm compared to 10cm were associated with worse survival compared to those 10cm (HR 1.57; 1.37-1.80; p

TPS153 Background: The clinical benefit of approved therapies in patients (pts) with metastatic colorectal cancer (mCRC) who progress on first- and second-line chemotherapy (FOLFOX and FOLFIRI) is limited. In pts with chemotherapy-refractory RAS wild type mCRC, antibodies targeting EGFR offer a monotherapy response rate of approximately 20% and a progression-free survival (PFS) of 4 months (Price 2014). HER2 is a validated target in gastric and breast cancers, with HER2 amplification occurring in ~3–5% of pts with mCRC. Tucatinib (TUC), recently approved for HER2+ metastatic breast cancer, is a tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR. In pt-derived xenograft models of HER2+ mCRC, the combination of TUC + trastuzumab (TRAS) showed significantly greater antitumor activity compared with either agent alone (Kulukian 2020). The MOUNTAINEER trial was initiated to evaluate the efficacy and safety of TUC in combination with TRAS in pts with HER2+ RAS wild-type mCRC. Interim analysis of the initial 26 pts enrolled in MOUNTAINEER demonstrated an objective response rate (ORR) of 52.2% (12 partial responses [PRs] in 23 evaluable pts), median duration of response of 10.4 months, with a median PFS of 8.1 months and a median overall survival (OS) of 18.7 months (Strickler 2019). Based on these results, the trial was expanded to enable better estimation of ORR and safety. Methods: MOUNTAINEER (NCT03043313) is an open-label, pivotal phase 2 trial that initially consisted of a single cohort of up to 45 pts (Cohort A) treated with TUC (300 mg BID) and TRAS (8 mg/kg IV followed by 6 mg/kg IV every 3 weeks). The trial was expanded to include an additional 70 pts randomized 4:3 into 2 cohorts: Cohort B (N = 40) who will receive TUC + TRAS, and Cohort C (N = 30) who will receive TUC monotherapy. Pts in Cohort C will be treated with TUC (300 mg orally twice daily) with the option to crossover to TUC + TRAS if an objective response is not achieved by 12 weeks, or if progressive disease develops at any time. Eligible pts have RAS wild-type and HER2+ mCRC, and must have previously received regimens that include fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and an anti-PD-1 if the tumor has dMMR proteins or is MSI-H. Pts who have received prior HER2-directed therapies are not eligible. Additionally, pts must have measurable disease and ECOG PS of 0 to 2. The primary endpoint of this trial is confirmed ORR (per RECIST v1.1) in Cohorts A + B as assessed by blinded independent central review. Secondary endpoints include duration of response, PFS, OS, and safety and tolerability. Enrollment is ongoing in the US and planned for the EU. Clinical trial information: NCT03043313.

95 Background: Preclinical data suggests metformin can improve immune exhaustion of tumor infiltrating lymphocytes and potentiate the effects of PD-1 blockade. By normalizing the hypoxic TME, metformin was shown to improve cytotoxic T cell function and efficacy of anti-PD-1 antibody in highly aggressive B16 melanoma and MC38 colon adenocarcinoma tumor models. Based on this preclinical rationale we conducted a phase II study with nivolumab and metformin combination in treatment refractory MSS metastatic colorectal cancer (mCRC). Methods: Nivolumab 480 mg IV every 4 weeks and Metformin 1000 mg po twice daily was administered in 28-day cycles following a 14-day metformin only lead-in phase.Eligible patients included stage IV metastatic treatment refractory MSS mCRC (patients must have received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, adequate organ function, no prior anti PD-1 agent. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS) and progression free survival (PFS). Simon’s two-stage Minimax design was employed (H0: ORR =4%; H1: ORR=15%; alpha = 0.1; power =80%). If ≥1 objective response was observed in the first evaluable 18 patients, 10 additional patients would be included in the cohort. ≥3 objective responders in 28 patients would be required to be considered positive study. Pre-treatment and on-treatment research biopsies and correlative peripheral blood specimens were collected. Results: A total of 24 patients were enrolled, 6 patients were replaced per protocol, and 18 patients had evaluable disease. Of the 18 evaluable patients 11/18 (61%) were female, median age 58 [IQR 50-67]. 2 patients had prolonged stable disease (4 and 10 cycles). No patients had objective response based on RECIST 1.1. Median OS and PFS was 5.1 months [95% CI (2-11.7)] and 2.3 months [95% CI (1.7-2.4)], respectively. Most common grade 3 and 4 toxicities were anemia (n=2) and diarrhea (n=2). Conclusions: In treatment refractory MSS mCRCnivolumab and metformin combination was well tolerated. Two patients achieved stable disease, but no objective response was seen; therefore, the study did not proceed with the second stage of enrollment. Immunologic correlative analysis of this study is ongoing. Clinical trial information: NCT03800602.

Background The survival impact of multi-agent (MAC) compared with single-agent (SAC) adjuvant chemotherapy (AC) in elderly patients with stage III colon cancer (CC) remains controversial. The aim of this study was to compare survival outcomes of MAC and SAC in this population utilizing the National Cancer Database (NCDB). Patients and Methods Patients aged ≥70 years with pathological stage III CC diagnosed in 2004-2015 were identified in the NCDB. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazard models were used to identify associations between MAC vs. SAC and overall survival (OS). Results Among 41 707 elderly patients (≥70 years old) with stage III CC, about half (n = 20 257; 48.5%) received AC; the majority (n = 12 923, 63.8%) received MAC. The median age was 79 (range 70-90). The majority were female (n = 11 201, 55.3%), Caucasians (88%) and had moderately differentiated tumor grade (n = 12 619, 62.3%), tumor size >4 cm (11 785, 58.2%), and negative surgical margins (18 496, 91.3%). Low-risk stage III CC constituted 50.6% (n = 10 264) of the study population. High-risk stage III CC was associated with worse OS compared with low-risk disease (HR 0.35, 0.34-0.36, P < .001). Multi-agent chemotherapy was associated with a better 5-year OS compared with SAC (P < .001). High-risk stage III patients who received MAC vs. SAC had an OS of 4.2 vs. 3.4 years, respectively (P < .001). Low-risk stage III patients who received MAC vs. SAC had a median OS of 8.5 vs. 7 years (P < .001). In univariate and multivariable analyses, male sex, positive surgical margin, insurance and facility types, age, year of diagnosis, tumor size, and Charlson-Deyo score of >2 were associated with worse OS (P < .05). Conclusions Any adjuvant chemotherapy has a trend of survival benefits. Multi-agent chemotherapy seems to have an enhanced benefit in the 70-75 age group. Multi-agent chemotherapy seemed to have similar efficacy as SAC in those aged >76 years.

