Prospective randomized study of azathioprine vs cyclosporine based therapy in primary haplo-identical living-donor kidney transplantation: 20-year experience

Background The achievements in short-term graft survival since the introduction of cyclosporine (CsA) have not been matched by improvements in long-term graft function. Chronic allograft nephropathy (CAN) remains the second most common cause of graft attrition over time, after patient mortality. We aimed to evaluate the long-term results of azathioprine vs CsA in live-donor kidney transplantation in a prospective randomized study. Methods We studied 475 renal transplant recipients who had had transplantations performed at the Urology and Nephrology Center, Mansoura University, before 1988 and who had received a primary immunosuppressive protocol consisting of either steroid and azathioprine (steroid/Aza; group 1, 300 patients) or steroid and CsA (steroid/CsA; group 2, 175 patients). Only adult primary renal transplant recipients aged between 18 and 60 years and with one haplotype HLA mismatch were included. All patients received kidneys from living-related donors, with previous donor nonspecific blood transfusions. The study was based on the long-term follow-up data of these renal transplant recipients. Comparative analyses included patient and graft survival rates, condition at last follow up, rejection (acute and chronic), and graft function (serum creatinine and creatinine clearance). Results The overall frequency of acute rejection episodes was not significantly different between the two groups. Graft survival rates were: group 1 vs group 2, 69% vs 58% at 5 years, and 52% vs 36% at 10 years, but at 20 years, graft survival rates had declined to 26% and 24%. No significant differences were encountered between the two groups regarding post-transplant malignancies, diabetes mellitus, hepatic impairment, or serious bacterial infections. Conclusions From this study we can conclude that the long-term result of historical conventional therapy (steroid/Aza) without induction therapy is effective for living-donor kidney transplants. In spite of the comparable graft function for the two groups, the steroid/CsA group experienced more hypertension, as well as many adverse reactions to CsA. Nowadays, since the introduction of induction therapy and the utilization of newer maintenance immunosuppressive agents – such as mycophenolate mofetil (MMF) and rapamycin – it is possible to achieve an excellent calcineurin inhibitors (CNI)-free regimen.     

Pyrrolidine Dithiocarbamate Prevents Deleterious Effects of Remote Ischemia/Reperfusion Injury on Healing of Colonic Anastomoses in Rats

Background Pyrrolidine dithiocarbamate (PDTC) is a low-molecular-weight thiol antioxidant and potent inhibitor of nuclear factor-κB (NF-κB) activation. It has been shown to attenuate local harmful effects of ischemia/reperfusion (I/R) injury in many organs. In recent animal studies, a delaying effect of remote organ I/R injury on the healing of colonic anastomoses has been demonstrated. In this study we investigated whether PDTC prevents harmful systemic effects of superior mesenteric I/R on left colonic anastomosis in rats. Methods Anastomosis of the left colon was performed in 40 rats randomly allocated into the following four groups: (1) Sham-operated group (group I, n = 10)—simultaneously with colonic anastomosis, the superior mesenteric artery and collateral branches divided from the celiac axis and the inferior mesenteric artery were isolated but not occluded. (2) Sham+PDTC group (group II, n = 10)—identical to sham-operated rats except for the administration of PDTC (100 mg/kg IV bolus) 30 minutes prior to commencing the experimental period. (3) I/R group (group III, n = 10)—60 minutes of intestinal I/R by superior mesenteric artery occlusion. (4) PDTC-treated group (group IV, n = 10)—PDTC 100 mg/kg before and after the I/R. On postoperative day 6, all animals were sacrificed, and anastomotic bursting pressures were measured in vivo. Tissue samples were obtained for investigation of anastomotic hydroxyproline (HP) contents, perianastomotic malondialdehyde (MDA) levels, myeloperoxidase activity (MPO), and glutathione (GSH) level. Results There was a statistically significant decrease in anastomotic bursting pressure values, tissue HP content and GSH level, along with an increase in MDA level and MPO activity in group III, when compared to groups I, II, and IV (p < 0.05). However, PDTC treatment led to a statistically significant increase in anastomotic bursting pressure values, tissue HP content and GSH level, along with a decrease in MDA level and MPO activity in group IV (p < 0.05). Conclusions This study showed that PDTC treatment significantly prevented the delaying effect of remote organ I/R injury on anastomotic healing in the colon. Further clinical studies are needed to clarify whether PDTC may be a useful therapeutic agent for increasing the safety of the anastomosis during particular operations where remote organ I/R injury occurs.     

