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Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Despite significant advances in outcomes with immunotherapy, most cancer patients do not benefit from currently approved immune checkpoint inhibitors (ICI). The reasons for ICI resistance are multi-faceted and suggest that additional immunomodulation is required to improve outcomes. MTL-CEBPA is a novel immunotherapy based on RNA activation that upregulates expression of a master myeloid transcription factor, CEBPA. The small activating RNA for CEBPA is encapsulated within a NOV340 liposome that targets the myeloid cell lineage. MTL-CEBPA has shown favorable safety and promising clinical activity in combination with tyrosine kinase inhibitors (Sorafenib) in hepatocellular carcinoma (NCT-02716012) [Hashimoto et al, CCR 2021; Sarker et al, CCR 2020]. We recently reported preliminary clinical data from the ongoing multi-center phase 1 TIMEPOINT study (NCT-04105335) evaluating the safety, pharmacokinetics, immunomodulation, and clinical activity of MTL-CEBPA in combination with pembrolizumab in patients with solid tumors who have exhausted standard therapy. This demonstrated a favorable safety profile and initial clinical activity [Plummer et al, JITC 2021]. Here we report the findings from a biomarker pharmacodynamic analysis of paired baseline and cycle 2 tumor sample biopsies in 23 patients from the TIMEPOINT trial. Brightplex® IHC and digital pathology analyses of the samples for myeloid and T cell panels were undertaken, alongside gene expression (Nanostring I/O 360). Prior to study treatment, nine patients out of 23 had an immune cold tumor microenvironment (TME) at baseline as measured by the Immunosign®21 score. Following the combination of MTL-CEBPA with pembrolizumab, seven of these patients converted to an inflamed TME by Immunosign®21 (P=0.008). This change in the TME was associated with infiltration of CD8 and cytotoxic T cells (CD8+, GrzB+, Ki-67+) (P=0.1). GSEA analysis indicated that a Tstem-like signature was enriched post-treatment. A Brightplex® IHC analysis of myeloid cells in these patients indicated that, post treatment, there was a significant influx of HLA-DR+ myeloid cells into the TME (P=0.04). We also observed a significant increase in the expression of CXCL9, 10, and 11. The remaining 14 patients had an inflamed TME at baseline. Here, we also observed an increase in HLA-DR+ cells, T cells, and chemokines, though to a lesser extent. Further, however, in these inflamed tumors—which have significantly greater infiltration of myeloid-derived suppressor cells (MDSCs) than desert tumors—we observed a reduction in 8/10 patients with detectable PMN-MDSCs (P=0.1) post treatment, consistent with the mechanism of action of CEBPA. An expression signature based on 18 genes significantly enriched for clinical response across all patients. Collectively, these data suggest a positive immunomodulatory TME effect of the combination of MTL-CEBPA with pembrolizumab. In both hot and cold TME tumors, the combination drives directed differentiation of progenitor monocytes into HLA-DR+ myeloid cells secreting chemokines that stimulate the ingress of T cells into the TME. We observe a significant positive correlation between the change in cytotoxic T cells and HLA-DR+ myeloid cells post treatment (P=0.004). These effects are most pronounced in cold tumors. Citation Format: Ruth Plummer, Mikael Sodergren, Brid Ryan, Ilian Tchakov, Nina Raulf, Rose Hodgson, CP Tan, Joanna P. Nicholls, Alison Adderkin, N Vasileiadou, Vikash Reebye, Tim Meyer, David J. Pinato, Debashis Sarker, Bristi Basu, Sarah Blagden, Natalie Cook, Jeff Evans, Jeffrey Yachnin, Cheng Ean Chee, Dan Li, Anthony El-Khoueiry, Maria Diab, Kai-Wen Huang, Marcus S. Noel, Bridget Keenan, Devalingam Mahalingam, Melanie Grosso, Denis Arnaud, Aurelie Auguste, Jan Storkholm, Iain McNeish, Robert Habib, John J. Rossi, Nagy Habib. MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB192.

