Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b+ GR1+ and CD11b+F4/80+ myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target.

In studies of mouse and human pancreatic tumors and precursors, we found that immune cell-derived IL17 regulated development of tuft cells and stem cell features of pancreatic cancer cells via increased expression of DCLK1, POU2F3, ALDH1A1, and IL17RC. Strategies to disrupt this pathway might be developed to prevent pancreatic tumor growth and progression.

This phase II trial was conducted to evaluate the safety and efficacy of concurrent gemcitabine and high-intensity focused ultrasound (HIFU) therapy in patients with locally advanced pancreatic cancer. Patients with localized unresectable pancreatic adenocarcinoma in the head or body of the pancreas received gemcitabine (1000 mg/m) intravenously over 30 min on days 1, 8, and 15, and concurrent HIFU therapy on days 1, 3, and 5. The treatment was given every 28 days. Thirty-seven (94.9%) of the 39 patients were assessable for response, and two cases of complete response and 15 cases of partial response were confirmed, giving an overall response rate of 43.6% [95% confidence interval (CI), 28.0-59.2%]. The median follow-up period was 16.5 months (range: 8.0-28.5 months). The median time to progression and overall survival for all patients were 8.4 months (95% CI, 5.4-11.2 months) and 12.6 months (95% CI, 10.2-15.0 months), respectively. The estimates of overall survival at 12 and 24 months were 50.6% (95% CI, 36.7-64.5%) and 17.1% (95%CI, 5.9-28.3%), respectively. A total of 16.2% of patients experienced grade 3/4 neutropenia. Grade 3 thrombocytopaenia was documented in two (5.4%) patients. Grade 3 nausea/vomiting and diarrhea were observed in three (8.1%), and two (5.4%) patients, respectively. Grade 1 or 2 fever was detected in 70.3% of patients. Twenty-eight patients (71.8%) complained of abdominal pain consistent with tumor-related pain before HIFU therapy. Pain was relieved in 22 patients (78.6%). In conclusion, concurrent gemcitabine and HIFU is a tolerated treatment modality with promising activity in patients with previously untreated locally advanced pancreatic cancer.