Prophylactic Mastectomy in BRCA1/2 Mutation Carriers and Women at Risk of Hereditary Breast Cancer: Long-Term Experiences at the Rotterdam Family Cancer Clinic

Background BRCA1/2 mutation carriers and women from a hereditary breast(/ovarian) cancer family have a highly increased risk of developing breast cancer (BC). Prophylactic mastectomy (PM) results in the greatest BC risk reduction. Long-term data on the efficacy and sequels of PM are scarce. Methods From 358 high-risk women (including 236 BRCA1/2 carriers) undergoing PM between 1994 and 2004, relevant data on the occurrence of BC in relation to PM, complications in relation to breast reconstruction (BR), mutation status, age at PM and preoperative imaging examination results were extracted from the medical records, and analyzed separately for women without (unaffected, n = 177) and with a BC history (affected, n = 181). Results No primary BCs occurred after PM (median follow-up 4.5 years). In one previously unaffected woman, metastatic BC was detected almost 4 years after PM (primary BC not found). Median age at PM was younger in unaffected women (P < .001), affected women more frequently were 50% risk carriers (P < .001). Unexpected (pre)malignant changes at PM were found in 3% of the patients (in 5 affected, and 5 unaffected women, respectively). In 49.6% of the women opting for BR one or more complications were registered, totaling 215 complications, leading to 153 surgical interventions (71%). Complications were mainly related to cosmetic outcome (36%) and capsular formation (24%). Conclusions The risk of developing a primary BC after PM remains low after longer follow-up. Preoperative imaging and careful histological examination is warranted because of potential unexpected (pre)malignant findings. The high complication rate after breast reconstruction mainly concerns cosmetic issues.     

Volvulus of an Appendiceal Mucocele: Report of a Case

Few cases of volvulus of an appendiceal mucocele have been reported. The mechanism of torsion seems to be similar to that suggested for ovarian or appendegeal torsion, where a solid organ or mass fixed onto a narrow stalk is a precondition. We report the case of a young woman who presented with signs and symptoms of acute appendicitis. Computed tomography showed a cystic mass of fluid consistency in the right lower quadrant. An emergency laparoscopy revealed a 720° torsion of a gangrenous mucocele around the proximal part of the appendix. We performed a laparoscopic appendectomy and she recovered uneventfully. The presentation of volvulus of an appendiceal mucocele can mimic other common conditions. Prompt surgical intervention is essential to prevent gangrene and perforation. The combination of a cystic, right lower quadrant mass, and clinical findings suggestive of acute appendicitis should alert the clinician to include volvulus of an appendiceal mucocele in the differential diagnosis.     

Prognosis and Results After Resection of Very Large (≥10 cm) Hepatocellular Carcinoma

Introduction Few potentially curative treatment options exist besides resection for patients with very large (≥10 cm) hepatocellular carcinoma (HCC). We sought to examine the outcomes and risk factors for recurrence after resection of ≥10 cm HCC. Methods Perioperative and long-term outcomes were examined for 189 consecutive patients from 1993 to 2004 who underwent potentially curative resection of HCC ≥10 cm (n = 24; 13%) vs. those with HCC <10 cm (n = 165; 87%). Disease-free survival (DFS) and overall survival (OS) were determined by Kaplan–Meier analysis and patient, tumor, and treatment characteristics were compared using univariate and multivariate analysis. Results Median follow-up was 34 months. Tumors ≥10 cm were more likely to be symptomatic, of poorer grade, and have vascular invasion (p < 0.05). Twelve patients (50%) underwent an extended resection of more than four hepatic segments or resection of adjacent organs for oncologic clearance (diaphragm-2, inferior vena cava (IVC)-2, median sternotomy-1). Postoperative complications were more common after resection of >10 cm HCC (12/24, 50% vs. 35/165, 21%; p = 0.04). Median DFS was significantly shorter in patients with large HCC (≥10 cm) group compared to patients with smaller HCC (8.4 vs. 38 months; p = 0.001), but overall survival was not different between the two groups (5-year survival 54% vs. 53%; p = 0.43). Seventeen patients (71%) with very large HCC developed recurrences (12 intrahepatic, five systemic); eight of these patients (47%) underwent additional therapy (resection-4, TACE-3, RFA-1). Pathological positive margins and vascular invasion were significant determinants of DFS in tumors ≥10 cm (p < 0.05), but only vascular invasion was an independent risk factor for recurrence after multivariate analysis (HR 0.17; 95% CI: 0.04–0.8). Median OS after recurrence was 24 months. Conclusion Surgical resection is the optimal therapy for very large (≥10 cm) HCC. Although recurrences are common after resection of these tumors, overall survival was not significantly different from patients after resection of smaller HCC in this series. Presented at the 2006 American Hepato-Pancreatico-Biliary Congress, Miami, FL, March 9–12, 2006.     