TPS143 Background: Patients with KRAS and NRAS ( RAS) wild-type mCRC benefit from the epidermal growth factor receptor (EGFR) monoclonal antibodies (Abs) panitumumab and cetuximab, but nearly all patients experience resistance. Blood-based profiling of cell free DNA (cfDNA) can identify genomic alterations that drive acquired EGFR Ab resistance. After discontinuation of anti-EGFR Abs, acquired genomic alterations decay over time to undetectable levels. Some studies have suggested clinical benefit from EGFR Ab rechallenge, but there is limited evidence that EGFR Ab rechallenge improves survival compared to standard of care (SOC) therapies. We hypothesize that cfDNA profiling will identify patients appropriate for panitumumab rechallenge, and that these molecularly selected patients will have improved survival compared to current SOC therapies. Methods: This is a randomized phase II, open label study designed to compare the overall survival (OS) of panitumumab rechallenge versus SOC (investigator choice TAS-102 or regorafenib). Secondary objectives include comparisons of progression free survival, objective response rate, clinical benefit rate, and quality of life as measured by the linear analogue self-assessment (LASA) questionnaire. Eligible patients have radiographically measurable KRAS, NRAS, and BRAF codon 600 wild-type mCRC based on tumor tissue testing, and must have experienced progression or intolerance to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF Ab, and an anti-PD-1 Ab if the tumor has mismatch repair deficiency or is MSI-H. Progression after at least 4 months treatment with an anti-EGFR Ab is required. All patients must be enrolled in the COLOMATE cfDNA screening protocol (NCT03765736) and meet molecular eligibility based on Guardant360 cfDNA profiling (absence of amplification of ERBB2, KRAS, NRAS, and MET; absence of mutations of BRAF, EGFR, ERBB2, KRAS, NRAS, and MET [mutant allele frequency > 0.5%]). Greater than 90 days must have elapsed between the most recent treatment with an anti-EGFR Ab and cfDNA profiling. Dosing for all study drugs is according to clinical SOC. 120 patients will be randomized 1:1 to panitumumab rechallenge or SOC. With 83 OS events, this study will have 80% power to detect an improvement in median OS from 6.5 to 10 months (HR=0.65; 1-sided α= 0.15). This study began enrollment in 6/2020. Recruitment is ongoing at 16 sites in the Academic and Community Cancer Research United (ACCRU) network (ACCRU-GI-1623). Clinical trial information: NCT03992456.

Background Left ventricular assist devices are increasingly being used in patients with advanced heart failure as both destination therapy and bridge to transplant. We aimed to identify histomorphometric, structural and inflammatory changes after pulsatile- and continuous-flow left ventricular assist device placement. Methods Clinical and echocardiographic data were collected from medical records. Aortic wall diameter, cellularity and inflammation were assessed by immunohistochemistry on aortic tissue collected at left ventricular assist device placement and at explantation during heart transplantation. Expression of adhesion molecules was quantified by Western blot. Results Decellularization of the aortic tunica media was observed in patients receiving continuous-flow support. Both device types showed an increased inflammatory response after left ventricular assist device placement with variable T-cell and macrophage accumulations and increased expression of vascular E-selectin, ICAM and VCAM in the aortic wall. Conclusions Left ventricular assist device implantation is associated with distinct vascular derangements with development of vascular inflammation. These changes are pronounced in patients on continuous-flow left ventricular assist and associated with aortic media decellularization. The present findings help to explain the progressive aortic root dilation and vascular dysfunction in patients after continuous-flow device placement.

Mismatch repair–deficient (dMMR) colorectal cancer (CRC) is caused by Lynch syndrome (LS) in 3% and sporadic inactivation of MLH1 by hypermethylation (MLH1-hm) in 12% of cases. It is not clear whether outcomes between LS-associated and MLH1-hm CRC differ. The objective of this study was to explore differences in clinical factors and outcomes in these two groups. Patients with dMMR CRC identified by immunohistochemistry staining and treated at a single institution from 1998 to 2012 were included. MLH1-hm was established with BRAF mutational analysis or hypermethylation testing. Patients’ charts were accessed for information on pathology, germ-line MMR mutation testing, and clinical course. A total of 143 patients had CRC associated with LS (37 patients, 26%) or MLH1-hm (106 patients, 74%). Patients with LS were younger, more often male, presented more often with stage III disease, and had more metachronous disease than patients with MLH1-hm tumors. There was no difference in cancer-specific survival (CSS) between the groups; overall survival was longer in patients with LS, but this difference was minimal after adjusting for age and stage at diagnosis. CSS did not differ in LS-associated CRC compared with MLH1-hm CRC, suggesting that they carry a similar prognosis. Genet Med 18 9, 863–868.

Background Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum-based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. Methods Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). Results When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single-mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. Conclusions In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66. © 2016 American Cancer Society.

