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A general method for Pd-catalyzed sulfonamidation of aryl nonafluorobutanesulfonates (aryl nonaflates) is described. A biaryl phosphine ligand, t-BuXPhos, formed the most active catalyst, and K(3)PO(4) in tert-amyl alcohol was found to be the optimal base-solvent combination for the reaction. The reaction conditions were tolerant of various functional groups such as cyano, nitro, ester, aldehyde, ketone, chloride, carbamate, and phenol. Heterocyclic aryl nonaflates were found to be suitable coupling partners. High yields of the coupled products were obtained from the reactions between inherently disfavored substrates such as electron-rich nonaflates and electron-poor sulfonamides. Kinetic data suggest reductive elimination to be the rate-limiting step for the reaction. The only limitation of this methodology that we have identified is the inability of 2,6-disubstituted aryl nonaflates to efficiently participate in the reaction.

Desensitization therapies have been used with modest success in kidney transplantation. Some candidates, however, have such great breadth and depth of anti-HLA antibodies that they remain incompatible with potential donors. Bortezomib has been used without much success in desensitization regimens, but we hypothesized that its use during induction may be helpful in targeting antibody production by long-lived plasma cells. This report describes a high-risk positive crossmatch son-to-mother transplant that was performed after desensitization. The induction immunosuppression was supplemented with bortezomib. Pre- and post-transplant immunosuppression, antibody monitoring, biopsy data, and the clinical course are described in detail. Following transplant, the patient had excellent early graft function. Serial biopsies did not reveal acute antibody mediated rejection. Despite excellent graft function, the patient underwent withdrawal of care and died due to complications of calciphylaxis and deconditioning. This case details the first report of bortezomib used as part of induction therapy in solid organ transplant. Donor specific antibody production remained stable after transplant, with near complete abrogation of class I specificities. There were no bortezomib-related complications.

Background and Purpose: Healthy older living donors (> 50 years) are helping meet increasing demands for kidney transplantation. Live donor grafts perform better than cadaveric donor grafts; however, concern surrounds the expected nephron loss of the donors as well as the relative safety to the donor. We examined the effect age had on living laparoscopic donor and recipient outcomes at a single institution., Patients and Methods: We retrospectively reviewed records of 101 patients who underwent laparoscopic donor nephrectomy (LDN) from October 2001 to December 2005. Twenty-nine (29%) who were aged 50 years or older, denoted as the "older" group, were compared with the remaining 72 (71%) donors who were younger than 50 years and served as controls. Perioperative and follow-up data were analyzed for both groups., Results: The mean age at the time of donation was 36.1 and 54.3 years for control and older donors, respectively (P < 0.001). Baseline mean creatinine level was 0.82 mg/dL for controls and 0.84 mg/dL for older donors (P = 0.78). Complications in controls and the older group were 18% and 17%, respectively. One-year transplant survival was 100% for the controls and 96% for the older group. Average creatinine level at longer follow-up of 19 months for controls and 23 months for the older group (P = 0.34) was 1.22 mg/dL and 1.16 mg/dL, respectively (P = 0.535)., Conclusion: LDN in donors older than 50 years of age appears safe and demonstrates similar outcomes compared with the control cohort of patients younger than 50 years. Age between 50 and 65 years should not exclude a potential donor who otherwise satisfies donor nephrectomy criteria.

We studied the impact of a first post-transplant cytomegalovirus (CMV) infection greater than one year after primary kidney transplantation. Risk factors for developing late CMV were acute rejection and donor-recipient CMV status. Of those developing late CMV, 35% were donor (D) positive, recipient (R) negative; however, 23% were D+R+, 22% D-R+, and 15% D-R-. Late CMV was associated with significantly decreased patient and graft survival., (© 2010 John Wiley & Sons A/S.)

