Prospective iterative trial of proteasome inhibitor-based desensitization.

A prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLA antibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3 mg/m(2) × 6-8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty-four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n = 20), Phase 2 (n = 12), Phase 3 (n = 10), Phase 4 (n = 5), Phase 5 (n = 5). iAb reductions were observed in 38 of 44 (86%) patients and persisted up to 10 months. In Phase 1, a 51.5% iAb reduction was observed at 28 days with bortezomib alone. iAb reductions increased with higher bortezomib dosing densities and included class I, II, and public antigens (HLA DRß3, HLA DRß4 and HLA DRß5). FCM median channel shifts decreased in 11/11 (100%) patients by a mean of 103 ± 54 mean channel shifts (log scale). Nineteen out of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). In conclusion, PI-based desensitization consistently and durably reduces HLA Ab levels providing an alternative to intravenous immune globulin-based desensitization.

Addressing morbid obesity as a barrier to renal transplantation with laparoscopic sleeve gastrectomy.

Morbid obesity is a barrier to renal transplantation and is inadequately addressed by medical therapy. We present results of a prospective evaluation of laparoscopic sleeve gastrectomy (LSG) for patients failing to achieve significant weight loss with medical therapy. Over a 25-month period, 52 obese renal transplant candidates meeting NIH guidelines for metabolic surgery underwent LSG. Mean age was 50.0 ± 10.0 years with an average preoperative BMI of 43.0 ± 5.4 kg/m(2) (range 35.8-67.7 kg/m(2)). Follow-up after LSG was 220 ± 152 days (range 26-733 days) with last BMI of 36.3 ± 5.3 kg/m(2) (range 29.2-49.8 kg/m(2)) with 29 (55.8%) patients achieving goal BMI of <35 kg/m(2) at 92 ± 92 days (range 13-420 days). The mean percentage of excess weight loss (%EWL) was 32.1 ± 17.6% (range 6.7-93.8%). A segmented regression model was used to compare medical therapy versus LSG. This revealed a statistically significant increase in the BMI reduction rate (0.3 kg/m(2)/month versus 1.1 kg/m(2)/month, p < 0.0001). Patients also experienced a 40.9% decrease in anti-hypertensive medications (p < 0.001) and a 49.7% decrease in total daily insulin dose (p < 0.001). LSG is a safe and effective means for addressing obesity in kidney transplant candidates in the context of a multidisciplinary approach.

Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss.

The effect of de novo DSA detected at the time of acute cellular rejection (ACR) and the response of DSA levels to rejection therapy on renal allograft survival were analyzed. Kidney transplant patients with acute rejection underwent DSA testing at rejection diagnosis with DSA levels quantified using Luminex single-antigen beads. Fifty-two patients experienced acute rejection with 16 (31%) testing positive for de novo DSA. Median follow-up was 27.0 +/- 17.4 months postacute rejection. Univariate analysis of factors influencing allograft survival demonstrated significance for African American race, DGF, cytotoxic PRA >20% (current) and/or >50% (peak), de novo DSA, C4d and repeat transplantation. Multivariate analysis showed only de novo DSA (6.6-fold increased allograft loss risk, p = 0.017) to be significant. Four-year allograft survival was higher with ACR (without DSA) (100%) than mixed acute rejection (ACR with DSA/C4d) (65%) or antibody-mediated rejection (35%) (p < 0.001). Patients with >50% reduction in DSA within 14 days experienced higher allograft survival (p = 0.039). De novo DSAs detected at rejection are associated with reduced allograft survival, but prompt DSA reduction was associated with improved allograft survival. DSA should be considered a potential new end point for rejection therapy.

Proteasome inhibition reduces donor-specific antibody levels.

BACKGROUND: Current antibody-mediated rejection (AMR) therapies (intravenous immunoglobulin, apheresis, rituximab, polyclonal antibodies) do not target the primary antibody producing B cells, that is, the plasma cell. We report the preliminary results from the first clinical experience with plasma cell targeted therapy with bortezomib. Bortezomib is approved by the US Food and Drug Administration for the treatment of plasma cell tumors (multiple myeloma). METHODS: Kidney transplant patients with mixed acute cellular rejection (ACR) and AMR episodes (by Banff '97 criteria, update 2005) were treated with bortezomib (1.3 mg/m(2) per dose x 4) at standard labeled doses. Patients were monitored by serial donor specific anti-HLA antibody (DSA) determinations [Luminex/Labscreen beads] and quantified by conversion to fluorescence intensity to molecules of equivalent soluble fluorescence (MESF). RESULTS: Five patients were treated with bortezomib. Each patient also had coexisting ACR. In each case, bortezomib treatment led to prompt ACR and AMR rejection reversal. DSA levels decreased significantly in all patients (except 1 patient who had short follow-up). Observed toxicities from bortezomib included a transient grade III thrombocytopenia (1 patient) and mild-to-moderate nausea, vomiting, and/or diarrhea (3/5 patients). Opportunistic infections were not observed. CONCLUSIONS: Bortezomib therapy provides effective reduction in DSA levels with long-term suppression. These preliminary results indicate that proteasome inhibition provides an effective means for reducing HLA antibody levels in transplant recipients.

