Treatment results of neoadjuvant chemoradiotherapy followed by radical esophagectomy in patients with initially inoperable thoracic esophageal cancer.

PURPOSE: We evaluated the effectiveness of neoadjuvant chemoradiotherapy (CRT) followed by esophagectomy for cT4 esophageal cancer or lymph node metastases (LNM) invading adjacent structures. MATERIALS AND METHODS: We retrospectively evaluated 42 consecutive patients with thoracic esophageal cancer who underwent CRT followed by esophagectomy between 2008 and 2013. All were initially considered to be unresectable because of cT4 (n = 32) disease or LN invasion (n = 10). Radiotherapy was administered at 41.4 Gy/23 fr with concurrent chemotherapy. At completion of CRT, restaging was performed using computed tomography (CT). RESULTS: All cT4 tumors were downstaged, LNM invading to adjacent structures were considered to be released, and subtotal esophagectomy was performed. The median follow-up period was 42 months. The curative resection (R0) rate was 94% in cT4 group and 70% in LN invasion group. The 3-year overall survival (OS) and 3-year locoregional control (LRC) rates were 65-80% in the cT4 group and 50-67% in LN invasion group, respectively. CONCLUSIONS: The cT4 group showed good rates of R0, OS, and LRC. Surgical resection should be an effective option when downstaging is achieved by CRT for patients with initially inoperable thoracic esophageal cancer.

Results of surgery plus postoperative radiotherapy for patients with malignant parotid tumor.

PURPOSE: The latest version of the World Health Organization (WHO) histologic classification of salivary gland malignancies was published in 2005. To contribute to data accumulation on the basis of this latest version, a retrospective study was performed. MATERIALS AND METHODS: Participants comprised 27 patients who underwent postoperative radiotherapy between 2000 and 2013. Two, eight, and 17 patients were allocated to low, intermediate, and high-grade groups, respectively, in accordance with the latest WHO classification. The radiation field included the tumor bed and ipsilateral regional lymph nodes for 25 patients. The radiation dose was 46-60 Gy (median 56 Gy). RESULTS: Median duration of follow-up was 41 months. Five-year locoregional control was 89 %. Two patients experienced local recurrence and 7 patients developed distant metastases. No patients in the low or intermediate-grade groups developed distant metastases. Overall 3 and 5-year survival for all patients were 81 and 75 %, respectively. Five-year overall survival for patients in the low and intermediate-grade groups was 100 %, compared with 59 % for patients in the high-grade group (p = 0.03). CONCLUSION: Favorable locoregional control was achieved for patients with malignant parotid tumors who underwent surgery plus postoperative radiotherapy. Patients with high-grade tumors frequently experienced distant metastases and prognosis was poor.

FoxO1 gain of function in the pancreas causes glucose intolerance, polycystic pancreas, and islet hypervascularization.

Genetic studies revealed that the ablation of insulin/IGF-1 signaling in the pancreas causes diabetes. FoxO1 is a downstream transcription factor of insulin/IGF-1 signaling. We previously reported that FoxO1 haploinsufficiency restored ß cell mass and rescued diabetes in IRS2 knockout mice. However, it is still unclear whether FoxO1 dysregulation in the pancreas could be the cause of diabetes. To test this hypothesis, we generated transgenic mice overexpressing constitutively active FoxO1 specifically in the pancreas (TG). TG mice had impaired glucose tolerance and some of them indeed developed diabetes due to the reduction of ß cell mass, which is associated with decreased Pdx1 and MafA in ß cells. We also observed increased proliferation of pancreatic duct epithelial cells in TG mice and some mice developed a polycystic pancreas as they aged. Furthermore, TG mice exhibited islet hypervascularities due to increased VEGF-A expression in ß cells. We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in ß cells. We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.

FoxO1 as a double-edged sword in the pancreas: analysis of pancreas- and ß-cell-specific FoxO1 knockout mice.

Diabetes is characterized by an absolute or relative deficiency of pancreatic ß-cells. New strategies to accelerate ß-cell neogenesis or maintain existing ß-cells are desired for future therapies against diabetes. We previously reported that forkhead box O1 (FoxO1) inhibits ß-cell growth through a Pdx1-mediated mechanism. However, we also reported that FoxO1 protects against ß-cell failure via the induction of NeuroD and MafA. Here, we investigate the physiological roles of FoxO1 in the pancreas by generating the mice with deletion of FoxO1 in the domains of the Pdx1 promoter (P-FoxO1-KO) or the insulin 2 promoter (ß-FoxO1-KO) and analyzing the metabolic parameters and pancreatic morphology under two different conditions of increased metabolic demand: high-fat high-sucrose diet (HFHSD) and db/db background. P-FoxO1-KO, but not ß-FoxO1-KO, showed improved glucose tolerance with HFHSD. Immunohistochemical analysis revealed that P-FoxO1-KO had increased ß-cell mass due to increased islet number rather than islet size, indicating accelerated ß-cell neogenesis. Furthermore, insulin-positive pancreatic duct cells were increased in P-FoxO1-KO but not ß-FoxO1-KO. In contrast, db/db mice crossed with P-FoxO1-KO or ß-FoxO1-KO showed more severe glucose intolerance than control db/db mice due to decreased glucose-responsive insulin secretion. Electron microscope analysis revealed fewer insulin granules in FoxO1 knockout db/db mice. We conclude that FoxO1 functions as a double-edged sword in the pancreas; FoxO1 essentially inhibits ß-cell neogenesis from pancreatic duct cells but is required for the maintenance of insulin secretion under metabolic stress.

Overexpression of FoxO1 in the hypothalamus and pancreas causes obesity and glucose intolerance.

Recent studies have revealed that insulin signaling in pancreatic ß-cells and the hypothalamus is critical for maintaining nutrient and energy homeostasis, the failure of which are hallmarks of metabolic syndrome. We previously reported that forkhead transcription factor forkhead box-containing protein of the O subfamily (FoxO)1, a downstream effector of insulin signaling, plays important roles in ß-cells and the hypothalamus when we investigated the roles of FoxO1 independently in the pancreas and hypothalamus. However, because metabolic syndrome is caused by the combined disorders in hypothalamus and pancreas, to elucidate the combined implications of FoxO1 in these organs, we generated constitutively active FoxO1 knockin (KI) mice with specific activation in both the hypothalamus and pancreas. The KI mice developed obesity, insulin resistance, glucose intolerance, and hypertriglyceridemia due to increased food intake, decreased energy expenditure, and impaired insulin secretion, which characterize metabolic syndrome. The KI mice also had increased hypothalamic Agouti-related protein and neuropeptide Y levels and decreased uncoupling protein 1 and peroxisome proliferator-activated receptor γ coactivator 1α levels in adipose tissue and skeletal muscle. Impaired insulin secretion was associated with decreased expression of pancreatic and duodenum homeobox 1 (Pdx1), muscyloaponeurotic fibrosarcoma oncogene homolog A (MafA), and neurogenic differentiation 1 (NeuroD) in islets, although ß-cell mass was paradoxically increased in KI mice. Based on these results, we propose that uncontrolled FoxO1 activation in the hypothalamus and pancreas accounts for the development of obesity and glucose intolerance, hallmarks of metabolic syndrome.