Hepatitis C inflection in dialysis patients: a link to poor clinical outcome?

Among the 350,000 maintenance dialysis patients in the USA, the mortality rate is high (20–23% per year) as is the prevalence of hepatitis C virus (HCV) infection (5–15%). An additional same number of dialysis patients in the USA may be infected with HCV but have undetectable HCV antibodies. Almost half of all deaths in dialysis patients, including HCV-infected patients, are due to cardiovascular disease. Since over two-thirds of dialysis patients die within 5 years of initiating dialysis and because markers of malnutrition–inflammation complex syndrome (MICS), rather than traditional cardiovascular risk factors, are among the strongest predictors of early death in these patients, the impact of HCV infection on nutritional status and inflammation may be a main cause of poor survival in this population. Based on data from our cross-sectional and limited longitudinal studies, we hypothesize that HCV infection confounds the association between MICS and clinical outcomes in dialysis patients and, by doing so, leads to higher short-term cardiovascular events and death. Understanding the natural history of HCV and its association with inflammation, nutrition and outcomes in dialysis patients may lead to testing more effective anti-HCV management strategies in this and other similar patient populations, providing benefits not only for HCV infection but the detrimental consequences associated with this infection. In this article, we review the link between the HCV infection and mortality in dialysis patients and compare HCV antibody to molecular methods to detect HCV infection in these individuals. Funding source: Supported by a Young Investigator Award from the National Kidney Foundation; the National Institute of Diabetes, Digestive and Kidney Disease grant # DK61162; and a research grant from DaVita (for KKZ); and the National Institute of Allergy and Infectious Diseases grant # AI01831 (for LGM and HD41224 (for ESD)).     

Thyroid Artery Erosion by Esophageal Cancer: Management with Interventional Radiology

Management of upper gastrointestinal bleeding because of erosion of vessels by esophageal cancer may be challenging. We present herein the angiographic images of a 49-year-old patient who was admitted with massive bleeding from a tumor-eroded inferior thyroid artery. Attempts to control the bleeding by means of flexible endoscopy and insertion of a Sengstaken–Blakemore tube had failed. The diagnosis was impressively demonstrated by multislice computed tomography with intravenous contrast in the arterial phase and multiplanar reconstructions (computed tomography angiography) and by digital subtraction angiography. The bleeding was successfully treated with superselective catheterization and coiling of the eroded vessel.     

Adding malabsorption for weight loss failure after gastric bypass

Objective To present a technique of revisional RY gastric bypass in patients with unsatisfactory weight loss after primary gastric bariatric operations. Methods The Roux limb was lengthened by creating a 75–100 cm common channel below the enteroenterostomy with concomitant revision of the gastrojejunostomy. Results Fifty-four patients had this distal modification of RYGB including 47 patients who had primary gastric bypass and 7 patients who failed pure restrictive operations. Mean excess weight loss was 47.9% in patients followed for ≥1 year. Conclusions This distal modification of RYGB resulted in satisfactory weight loss for nearly half of the 54 patients in this series.     