Late-Onset Allograft Aspergillosis in an HIV-Positive Renal Transplant Recipient: A Case Report.

Aspergillus infection of the allograft in renal transplant patients is rare and associated with a high mortality. We report a case of a 21-year-old, human immunodeficiency virus-positive, deceased-donor kidney recipient who presented 1 year after transplant with oliguric kidney injury. A nuclear medicine renal scan revealed absence of flow to the transplanted kidney, and a urine fungal culture was positive for Aspergillus flavus. The diagnosis was confirmed with the presence of fungal hyphae along with thrombosis in the vascular structures in renal allograft pathology. We found no evidence of disseminated aspergillosis or involvement of any other organ in the patient. To our knowledge, this case is the first reported in the literature of late-onset non-disseminated renal-limited aspergillosis in a human immunodeficiency virus-positive renal transplant patient.

Eculizumab and Belatacept for De Novo Atypical Hemolytic Uremic Syndrome Associated With CFHR3-CFHR1 Deletion in a Kidney Transplant Recipient: A Case Report.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway. CASE REPORT: We report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus. The patient responded well to eculizumab and substituting belatacept for tacrolimus. Her serum creatinine level was stable at 1.5 mg/dL after 2.5 years of follow-up. CONCLUSION: This case highlights the success of using a strategy that combines eculizumab and belatacept, as an alternative to calcineurin inhibitors, in treating aHUS in a patient with heterozygous deletion in the CFHR3-CFHR1 gene.

Complete Remission of Post-transplantation Recurrence of Focal Segmental Glomerulosclerosis With the Use of Adrenocorticotrophic Hormone Gel: Case Report.

BACKGROUND: Post-transplantation recurrence of primary focal and segmental glomerulosclerosis (FSGS) is estimated to occur in 30%-50% of cases and doubles the risk of allograft failure. Treatment of recurrent FSGS is challenging because specific pathogenic targets are unknown and available therapeutic options have limited efficacy. CASE REPORT: We report a case of recurrent FSGS with nephrotic-range proteinuria (urine protein creatinine ratio [UPCR], >50) and debilitating edema that was resistant to rituximab and plasmapheresis. The patient had a remarkable response to adrenocorticotropic hormone (ACTH) gel and achieved complete remission (UPCR, 0.5; serum albumin, 4.1 g/dL; serum creatinine, 1.0 mg/dL) which was maintained over 10 months on this treatment. CONCLUSIONS: We conclude that ACTH gel is a potential therapeutic option for post-transplantation recurrence of FSGS and warrants further evaluation.

Mutagenicity of aminocarbazoles and nitrocarbazoles.

The mutagenic activity of all 4 isomeric aminocarbazoles and 4 nitrocarbazoles was evaluated in Salmonella typhimurium tester strains TA98. TA100 and TA1535. All compounds were assayed both in the presence and absence of liver homogenate from Aroclor-treated rats. Among the aminocarbazoles, 2-aminocarbazole was found to be most active in both tester strains, although somewhat less active than 2-aminofluorene. 3-Aminocarbazole was the only other isomer that was mutagenic towards TA98 at the dose levels employed (5--200 micrograms). 4-Aminocarbazole was moderately active in TA100, and 1-aminocarbazole was inactive in both TA98 and TA100. Similar differences in mutagenic potency and specificity towards the tester strains were observed for the related series of nitrocarbazoles.

The 3D and 2D color flow display of breast masses.

A prospective study was performed in 24 women with breast masses on mammography going on to surgical biopsy. 2D and 3D power mode and frequency shift color flow Doppler scanning and display were compared. Vessels were displayed as rotatable color volumes in 3D, superimposed on gray-scale slices. The latter were stepped sequentially through the imaged volume. Radiologists rated the masses in each display (3D, 2D and videotapes) on a scale of 1 to 5 (5 = most suspicious) for each of six conventional gray-scale and six new vascular criteria. Thirteen masses proved to be benign and 11 were malignant. 3D provided a stronger subjective appreciation of vascular morphology and allowed somewhat better ultrasound discrimination of malignant masses than did the 2D images or videotapes (specificities of 85%, 79% and 71%, respectively, at a sensitivity of 90%). Only in 3D did the vascularity measures display a trend towards significance in this small study.

3-D color Doppler image quantification of breast masses.