To determine the state of the health and supportive services available to elderly people with dementia - and their families - in rural Lanxi county, in the province of Zhejiang, China.In November 2014 and January 2015, we interviewed 14 key informants on dementia care face-to-face, using a semi-structured questionnaire. The informants included three rural physicians, an urban geriatrician, seven directors of institutions for the care of the elderly and three officials of the civil affairs bureau. We also completed in-depth interviews with five family caregivers of elderly people with dementia.The interviewees indicated that there was a lack of specialized services designed specifically to address the needs of individuals with dementia and their family members. Non-psychiatric medical services and the available facilities for long-term care appeared to be ill-equipped to manage these needs. They lacked both clinical staff and standardized, evidence-based practices for the diagnosis, care, treatment and rehabilitation of patients with dementia. As care facilities often refused to admit elderly people with dementia, families were generally forced to care for elderly relatives with dementia at home.In Lanxi county - and probably in much of rural China - more public resources are needed to support family caregivers and to improve the capacity of care facilities for the elderly to care for individuals with dementia.Déterminer la situation en matière de services médicaux et de services d’aide proposés aux personnes âgées atteintes de démence – et à leurs familles – dans le comté rural de Lanxi, province de Zhejiang, en Chine.En novembre 2014 et janvier 2015, nous avons interrogé en face à face 14 informateurs clés au sujet de la prise en charge des personnes atteintes de démence, à l'aide d'un questionnaire semi-directif. Ces informateurs comprenaient trois médecins de campagne, un gériatre de ville, sept directeurs d'institutions accueillant des personnes âgées et trois fonctionnaires du bureau des affaires civiles. Nous nous sommes également entretenus en détail avec cinq aidants familiaux s'occupant de personnes âgées atteintes de démence.Les personnes interrogées ont fait part de l'absence de services spécialisés permettant de répondre aux besoins des personnes atteintes de démence et de leurs proches. Il est apparu que les services médicaux non psychiatriques et les structures de soins de longue durée disponibles étaient mal outillés pour répondre à ces besoins. Ils manquaient autant de personnel clinique que de pratiques standardisées reposant sur l'expérience pour le diagnostic, la prise en charge, le traitement et la rééducation des patients atteints de démence. Comme les établissements de soins refusaient souvent d'admettre les personnes âgées atteintes de démence, les familles étaient généralement obligées de s'en occuper à la maison.Le comté de Lanxi – et probablement de nombreuses autres régions de Chine rurale – nécessite davantage de ressources publiques pour soutenir les aidants familiaux et renforcer la capacité des établissements accueillant des personnes âgées à prendre en charge les personnes atteintes de démence.Determinar el estado de los servicios de salud y de apoyo disponibles para las personas mayores con demencia (y sus familias) en el condado rural de Lanxi, en la provincia de Zhejiang, China.En noviembre de 2014 y enero de 2015 se entrevistó a 14 informadores clave sobre el cuidado de la demencia de forma presencial, utilizando un cuestionario semiestructurado. Entre los informadores se encontraban tres médicos rurales, un geriátrico urbano, siete directores de instituciones de cuidados a las personas mayores y tres empleados públicos de la oficina de asuntos civiles. También se realizaron entrevistas a fondo con cinco cuidadores familiares de personas mayores con demencia.Los entrevistados indicaron que había una falta de servicios especializados diseñados especialmente para tratar las necesidades de individuos con demencia y sus familiares. Los servicios médicos no psiquiátricos y las instalaciones disponibles para cuidados a largo plazo no parecían estar bien pertrechados para abordar estas necesidades. Carecían de personal clínico y prácticas estandarizadas basadas en pruebas para el diagnóstico, cuidado, tratamiento y rehabilitación de pacientes con demencia. Puesto que las instalaciones de atención solían rechazar a personas mayores con demencia, las familias normalmente se veían obligadas a cuidar de sus parientes ancianos con demencia en sus hogares.En el condado de Lanxi (y probablemente en gran parte de la China rural) se necesitan más recursos públicos para apoyar a los cuidadores familiares y mejorar la capacidad de las instalaciones de atención para las personas mayores, de modo que puedan tratar a personas con demencia.الوقوف على الحالة الصحية والخدمات الداعمة المتاحة لكبار السن المصابين بالخَرَف (تدهور القدرات الذهنية) وأسرهم في مقاطعة "لانشي" الريفية في إقليم "تشجيانغ" بالصين.في نوفمبر/تشرين الثاني من عام 2014 ويناير/كانون الثاني من عام 2015، قمنا بإجراء مقابلات مع 14 من المبلّغين الرئيسيين عن رعاية الخَرَف مباشرةً، وذلك باستخدام استبيان شبه مقنن. وتضمنت مجموعة المبلّغين ثلاثة أطباء ريفيين، واختصاصيًا في أمراض الشيخوخة بالمناطق الحضرية، وسبعة مدراء في مؤسسات لرعاية كبار السن، وثلاثة مسؤولين من مكتب الشؤون المدنية. كما قمنا أيضًا باستكمال مقابلات متعمقة مع خمسة من عائلات مقدمي الرعاية الصحية لكبار السن المصابين بالخَرَف.أشار الأشخاص الذين جرت مقابلتهم إلى وجود نقص في الخدمات المتخصصة المصممة خصيصًا لتلائم احتياجات المصابين بالخَرَف وأفراد أسرهم. وبدت الخدمات الطبية غير النفسية والمرافق المتاحة للحصول على الرعاية طويلة الأمد غير مؤهلة لملاءمة هذه الاحتياجات، فقد كانت تفتقد إلى وجود الطاقم الطبي والممارسات المعيارية والمبنية على الشواهد لأغراض التشخيص وتقديم الرعاية والعلاج وإعادة التأهيل للمرضى المصابين بالخَرَف. ونظرًا لأن مرافق الرعاية الصحية غالبًا ما ترفض قبول علاج كبار السن المصابين بالخَرَف، فقد أجبرت الأسر بشكل عام على رعاية الأقارب المسنين المصابين بالخَرَف في المنزل.في مقاطعة "لانشي" – وربما في العديد من المناطق الريفية في الصين – هناك حاجة إلى المزيد من الموارد العمومية لدعم مقدمي الرعاية من بين أفراد الأسرة وتحسين قدرة مرافق رعاية كبار السن لرعاية المصابين بالخَرَف.旨在确定——中国浙江省兰溪县农村——痴 呆老人的健康状态及其家人享有的支持服务。.2014 年 11 月至 2015 年 1 月，我们利用半结构式 问卷面对面访问了 14 名痴呆护理方面的关键受访者。此受访者包括三名农村医师、一名城市老年病学专家、 七名养老院主任和三名民政局的办事人员。我们还对 五名老年痴呆的家庭护理人员进行了深度访问。.此受访者指出缺乏专门针对满足痴呆老人和其家 庭成员需求的专业服务。非精神科医疗服务和长期护 理的有效机构在管理这些需求时貌似装备不良。他们 缺乏临床人员和标准、基于证据的实践，以诊断、护理、治疗和康复痴呆患者。由于养老院经常拒绝接纳老年 痴呆症患者，其家人通常被迫在家护理痴呆老人。.兰溪县——或中国大部分农村地区——需要更多 的公共资源支持家庭护理人员和提升养老院护理痴呆 老人的能力。.Определить состояние медико-санитарных служб и поддерживающих услуг, доступных пожилым людям, страдающим от деменции, и их родным, которые проживают на сельской территории уезда Ланьси, провинция Чжэцзян, Китай.В ноябре 2014 года и январе 2015 года был проведен опрос 14 ключевых информаторов, предоставляющих информацию по уходу за людьми с деменцией, который осуществлялся при очной встрече с помощью полуструктурированного интервью. В число информаторов входили три сельских врача, городской врач-гериатр, семь руководителей учреждений, предоставляющих услуги по уходу за престарелыми, и три должностных лица из бюро по гражданским вопросам. Были также проведены содержательные интервью с пятью лицами, осуществляющими уход за престарелыми людьми с деменцией, которые являются членами их семей.Опрошенные лица отметили недостаток специализированных услуг, предназначенных для удовлетворения потребностей лиц, страдающих от деменции, и членов их семей. Медицинские службы непсихиатрического профиля и доступные учреждения для долгосрочного ухода оказались недостаточно оборудованы для удовлетворения этих потребностей. Нехватка персонала в них сочеталась с недостатком стандартизированных, основанных на опыте практик для диагностики, осуществления ухода, лечения и реабилитации пациентов с деменцией. Поскольку организации по уходу часто отказывались принимать на лечение пожилых людей с деменцией, их семьям обычно приходилось самим обеспечивать уход за ними дома.В уезде Ланьси и, скорее всего, в большинстве сел Китая требуются дополнительные государственные ресурсы для поддержки лиц, осуществляющих уход на дому, или для увеличения возможностей организаций по уходу за пожилыми людьми осуществлять помощь в обслуживании людей с деменцией.