Background: Calcineurin inhibitors (CNI) are the basis of contemporary immunosuppression in clinical pancreas transplantation (PT). Nevertheless, CNI toxicities, especially nephrotoxicity, have stimulated the search for CNI-sparing protocols. We performed a retrospective analysis of 25 PT patients with progressive CNI toxicities that were switched to a daclizumab (DAC)-based maintenance regimen., Methods: From 2003 to 2007, 25 PT patients with progressive CNI toxicity (predominantly nephrotoxicity) were identified and switched from CNI to monthly DAC maintenance therapy. The DAC group was compared with matched control subjects (1:1) by transplant type and number, age, year of transplant, and duct management., Results and Conclusions: Results showed improved graft survival rates and decreased immunologic loss rates at 1, 3, and 5 years in the DAC group compared with the control group. There was no difference in patient survival rate between the 2 groups. Analysis demonstrates that DAC maintenance therapy is safe and effective for PT patients experiencing CNI toxicities. A randomized trial to compare DAC- and CNI-based regimens is needed in CNI-intolerant patients, with particular attention to the impact on renal function and patient morbidity (eg, infection rates)., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background/objective: Chronic pancreatitis (CP) in children is associated with significant morbidity and can lead to narcotic dependence. Total pancreatectomy (TP) may be indicated in refractory CP to relieve pain; simultaneous islet autotransplant (IAT) may prevent postsurgical diabetes. About half of pediatric patients are insulin independent 1 yr after IAT. Insulin independence correlates best with the number of islets available for transplantation (islet yield). Currently there is no known method to predict islet yield in a given patient. We assessed the ability of preoperative metabolic tests to predict islet yields in 10 children undergoing TP/IAT., Design/methods: Hemoglobin A1c (HbA(1c)) and mixed meal tolerance tests (MMTT) were obtained prior to surgery in 10 patients age

The aza-Cope-Mannich reaction and ring-closing metathesis are key steps in the assembly of intermediates containing rings A-D of Daphniphyllum alkaloids of the daphnicyclidin type such as daphnipaxinin and oldhamine A.

Nonadherence (NA) is a difficult posttransplant problem that can lead to graft loss. A retransplant is controversial because of a fear of recurrent NA. We reviewed our center's data base and identified 114 kidney recipients who lost their graft to overt NA; of this group, 35 (31%) underwent a retransplant after a thorough reevaluation. We compared this NA retransplant group to a control group of second transplant recipients who did not lose their first graft to overt NA (non-NA) (n = 552). After 8 years of follow-up, we found no significant differences between the groups in actuarial graft or patient survival rates, renal function, or the incidence of biopsy-proven chronic rejection. However, 5 of 35 (14%) NA recipients versus 10 of 552 (2%) non-NA recipients lost their retransplant to NA (p = 0.0001). Twenty of 35 (57%) of the NA group exhibited repeat NA behavior after retransplant. We conclude that prior graft loss to NA is associated with increased graft loss to NA after retransplant. However, the majority of NA retransplant recipients did well-with overall long-term outcomes similar to those of the non-NA group. With careful patient selection and aggressive intervention, prior overt NA should not be an absolute contraindication to retransplantation.

Protocols incorporating rapid discontinuation of prednisone (RDP) after kidney transplantation have been associated with good short-term results. However, concern remains that RDP will be associated with decreased long-term graft survival rates. We compared kidney transplant half-life (t1/2) for recipients treated with antibody induction, calcineurin inhibitor, antimetabolite, and RDP versus historical controls treated with antibody induction, calcineurin inhibitor, antimetabolite, and maintenance prednisone. For both living and deceased donor recipients, we found no difference between groups. We also found no differences in rate of graft loss to acute rejection or to tubular atrophy and interstitial fibrosis. Our study suggests that long-term graft outcome is not decreased when using RDP protocols versus chronic maintenance prednisone.

The synthesis of the marine neurotoxin azaspiracid-1 has been accomplished. The individual fragments were synthesized by catalytic enantioselective processes: A hetero-Diels-Alder reaction to afford the E- and HI-ring fragments, a carbonyl-ene reaction to furnish the CD-ring fragment, and a Mukaiyama aldol reaction to deliver the FG-ring fragment. The subsequent fragment couplings were accomplished by aldol and sulfone anion methodologies. All ketalization events to form the nonacyclic target were accomplished under equilibrating conditions utilizing the imbedded configurations of the molecule to adopt one favored conformation. A final fragment coupling of the anomeric EFGHI-sulfone anion to the ABCD-aldehyde completed the convergent synthesis of (+)-azaspiracid-1.

