EMVI-positive stage II rectal cancer has similar clinical outcomes as stage III disease following pre-operative chemoradiotherapy.

BACKGROUND: Stage II rectal cancers comprise a heterogeneous group, and there is significant variability in practise with regards to adjuvant chemotherapy; the survival benefit of chemotherapy is perceived to be <4% in these patients. However, in recent years, the emergence of additional prognostic factors such as extramural venous invasion (EMVI) suggests that there may be sub-stratification of stage II tumours and, further, we may be under-estimating the benefit adjuvant chemotherapy provides in high-risk patients. This study examined the outcomes of patients with stage II and III rectal cancer to determine whether EMVI status influences disease-free survival (DFS). PATIENTS AND METHODS: An analysis of a prospectively maintained database was conducted of patients presenting with rectal cancer between 2006 and 2012. All patients underwent curative surgery and had no evidence of metastases at presentation. Clinicopathological factors were compared between stage II and III disease. The primary end point was 3-year DFS; univariate and multivariate analysis was carried out using Cox proportional hazards regression models; hazard ratios (HR) with 95% confidence intervals (CIs) were calculated. RESULTS: Four hundred and seventy-eight patients were included: 233 stage II; 245 stage III. The prevalence of EMVI was 34.9%; 57 stage II patients (24.5%) and 110 stage III patients (44.9%). On multivariate analysis, only EMVI status was a significant factor for DFS. The adjusted HR for EMVI either alone or in combination with nodal involvement was 2.08 (95% CI 1.10-2.95) and 2.74 (95% CI 1.66-4.52), respectively. CONCLUSION: EMVI is an independently poor prognostic factor for DFS for both stage II and stage III rectal cancer. These results demonstrate that there is risk-stratification within stage II tumours which affects prognosis. When discussing the use of adjuvant chemotherapy with patients that have EMVI-positive stage II tumours, these results provide evidence for a similarly increased risk of distant failure as stage III disease without venous invasion.

Adjuvant chemotherapy improves overall survival after TME surgery in mucinous carcinoma of the rectum.

INTRODUCTION: Mucinous tumours of the rectum are characterised by an abundance of extracellular mucin within the tumour complex. They are known to have a poor prognosis compared to non-mucinous adenocarcinomas. The effect of adjuvant chemotherapy on the survival outcomes of patients with mucinous cancer remains unclear. This study evaluated the 5-year overall survival of patients with mucinous rectal cancer following optimal TME surgery to determine whether adjuvant chemotherapy conferred a survival benefit. METHODS: An analysis of a prospectively-maintained database was conducted of patients presenting with mucinous rectal cancer between 2000 and 2010. Patients with mucinous tumours were identified from final pathology reports of the surgical resection specimens. The primary outcome was 5-year overall survival; univariate and multivariate analysis was performed using Cox proportional hazards regression models. RESULTS: A total of 191 patients were included for analysis with mean age of presentation 64.6 years (36-88 ± 11). On the fully adjusted multivariate model, EMVI status (HR 1.853, 95% CI 1.081-3.175) and not being given adjuvant chemotherapy (HR 2.888, 95% CI 1.801-4.633) were significant for disease recurrence. The 5-year overall survival for patients that had undergone adjuvant chemotherapy was 66.1% compared with 35.2% (Mantel Cox log-rank test - p < 0.0001). CONCLUSION: This study demonstrates that adjuvant chemotherapy is an independent factor for improvement in overall survival in patients with mucinous adenocarcinoma. Therefore, patients who have undergone TME surgery for mucinous carcinoma of the rectum should be offered adjuvant chemotherapy even in the absence of other high-risk features for poor outcomes.

Kisspeptin-54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms.