Background— Skeletal muscle dysfunction and exercise intolerance are clinical hallmarks of patients with heart failure. These have been linked to a progressive catabolic state, skeletal muscle inflammation, and impaired oxidative metabolism. Previous studies suggest beneficial effects of ω-3 polyunsaturated fatty acids and glutamine on exercise performance and muscle protein balance. Methods and Results— In a randomized double-blind, placebo-controlled trial, 31 patients with heart failure were randomized to either l -alanyl- l -glutamine (8 g/d) and polyunsaturated fatty acid (6.5 g/d) or placebo (safflower oil and milk powder) for 3 months. Cardiopulmonary exercise testing, dual-energy x-ray absorptiometry, 6-minute walk test, hand grip strength, functional muscle testing, echocardiography, and quality of life and lateral quadriceps muscle biopsy were performed at baseline and at follow-up. Oxidative capacity and metabolic gene expression were analyzed on muscle biopsies. No differences in muscle function, echocardiography, 6-minute walk test, or hand grip strength and a nonsignificant increase in peak V O 2 in the treatment group were found. Lean body mass increased and quality of life improved in the active treatment group. Molecular analysis revealed no differences in muscle fiber composition, fiber cross-sectional area, gene expression of metabolic marker genes (PGC1α, CPT1, PDK4, and GLUT4), and skeletal muscle oxidative capacity. Conclusions— The combined supplementation of l -alanyl- l -glutamine and polyunsaturated fatty acid did not improve exercise performance or muscle function but increased lean body mass and quality of life in patients with chronic stable heart failure. These findings suggest potentially beneficial effects of high-dose nutritional polyunsaturated fatty acids and amino acid supplementations in patients with chronic stable heart failure. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01534663.

Recruitment of immunosuppressive myeloid cells into the tumor microenvironment (TME) is a critical limitation to the efficacy of immune checkpoint inhibitors (ICIs) in patients with head and neck squamous cell carcinoma (HNSCC). In preclinical models, antibody blockade of Semaphorin 4D (SEMA4D, CD100) reduced function and recruitment of immunosuppressive myeloid cells within the TME. Importantly, combinations of anti-SEMA4D with ICIs enhanced T-cell activity and tumor regression. Pepinemab, an IgG4 humanized monoclonal antibody targeting SEMA4D, is currently being evaluated in window of opportunity, integrated biomarker trials to characterize immunomodulatory effects of treatment. SEMA4D exerts multifaceted effects within the tumor microenvironment by creating a barrier at the tumor-stroma margin, restricting immune cell infiltration and promoting immunosuppressive activity of myeloid-derived cells. In preclinical in vitro and in vivo studies, blocking antibody to SEMA4D directly enhanced M1/M2 ratio and reduced both expression of chemokines that recruit MDSC and the ability of MDSC to suppress T-cell activity. SEMA4D antibody treatment simultaneously restored the ability of dendritic cells and cytotoxic T cells to infiltrate the TME and increased ratio of Teffector to Tregulatory cells. This coordinated shift from immunosuppression to tumoricidal activity complemented effects of other immunotherapies in syngeneic tumor models. At present, three biomarker-driven window of opportunity trials are recruiting patients with four resectable indications to investigate novel combinations of pepinemab with ICIs: 1) HNSCC (NCT03690986, n=36), 2) pancreatic ductal adenocarcinoma and colorectal cancer with resectable liver metastases (NCT03373188, n=32), and 3) metastatic melanoma (NCT03769155, n=36). Presurgical treatment cohorts include combinations of pepinemab with nivolumab and /or ipilimumab, single agents, or no treatment. Three to seven weeks later, surgically resected tumors are collected under the guidance of a pathologist for comparison of tumor infiltrates across treatment groups and with a predose tissue biopsy. Blood is collected for PK, PD, and additional correlative biomarker assessments. Correlative multiplex flow cytometric and immunohistochemistry panels have been established to phenotype cells in the TME and periphery; preliminary biomarker analysis will be presented. Additional objectives include evaluation of pathologic response and extension of the previously reported safety profile of pepinemab to additional ICI combination therapies. Twelve subjects, including two HNSCC patients, have been enrolled in these studies as of 01 Feb 2019. These trials will provide the first integrated clinical assessment of the use of anti-SEMA4D antibody to reprogram the TME. Citation Format: Elizabeth E. Evans, Gregory B. Lesinski, Terrence L. Fisher, Crystal Mallow, Brian Olson, Paul E. Clavijo, John E. Leonard, Desa Rae Pastore, Ernest S. Smith, Maurice Zauderer, Clint T. Allen, Michael Lowe, Ragini Kudchadkar, Christina Wu, Conor Steuer, Nabil F. Saba. Integrated biomarker trials to evaluate myeloid and lymphoid composition of HNSCC and solid tumors treated with pepinemab and combinations with checkpoint inhibitors [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A15.

7079 Background: Pain is a common symptom of cancer, affecting patients' function and quality of life. It is also a common cause of hospitalization for cancer patients. The aim of this study was to evaluate the cost of in-hospital pain management among US cancer patients. Methods: A retrospective analysis of data from all US hospitals that contributed to the National Inpatient Sample for 2011-2015 was conducted. All cancer patients admitted for pain management were included in the analysis. Main outcomes were factors significantly associated with hospital length of stay, total charge per hospital stay, and in-hospital mortality. Weighted chi-square test was used for categorical covariates and univariate analysis was performed using a logistic model. Results: 122,776 patient discharges were identified. Mean age was 59.3 years and 52.3% were female. 65.9% stayed in the hospital for longer than 72 hours, with a median total hospital charge of $48,156. Conversely, the median total hospital charge for those spending less than 72 hours on admission was $15,966. Median total charge per hospital stay was similar among insured and uninsured/self-pay patients ($32,879 vs. $32,323; p=0.013), but higher in patients without metastatic disease ($33,315 vs. $29,369; p

4583 Background: Resected cholangiocarcinomas are rare and have high relapse rates. Adjuvant chemotherapy is the standard of care (BiLCAP Trial). Adjuvant radiation therapy benefit is not well defined. This study aims to evaluate survival outcomes of the effect of adjuvant chemoradiotherapy compared to chemotherapy in extrahepatic cholangiocarcinoma (EHC) using the National Cancer Database (NCDB). Methods: Patients with resected EHC between 2004 and 2013 were identified from the NCDB using ICD-O-3 histology and topography codes: 8140, 8160, 8161, 8162 and C24.0. Patients with neoadjuvant therapy were excluded from this analysis. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received. Results: A total of 236 EHC patients were identified. Males comprised 60.6% and 88.1% were Caucasian. Median age was 64 (range, 31-84) years. The majority were distal (72.0%, N = 157) followed by perihilar (20.6%, N = 45), hilar (6.4%, N = 14) and cystic (0.9%, N = 2). Distribution across stages I-III was 28.8% (N = 68), 56.8% (N = 134), and 14.4% (N = 34), consecutively. Adjuvant chemotherapy was given in 37.7% (N = 89) and adjuvant chemoradiotherapy in 62.3% (N = 147). The median dose of radiation was 50.4 Gy. Adjuvant chemoradiotherapy was mostly given in regional node positive disease (p = 0.016) and negative surgical margin (p = 0.002) compared to regional node negative disease and positive surgical margin, respectively. The use of adjuvant chemoradiotherapy was associated with improved OS compared to chemotherapy alone in univariate (HR 0.64; 95% CI 0.44-0.93; p = 0.019) and multivariable analysis (HR 0.65; 95% CI 0.44-0.96; p = 0.030). Median survival and 1 year-OS for patients that received chemoradiotherapy was 33.8 months (95% CI 28, NA) and 87.7% (80.9%, 92.1%) compared to chemotherapy alone which was 23.8 months (95% CI 18.9, 35.4) and 75.5% (64.9%, 83.3%). Conclusions: Adjuvant chemoradiotherapy was associated with improved survival in patients with resected EHC compared to chemotherapy alone. This conclusion warrants further prospective studies to confirm these results.