The ultimate goal of clinical transplantation is for the recipients to achieve long-term survival, with continuing graft function, that is equivalent to that of the age-matched general population. We studied subsequent outcome in kidney transplant recipients with 10 years of graft function. In all, 2202 kidney transplant recipients survived with graft function >10 years. For 10-year survivors, the actuarial 25-year patient survival rate for primary transplant living donor (LD) recipients was 57%; graft survival, 43%. For primary transplant deceased donor (DD) recipients, the actuarial 25-year patient survival rate was 39%; graft survival, 27%. The two major causes of late graft loss were death (with graft function) and chronic allograft nephropathy (tubular atrophy and interstitial fibrosis). The two major causes of death with function were cardiovascular disease (CVD) and malignancy. For nondiabetic recipients, the mean age at death with function from CVD was 54 +/- 13 years; for diabetic recipients, 53 +/- 7 years. By 20 years posttransplant, morbidity was common: >40% recipients had skin cancer (mean age for nondiabetic recipients, 53 +/- 13 years; for diabetics, 49 +/- 8 years), >10% had non-skin cancer (mean age for nondiabetic recipients, 53 +/- 16 years; for diabetics, 46 +/- 9 years), and >30% had CVD (mean age for nondiabetic recipients, 53 +/- 15 years; for diabetics, 47 +/- 9 years). We conclude that long-term transplant recipients have a high rate of morbidity and early mortality. As short-term results have improved, more focus is needed on long-term outcome.

We reviewed pancreas transplantation outcomes after Histidine-Tryptophan-Ketoglutarate (HTK) and University of Wisconsin (UW) preservation solution use between 2001 and 2007 at two transplant centers. While equivalence has been claimed for kidney and liver transplant outcomes after the use of HTK or UW preservation solution, consensus has not been reached on equivalence when flushing pancreata. Others have reported comparable patient and graft survival rates, but found an association between the use of HTK and an increase in the incidence of acute rejection and pancreatitis. In reviewing our experiences, we found in pancreata flushed with HTK a higher incidence of postoperative complications including graft pancreatitis, use of octreotide and a decreased rate of insulin-independence at hospital discharge. These findings prompted us to critically review our centers' experience to determine if there is a basis for suspecting a causal relationship.

Background: The benefits (e.g., low acute rejection [AR] rate) vs. the long-term risk of each immunosuppressive protocol may determine the protocol's value., Methods: We studied the long-term impact of new-onset posttransplant diabetes (PTDM) and/or AR in 1,487 adult, primary transplant, nondiabetic recipients. Per Cox regression, donor source, AR, and PTDM were independent risk factors for graft loss (each, p<.0001). Recipients were subdivided by donor source and into these 4 groups: no AR, no PTDM [n=857]; no AR, PTDM [n=134]; > or =1 AR, no PTDM [n=403]; > or =1 AR, PTDM [n=93]., Results: There was a significant difference between groups in 15-yr actuarial graft survival (GS) and death-censored (DC) GS (p<.0001). Importantly, > or =1 AR had more impact on 15-yr GS and DC GS than did PTDM; the worst outcome was for those having both AR and PTDM. In separate analyses, we censored those with >1 AR; and then only compared those developing AR or PTDM in the first year. The results were similar--the AR (no PTDM) group did worse than the PTDM (no AR) group (p<.001)., Conclusions: Determining long-term risks associated with immunosuppressive protocols is important for treating future patients. Our data suggests that 15-year actuarial outcome (GS and DC GS) is worse for those developing AR than for those developing PTDM.

Recently, donation after cardiac death (DCD) has been encouraged in order to expand the donor pool. We present a case of anaplastic T-cell lymphoma transmitted to four recipients of solid organ transplants from a DCD donor suspected of having bacterial meningitis. On brain biopsy, the donor was found to have anaplastic central nervous system T-cell lymphoma, and the recipient of the donor's pancreas, liver and kidneys were found to have involvement of T-cell lymphoma. The transplanted kidneys and pancreas were excised from the respective recipients, and the kidney and pancreas recipients responded well to chemotherapy. The liver recipient underwent three cycles of chemotherapy, but later died due to complications of severe tumor burden. We recommend transplanting organs from donors with suspected bacterial meningitis only after identification of the infectious organism. In cases of lymphoma transmission, excision of the graft may be the only chance at long-term survival.