Background: The cytokine GDF15 is overexpressed in solid malignant tumors such as colorectal, lung and urothelial cancer, where it modulates T cells, dendritic cells (DCs) and myeloid-derived cells, driving the tumor microenvironment toward an immunosuppressive, tumor-promoting state. AZD8853 is a humanized immunoglobulin G1 monoclonal antibody that binds to, and neutralizes, GDF15. Anti-GDF15 treatment increased T cell proliferation and DC activation, leading to an antitumor immune response in preclinical studies of anti-PD-L1 resistant models. In vitro and in vivo preclinical data support the potential antitumor activity of AZD8853 in pts with selected advanced/metastatic cancers. Methods: This Phase I/IIa, first-in-human, open-label study (NCT05397171) assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD8853 in pts with histologically or cytologically confirmed locally advanced, unresectable or metastatic mismatch repair-proficient colorectal cancer (pMMR-CRC), non-small-cell lung cancer (NSCLC) and urothelial carcinoma (UC). Up to 165 pts will be enrolled in 3 parts: Part A, dose escalation; Part B, pharmacodynamics expansion; and Part C, efficacy expansion. All pts receive AZD8853 IV. Eligible pts are ≥18 years old with ≥1 measurable target lesion per RECIST v1.1, ECOG PS of 0/1, life expectancy ≥12 weeks and adequate organ and bone marrow function. Pts with NSCLC must have had ≥1 prior line of systemic treatment in the advanced/metastatic setting, and no sensitizing EGFR or ALK aberrations. Pts with pMMR-CRC must have had ≥2 prior treatments in the advanced/metastatic setting. Pts with UC must have had ≥1 prior treatment in the advanced/metastatic setting including platinum-containing therapy and/or a PD-(L)1-inhibitor. Pts with Grade ≥2 unresolved toxicities from prior therapy, symptomatic CNS metastases or leptomeningeal disease, or prespecified active/ongoing infections are excluded. The primary objective is safety, including dose-limiting toxicities, adverse events (AEs), serious AEs and AEs leading to AZD8853 discontinuation. The secondary objectives include assessment of efficacy (objective response rate, disease control rate, duration of response, percentage change from baseline in target lesion size, change from baseline in circulating tumor DNA, and progression-free and overall survival), PK and immunogenicity. Changes in GDF15 serum levels are measured in Parts A and B. Tumoral CD8+ T cell infiltration is measured in a subset of pts from Part B using PET/CT imaging and IHC of paired biopsies. The study is currently recruiting at centers in the USA and Canada with additional sites planned in the UK, France and Spain. Citation Format: Benedito A. Carneiro, Maria Diab, Brian A. Van Tine, Anthony F. Shields, Albiruni Abdul Razak, John F. Hilton, Rafael Santana-Davila, Elhan Sanai, Jorge Zeron-Medina, Veronique Bragulat, Kath Lowery, Arthur Lambert, John Hood, Rakesh Kumar, Duncan Jodrell, Patricia LoRusso. First-in-human study of AZD8853, an anti-growth and differentiation factor 15 (GDF15) antibody, in patients (pts) with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT116.

Prognosis from pancreatic ductal adenocarcinoma (PDAC) continues to be poor despite the many efforts channeled to improve its management. Although the mainstay treatment is still traditional chemotherapy, recent advances highlighted a promising potential for targeted therapy in the management of this disease. Those advances emphasize the significance of timely genomic profiling of tumor tissue as well as germline testing of patients to identify potential markers of targeted therapy. While targeted therapy is reserved for a relatively small subset of patients with PDAC, ongoing research is uncovering additional markers, and targeted agents, that will hopefully translate to better outcomes for patients.

About 10-20% of patients with anal squamous cell carcinoma (SCCa) present with metastatic disease and are usually treated with systemic chemotherapy. However, primary tumor control is crucial as local failure is associated with significant morbidity. Using the largest cohort to date, we report the impact of local therapy on survival among patients with metastatic anal SCCa.Data were collected from US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2015. Patients who did not receive palliative systemic chemotherapy were excluded from analysis. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to evaluate the association between tumor/patient characteristics and overall survival (OS).A total of 1,160 patients were identified over the 12 years of study. Median age was 57 years. Majority were female (64.9%), non-Hispanic Whites (79.1%) and had Charlson-Deyo Score of 0 (83.6%). Most common metastatic sites were liver (25.9%), lung (11.6%) and bone (8.5%). More than 79% of the patients had received radiation to the primary site, and 10.4% underwent surgical resection for local control. Use of local therapy correlated closely with OS on MVA (HR 0.66; 0.55-0.79; P0.001), with a 12-month and 5-year OS rates of 72.8% and 25.7% respectively, compared with 61.1% and 14.6% for patients treated with chemotherapy only. Poor prognostic factors included male gender (HR 1.44; 1.24-1.67; P0.001), age70 years (HR 1.28; 1.02-1.62; P=0.034), lack of health insurance (HR 1.32; 1.02-1.71; P=0.034), and cloacogenic zone location (HR 4.02; 1.43-11.30; P=0.008). There was no benefit from abdominoperineal resection (mOS =19.7 months; HR 1.05; 0.48-2.29; P=0.909), but both local resection of the primary (mOS =24.8 months, HR 0.48; 0.29-0.80; P=0.005) and palliative radiation (mOS =22.6 months; HR 0.66; 0.55-0.79; P0.001) were associated with improved OS.In addition to systemic therapy, resection of the primary tumor or palliative radiation improved OS in patients with anal SCCa. Patients unlikely to benefit from local control were those70 years of age, male, lack of health insurance and cloacogenic carcinoma.

