Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts

Background: Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with F-18-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. Methods: In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 mu L PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 mu l NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. F-18-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation). Results: A T/B= 3.59 on pre-treatment F-18-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B = 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth. Conclusions: Tumor tissue hypoxia as measured with F-18-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation

Vaginal elongation with descending colon in patients with gender identity disorder

Background: The penile-scrotal skin flap technique is the method of choice for vaginoplasty in male-to-female transsexuals. A limited amount of available flap or postoperative complications may result in a lack of vaginal cavity depth and width, interfering with sexual intercourse. Vaginal elongation can be performed with different bowel segments, which have their merits and limitations. Elongation with descending colon has never been reported. We describe our experience using this bowel segment. Methods: We searched our hospital database for patients who underwent a vaginal elongation with descending colon after failed vaginoplasty. We analysed the postoperative course after vaginoplasty; the indications to perform an elongation; and technical details of this procedure. Patients’ further recovery was also noted. Results: From April 2010 till January 2014, 11 patients underwent vaginal elongation after failed vaginoplasty. The time interval between both operations ranged from 5 months to 30 years. Every patient had insufficient vaginal length, which was often combined with stenosis of its introitus. Reconstruction was done with descending colon and lasted 185 to 395 minutes. The last three procedures were performed laparoscopically. During the early postoperative period, one patient developed a hematoma at the colovaginal anastomosis, which was conservatively treated. Hospital stay ranged from 6 to 20 days. Conclusion: Descending colon is suitable for failed vaginoplasty. No major events during surgery or technical failures in the early postoperative phase were encountered, emphasizing that both experience and team work are of paramount importance in this challenging operation which can even be executed laparoscopically

Vaginal elongation with descending colon in patients with gender identity disorder

Background: The penile-scrotal skin flap technique is the method of choice for vaginoplasty in male-to-female transsexuals. A limited amount of available flap or postoperative complications may result in a lack of vaginal cavity depth and width, interfering with sexual intercourse. Vaginal elongation can be performed with different bowel segments, which have their merits and limitations. Elongation with descending colon has never been reported. We describe our experience using this bowel segment. Methods: We searched our hospital database for patients who underwent a vaginal elongation with descending colon after failed vaginoplasty. We analysed the postoperative course after vaginoplasty; the indications to perform an elongation; and technical details of this procedure. Patients’ further recovery was also noted. Results: From April 2010 till January 2014, 11 patients underwent vaginal elongation after failed vaginoplasty. The time interval between both operations ranged from 5 months to 30 years. Every patient had insufficient vaginal length, which was often combined with stenosis of its introitus. Reconstruction was done with descending colon and lasted 185 to 395 minutes. The last three procedures were performed laparoscopically. During the early postoperative period, one patient developed a hematoma at the colovaginal anastomosis, which was conservatively treated. Hospital stay ranged from 6 to 20 days. Conclusion: Descending colon is suitable for failed vaginoplasty. No major events during surgery or technical failures in the early postoperative phase were encountered, emphasizing that both experience and team work are of paramount importance in this challenging operation which can even be executed laparoscopically

The VEGFR inhibitor cediranib improves the efficacy of fractionated radiotherapy in a colorectal cancer xenograft model

Background/Purpose: Radiotherapy (RT) increases local tumor control in locally advanced rectal cancer, but complete histological response is seen in only a minority of cases. Antiangiogenic therapy has been proposed to improve RT efficacy by "normalizing" the tumor microvasculature. Here, we examined whether cediranib, a pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, improves microvascular function and tumor control in combination with RT in a mouse colorectal cancer (CRC) model. Methods: CRC xenografts (HT29) were grown subcutaneously in mice. Animals were treated for 5 consecutive days with vehicle, RT (1.8 Gy daily), cediranib (6 mg/kg po), or combined therapy (cediranib 2 h prior to radiation). Tumor volume was measured with calipers. Vascular changes were analyzed by dynamic contrast-enhanced MRI, oxygenation and interstitial fluid pressure probes and histology. To investigate vascular changes more in detail, a second set of mice were fitted with titanium dorsal skinfold window chambers, wherein a HT29 tumor cell suspension was injected. In vivo fluorescence microscopy was performed before and after treatment (same treatment protocol). Results: In vivo microscopy analyses showed that VEGFR inhibition with cediranib led to a "normalization" of the vessel wall, with decreased microvessel permeability (p < 0.0001) and tortuosity (p < 0.01), and a trend to decreased vessel diameters. This seemed to lead to lower tumor hypoxia rates in the cediranib and combination groups compared to the control and RT groups. This led to an increased tumor control in the combination group compared to controls or monotherapy (p < 0.0001). Conclusions: The combination of RT with cediranib enhances tumor control in a CRC xenograft mouse model. Microvascular analyses suggest that cediranib leads to vascular normalization and improved oxygenation. (C) 2016 S. Karger AG, Base