Factor V Leiden (FVL) and other thrombophilias can be acquired during liver transplantation and can have a significant impact on clinical outcomes as well as cost. Standard practice does not include screening deceased donors for heritable thrombophilias, even if they have a personal history of thrombosis. Here we report a case of hepatic artery thrombosis in a liver recipient whose native and donor livers were heterozygous for FVL. The patient subsequently underwent a successful retransplant. FVL and its variants are expressed phenotypically as activated protein C (APC) resistance. We believe that testing liver donors (deceased or living) for APC resistance - a surrogate marker for the most common liver-based thrombophilia - will reduce the incidence of thrombotic events by identifying a need for posttransplant prophylactic anticoagulation in patients at risk. The estimated cost of testing all liver donors in the US for APC resistance is less than the cost of two complications secondary to thrombosis. Testing for APC resistance may further improve outcome and reduce cost after liver transplantation.

Prednisone-minimization protocols have been successful in low-risk recipients. We report on the use of a protocol incorporating rapid discontinuation of prednisone in a cohort of kidney transplant recipients (n = 79) at increased immunologic risk. Our data suggests that such recipients should not be excluded from prednisone-minimization protocols.

Background: Hepatocyte transplantation is an attractive potential treatment for liver-based inborn errors of metabolism and for fulminant hepatic failure. Dalmatian dogs have a metabolic error that results in hyperuricosuria. This report focuses on the effect of multiple, sequential intrasplenic transplants of fresh and cryopreserved hepatocytes in dalmatians., Methods: Dalmatians underwent intrasplenic hepatocyte transplantation with hepatocytes taken from healthy mongrels. Dalmatian urinary uric acid excretion was measured preoperatively, and this served as the control value. Three hepatocyte transplantations were performed at 30-day intervals--the first with freshly isolated cells, and both the second and the third with cryopreserved hepatocytes from the same donor. Urinary uric acid excretion was measured postoperatively twice per week., Results: The urinary uric acid excretion decreased an average of 54% after the first hepatocyte transplantation. The effect was transient and lasted an average of 22 days (range, 19-50 days). Subsequent intrasplenic hepatocyte transplantation with cryopreserved hepatocytes resulted in similar decreases in urinary uric acid excretion. Each transplant resulted in a significant decrease in urinary uric acid excretion when compared with baseline values (P = < .001)., Conclusions: Sequential intrasplenic hepatocyte transplantation is feasible in this model. This method provided a significant, but transient, correction in urinary uric acid excretion that was similar with either fresh or cryopreserved hepatocytes. A substantial biologic effect provided by cryopreserved hepatocytes has important implications in clinical hepatocyte transplantation.

Preservation of the ileocecal valve improves absorptive function and decreases the amount of small bowel needed for survival in patients with short gut syndrome. We compared the results of small and large bowel transplant (SLBTx), small bowel transplant only (SBTx), and SBTx with the ileocecal valve (ICVTx) in a porcine model. Total enterectomy was performed on 18 Yorkshire-Landrace pigs followed by orthotopic SBLTx (n = 6), SBTx (n = 6), and ICVTx (n = 6). A jejunostomy and an ileostomy were constructed for biopsies. Overall mean survival was 17 d with no statistically significant difference between groups. Rejection was seen in 6/6 SLBTx, 4/6 SBTx, and 4/6 ICVTx recipients. Acute rejection was seen in 84.3% of SLBTx, 52.3% of SBTx, and 42.5% of the ICVTx mucosal biopsy samples. Two cases of intra-abdominal infection were in the ICVTx group only. Weight loss was 147 g/d in the SLBTx group, 643 g/d in the SBTx group, and 393 g/d in the ICVTx group. While the functional outcome after SLBTx and ICVTx was noticeably better than the SBTx group, the increased rejection and intra-abdominal infection rates make transplanting the large bowel or the ileocecal valve a less attractive clinical option.