The protocol is out of date. The authors have abandoned it.

BackgroundHigh-risk features, such as T4 disease, bowel obstruction, poorly/undifferentiated histology, lymphovascular, perineural invasion, and MethodsUnivariate (UVA) and multivariate (MVA) Cox proportional hazards (Cox-PH) models were built to assess the association between clinical and demographic characteristics and overall survival. Kaplan–Meier survival curves were generated with log-rank tests to evaluate the association between adjuvant chemotherapy in high-risk and low-risk cohorts separately.ResultsA total of 2,293 stage II CC patients have dMMR/MSI-H; of those, 29.5% (n = 676) had high-risk features. The high-risk dMMR/MSI-H patients had worse overall survival [5-year survival and 95%CI, 73.2% (67.3–78.1%) vs. 80.3% (76.7–83.5%), p = 0.0001]. In patients with stage II dMMR/MSI-H CC, the high-risk features were associated with shorter overall survival (OS) along with male sex, positive carcinoembryonic antigen, Charlson–Deyo score >1, and older age. Adjuvant chemotherapy administration was associated with better OS, regardless of the high-risk features in dMMR/MSI-H (log-rank test, p = 0.001) or not (p = 0.0006). When stratified by age, the benefit of chemotherapy was evident only in patients age ≥65 with high-risk features.ConclusionHigh-risk features are prognostic in the setting of dMMR/MSI-H stage II CC. Adjuvant chemotherapy may improve survival specifically in patients ≥65 years and with high-risk features.

Background: Paragangliomas (PGLs) and Pheochromocytomas (PCCs) are rare neuroendocrine tumors (NETs). PGLs arise from chromaffin cells in the ganglia of the autonomic nervous system, while PCCs arise from chromaffin cells in the adrenal medulla. The genomic landscapes of PGLs and PCCs have not been well studied. Thus, the aim of this study is to report differences of mutational occurrences and confirm the feasibility of next generation sequencing (NGS) testing circulating tumor DNA (ctDNA) in patients with PGL and PCC. Patients and Methods: Molecular alterations in 46 plasma samples were evaluated using a commercially available ctDNA assay (Guardant360® or Guardant360® CDx) across multiple institutions from 2016-2021. The tests detect single nucleotide variants and indels in 54-83 genes with copy number amplifications and fusions in selected genes. Results: Of the 24 PGL patients, there was a median age of 55 (range:28-78) years and 14 (58%) patients were male. Of the 22 PCC patients, there was a median age of 56 (range:28-86) years and 12 (54.5%) patients were male. Genetic alterations were identified in 16 (67%) PGL and 17 (77%) PCC patients. Of the 16 PGL samples with alterations, TP53 associated genes were most commonly altered (44%), followed by ATM (25%), FGFR2 (19%), APC (13%), BRAF (13%), BRCA1 (13%), CCND2 (13%), FGFR3 (13%), IDH2 (13%), KRAS (13%), PDGFRA (13%), RB1 (13%), TERT(13%), ALK (6%), ARID1A (6%), BRCA2 (6%), CCND1 (6%), CDK6 (6%), CDK12 (6%), EGFR (6%), FGFR1 (6%), KIT (6%), MET (6%), NF1 (6%), NRAS (6%), PIK3CA (6%), PTEN (6%), and ROS1 (6%). Of the 17 PCC samples with alterations, TP53 was most commonly altered (41%), followed by ATM (35%), NF1 (24%), FGFR1 (18%), APC (13%), EGFR (12%), MET (12%), MYC (12%), NOTCH1 (12%), PDGFRA (12%), TSC1 (12%), AR (6%), ARID1A(13%), BRAF (6%), BRCA1 (6%), BRCA2 (6%), CCND1 (6%), CDK6 (6%), CHEK2 (6%), ERBB2 (6%), EZH2 (6%), FGFR2 (6%), IDH2 (6%), KIT (6%), KRAS (6%), NRAS (6%), NTRK1 (6%), NTRK2 (6%), and VHL (6%). 21% of PGL and 41% of PCC patients reported alterations associated with therapies approved in other indications including genes in the MAPK pathway and the homologous recombination repair pathway. Conclusions: Liquid biopsy is a non-invasive method that can provide personalized treatment options for patients. In this study, we found that evaluation of ctDNA was feasible among individuals with advanced PGL and PCC. We report a high rate of homologous recombinant deficiencies that are in need of evaluation in future Percentage refers to frequency of patients with an alteration detected. Citation Format: Lana Khalil, Jill Tsai, Leylah Drusbosky, Olatunji Alese, Maria Diab, Mehmet Akce, Christina Wu, Olumide Babjide Gbolahan, Bassel El-Rayes, Walid Shaib. Genomic landscape of circulating tumor DNA alterations in patients with paraganglioma and pheochromocytoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5790.

