Preclinical murine platform to evaluate therapeutic countermeasures against radiation-induced gastrointestinal syndrome.

Radiation-induced gastrointestinal syndrome (RIGS) is a limiting factor for therapeutic abdominopelvic radiation and is predicted to be a major source of morbidity in the event of a nuclear accident or radiological terrorism. In this study, we developed an in vivo mouse-modeling platform that enables spatial and temporal manipulation of potential RIGS targets in mice following whole-abdomen irradiation without the confounding effects of concomitant hematopoietic syndrome that occur following whole-body irradiation. We then tested the utility of this platform to explore the effects of transient Wnt pathway activation on intestinal regeneration and animal recovery following induction of RIGS. Our results demonstrate that intestinal epithelial suppression of adenomatous polyposis coli (Apc) mitigates RIGS lethality in vivo after lethal ionizing radiation injury-induced intestinal epithelial damage. These results highlight the potential of short-term Wnt agonism as a therapeutic target and establish a platform to evaluate other strategies to stimulate intestinal regeneration after ionizing radiation damage.

Pancreatic neuroendocrine tumors: presentation, management, and outcomes.

Pancreatic neuroendocrine tumors (pNETs) are an uncommon pancreatic neoplasm. We reviewed the presentation, management, and outcome of patients with pNETs treated at a single center by a multidisciplinary approach between 2004 and 2008. Over this time period, 154 patients with carcinoid and neuroendocrine tumors were treated, which included 46 patients (30% of total) with pNETs. The most common presentations included abdominal pain (20 of 46 [43%]), systemic symptoms such as hypoglycemia (15 of 46 [33%]), and incidental mass (7 of 46 [15%]). Fourteen patients had functional tumors. At the time of diagnosis, 22 patients (48%) presented without metastases and 24 (52%) had metastatic disease. Median follow up for the entire group was 42 months. All patients with nonmetastatic pNET underwent pancreatic resection with 95 per cent postoperative survival. Overall survival in this group at 3 years was 86 per cent and disease-free survival was 81 per cent. In patients presenting with metastatic pNET, multiple treatment modalities were used, including liver resection or ablation (n = 15), hepatic chemoembolization (n = 17), pancreatic resection (n = 12), and systemic treatments (n = 7). Three-year survival was 70 per cent. Pancreatic resection results in greater than 80 per cent 3-year survival in nonmetastatic pNET. In patients presenting with metastatic pNET, excellent survival rates are also achievable using a multidisciplinary multimodal approach.

A rectal cancer organoid platform to study individual responses to chemoradiation.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.