Background: The optimal biopsy site of bowel allografts for rejection surveillance remains controversial. We compared the results of jejunal (JBx) and ileal (IBx) biopsies after bowel transplantation in a porcine model., Methods: Eighteen Yorkshire-Landrace pigs served as donors. Eighteen recipient pigs underwent total enterectomy followed by orthotopic small bowel transplantation with or without the colon. A jejunostomy and a Bishop-Koop ileostomy were constructed for biopsies. Immunosuppression consisted of FK506 (target level 10-15 ng/ml by enzyme immunoparticle assay) and prednisone administered via the jejunostomy. Simultaneous JBx and IBx were performed twice weekly. Acute rejection was graded as mild, moderate, or severe based on previously published criteria., Results: Mean overall survival after the transplant was 17.4 days. A total of 162 specimens were collected and evaluated for rejection (JBx, 81; IBx, 81). Acute rejection was detected in 41 JBx cases (50.7%) and 40 IBx cases (49.4%). The presence or absence of rejection was concordant between JBx and IBx in 70 of 81 case pairs (86.4%). Of the 11 discordant case pairs, 6 were JBx positive/IBx negative, whereas 5 were JBx negative/IBx positive. A total of 35 case pairs were synchronously positive, 24 (68.8%) of which demonstrated the same degree of rejection., Conclusions: The correlation between JBx and IBx of bowel allografts in diagnosing the presence of acute rejection is quite good. However, performing IBx alone would have missed about 7.5% of the rejection episodes. Because the early treatment of rejection in bowel transplantation is of paramount importance, in selected cases, biopsies from both the ileum and jejunum should be considered if technically feasible.

Background: We performed a prospective randomized trial to compare the efficacy and safety of tacrolimus (FK506) versus cyclosporine (CSA) in black primary cadaveric renal transplant (CRT) recipients., Methods: Between December 1994 and February 1997, 35 black primary CRT recipients were enrolled in this trial. All patients received 7 days of induction therapy with OKT3. Fourteen patients received FK506 and prednisone only. Twenty-one patients received CSA, azathioprine, and prednisone. The two groups were comparable in terms of age, gender, plasma renin activity, human leukocyte antigen mismatches, and cause of renal failure., Results: Patient and graft survival were 12 of 14 (86%) for the FK506 group and 20 of 21 (95%) for the CSA group (P = 0.71). Three patients died owing to cardiac events with functioning grafts. Acute rejection was 2 of 14 (14%) for the FK506 and 8 of 21 (38%) for the CSA group (P = 0.25). Two other patients on CSA were converted to FK506 as rescue for OKT3-resistant rejection. Mean serum cholesterol at 1 year was 198 +/- 45 mg/dL for the FK506 group and 244 +/- 49 mg/dL for the CSA group (P = 0.03). Mean serum creatinine at 1 year was 1.39 +/- 0.38 mg/dL for the FK506 group and 1.94 +/- 0.64 mg/dL for the CSA group (P = 0.02)., Conclusion: Patient and graft survival were similar in both groups at 1 year posttransplant. Although statistically not significant, the incidence of acute rejection was lower in the FK506 group. Furthermore, FK506-treated patients had significantly lower serum creatinine and cholesterol levels at 1 year posttransplant.

Background: Steroid withdrawal (SW) after kidney transplantation is desirable to avoid associated serious side effects. We studied the long-term outcome of a group of kidney transplant recipients who underwent SW., Methods: Between 1991 and 1993, kidney transplant recipients (N = 12) who had posttransplantation diabetes were entered in a prospective trial of SW. These patients were compared with a demographically similar comparison cohort (N = 66). End points of the study were patient and graft survival, incidence of late acute and chronic rejection, and changes in diabetes management., Results: Previously published data from the SW group at 15 months of follow-up indicated improvement in diabetes control without any adverse effect on patient or graft actuarial survival. At long-term follow-up (mean, 56 months) the improvement in diabetes management was not detectable. The incidence of late acute rejection in SW and cohort groups was 42% and 8%, respectively (P = .006). Likewise, the incidence of chronic rejection in the SW versus cohort group was 42% and 12%, respectively (P = .014)., Conclusions: Although SW appeared to be successful initially, our long-term data indicate that SW significantly increases the risk of late acute rejection and chronic rejection episodes without benefits in posttransplantation diabetes management. Steroid withdrawal in patients with posttransplantation diabetes should be approached with caution.