The Effect of <Emphasis Type="SmallCaps">l</Emphasis>-arginine and Aprotinin on Intestinal Ischemia–reperfusion Injury

Background Intestinal ischemia/reperfusion (I/R) results in local mucosal injury, systemic injuries, and organ dysfunction. These injuries are characterized by altered microvascular and epithelial permeability and villous damage. Activation of neutrophils, platelets, and endothelial factors are known to be involved in this process. Cytokines such as TNF-α, IL-1, IL-6, and oxygen-derived free radicals are believed to be important pathogenic mediators. Capillary no-reflow is also known to play a role in I/R. The aim of our study was to examine the role of l-arginine, a known nitric oxide (NO) donor, and aprotinin, a protease inhibitor with multiple effects, on intestinal I/R. Methods Pigs weighing 20–25 kg were used. Ischemia was established by clamping the superior mesenteric artery (SMA) at its origin and was sustained for 2 hours. Duration of reperfusion was 2 hours. The animals were divided into four groups: group A, the control group, which was submitted to I/R injury only; group B, in which l-arginine was administered at a rate of 5 mg/kg/min during ischemia and continuing throughout reperfusion; group C, in which aprotinin was administered with an initial bolus dose of 20,000 U/kg during ischemia followed by a continuous dose at 50 U/hour throughout reperfusion; and group D in which both substances were administered. In all groups TNF-α, IL-1, and IL-6 levels were measured using ELISA at baseline, 2 hours of ischemia, and 1 hour and 2 hours of reperfusion. SMA blood flow was measured with a Doppler probe at baseline, 10 min, 1 hour, and 2 hours of reperfusion. Histological changes of the intestinal mucosa were examined and graded on a five-point scale in all groups. Results In the control group, levels of TNF-α, IL-1, and IL-6 were significantly increased during reperfusion (p < 0.05) compared to baseline. Administration of l-arginine and aprotinin led to suppression of the release of TNF-α, IL-1, and IL-6 during reperfusion in a statistically significant manner (all p < 0.05). A synergistic or additive effect of l-arginine and aprotinin was not observed. SMA blood flow in the control group was decreased (p > 0.05) during reperfusion compared to baseline. In animals treated with l-arginine and aprotinin, SMA blood flow during reperfusion was significantly increased (p < 0.05) compared to the control group. Histologic examination of the intestinal mucosa was characterized by flattening of the villi and necrosis in the control group. In the treated animals, less severe histological changes were noted. Conclusions Administration of l-arginine and aprotinin may lead to amelioration of intestinal I/R injury. We did not note a synergistic or additive effect of these two substances. These findings warrant further studies in clinical settings for future treatment efforts. This paper was presented as a poster at the 47th Annual Meeting of the Society for Surgery of the Alimentary Tract, Los Angeles, California, May 20–24, 2006.     

Effect of Antioxidant Treatments on the Gut–Liver Axis Oxidative Status and Function in Bile Duct-Ligated Rats

Background Experimental and clinical studies have demonstrated the pivotal role of oxidative stress in the promotion of hepatic and intestinal injury in obstructive jaundice. The present study was undertaken to investigate the effect of well known antioxidant treatments on the gut–liver axis oxidative status and function in bile duct-ligated rats. Methods A total of 60 male Wistar rats were randomly divided into six groups of 10 animals each: controls, sham operated, bile duct ligated (BDL), and BDL treated with either N-acetylcysteine (NAC), allopurinol, or α-tocopherol (α-TC). Ten days after treatment, the hepatic and intestinal oxidative status was estimated by measuring lipid peroxidation and a battery of biochemical markers comprising the organ’s thiol redox state (i.e., glutathione, cysteine, protein thiols, oxidized glutathione, nonprotein mixed disulfides, oxidized cysteine derivatives, protein symmetrical disulfides, and protein mixed disulfides). Portal and aortic endotoxin concentrations and alanine aminotransferase (ALT) levels were also determined. Results All antioxidant treatments significantly improved intestinal barrier function and protected from cholestatic liver injury, as evidenced by reduction of the portal and aortic endotoxin concentration and ALT levels, respectively. This effect accompanied their significant antioxidant action in both organs, mediated by a certain influence profile on the thiol redox state by each treatment. Conclusion NAC, allopurinol, and α-TC, exerting a potent combined antioxidant effect on the intestine and liver in experimental obstructive jaundice, significantly prevented intestinal barrier dysfunction and liver injury. The variety of results depending on the antioxidant agent that was administered and the marker of oxidative stress that was estimated, indicates that a battery of biomarkers would be more appropriate in assessing pharmacologic responses to therapeutic interventions.