Background: Preclinical results indicate that metformin can modulate immune cell populations in the tumor microenvironment of solid tumors by diminishing exhaustion of CD8+ tumor infiltrating cells and improving T cell responses. Studies also suggest that metformin could complement PD-1 blockade and potentiate its antitumor activity. Previously we reported the results of a phase II trial with metformin and nivolumab and here we report the findings of correlative analysis of the prospectively collected research samples of 18 patients. Methods: We conducted a phase II trial with nivolumab and metformin in treatment-refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Nivolumab 480 mg IV every 4 weeks and metformin 1000 mg orally twice daily was administered in 28-day cycles following a 14-day metformin only lead-in phase. The primary endpoint was overall response rate (ORR). Secondary endpoints were overall survival (OS) and progression free survival (PFS). Pre-treatment and on-treatment research biopsies and correlative peripheral blood specimens were collected. Paired biopsies obtained at baseline and following treatment with metformin only (n=9) or metformin and nivolumab (n=9) and were stained with a panel of 13 markers using ChipCytometry technology by Canopy Biosciences. Sample was assessed prior to establishing the multiplex assay. 30 out of 36 samples were imaged and analyzed up to 30 Fields of View. Single cell recognition and quantitative biomarker analysis were performed to compare immune cell numbers and population distribution in pre- versus post-treatment samples. Results: As previously reported, no patients had objective response based on RECIST version 1.1 and the study was stopped after the first stage for futility. Median OS and PFS was 5.1 months [95% CI (2-11.7)] and 2.3 months [95% CI (1.7-2.4)], respectively. Multiplex analysis of tissues from patients receiving lead in with metformin alone revealed fewer effector CD4 T cells and effector and effector memory CD8 T cells after treatment vs. baseline biopsy. Biopsy tissue from patients treated with metformin and nivolumab had lower pAMPK and decreased PDL-1 expression vs. baseline. The combination also increased percentages of leukocytes, effector CD4 T cells, effector and effector memory CD8 T cells as well as levels of PDL1-Tim3+ cells. Conclusion: In the setting of MSS mCRC, metformin as a single agent did not enhance effector CD4 and CD8 T cell percentages in clinical samples in our patient cohort. Metformin in combination with nivolumab was associated with increased percentages of effector CD4 and CD8 T cells in biopsy specimens, although these improvements did not translate into enhanced clinical endpoints. Analysis of peripheral blood samples are currently underway to corroborate the findings in the tissue samples. Citation Format: Batoul Farran, Jeffrey M. Switchenko, Lana Khalil, Walid L. Shaib, Brian Olson, Amanda Ruggieri, Christina Wu, Olatunji B. Alese, Maria Diab, Gregory B. Lesinski, Bassel El-Rayes, Mehmet Akce. Correlative analysis of metformin and nivolumab combination in treatment-refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3482.

4118 Background: Non-alcoholic steatohepatitis (NASH) is an emerging etiology for hepatocellular carcinoma (HCC) and contributes to the increasing incidence of HCC worldwide. Patients with NASH often have risk factors of metabolic syndrome including hypertension, obesity, and type 2 diabetes (T2DM). NASH induced HCC has been shown to be associated with less response to immune check point inhibitors (ICIs) in HCC. Anti-diabetic agent metformin has been shown to be associated with improved outcomes in patients treated with ICIs in melanoma and non-small cell lung cancer. However, the impact of metformin on the efficacy of ICIs is not well defined in HCC. The main purpose of this study was to examine the effect of metformin on clinical outcomes in patients with advanced HCC treated with ICIs. Methods: We performed a retrospective analysis of patients with advanced HCC treated with ICIs in first and later-line settings between 2015 and 2021. The primary endpoints were overall survival (OS), progression free survival (PFS), and objective response rate (ORR) as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients were stratified based on their usage of metformin. OS and PFS were analyzed using Cox proportional hazard models and Kaplan-Meier analysis with log-rank test. Results: A total of 111 patients met inclusion criteria, 18 patients in the metformin group and 93 patients in the non-metformin group. Most common cause of HCC was viral hepatitis (52%), followed by NASH (29%), alcohol (8%) and other (11%). Baseline characteristics between the two groups were similar except all patients in the metformin group had a diagnosis of T2DM. ORR was 5.6%. (1 partial response) in the metformin group vs 22.6% (5 complete responses, 16 partial responses) in the non-metformin group. Median OS was 45.9 months in the non-metformin group vs 10.8 months in metformin group (HR 1.99, 95% CI 0.95-4.21, p = 0.064). Median PFS of 6.6 months vs 2.5 months (HR 1.75, 95% CI 0.93-3.29, p = 0.077). Moreover, metformin usage was associated with shorter median OS of 10.8 months (HR 1.96, 95% CI 0.75-5.09, p = 0.16) vs 20.9 months among patients with T2DM. OS was significantly worse in patients with poor ECOG performance status 2-3, MELD score 10-23, higher grade tumor histology, AFP > = 400, and use of IO in later lines of therapy. Conclusions: In this retrospective study metformin use was associated with worse clinical outcomes in advanced HCC patients treated with ICIs.

Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease.This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease.Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.

4 Background: About 10-20% of patients with anal squamous cell carcinoma (SCCa) present with metastatic disease, and are usually treated with systemic chemotherapy. The role of local therapy to control the primary tumor is controversial in this setting. We evaluated survival impact of local therapy in metastatic anal SCCa. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2015. We excluded patients who did not receive palliative systemic chemotherapy. Univariate (UVA) and multivariable analyses (MVA) 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: 1,160 patients were identified over 12 years. Median age was 57 years. Majority were female (64.9%), non-Hispanic Whites (79.1%) and had Charlson-Deyo Score of 0 (83.6%). Most common metastatic sites were liver (25.9%), lung (11.6%) and bone (8.5%). More than 79% of the patients received radiation to the primary site, and 10.4% underwent surgical resection for local control. Use of local therapy correlated closely with a significant improvement in OS on MVA (HR 0.66; 0.55-0.79; p < 0.001), with a 12-month and 5-year OS rates of 72.8% and 25.7% respectively, compared with 61.1% and 14.6% for patients treated with chemotherapy only. Poor prognostic factors included male gender (HR 1.44; 1.24-1.67; p < 0.001), age > 70 years (HR 1.28; 1.02-1.62; p = 0.034), lack of health insurance (HR 1.32; 1.02-1.71; p = 0.034), and cloacogenic zone location (HR 4.02; 1.43-11.30; p = 0.008). There was no benefit from abdominoperineal resection (mOS = 19.7mos; HR 1.05; 0.48-2.29; p = 0.909), but both local resection of the primary (mOS = 24.8mos, HR 0.48; 0.29-0.80; p = 0.005) and palliative radiation (mOS = 22.6 mos; HR 0.66; 0.55-0.79; p < 0.001) were associated with improved OS. Conclusions: This is the largest reported study on management of de novo stage IV SCCa. The data suggest that local control of the primary tumor through resection or radiation improved OS in patients with anal SCCa. Patients unlikely to benefit from local therapy include age over 70 years, male, lack of health insurance and cloacogenic carcinoma.

194 Background: Patients (pts) with multiple synchronous colon cancer primaries (MCPs) constitute a unique subset of pts with colon cancer. However, there are limited published studies about these pts. The objective of this study is to compare the characteristics and outcomes of pts with MCPs to those with single colon cancer primaries (SCPs) using the largest study population to date. Methods: Data was obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Pts with synchronous MCPs were included and were matched 1:3 with pts with SCPs based on the Coarsened Exact Matching method for age, gender, and race. Only patients with multiple synchronous primaries were included (time since index = 0 months). We excluded pts with a lag time since diagnosis of index primary of 1 month or more. Univariate (UNA) and multivariable (MVA) analyses were performed to identify factors associated with patient outcomes. Kaplan-Meier analyses and Cox proportional hazards models were used to assess the association between tumor/patient characteristics and overall survival (OS). Results: A total of 3322 pts with MCPs and 9966 pts with SCPs were identified. Median age was 71 years. Majority were male (51.5%) and White (80.1%). 73.4% and 69.6% of pts had 12 or more lymph nodes examined for the MCPs and SCPs cohorts, respectively. The SCPs cohort included more T4 stage and more well- and moderately-differentiated histology. OS was significantly shorter in MCPs compared to SCPs (HR 1.29; 1.22-1.36; p < 0.001), with a 5- and 10-year OS rate of 47.8% and 28.2% for the MCPs and 56.4% and 41.6% for the SCPs, respectively, for all stages combined. In the MCPs cohort, the use of adjuvant chemotherapy was associated with an improved survival in AJCC stages II, III, and IV but not stage I. Conclusions: This is the largest study evaluating the impact of MCPs on outcomes. Across stages II to IV, pts with MCPs have a shorter survival than those with SCPs. Pts with stage II MCPs who receive adjuvant chemotherapy derive a survival benefit. Current guidelines do not list multiple synchronous primaries as a high-risk feature for stage II.