Background: The purpose of this study was to define the factors that predict successful ultrasound-guided compression repair (UGCR) of postcatheterization femoral pseudoaneurysms (PA) and to determine risks for recurrence, the most appropriate follow-up, and the optimal management of compression failures and recurrences., Methods: A retrospective chart review was made., Results: UGCR thrombosed 52 of 60 PA (87%). Predictors of compression failure were PA size of 8 cm and an associated arteriovenous fistula (AVF). AVF was the only predictor of recurrence. All seven recurrences (13%) were discovered on the first follow-up scan. Four were thrombosed with additional UGCR. Late rescanning after a mean of 264 days identified no recurrences. Four anticoagulated patients failed initial UGCR but were thrombosed in another session when their anticoagulation was briefly reversed., Conclusions: UGCR should be the initial management of PA because it is safe, effective, and durable. Temporary discontinuation of anticoagulation and multiple prolonged compression sessions may help treat recalcitrant cases. One follow-up scan is adequate for most patients. Recurrences should be initially treated with repeat UGCR.

This report covered the pathologic features, behavior, metastases, and results of transplantation of pure yolk sac carcinomas that were primary in the uterine horn of 8 mice; 6 mice were strain C3H and 2 were strain HR, and they varied from 10 to 23 months of age. Three of the mice had never been treated. Of the 5 that had, the treatment was different for each mouse. Therefore, treatment could not be correlated with tumor development. At least 5 mice were nulliparous; in fact they had never been mated, so in these some mechanism involving parthenogenesis must have been operative to account for the tumor. The tumors were identified as being primary in the uterus and occupied and distended the cavity of one uterine horn where they were polypoid or plaquelike. The neoplastic yolk cells replaced the endometrial stroma forming a support for the original endometrial glands. In time the tumor cells destroyed many of the endometrial glands. That the glands present in the primary uterine horn tumors were the original glands of the endometrium and not neoplastic glands was attested by their absence from the secondary neoplastic deposits in 4 mice in which the tumor had spread to areas outside the cavity of the uterus and from the neoplastic tissue of the tumor transplants in the recipient mice.

A classification of mouse mammary tumors in Dunn's miscellaneous group including recently reported types is presented. Adenocarcinoma type Y, first reported in (C3H X Y)F1 mice, is characterized by tubules that branch at acute angles and are lined by cuboidal epithelium. Adenocarcinoma type L is characterized by alcelike appearance and has projections of tumor cells with cytoplasmic vacuoles into lumina. Undifferentiated carcinomas in strains SWR/J and BABL/c contain sheetlike masses of epithelial cells with very little tendency to form glands but which may contain foci of cells with keratohyaline granules. Pale cell carcinomas, which occur in strain GR mice, are hormonally responsive and are characterized by the presence of pale cells and cystic spaces lined by basophilic cells. Foci of cells with acidophilic hyaline bodies and keratohyaline granules and with intercellular bridges distinguish this neoplasm from adenocarcinoma type B. A second hormonally responsive mammary tumor in strain GR mice is adenocarcinoma type P, which consists mainly of acini lined by a single layer of polyhedral cells. Carcinosarcomas of BALB/c mice have a myxoid stoma and, also containing glands, resemble mixed mammary tumors of the bitch. Criteria for differentiating trichoepitheliomas from mammary tumors are discussed.

This report describes the organization and functions of the Registry of Experimental Cancers and gives the chronology of events that led to its establishment. Currently 21,500 accessions have been coded; the vast majority are spontaneous and induced cancers, chiefly of rodents, and also a wide variety of nonneoplastic diseases. Accessions are accepted from contributors working in laboratories in this country and abroad. The material is available for study by responsible scientists, and a limited number of study sets is available for loan on request.