In this article, new measures obtained from color Doppler images are introduced and a pilot study is described, in which these and previously published indices are evaluated for use in future work. Twenty women with breast masses observed on mammography and going to surgical biopsy were studied. Of the masses, 11 proved to be benign and 9 were malignant. Both 3-D mean frequency shift (f-CDI) and power mode Doppler (p-CDI) imaging were performed. To identify the mass and other regions of interest, vessels were displayed as rotatable 3-D color volumes, superimposed on selectable grey-scale/color flow slices. Doppler signals were recorded in each of 6 ellipsoidal regions of interest in and around the mass and 2 in normal tissues. Seven measures were computed in each region, three from power mode, two from mean frequency and two from combinations of both. Radiologists rated the grey-scale appearances of the masses on a scale of 1 to 5 (5=most suspicious) for each of 6 conventional grey-scale criteria. Of the individual vascularity measures in individual ROIs, the log speed-weighted pixel density and log power-weighted pixel density in the lesion internal periphery showed the greatest discrimination of malignancy, although neither was statistically significant nor as good as the peak variables described below. The mean visual grey-scale rating was the best discriminator overall, but two peak vascularity measures each made promising scatterplots in conjunction with the average visual grey-scale rating. These two vascularity measures were the log peak normalized power-weighted pixel density (peak NPD) and log of peak mean Doppler frequency times the peak NPD (vM x NPD(M)). Each of these two values was the maximum in any one of the five chosen ROIs closely associated with the mass. A possible rationale for the relative success of these peak values is the blood signal's normalization and the inhomogeneity of most breast cancers and the expectation that the highest velocities (shunting) and largest collections of blood are not necessarily in the same region in and around the tumor. Peak NPD of cancers varied with age, decreasing by a factor of 45 from 33 to 77 y.

Endoscopic management of large bile duct stones by mechanical lithotripsy.

OBJECTIVE: Our experience in treating large common bile duct stones using Olympus basket mechanical lithotripter (BML 2Q) and Soehendra lithotripter is reported. METHODS: Between July 1990 and December 1993, twenty two patients with common bile duct stones too large to be extracted by Dormia basket or balloon were treated with BML lithotripter or Soehendra lithotripter. RESULTS: The stone diameters ranged from 1.5 to 2.8 cm. Fourteen patients required one session of lithotripsy, four patients two sessions each, and two patients three sessions each. BML lithotripter was used in 14 patients. In the remaining eight patients the stones were fragmented with Soehendra lithotripter when the basket got impacted while attempting extraction. Mechanical lithotripsy was successful in 20 patients (91%). Indwelling stent was used in one patient; one patient underwent surgery. CONCLUSION: Mechanical lithotripsy is safe for the treatment of large common bile duct stones, with a success rate above ninety percent.

Esophageal prosthesis in palliation of malignant esophageal obstruction.

Esophageal intubation with a plastic prosthesis is a well established palliative treatment for esophageal carcinoma. The technique is safer with endoscopy than previous surgical techniques. Advantages of stent include rapid and long lasting relief of dysphagia in most patients with carcinoma esophagus. Repeated procedures are not required. Placement of prosthesis is the treatment of choice in BEF. Cost is less compared to other palliative modalities such as laser. SEMS have distinct advantages over conventional prosthesis as they may be inserted with less trauma and fewer complications. Diet needs occasionally to be limited to soft or blenderized foods to prevent occlusion. A disadvantage of uncovered SEMS is short duration of palliation due to tumor ingrowth which can be overcome with availability of covered SEMS. Starvation is the most common cause of death in patients with esophageal malignancy. Prosthesis combats deterioration and leads to rapid weight gain. Overall, single time procedure without general anaesthesia, short hospital stay and immediate improvement in dysphagia are considerable gains.

Tuberculosis in ulcerative colitis: bird in the bush.

Records of one hundred and two patients with idiopathic ulcerative colitis were retrospectively studied to estimate the prevalence of associated tuberculosis. There were 49 males and 53 females with a mean age of 33 +/- 13 years. Seven patients (3 pulmonary and 4 intestinal) had associated tuberculosis. All patients with intestinal tuberculosis were females and had small bowel involvement. Patients with co-existing tuberculosis were on steroids at the time of presentation and responded well to anti tubercular treatment with gradual weight gain and remission of diarrhoea and fever. We conclude that in India, the prevalence of tuberculosis is high in patients with idiopathic ulcerative colitis on steroids and a high degree of suspicion is required to detect these cases.

Course of severe ulcerative colitis in northern India.

Thirty patients with severe ulcerative colitis were studied prospectively. Sixty percent (18/30) of severe ulcerative colitis were in remission after mean duration of 9.2 days (range 2-20 days) of intensive intravenous therapy without major side effects of steroids. Factors predicting poor response to medical therapy on admission are: stool frequency > or = 9 per day, pulse rate > or = 120/minute, temperature > or = 38 degrees C, Albumin < or = 2 gm, mucosal tags on plain x-ray abdomen and pancolitis.