TPS626 Background: Interleukin-6 (IL-6) is associated with carcinogenesis, immune suppression, and poor prognosis in pancreatic adenocarcinoma (PDAC). Preclinical data demonstrated dual inhibition of IL-6 and (programmed death ligand-1) PD-L1 facilitates CD8+ T cell migration into pancreatic tumors and was effective in controlling tumor growth in syngeneic and genetically engineered PDAC mouse models. Siltuximab is a chimeric monoclonal antibody which targets the IL-6 molecule specifically and spartalizumab is a high-affinity ligand-blocking humanized IgG4 antibody against the PD-1 receptor. Based on this preclinical rationale, we developed a phase Ib/II trial to determine the recommended phase II dose (RP2D), evaluate the safety, toxicity profile, preliminary antitumor activity, and immunogenicity of the siltuximab and spartalizumab in patients with previously treated metastatic PDAC. Methods: The phase Ib trial design is standard 3+3. Primary endpoint is to determine RP2D. Siltuximab is administered intravenously (IV) in three dose levels of 6 mg/kg (DL1), 11 mg/kg (DL2), 9 mg/kg (only if 2 DLTs observed on DL2) every 3 weeks with spartalizumab at 300 mg IV every 3 weeks. Eligible patients must have stage IV PDAC who have failed at least one prior therapy age ≥18 years, ECOG PS 0-1, no prior anti PD-1 or anti-PD-L1 agent. After RP2D is established, an expansion phase will enroll 24 patients with PDAC. Pre and on-treatment biopsy will be performed in 24 patients in the expansion cohort for correlative analysis. Pre-treatment and on-treatment peripheral blood samples will be collected from all patients. In the expansion phase patients will receive initial cycle (every 3 weeks) treatment with either spartalizumab or spartalizumab plus siltuximab and then starting cycle 2 all patients receive the combination following the on-treatment research biopsy. This design will enable us to evaluate the immunological effects of spartalizumab alone versus the combination in the tumor microenvironment and peripheral blood. This study was activated in January 2020 and to date 12 patients were enrolled in dose escalation phase. The dose expansion phase has recently started accrual. Clinical trial information: NCT04191421.

Over the past decade, researchers have identified and characterized the diverse cell populations within the tumor microenvironment of pancreatic cancer. The interplay between these cells in the TME either promotes or inhibits the malignant behavior of pancreatic cancer cells. Cancer-associated fibroblasts, previously thought to be one main subset, can now be broadly subclassified into three main types: inflammatory, myofibroblastic, and antigen-presenting, with the former and the latter two exerting pro-tumoral and anti-tumoral functions, respectively. Myeloid cells include myeloid-derived suppressor cells and tumor-associated macrophages. Myeloid-derived suppressor cells can be further divided into polymorphonuclear and monocytic and exhibit pro-tumoral activities. Tumor-associated macrophages exhibit M1 (anti-tumoral) or M2 (pro-tumoral) phenotypes, which are present in a dynamic fashion between the two phenotypes. Other constituents of the immune make-up of the tumor microenvironment include T and B cells and less described subsets which include natural killer cells, γδ T cells, and group 2 innate lymphoid cells. This review provides an overview of the studies that lead to the discovery of those cellular populations and highlights the recent efforts to utilize them as therapeutic targets in pancreatic cancer.

Gastric cancer remains a major unmet clinical problem with over 1 million new cases in 2018 worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60% and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18% and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success and challenges with available therapeutic targets along with newer biomarkers and emerging targets.

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.

3563 Background: The tumor microenvironment (TME) of colorectal cancers (CRC) is modulated by oncogenic drivers such as KRAS. The TME comprises a broad landscape of immune infiltration. How tumor genomics associates with the immune cell landscape is less known. We aim to characterize immune cell types in RAS wild-type (WT) and mutant (MT) CRC, and to examine the prevalence of immuno-oncologic (IO) biomarkers (e.g. tumor mutation burden (TMB), PD-L1, MSI-H/dMMR) in these tumors. We performed genomic and transcriptomic analysis to confirm associations of mutant RAS with immune infiltration of the TME conducive to metastasis vs. potential response to immunotherapies. Methods: A total of 7,801 CRC were analyzed using next-generation sequencing on DNA (NextSeq, 592 Genes and WES, NovaSEQ), RNA (NovaSeq, whole transcriptome equencing) and IHC (Caris Life Sciences, Phoenix, AZ). MSI/MMR was tested by FA, IHC and NGS. TMB-H was based on a cut-off of > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons (q) was = than 50 yrs. In MSS tumors, there was a significantly higher neutrophil infiltration in KRAS MT (median cell fraction 6.6% vs. 5.9%) and NRAS MT (6.9%) overall and also when individual codons were studied. B cells, M2 macrophages, CD8+ T cells, dendritic cells and fibroblasts were lower in KRAS mutant tumors; B cells and M1 macrophages are lower in NRAS (q

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.

