Thanks to the development of modern chemotherapeutic regimens, survival after surgery for pancreatic ductal adenocarcinoma (PDAC) has improved and pancreatologists worldwide agree that the treatment of PDAC demands a multidisciplinary approach. Neoadjuvant treatment (NAT) plays a major role in the treatment of PDAC since only about 20% of patients are considered resectable at the time of diagnosis. Moreover, increasing data demonstrating the benefits of NAT for borderline resectable/locally advanced PDAC are driving a shift from up-front surgery to NAT in the multidisciplinary treatment of even resectable PDAC. Our understanding of the role of NAT in PDAC has evolved from tumor shrinkage to controlling potential micrometastases and selecting patients who may benefit from radical resection. The present review gives an overview on the current literature of NAT concepts for BR/LA PDAC and resectable PDAC.
Summary
Objectives
While surgery with or without adjuvant radiation therapy (RT) is the standard of care for oral cavity cancer (OCC), a select group requires nonsurgical treatment. We provide a single-institution experience using definitive chemotherapy and RT for primary OCC.
Materials and methods
We examined 73 patients with previously untreated, non-metastatic primary OCC treated definitively from 1990 to 2011. There were 39 male and 34 female, with a median age of 63 years (range, 35–89). The disease distribution was Stage I and II (7% each), Stage III (14%), and Stage IV (73%). Oral tongue was the most common (48%), followed by floor of mouth (19%), retromolar trigone (13.7%), and others (8.2%). Median tumor dose was 70 Gy. Sixty-two percent of patients (n = 45) were treated with concurrent chemotherapy, predominantly platinum-based.
Results
Median follow-up among surviving patients was 73.1 months (interquartile range 14.2– 81.4 months). Actuarial 5-year overall survival was 15%. Incidences of locoregional and distant failures were 41.1% and 20.5%, respectively. Kaplan-Meier estimated 5-year rates of locoregional control and freedom from distant metastasis were 37% and 70%, respectively. Mucositis was the most common ≥ Grade 3 acute toxicity (49%). Incidences of Grade 3 late dysphagia and trismus were 15% and 13%, respectively.
Conclusion
This study demonstrates over 20 years of experience using definitive chemoradiation for OCC at our institution. Our results illustrate the challenges in treating patients with advanced disease who are not surgical candidates, and the need for adequate and early treatment to prevent distant disease and improve survival outcomes.
For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.
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