Dose-dependent protection by lipoic acid against cisplatin-induced nephrotoxicity in rats: antioxidant defense system

This study was designed to investigate the role of graded doses of lipoic acid pretreatment against cisplatin-induced nephrotoxicity. Male Wistar rats were divided into six groups and treated as follows: 1) vehicle (saline) control; 2) cisplatin (16 mg/kg, intraperitoneally); 3) lipoic acid (100 mg/kg, intraperitoneally); 4) cisplatin plus lipoic acid (25 mg/kg); 5) cisplatin plus lipoic acid (50 mg/kg) and 6) cisplatin plus lipoic acid (100 mg/kg). Rats were sacrificed three days after treatment, and plasma as well as kidneys were isolated and analyzed. Plasma creatinine increased (677% of control) following cisplatin administration alone which was decreased by lipoic acid in a dose-dependent manner. Cisplatin-treated rats showed a depletion of renal glutathione (GSH), increased oxidized GSH and decreased GSH/GSH oxidized ratio (62%, 166% and 62% of control), respectively which were restored with lipoic acid pretreatment. Renal superoxide dismutase, catalase, glutathione peroxidase (GSH peroxidase) and glutathione reductase activities decreased (62%, 75%, 62% and 80% of control), respectively, and malondialdehyde content increased (204% of control) following cisplatin administration, which were restored with increasing doses of lipoic acid. The renal platinum concentration increased following cisplatin administration, which was possibly decreased by chelation with lipoic acid. The data suggest that the graded doses of lipoic acid effectively prevented a decrease in renal antioxidant defense system and prevented an increase in lipid peroxidation, platinum content and plasma creatinine concentrations in a dose-dependent manner.     

Long-Term Results of Transanal Excision After Neoadjuvant Chemoradiation for T2 and T3 Adenocarcinomas of the Rectum

Introduction  Traditionally, selected early distal rectal cancers have been considered for treatment by transanal excision (TAE) with acceptable oncologic results. With the frequent use of neoadjuvant chemoradiation (NCR) for the treatment of locally advanced rectal cancer, there is growing interest in the application of TAE for such lesions. We report our experience of TAE for T2 and T3 rectal cancers following NCR. Material and Methods  Between July 1994 and August 2006, 44 patients were identified as having undergone full-thickness TAE of pretreatment ultrasound-staged T2 and T3 rectal cancers that were treated with NCR. Fifteen patients were deemed medically unfit for radical resection, and 29 would have required abdominoperineal resection but were opposed to colostomy. Results  Our patient population consisted of 26 men and 18 women, with a median age of 69 (range, 43–89) and a median follow up of 64 months (6–153). Thirty-one patients had a clinical complete response (cCR) to NCR of which 19 (61%) had a pathologic CR (pCR). Seven (16%) of 44 patients sustained disease recurrence of which two were local only, two local and systemic, and three systemic only. Only four (9%) patients had died of disease at current follow up. Overall 5-year survival rates for T2/T3N0 and T2/T3N1 patients were 84% and 81%, respectively. Five patients underwent radical resection immediately following TAE for either positive margins or residual cancer. There was minimal morbidity with no perioperative mortality associated with TAE. Conclusions  TAE of T2 and T3 rectal cancers following NCR is a safe alternative to radical resection in a highly select group of patients for which recurrence and survival rates comparable to radical resection can be achieved. This study supports ongoing efforts to assess this approach in prospective, multi-center trials.     

Effect of cisplatin on the expression of glutathione-S-transferase in the cochlea of the rat

Glutathione-S-transferase (GST) has been found to conjugate glutathione (GSH) to diverse electrophiles and play a major role in the detoxification of alkylating and platinating agents. However, there is little information regarding the pattern of GST expression in the cochlea. Although cisplatin is ototoxic, its effect on GST in the cochlea is unknown. In the present study we investigated the pattern of GST expression in control and cisplatin-treated cochleas by using the laboratory rat as animal model. Sixteen mature rats were randomly assigned to control or cisplatin groups. After treatment, cochleas were procured and tissues stained by immunohistochemical methods to detect the presence of GST. Optical density measurements were determined to gauge intensity of GST immunostaining. Strong positive GST immunostaining was demonstrated in all cochleas, with the most intense staining found in the spiral ligament and the least in Reissner's membrane. Mean optic density scores were lower for cisplatin-treated cochleas than for control cochleas in all areas analyzed. These findings showed that GST is expressed throughout the rat cochlea, with cisplatin treatment causing its decreased expression.     

Somatostatin receptor profiling in hepatic metastases from small intestinal and pancreatic neuroendocrine neoplasms: immunohistochemical approach with potential clinical utility.