Despite its rare prevalence, gallbladder cancer (GBC) is associated with a poor prognosis. Patients typically experience vague symptoms and present with advanced stages of disease. Gallstones are the most prevalent risk factors. Tumors that are associated with gallstones have a different pathogenesis compared to those originating from anomalous pancreaticobiliary duct junction or on a background of adenomatous polyps. Approximately 10–30% of patients will qualify for surgical resection, which is the only potentially curable treatment. Patients with resected, node- or margin-positive disease are candidates for adjuvant therapy. Options include fluoropyrimidine-based chemoradiation with or without chemotherapy, as well as fluoropyrimidine- or gemcitabine-based chemotherapy alone. For patients with advanced disease, prognosis is poor despite treatment, which includes fluoropyrimidine- or gemcitabine-based chemotherapy, with or without fluoropyrimidine chemoradiation. Targeted biologic therapy, such as inhibitors of VEGF, EGFR, and HER2, as well as pathways with aberrant expression, have been evaluated in the setting of advanced disease. Unfortunately, the trials are underpowered. Further studies are in dire need.

Pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related death in the United States. Since the hallmark clinical trial in 1997 that showed superiority of gemcitabine over 5-fluorouracil, gemcitabine has been the mainstay of treatment of PDAC, either as single agent or in combination with other treatments. FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) was also recently introduced for the treatment of patients with a good performance status. However, despite large cancer sequencing initiatives in the past decade that have allowed for a better understanding of the molecular biology of PDAC, highly efficacious therapies, especially in the setting of locally advanced and metastatic disease, are still lacking. Although several target agents have been investigated in PDAC, almost all have failed to demonstrate a survival benefit in late-phase clinical trials. In this chapter, we will review novel target agents that were evaluated in clinical trials for the treatment of PDAC, focusing on small-molecule therapies.

Platinum-based chemotherapy is the standard of care treatment for patients with non-resectable, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).1 However, the toxicides of platinum must not be ignored. In reality, many patients with non-resectable R/M HNSCC cannot tolerate platinum-based chemotherapy due to their performance status (PS) and/or comorbidities. Methotrexate (MTX), a folate antimetabolite that inhibits DNA synthesis, repair and cellular replication, has shown a modest response rate (RR) of 10% while RR was 32% for ciplatin/5-FU in R/M HNSCC, although this was in exchange with significantly increased toxicides with dsplatin/5-FU compared to MTX (P = 0.001).2 Cetuximab (CTX) is a chimeric monoclonal antibody directed against the extracellular portion of the epidermal growth factor receptor (EGFR). CTX monotherapy has shown RR of 13% in R/M HNSCC post-platinum-failure.3 Both CTX and MTX have shown single-agent activity in non-resectable R/M HNSCC with favourable toxicity profiles. However, data on combination CTX/MTX are limited. The purpose of this study is to provide outcomes data on combination CTX/MTX in non-resectable R/M HNSCC patients.

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

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.

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%(IS)) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR(4.5) ≤ 0.0032%(IS)) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons.

Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models. PDAC cell lines were exposed to a novel CRAC channel inhibitor, RP4010, in the presence or absence of standard of care drugs such as gemcitabine and nab-paclitaxel. The in vivo efficacy of RP4010 was evaluated in a hyaluronan-positive PDAC patient-derived xenograft (PDx) in the presence or absence of chemotherapeutic agents. Treatment of PDAC cell lines with single-agent RP4010 decreased cell growth, while the combination with gemcitabine/nab-paclitaxel exhibited synergy at certain dose combinations. Molecular analysis showed that RP4010 modulated the levels of markers associated with CRAC channel signaling pathways. Further, the combination treatment was observed to accentuate the effect of RP4010 on molecular markers of CRAC signaling. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine/nab-paclitaxel in a PDAC PDx model. Our study indicates that targeting CRAC channel could be a viable therapeutic option in PDAC that warrants further clinical evaluation.

Gastric adenocarcinoma is a highly aggressive disease with poor overall survival. The aggressive nature of this disease is in part due to the high intra and inter tumoral heterogeneity and also due to the late diagnosis at presentation. Once progression occurs, treatment is more difficult due to the adaptation of tumors, which acquires resistance to commonly used chemotherapeutics. In this report, using publicly available data sets and pathway analysis, we highlight the vast heterogeneity of gastric cancer by investigating genes found to be significantly perturbed. We found several upregulated genes in the diffuse gastric cancer subtypes share similarity to gastric cancer as a whole which can be explained by the increase in this subtype of gastric cancer throughout the world. We report significant downregulation of genes that are underrepresented within the literature, such as ADH7, GCNT2, and LIF1, while other genes have not been explored within gastric cancer to the best of our knowledge such as METTL7A, MAL, CWD43, and SLC2A12. We identified gender to be another heterogeneous component of this disease and suggested targeted treatment strategies specific to this heterogeneity. In this study, we provide an in-depth exploration of the molecular landscape of gastric cancer in order to shed light onto novel areas of gastric cancer research and explore potential new therapeutic targets.