TPS3163 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects are being enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy (Part 1a) or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of February 4, 2020, Phase 1 dose escalation has been completed and a recommended Phase 2 dose chosen for both FLX475 monotherapy and combination therapy with pembrolizumab. Enrollment into Phase 2 expansion cohorts has been initiated. Clinical trial information: NCT03674567 .

553 Background: Sarcopenia and inflammation are independently associated with worse survival in cancer patients. This study aims to determine the impact of inflammatory biomarkers, BMI and sarcopenia on survival in advanced hepatocellular carcinoma (HCC) patients treated with immunotherapy. Methods: We performed a retrospective review of advanced HCC patients treated with immunotherapy-based therapies at Winship Cancer Institute between 2015 and 2019. Baseline computed tomography and magnetic resonance imaging scans were collected at mid-L3 level, assessed for skeletal muscle density using SliceOmatic (TomoVision, version 5.0) and converted to skeletal muscle index (SMI) by dividing it by height (m)2. Gender-specific sarcopenia was defined by median value of SMI. The optimal cut for continuous inflammation biomarker was determined by bias-adjusted log-rank test. Overall Survival (OS) was set as primary outcome and Cox proportional hazard model was performed. Results: 57 patients were included; 77.2% male, 52.6% Caucasian, 58.5% ECOG PS 0-1, 80.7% Child Pugh A. Treatment was second line and beyond in 71.9%. The median follow-up time was 6 months. Sarcopenia cut-off for males and females was SMI of 43 and 39, respectively. 49.1% of patients had sarcopenia. Median OS was 5 vs. 14.3 months in sarcopenic vs. non-sarcopenic patients (p=0.054). Median OS was 5 and 17.5 months in patients with BMI

TPS269 Background: Panitumumab (Pmab) is a recombinant monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR), and is indicated for metastatic colorectal carcinoma (mCRC). EGFR inhibition induces synthetic lethality with poly ADP ribose polymerase inhibitors (PARPi) by attenuating DNA repair pathways. This susceptibility to PARPi-induced cell death by EGFR inhibition is associated with deficient Non-homologous end joining (NHEJ), and Homologous recombination (HR) mediated DNA repair and persistence of DNA damage. Furthermore, efficacy of PARPi (such as niraparib) is highly correlated with platinum sensitivity. Cancer cell sensitivity and resistance to both PARPi and platinum have been associated with loss and restoration of HR DNA repair, indicating similar mechanisms of anticancer activity and resistance. Platinum sensitivity in CRC could therefore predict for anticancer properties of PARPi when utilized in the setting of synthetic lethality. Combining PARP and EGFR inhibition has the potential to confer synergistic benefit, while ameliorating resistance mechanism to PARPi. This study aims to evaluate the activity of the combination of niraparib and Pmab in RAS wildtype (WT) mCRC. Methods: Eligible patients for the trial include advanced, RAS WT mCRC who have been intolerant of, progressed on, or failed at least one line of systemic chemotherapy. Those currently on first line oxaliplatin-containing regimen are allowed on the trial if they have remained stable or better (PR or CR) for at least 4 months on that line of treatment, and are being considered for maintenance therapy as standard of care. Patients must also be 18 years old, ECOG PS 0-1 and measurable disease per RECIST 1.1. A safety run-in cohort of 6 eligible patients, and additional 20 patients with the same inclusion criteria will be enrolled. Pmab dose - 6 mg/kg IV on days 1 & 15 of each 28-day cycle; Niraparib - 200mg or 300mg (based on body weight and platelet count) orally continuously. Primary endpoint: clinical benefit rate (CR +PR + SD). Biomarker analysis includes skin biopsies evaluated for p-Caspace-3, PARP, p-MAPK, Ki-67, and p27. The study was activated in Sept. 2019. Clinical trial information: NCT03983993.

830 Background: XL888 is a selective inhibitor of heat shock protein 90 (HSP90). It modulates several oncogenic signaling pathways, and the tumor microenvironment. In preclinical models, XL888 potentiates efficacy of PD-1 inhibition. We report the results of the dose escalation (DE) portion of a phase Ib trial of combined XL888 and pembrolizumab (P) in advanced gastrointestinal adenocarcinomas. Methods: XL888 was administered orally (PO) in three dose levels of 45 (DL1), 90 (DL2), 60 (only if DLT on DL2) mg twice weekly with P 200 mg IV on day 1, in 21-day cycles. Eligible patients included stage IV or locally advanced unresectable gastrointestinal adenocarcinomas with at least one prior therapy (patients with colorectal (CRC) adenocarcinoma must have received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, adequate organ function, no prior anti-PD-1 or anti-PD-L1 agent. The primary endpoint was recommended phase II dose (RP2D), while secondary endpoints included safety and tolerability. Pre-treatment and on-treatment correlative peripheral blood specimens were collected. Results: A total of 14 patients were enrolled in the DE phase. 9 male, median age 66.5. Diagnoses included CRC (6), pancreatic adenocarcinoma (5), biliary tract cancer (1), ampullary (1), and duodenal (1). Two patients were ineligible for assessing the primary endpoint (DL2) due to biliary stent obstruction and sepsis. One DLT (grade 3 autoimmune hepatitis) was observed on DL2. We enrolled three patients on DL3. Five additional patients were subsequently enrolled on DL2 with no additional DLT. Three patients (1 duodenal, 2 CRC) had prolonged stable disease (6, 9 and 15 cycles). The most common treatment-related toxicities included autoimmune hepatitis (G3; n = 1), retinopathy (G2; n = 2), nausea (G2; n = 1), constipation (G2; n = 1), and diarrhea (G2; n = 3). Conclusions: The XL888 and pembrolizumab combination had an acceptable safety profile and the RP2D of XL888 was 90 mg twice weekly combined with P 200 mg, every 3 weeks. The dose expansion portion and a robust series of immunologic correlative laboratory studies for this study is ongoing. Clinical trial information: NCT03095781.