BACKGROUND AND PURPOSE: The kisspeptins are critical regulators of reproduction and a therapeutic target for reproductive disease. Intracerebroventricular (i.c.v.) or peripheral injection of kisspeptin potently stimulates the hypothalamic-pituitary gonadal (HPG) axis via gonadotrophin-releasing hormone (GnRH). However, little is known regarding the effects of kisspeptin administration on testicular function. We investigated the mechanism(s) of kisspeptin-induced testicular degeneration in the rat. EXPERIMENTAL APPROACH: Kisspeptin-54 (50 nmol.day(-1)) was continuously administered subcutaneously (6 h to 3 days) to male Wistar rats and reproductive hormones and testicular histology analysed. We also investigated the effects of a single subcutaneous injection of 0.5, 5 or 50 nmol kisspeptin-54. In order to determine whether the testicular degeneration observed is peripherally or centrally mediated, we investigated effects of i.c.v. injections of 5 nmol kisspeptin-54 and pre-administered a GnRH-receptor antagonist (cetrorelix) to rats peripherally treated with kisspeptin-54. KEY RESULTS: Continuous subcutaneous administration of kisspeptin-54 caused testicular degeneration after only 12 h, when gonadotrophins were still markedly raised, suggesting that the degeneration is independent of the desensitization of the HPG axis to kisspeptin-54. Furthermore, a single subcutaneous injection of kisspeptin-54 caused dose-dependent testicular degeneration. Continuous kisspeptin-54 administration is thus not required to cause testicular degeneration. Pretreatment with cetrorelix blocked kisspeptin-induced testicular degeneration, and a single i.c.v. injection of kisspeptin-54 caused testicular degeneration, suggesting it is GnRH-mediated. CONCLUSIONS AND IMPLICATIONS: Kisspeptin-induced testicular degeneration appears to be centrally mediated, and result from acute hyper-stimulation of the HPG axis. Doses must be carefully considered if kisspeptin is to be used therapeutically.

Toward the clinical application of time-domain fluorescence lifetime imaging.

High-speed (video-rate) fluorescence lifetime imaging (FLIM) through a flexible endoscope is reported based on gated optical image intensifier technology. The optimization and potential application of FLIM to tissue autofluorescence for clinical applications are discussed.

High-speed wide-field time-gated endoscopic fluorescence-lifetime imaging.

We report the development of a high-speed wide-field fluorescence-lifetime imaging (FLIM) system that provides fluorescence-lifetime images at rates of as many as 29 frames/s. A FLIM multiwell plate reader and a potentially portable FLIM endoscopic system operating at 355-nm excitation have been demonstrated.

Inverse correlation between high level expression of cyclin E and proliferation index in transitional cell carcinoma of the bladder.

BACKGROUND/AIMS: Overexpression of the G1 cyclins, D1 and E, and/or downregulation of p27(Kip1) allow uncontrolled tumour cell proliferation. This study investigated the relation between these three cell cycle proteins and tumour proliferation in bladder cancer. METHOD: Nuclear expression of cyclin D1, cyclin E, and p27(Kip1) was determined immunohistochemically in 52 primary transitional cell carcinomas, and the Ki-67 proliferation marker was also assessed. For each protein, the percentage of positive tumour cell nuclei was determined and analysed as a continuous variable. RESULTS: Advancing tumour grade and pathological stage were accompanied by increasing proliferation indices, but decreasing p27(Kip1) and cyclin D1 expression, with no significant change in cyclin E expression. Overall, cyclin D1 and E expression did not correlate with proliferation. However, in cyclin D1 overexpressing tumours (> or = 5% nuclei positive), the level of cyclin D1 expression positively correlated with proliferation. The correlation between cyclin E expression and proliferation changed from positive to negative with increasing levels of cyclin E expression, accompanied by a coordinate increase in p27(Kip1) expression. Overall, there was an inverse association between p27(Kip1) expression and proliferation. However, a subset of tumours displayed high proliferation indices despite high p27(Kip1) expression. The G1 cyclin index (sum of the level of expression of cyclins D1 and E) correlated positively with proliferation in superficial but not muscle invasive tumours. This correlation was stronger when the G1 cyclin index was adjusted for p27(Kip1) expression. CONCLUSION: These findings support a role for these proteins in the proliferation, differentiation, and progression of bladder transitional cell carcinomas.