Pancreatic cancer (PC) continues to be the fourth leading cause of cancer-related mortality despite decades of attempts to eradicate this disease. To this day, an effective tool for the screening and early diagnosis of pancreatic cancer is missing. A number of biomarkers was evaluated in the diagnostic, therapeutic, and prognostic settings of pancreatic cancer. KRAS, which is mutated in >90% of cases, is considered a rational target in treating pancreatic cancer. Unfortunately, therapy targeting KRAS is still lacking. MicroRNAs represent an attractive biomarker due to their abundance and feasibility of analysis. Multiple panels of microRNAs can differentiate pancreatic cancer from healthy and nonmalignant tissues. Biomarkers, such as hENT1 and SPARC, may assist in predicting benefit from specific therapeutic agents and be a tool to provide patients with an “individualized” treatment plan. Furthermore, “liquid biopsies” may allow monitoring circulating tumor DNA and circulating tumor cells during therapy. However, to this date, CA 19-9 remains the only FDA-approved biomarker for use in the clinic.

Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy. Disease is diagnosed in an advanced stage in the vast majority of patients, and PDAC cells are often resistant to conventional cytotoxic drugs. Targeted therapies have made no progress in the management of this disease, unlike other cancers. microRNAs (miRs) are small non-coding RNAs that regulate the expression of multitude number of genes by targeting their 3′-UTR mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. In PDAC, a series of miRs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for therapeutic response in patients. In this mini-review, we present an update on the various different miRs that have been defined in PDAC biology.

Both autologous and allogeneic hematopoietic stem cell transplants are important therapeutic options for several benign and malignant disorders. Pulmonary complications, although they have become less frequent, remain a significant cause of morbidity and mortality after hematopoietic stem cell transplant. These complications range from bacterial, fungal, and viral pulmonary infections to noninfectious conditions such as diffuse alveolar hemorrhage and idiopathic pneumonia syndrome. Bronchiolitis obliterans syndrome is the primary chronic pulmonary complication, and treatment of this condition remains challenging. This report highlights the advances in the diagnosis and management of the major pulmonary complications after hematopoietic stem cell transplant. It also underscores the need for prospective and multicenter research to have a better understanding of the mechanisms behind these complications and to obtain more effective diagnostic tool and therapeutic options.

Context: Scientific research output measured by the number and quality of publications reflects the research productivity of a certain community. Aims: To examine the quantity and quality of research produced by Syrian institutions with particular emphasis on the clinical and biomedical research. Settings and Design: Retrospective observational analysis of research originating from Syrian institutions indexed by Medline and Science Citation Index (SciVerse) Scopus bibliographic databases. Materials and Methods: Comprehensive review of the literature indexed by Medline and SciVerse was conducted including data from Jan 01, 1980 till February 2011 searching for authors affiliated with Syrian institutions. Clinical and biomedical research data were further analyzed quantitatively and qualitatively. Results: The total of manuscripts indexed by SciVerse originating from Syrian institutions during the last 3 decades is 3540. A total of 458 publications cover clinical and biomedical subject areas. The quality of these 458 publications was evaluated by the citation frequency and impact factor of publishing journals with h-index of 24. Conclusions: Although the spectrum of research originating from Syrian institutions is broad, the overall number of publications particularly in clinical and biomedical subjects is minuscule and of limited quality. The presented data indicate the need to promote research capabilities and to bridge the gap in research productivity by Syrian institutions.

e16236Background: Limited treatment options in patients with pancreatic adenocarcinoma (PDA) necessitate the search for new therapeutic targets. One area of major interest is the exploitation of DN...

3604Background: Randomized phase III trials have shown that patients with dMMR/ MSI-H stage II colon cancer (CC) do not benefit from adjuvant chemotherapy. However, a subgroup of stage II patients ...

Neutropenic diets (ND) are often prescribed to cancer patients aiming to reduce infection risk. The goal of this meta-analysis was to determine if ND indeed reduced the risk of infection and death in cancer patients compared to regular diets (RD). We identified studies in cancer patients that compared the effect of ND vs. RD on the risk of infections and mortality of any cause. The overall effect was calculated by use of a random effects model. Four studies were identified encompassing 918 patients. There was no difference in major infection or mortality rates between ND and RD groups. When analyzing for the overall composite outcome of any infection or fever, the hazard ratio was significantly higher in the ND arm (relative risk = 1.18, confidence interval: 1.05 to 1.34, P= 0.007). When the analysis was restricted to only the randomized trials, both groups had a comparable composite outcome. This meta-analysis shows no superiority with respect to mortality or infection of using a neutropenic diet in cancer patients. Larger studies are needed that study a broader range of nutritional issues, including the microbiome, in this patient population. Until then, it may be time to relax the restrictions of ND.