Angiogenesis, a hallmark of cancer, is induced by vascular endothelial growth factor–A (hereafter VEGF). As a result, anti-VEGF therapy is commonly used for cancer treatment. Recent studies have found that VEGF expression is also associated with immune suppression in patients with cancer. This connection has been investigated in preclinical and clinical studies by evaluating the therapeutic effect of combining antiangiogenic reagents with immune therapy. However, the mechanisms of how anti-VEGF strategies enhance immune therapy are not fully understood. We and others have shown selective elevation of VEGFR2 expression on tumor-associated myeloid cells in tumor-bearing animals. Here, we investigated the function of VEGFR2 ⁺ myeloid cells in regulating tumor immunity and found VEGF induced an immunosuppressive phenotype in VEGFR2 ⁺ myeloid cells, including directly upregulating the expression of programmed cell death 1 ligand 1. Moreover, we found that VEGF blockade inhibited the immunosuppressive phenotype of VEGFR2 ⁺ myeloid cells, increased T cell activation, and enhanced the efficacy of immune checkpoint blockade. This study highlights the function of VEGFR2 on myeloid cells and provides mechanistic insight on how VEGF inhibition potentiates immune checkpoint blockade.

Gallbladder cancer is a highly aggressive disease with a late presentation and poor prognosis.^1,2 Complete surgical excision remains the only potentially curative treatment for early-stage gallbladder cancer.^3,4 Adjuvant chemotherapy is used in some patients, with gemcitabine plus cisplatin being the most commonly used adjuvant regimen; however, to our knowledge, no phase 3 randomized clinical trials have evaluated this regimen.^5,6 In intrahepatic, hilar cholangiocarcinoma, or muscle-invasive gallbladder cancers, the Capecitabine or Observation After Surgery in Treating Patients With Biliary Tract Cancer (BILCAP) trial of adjuvant capecitabine starting within 12 weeks postoperatively and given twice a day on days 1 to 14 of a 3-weekly cycle for 24 weeks (8 cycles) vs observation failed to reach its intention-to-treat primary end point of improvement in median overall survival.⁷ One limitation of the BILCAP trial is that the adherence to adjuvant chemotherapy was 55%. In other aggressive tumors with the similar dilemma of early recurrence and poor tolerance to adjuvant chemotherapy, neoadjuvant chemotherapy has provided several advantages.^8-12 These advantages include early management of micrometastatic disease, identifying patients with chemotherapy-responsive disease, downstaging tumors leading to margin-negative resection, and avoiding surgical resection in patients with early progression.³ Neoadjuvant chemotherapy is now a preferred approach in several gastrointestinal cancers, such as pancreatic, gastric, and rectal cancer. The use and benefit of chemotherapy in resectable gallbladder cancer, especially in the neoadjuvant setting, is not well studied in the US and, to our knowledge, neoadjuvant chemotherapy has not been evaluated in any randomized clinical trial. In this study, we report on the use and outcomes with chemotherapy, both in the neoadjuvant and adjuvant settings, compared with surgery alone in patients with localized or locoregionally advanced but resectable gallbladder cancers.

Background: While the incidence of cholangiocarcinoma is rising, little is known about young‐onset disease. We compared clinical characteristics and outcomes between patients with young‐onset cholangiocarcinoma, diagnosed between the ages of 18 and <50 years, and patients with typical‐onset cholangiocarcinoma, diagnosed at age 50 years or greater.Methods: We used the National Cancer Database to identify patients with young‐onset cholangiocarcinoma (n = 2520) and typical‐onset cholangiocarcinoma (n = 23,826). We compared the frequency of demographic and clinical characteristics between the two groups. We compared overall survival between the two groups using multivariable Cox regression analysis after adjusting for age, gender, race/ethnicity, comorbidity, facility type, tumor location, tumor stage, surgical status, and receipt of radiotherapy, chemotherapy and surgery.Results: When compared to patients with typical‐onset disease (median age 68 years), patients with young‐onset cholangiocarcinoma (median age 44 years) were more likely to be non‐White (35.0% vs. 27.4%, p < 0.01), and had lower overall comorbidity burden. Patients with young‐onset disease had a greater proportion of intrahepatic cholangiocarcinoma (56.0% vs. 45.5%, p < 0.001) and stage IV disease (50.5% vs. 43.5%, p < 0.001). Younger patients were more likely than typical‐onset patients to receive definitive surgery (30.9% vs. 25.0%, p < 0.001), radiation (27.7% vs. 19.6%, p < 0.001) and chemotherapy (73.1% vs. 50.1%, p < 0.001). In adjusted analyses, patients with young‐onset disease had a 15% decreased risk of death, compared with patients with typical‐onset disease (HR 0.85 [95% CI 0.80–0.89], p < 0.001).Conclusions: Patients with young‐onset cholangiocarcinoma may represent a demographically and clinically distinct group from those with more typical‐onset disease.

Background: We aimed to study the effect of socioeconomic differences and molecular characteristics on survival in patients with young-onset pancreatic neuroendocrine tumors (YOPNET) and typical-onset PNET (TOPNET). Methods: We identified the patients with YOPNET (<50 years) and TOPNET (≥50 years) who underwent definitive surgery diagnosed between 2004 and 2016 using the National Cancer Database. We evaluated overall survival (OS) using the Kaplan–Meier and Cox regression methods before and after propensity score matching. A publicly available genomic dataset was used to compare mutation frequencies among the two groups. Results: A total of 6259 patients with PNET were included, of which 27% were YOPNET. Patients with YOPNET were more likely to be Black, Hispanic, female, and have private insurance versus patients with TOPNET (all p < 0.001). Patients with YOPNET had a lower comorbidity score, but higher stage and tumor size (all p < 0.001). YOPNET was associated with a greater improved OS than TOPNET before and after propensity score matching (p < 0.001). On multivariable analysis, this survival difference persisted for YOPNET as an independent prognostic factor (unmatched p = 0.008; matched p = 0.01). For genomic analysis, patients with YOPNET had a lower rate of multiple endocrine neoplasia type-1 (MEN-1) mutation than patients with TOPNET (26% vs. 56%, p < 0.001). Conclusions: YOPNET represents a disease with distinct clinical features. Patients with YOPNET who underwent definitive surgery had better OS than patients with TOPNET despite having higher stage and tumor size. YOPNET also had lower rate of MEN-1 mutation.

Background: The age-dependent prognostic impact of KRAS status in metastatic colorectal cancer (mCRC) is unknown. Materials & Methods: We used the National Cancer Database to evaluate the survival ...