703 Background: Locally advanced pancreatic cancer (LAPC) is managed with multimodality therapy. A subset of patients with LAPC are not good candidates for aggressive treatment. The aim here is to evaluate the outcomes of single modality radiation therapy for LAPC using the National Cancer Database (NCDB). Methods: Data was obtained between years 2004 and 2013. Pancreatic ductal adenocarcinoma (PDAC) patients with unresectable local disease were identified excluding patients who received chemotherapy or surgery. Univariate and multivariable analyses identified factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used for patient characteristics and overall survival (OS). Results: A total of 6,590 patients were included; 480 (6.9%) received radiation therapy only and 6470 (93.1%) received no treatment. Mean age was 73.5 (range, 28‐90) years, with the majority being White (N = 5685; 83.2%) and female (N = 3779; 54.4%). Poorly differentiated histology and tumors ≥ 4 cm ( > T3 stage) accounted for 47.8% and 52.7%, respectively. The median dose of radiation was 39.6 Gy. Stereotactic body radiation (SBRT) was given in 64 patients and external-beam/Intensity modulated radiotherapy (IMRT) in 416 patients. Charlson-Deyo score of +1 was seen in 34.4% of patients who received no treatment, 32.8% of patients who received SBRT and in 29.8% of patients who received external-beam IMRT. Radiation therapy was associated with improved OS compared to no treatment in univariate and multivariable analyses controlling for sex, Charlson-Deyo score, age, tumor size, amongst other covariates. Median OS for patients who received SBRT, external-beam/IMRT or no radiation was 8.6, 6.7 and 3.4 months; respectively (P < 0.001). There is a significant difference in 12-month OS for the SBRT cohort (31.9%; 95% CI 20.9%-43.5%) compared to patients who received no radiation (15.1%; 95% CI 14.2%-16.0%), similarly seen on multivariable analysis (HR 0.50; 95% CI 0.38-0.65; P < 0.001). Conclusions: The current study is the first to evaluate the efficacy of radiation as single modality therapy in LAPC. The results suggest a potential benefit for radiation therapy alone, in comparison to no treatment.

Background: Clinico-pathological high-risk features are frequently utilized in adjuvant chemotherapy (AC) decisions in stage II colorectal cancer and their utility in stage II appendiceal adenocarcinoma (AA) is not established. The aim of this study is to determine the impact of high-risk features in clinical outcomes and whether high risk features are predictive of AC benefit in stage II AA. Methods: Patients with pathological stage II AA between 2010-2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8140, 8480 and C18.1. High risk stage II AA was defined as having at least one of the following clinicopathological features: T4 tumor, Results: A total of 1,040 patients with pathological stage II AA were identified. 51.0% males, 84.5% Caucasian; median age 61 (range, 19-90). 46.4% were determined to have high-risk stage II AA. High-risk status was associated with worse OS compared to low-risk in univariate (HR 1.55; 95% CI 1.18-2.02; p=0.001) and multivariable analyses (HR 1.36; 95% CI 1.03-1.79; p=0.028). High-risk stage II AA patients had significantly worse 5-year OS compared to low-risk patients (67.1% vs. 74.5%, p=0.0013). AC was administered in 34.4% (n=166) of high-risk patients and in 36.5% (n=203) of low-risk patients. Among high-risk patients, AC was not associated with better OS in univariate (HR 0.86; 95% CI 0.59-1.26; p=0.448) and multivariable analyses (HR 1.35; 95% CI 0.90-2.04; p=0.151) compared to no AC. Similarly, among low-risk patients, AC was not associated with better OS in univariate (HR 0.92; 95% CI 0.60-1.39; p=0.679) and multivariable analyses (HR 1.27; 95% CI 0.81-2.02; p=0.299) compared to no AC. For high-risk patients, 5-year OS was 68.3% in patients that received AC vs. 66.5% in patients that did not (p=0.722). For low-risk patients, 5-year OS was 74.0% in patients that received AC vs. 76.3% in patients that did not (p=0.813).Conclusion: High-risk stage II AA patients had significantly worse 5-year OS compared to low-risk patients. AC did not improve survival regardless of high-risk features in stage II AA.

796 Background: Goblet cell tumors (GCT) of the appendix are very rare tumors constituting 2.5%-5% of all primary appendiceal neoplasms. Role of adjuvant chemotherapy (AC) is not established for GCT. This study aims to evaluate the impact of AC in stage II-III appendiceal GCT. Methods: Patients with pathological stage II and III GCT who underwent surgical resection between 2006 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8243/3, 8245/3 and C18.1. Patients treated with neoadjuvant systemic and/or radiation therapy and adjuvant radiation were excluded. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received with Log-rank test. Results: A total of 1,046 patients were identified. 53.7% males and 89.0% Caucasian; median age 56 (range, 20-90) years. Distribution across pathological stages II-III was 83.6% (N = 874) and 16.4% (N = 172) consecutively. 8.3% (N = 73) of stage II and 50.6% (N = 87) of stage III patients received AC. In the total cohort, AC was not associated with better OS compared to no AC in univariate analysis (HR 1.84; 95% CI 1.26-2.67; p = 0.001) or multivariable analysis (HR 0.94; 95% CI 0.57-1.52; p = 0.790). For stage II patients, AC was not associated with better OS in univariate (HR 1.24; 95% CI 0.60-2.57; p = 0.562) or multivariable analyses (HR 1.67; 95% CI 0.76-3.64; p = 0.199). Similarly, in stage III patients, AC was not associated with better OS in univariate (HR 0.78; 95% CI 0.48-1.29; p = 0.340) or multivariable analyses (HR 0.55; 95% CI 0.28-1.04; p = 0.067). In the entire cohort 5-year OS for patients that received AC was 83.9% (80.3%, 86.9%) versus 70.7% (60.9%, 78.5%) (p = 0.001) with no AC. For stage II patients, 5-year OS was 77.3% with AC vs. 87.7% with no AC (p = 0.562). For stage III patients, 5-year OS was 64.8% with AC vs. 54.4% with no AC (p = 0.340). Conclusions: AC was not associated with improved 5-year OS in patients with pathological stage II and III GCT compared to no AC.

Background Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO. Methods We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient’s histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology. Results The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node (n = 58), liver (n = 40), lung (n = 37), bone (n = 24), and brain (n = 8). Most patients (80.7%) were RMH good risk. Most patients (n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17–0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41–1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048). Conclusions Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.

Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality, with dismal 5-year prognosis of 8%, in part due to poor response to available therapies. Thus, new systemic cancer control therapies are in dire need. Semaphorin 4D (SEMA4D) is a soluble and membrane bound glycoprotein that binds its cognate Plexin B1/B2 receptors, expressed on monocytic and granulocytic leukocytes. Prior work has shown that increased expression of SEMA4D and Plexin B in resected PDAC patients is associated with lymph node and distant metastasis, as well as a worse prognosis. Additionally, SEMA4D blockade has conferred improved immune checkpoint blockade response in murine models of colorectal carcinoma and head and neck squamous cell carcinoma via abrogation of myeloid-derived suppressor cell recruitment and function, as well as enhanced T-cell recruitment and activity within the tumor microenvironment. Here we study the effects of SEMA4D blockade in a murine model of PDAC. Methods: C57b/6 mice were orthotopically injected with murine PDAC line (KP2) derived from KRASG12D,TP53Flox/Wt;P48-Cre autochthonous tumors. Mice were treated with Folfirinox (5-FU, irinotecan, oxaliplatin, weekly), immune checkpoint blockade (ICB) (anti-PD1, anti-CTLA-4 mAbs bi-weekly), and anti-SEMA4D mAB (biweekly). Peripheral blood and tumor-infiltrating leukocytes from patients with PDAC undergoing pancreaticoduodenectomy were assessed for Plexin B1 via flow cytometry. Results: Human PDAC demonstrates penetration of Plexin B1 positive leukocytes, most notably tumor-associated macrophages, neutrophils, and monocytes. Mice injected with KP2 developed tumors detectable via high-frequency ultrasound and exhibited longer survival when treated with the combination of Folfirinox, ICB, and anti-SEMA4D antibody, compared to Folfirinox alone, Folfirinox plus ICB, or Folfirinox plus anti-SEMA4D antibody. Conclusions: Plexin B1+ myeloid subsets penetrate human PDAC tumors, and treatment with SEMA4D-blocking antibody improved response to ICB in combination with standard-of-care Folfirinox in preclinical murine studies. Future work will focus on understanding the immune mechanism of improved therapeutic response, as well as further characterization of the prevalence and prognostic ramifications of the SEMA4D-Plexin B axis in PDAC. Citation Format: Luis I. Ruffolo, Katherine M. Jackson, Nicholas Ullman, Alexander Chacon, Alexa Melucci, Paul Burchard, Mary Georger, Rachel Jewell, Peter Prieto, Brian Belt, Crystal Mallow, Elizabeth Evans, Terrence Fisher, Maurice Zauderer, Christina Wu, Brian Olson, Gregory B. Lesinski, David C. Linehan. Targeting the semaphorin 4D-plexin B axis to augment FOLFIRINOX in a murine model of pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B48.

Background The benefit of immune checkpoint blockade in mCRC is currently limited to mismatch repair (MMR) deficient tumours. Increasing evidence suggests that the vascular endothelial growth factor (VEGF) pathway plays a role in cancer immune evasion. Co-targeting the PD-1/PD-L1 and VEGF axes may result in clinical activity in mCRC. Methods 133 patients (pts) were randomized 2:1 to receive C/B/P (Arm A) or C/B/A (Arm B), stratifying by ECOG and RAS. Pts had progressed on 5-FU, oxaliplatin, irinotecan, bevacizumab, and anti-EGFR therapy (if RAS wt). Prior anti-PD-1/PD-L1 therapy was not permitted. Doses were C 850 or 1000 mg/m² d1-14, B 7.5 mg/kg d1, and A 1200 mg d1 in 21 day cycles. Primary endpoint was progression free survival (PFS). 110 events were required to detect PFS hazard ratio (HR) of 0.65 at 1-sided α = 0.1 with 80% power. Secondary endpoints were objective response rate (ORR), overall survival (OS), and safety/tolerability. Primary and secondary efficacy analyses were performed using modified intent to treat analysis (mITT). Results Analysis includes 46 pts (Arm A) and 82 pts (Arm B) with median age 58 yo, 40% female, 47% ECOG 0. As of 4/12/19, median follow-up was 12.35 months (mo). Proficient MMR or microsatellite stable (MSS) is present in 86.7% vs 85.7%. In mITT analysis, median PFS is 3.3 mo (2.1-6.2) vs 4.4 mo (4.1-6.4) with a HR of 0.725 (0.491-1.07), 1-sided log-rank p-value 0.051. In MSS only pts, HR for PFS is 0.67 (0.44-1.03). ORR is 4.35% (0.5-14.8) vs 8.54% (3.5-16.8), p = 0.5. The 12 mo OS is 43% (29-63) vs 52% (42-65), HR 0.94 (0.56-1.56), p = 0.4. Most common grade > = 3 related adverse events are hypertension (7% vs 9%), hand-foot syndrome (4% vs 6%), and diarrhea (2% vs 7%). Conclusions The study reached its prespecified primary endpoint and the addition of A to CB results in a significantly longer PFS. No new or increased safety signals are identified. Further investigation in a larger phase III study may be warranted. This is the first positive study co-targeting PD-1/PD-L1 and VEGF axes in mCRC and correlative analyses may help identify predictors of benefit. Clinical trial identification NCT0287319. Legal entity responsible for the study ACCRU. Funding Genentech Roche. Disclosure H.J. Lenz: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb. P.M. Boland: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Hemispherx; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Isofol Medical; Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Athenex; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Clinical Genomics. A.B. Nixon: Research grant / Funding (self): Seattle Genetics; Research grant / Funding (self): MedPacto; Research grant / Funding (self): Genentech Roche; Advisory / Consultancy, Research grant / Funding (self): Tracon Pharma; Research grant / Funding (self): Acceleron Pharma; Research grant / Funding (self): Leadiant Biosciences; Research grant / Funding (self): Sanofi-Aventis; Advisory / Consultancy: Eli Lilly. H. Hurwitz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech Roche. M.G. Fakih: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Advisory / Consultancy: Array; Advisory / Consultancy: Bayer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Novartis. All other authors have declared no conflicts of interest.

Background HER2 (ERBB2) amplification is present in 5-10% of patients (pts) with KRAS and NRAS (RAS) WT mCRC. Tucatinib (Seattle Genetics, Bothell, WA) is a potent, highly selective oral tyrosine kinase inhibitor of the HER2 receptor. In patient-derived xenograft models of HER2+ mCRC, the combination of tucatinib and trastuzumab showed significantly greater antitumor activity compared with tucatinib or trastuzumab alone. Here we present initial results from a trial of tucatinib and trastuzumab in pts with HER2 amplified mCRC. Methods MOUNTAINEER is a multicenter open-label single-arm phase II trial. Pts with RAS WT mCRC had HER2 amplification/overexpression by NGS, FISH, or IHC (3+ or 2+ and amplified by FISH). Prior treatment with 5FU, oxaliplatin, irinotecan, and an anti-VEGF antibody was required. Prior anti-HER2 therapy was excluded. Pts received tucatinib 300mg PO bid and standard doses of trastuzumab (IV, Q3 weeks). The primary endpoint was objective response rate (ORR) per RECIST v1.1. Using a 2-Stage Fleming design, this study compared ORR of 20% (null) vs 40% (alt) in 10 or 25 evaluable pts (1-sided α = 0.11; β=.16). At least 8 responses were needed to meet the primary efficacy endpoint. Results As of 26 April 2019, 26 pts enrolled, and 22 pts completed ≥1 evaluation of response. 16/26 pts (62%) were male. Median age= 52.5 (range 24-70). The primary tumor site of origin included right colon (N = 4), left colon/rectum (N = 17), transverse colon (N = 3), and overlapping (N = 2). Among 22 evaluable pts, ORR= 55% (CR/PR= 12; SD = 5; PD = 5). Clinical benefit rate (CR+PR+SD≥4 months) = 64%. At a median follow-up of 10.6 months, median PFS= 6.2 months (95% CI 3.5-NE). Median OS = 17.3 months (95% CI 12.3-NE). Median duration of response has not been reached. There were 2 (9%) grade 3 treatment-related adverse events (TRAEs) and no grade 4/5 TRAEs. The most common TRAEs were AST elevation (48%; all G1), ALT elevation (30%; all G1), and diarrhea (26%; G1/G2/G3=4%/17%/4%). Conclusions The combination of tucatinib and trastuzumab is well tolerated and has met its primary efficacy endpoint. Based on these results, further expansion of the MOUNTAINEER trial in pts with HER2 amplified mCRC is justified. Updated results will be presented. Clinical trial identification NCT03043313. Legal entity responsible for the study Academic and Community Cancer Research United. Funding Seattle Genetics. Disclosure J.H. Strickler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Chugai; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: OncoMed; Advisory / Consultancy: Celgene; Advisory / Consultancy: Proteus Digital Health; Advisory / Consultancy: Chengdu Kanghong Biotechnology Ltd; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Leap Therapeutics. A. Cercek: Advisory / Consultancy: Bayer; Advisory / Consultancy: Proteus; Research grant / Funding (institution): Seattle Genetics. C. Wu: Research grant / Funding (institution): Vaccinex; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): FLX Bio. J. Hubbard: Research grant / Funding (institution): Seattle Genetics; Honoraria (institution), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Treos Bio; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Senhwa pharmaceuticals. N. Kemeny: Research grant / Funding (institution): Amgen. P.M. Boland: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Hemispherx; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Isofol Medical; Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Athenex; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Clinical Genomics. K. Ng: Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Tarrex Biopharma; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Trovagene; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Pharmavite; Research grant / Funding (institution): Consano. T. Bekaii-Saab: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics. All other authors have declared no conflicts of interest.