BACKGROUND: The expression of somatostatin receptors (SSTRs) on endocrine tumor (ET) cells forms the basis for somatostatin analog treatment of patients with SSTR-positive, hormonally active ETs. In patients with SSTR-negative ETs, the clinical response is generally absent or suboptimal, while nonfunctioning ETs with SSTR positivity show a variable response to such therapy. METHODS: We retrospectively studied SSTR subtype expression in hepatic metastases from 14 adult patients with primary endocrine carcinomas (ECAs) of the small intestine and pancreas and compared SSTR subtype expression among the primary and metastatic ECAs. Polyclonal antibodies against the 5 SSTR subtypes were used on formalin-fixed, paraffin sections from each primary and metastatic ECA. Both qualitative and semiquantitative evaluation of the stained ECA sections was carried out. RESULTS: Eleven (61%) of 18 hepatic metastases from small intestinal and pancreatic ECAs were positive for SSTR-1, 15 (83%) for SSTR-2, 13 (72%) for SSTR-3, 10 (56%) for SSTR-4, and 15 (83%) for SSTR-5. Among 11 hepatic ECA metastases from small intestinal ECAs (carcinoids), 7 (63%) expressed SSTR-1, 9 (81%) expressed SSTR-2, 8 (72%) expressed SSTR-3, 6 (54%) expressed SSTR-4, and 10 (91%) expressed SSTR-5. Of 7 hepatic ECA metastases from pancreatic ECAs, 4 expressed SSTR-1, 6 expressed SSTR-2, and 5 expressed SSTR-3 and SSTR-5 each. We also observed the immunohistochemical evidence of heterogeneity of expression of various SSTR subtypes in the primary enteropancreatic ECAs and their hepatic metastases. CONCLUSIONS: SSTR subtype expression needs to be correlated to somatostatin analog therapy. Immunohistochemical profiling of various SSTR subtypes as a part of routine surgical pathologic analysis of enteropancreatic ETs may become a useful predictor of responsiveness of ETs to various SSTR analogs.     

Prosthetic breast reconstruction after implant-sparing mastectomy in patients with submuscular implants

Women with previous submuscular breast augmentation who contract breast cancer have several options for breast reconstruction. Our institution offers implant-sparing mastectomy with delayed implant exchange. A retrospective review of 10 patients who underwent implant-sparing mastectomies with delayed implant exchange between 2006 and 2010 was performed. The average age at implant exchange was 48.7 years. The average time between initial augmentation and mastectomy was 7.45 years. The average time between mastectomy and implant exchange was 7.1 months. One patient underwent partial mastectomy with radiation. The average size of implant at initial augmentation was 366 mL. The average size of implant exchange on side of mastectomy was 565.5 mL. One patient underwent a second exchange for larger implants. No other complications were noted. Implant-sparing mastectomy with delayed exchange provides an alternative to tissue expander placement and associated morbidities. This technique provides excellent results with minimal complications for this patient population.     

Biomarkers Predict Outcomes Following Cytoreductive Surgery for Hepatic Metastases from Functional Carcinoid Tumors

BACKGROUND: Cytoreductive therapy for metastatic carcinoid provides symptomatic relief and improvement in overall survival. We evaluated whether CgA and 5HIAA could predict symptomatic relief and control of disease progression after cytoreductive surgery. METHODS: We retrospectively reviewed 70 patients who underwent cytoreductive surgery for neuroendocrine hepatic metastases between 1996 and 2005. Twenty-two patients had pre and post-operative CgA and/or 5HIAA levels measured. Reduction of biomarkers following cytoreduction was correlated with patient symptoms and progression of disease following surgery. RESULTS: Our study consisted of 14 males and 8 females with a mean age of 55 (+/-12 years). Median follow-up was 18 months (range 5-64 months). Six patients (26.1%) had complete (R0) cytoreduction, while 4 (17.4%) and 13 (56.5%) had microscopic (R1) and gross (R2) disease remaining. All patients reported improvements in their symptoms, with 12 (54.5%) reporting complete resolution (CR) and 10 (45.5%) reporting partial resolution (PR). Reduction of CgA of >or= 80% was highly predictive of complete resolution of symptoms (P = 0.007) and stabilization of disease (P = 0.034). Reduction of 5HIAA levels of >or= 80% (or normalization) was predictive of symptomatic relief, but not progression of disease (P = 0.026 and P = 0.725). Five of six patients who had R0 resections had CR and were free of disease at last follow-up (median 24.5 months, range: 11-48, P = 0.002). CONCLUSIONS: We conclude that >or= 80% reduction in CgA level following cytoreductive surgery for carcinoid tumors is predictive of subsequent symptom relief and disease control. Substantial reduction in CgA is associated with improved patient outcomes, even after incomplete cytoreduction.