Evaluation of significance of AgNOR counts in differentiating benign from malignant lesions in the breast.

Nucleolar organizer regions (NORs) have been identified by means of an argyrophilic technique (AgNOR) in routinely processed formalin-fixed paraffin sections of breast lesions. 85 cases of different breast lesions were examined. The AgNOR counts were, normal breast 1.2 (1.0-1.5) Fibroadenoma 1.74 (1.6-2.7), purely cystic disease 1.6 (1.5-1.82) adenosis 2.1 (1.7-2.8), Epitheliosis 2.4 (1.9-3.2) gynaecomastia 3.7 (3.6-4.7), Noninvasive caccinoma 2.8 (2.6-4.4) invasive carcimomas 3.89 (2.7-9.9) i.e. mean AgNOR counts between benign and malignant lesions. Also gynaecomastia, a benign condition had a high mean AgNOR count. There was no significant difference in the mean AgNOR count of various types of invasive breast caninoma. Higher the histological grade, higher was the AgNOR count. To conclude, AgNOR technique does not enable a clear distinction between benign & malignant lesions. But, it could be used with other prognostic indices to predict the behaviour of breast malignancy.

Endoscopic management of pancreatic pseudocyst: a long-term follow-up.

BACKGROUND AND STUDY AIMS: No studies with real long-term follow-up after endoscopic drainage of pancreatic pseudocysts are available. The present study was undertaken to investigate the long-term outcome of endoscopic management of pancreatic pseudocyst with a minimum follow-up of 2 years. PATIENTS AND METHODS: A total of 38 consecutive patients with pancreatic pseudocyst underwent endoscopic cystogastrostomy (n = 27), endoscopic cystoduodenostomy (n = 6) and transpapillary drainage (n = 5). Patients were monitored at 1 and 3 months after drainage, and finally between 24 and 80 months. Upper gastrointestinal endoscopy was done at 1 and 3 months after drainage while ultrasound was done at 3 months and at the end of follow-up. Endoscopic retrograde cholangiopancreatography (ERCP) was only done before cyst drainage if no cyst bulge was visible in the stomach or duodenum or if obstructive jaundice was present. RESULTS: Biliary pancreatitis was responsible for the pseudocyst in 19 cases while the remaining occurrences were caused by alcohol (n = 12) and trauma (n = 7). All forms of endoscopic drainage were effective in treating pancreatic pseudocyst and there was complete disappearance of the cyst within 3 months of drainage, irrespective of cause. Over a mean follow-up of 44.23 months (24 - 80 months). Three patients had symptomatic recurrences while three had asymptomatic recurrences; all had alcohol-induced pancreatitis. No recurrences were seen in the biliary pancreatitis and trauma group. All symptomatic recurrences were successfully managed with endoscopic cystogastrostomy and stenting. A massive bleed in one patient required surgery while stent block and cyst infection in three patients and perforation in one patient were managed conservatively. ERCP was done before cyst drainage in eight patients because there was no visible bulge into the stomach or duodenum (n = 5), or because obstructive jaundice was present (n = 3). In five patients ERCP revealed cyst duct communication. All these patients were managed by transpapillary drainage and there was only one asymptomatic recurrence in this group. CONCLUSION: Endoscopic management of pancreatic pseudocyst is quite an effective and safe mode of treatment in experienced hands. ERCP before the procedure is only required when the cyst does not bulge into gut lumen, for a decision about the feasibility of transpancreatic drainage. On long-term follow-up, recurrences were seen only in the alcoholic pancreatitis group. In the biliary pancreatitis group, no recurrences were seen after cholecystectomy and removal of common bile duct (CBD) stones if present. No recurrences were seen in the trauma group.

Endoscopic biliary endoprosthesis for palliation of gallbladder carcinoma.

BACKGROUND: Carcinoma of the gallbladder is a major cause of malignant obstructive jaundice in India. It usually presents at an advanced stage and endoscopic palliation is the mainstay of treatment. We prospectively studied our results with endoscopic stenting in patients with carcinoma of the gallbladder. METHODS: Patients unfit for surgery were included in the study. Straight 10F plastic prostheses were placed endoscopically. Patients were assessed for procedure success, early and late complications, and stent patency. RESULTS: The success rate of stent placement was 84% (27 of 32). The five failures were caused by an inability to pass the guide wire across the stricture. Relief of pruritus and reduction in jaundice was seen in 25 of 27 (92%) patients. Double stents were placed in three patients. Four patients (11%) developed cholangitis in the first 30 days. Stent occlusion was detected in four patients after longer follow-up. The 30-day mortality was 5 of 27 (18%). There were no procedure-related deaths. CONCLUSION: Endoscopic endoprosthesis is a safe and relatively effective palliative measure for the majority of patients with unresectable carcinoma of the gallbladder.