The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB).A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment.A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring1 cm (T1a/T1b). Approximately 94.2% of patients had negative surgical margins (815 patients) and 46.9% (410 patients) received adjuvant therapy. The median OS was significantly different for patients who received adjuvant therapy compared with patients who did not (70.7 months vs 46.9 months; P = .0001). For patients with tumors measuring1 cm, survival was not found to be significantly different between patients who received adjuvant treatment compared with those who did not (not reached vs 85.3 months; P = .54). In the multivariable analysis, none of the covariates (treatment group, Charlson-Deyo Score, age, insurance, and facility status) demonstrated significant differences for patients with tumors measuring1 cm.The current study is the first to demonstrate no survival benefit for adjuvant therapy in patients with resected subcentimeter PDAC.

Systemic treatments for patients with colon cancer has expanded broadly beyond 5-fluorouracil based chemotherapy. For early stage colon cancer patients who are considering adjuvant chemotherapy, multiple factors such as the risk of disease recurrence, absolute survival benefit of chemotherapy, treatment toxicity, and patient comorbid medical conditions must be taken into account. In the metastatic setting, biomarkers such as KRAS/NRAS/BRAF mutation, microsatellite instability status, and left- versus right-sided colon cancer have helped oncologists to tailor systemic treatment regimens, which include chemotherapy, targeted therapy, and immunotherapy.

In August 2016, on the heels of the summer heat surrounding the Olympics, a major celebrity family scandal gripped mainland China. The nation watched closely as a well-known actor struggled through revelations about his wife’s scandalous infidelities, her disgraceful possession over their family properties, and most dramatically, her unilateral decision to flee to America with their two children—all while their divorce unfolded in front of the nation’s gaze. Not a political affair, this scandal was able to attract as much publicity as the Chinese people were thirsty for. Sina Weibo (Microblogging) became one of the biggest winners of this storm, as its NASDAQ stock price rose 7.05% the day after the actor made his announcement on Sina Weibo about his plan to divorce, and Sina Weibo’s market value broke through 10 billion U.S. dollars for the first time (according to Sohu Business in 2016). Within 14 hours of that announcement, the actor’s original Sina Weibo post had been forwarded 520,000 times and commented on 1,240,000 times (according to Sohu Business in 2016). Like all other major news events, many of which are often more politically sensitive and civically relevant, ordinary citizens in mainland China have grown used to looking to their social media sites for information and guidance. As of December 2015, mainland China’s social media population reached 530 million, amounting to 77% of its total Internet users (according to CINNIC in 2016). A Western media invention, social media platforms have largely permeated the lives of regular Chinese users, although not without “Chinese characteristics.” This article reviews an important body of literature that takes keen interest in the civic implications of mainland China’s social media sites, which render themselves more relevant than ever in everyday life as well as amid high-profile public events. Following in the footsteps of many influential foreign Internet sites, including Google and the New York Times, such leading social media entities as Facebook, Twitter, and YouTube have all been blocked by the Great Firewall of China, officially known as the Golden Shield Project. This exclusive characteristic, along with other unique Chinese phenomena, has given rise to a separate social media universe that China calls its own. This article draws connections among explorations about the civic significance of China’s social media landscape for the world’s largest Internet population (according to CNNIC in 2008). While unique Chinese conditions do not necessarily disconnect China’s users from universal features of social media use, this article focuses specifically on works that examine how local social media platforms have shaped civic engagement in mainland China’s restrictive political environment. Like the spread of Internet technology to modern China, recent developments in social media have invited competing narratives about their democratic implications, which often echo Western academia’s evaluative position taking between utopian and pessimistic narratives of digital technology’s social impact. The former state that Chinese citizens have availed themselves of the unprecedented opportunities afforded by social media to keep governmental actions in check, whereas the latter voice the concern that social media simply provide new and more ready channels for governmental monitoring and manipulating of public opinion. In 2010, Deng and Jing suggested that although the concept of civil society originated in the West, we need to understand it as historically, culturally, and socially specific. The Chinese civil society, according to the two scholars, is both separate from and interdependent with the state. Its origin stemmed from China’s state-guided transition from a planned economy to marketization, leading China’s civil society to be more dependent on state policies, while the Western civil society gains more independence from private capital. Deng and Jing note that theories of state-society relations have primarily positioned the two as confrontational entities and instead propose a “Positive Interaction Theory (BIT)” for the case of China. Under this notion, the state allows for the civil society’s independent operation and protects it with laws and abstract legislation. While there is great diversity within the civil society and often conflicts of interest, the state should interfere and mediate in legal and economic terms, when members of the civil society fail to reconcile on contractual grounds. Under BIT as an ideal type, Deng and Jing asserted that the state should not intervene in the civil society’s political rights, and the latter should reserve the freedom to organize their political voices and push for democratization. The closer state-society relation can be to this ideal, the more robust a civil society will be. Once China’s civil society establishes its independence and autonomy, the scholars suggest, it will then participate in China’s politics and provide effective checks and balances on state decision making. However, these two stages are not neatly separate from each other. As can be seen in the cases reviewed in this article, the Chinese civil society in its current state is not a unitary and static entity. While limited in sensitive political and religious domains, it has achieved a strong voice in other social issues and positive interaction with the state at times. This investigation into a burgeoning literature on social media in mainland China finds that although the Chinese people’s use of social media does not strike one as immediately liberating in terms of new political freedom, it bears the potential of creating a civil society that may be particularly meaningful for the idiosyncratic political environment of China. In other words, there may be a lot left to desire, but researchers can look more closely into the various ways in which users in China actively, and often creatively, organize their voices and actions via new social media outlets. In the absence of a democracy, a civil society continues to emerge.