Search

Bacterial colonization of preservative solutions (PS) remains poorly described in renal transplantation. We investigated the bacterial colonization of the PS and its influence on graft pyelonephritis within one year from the renal transplantation.

To describe the technique and report our first experience of robotic-assisted renal transplantation (RART) with more than one year follow up.

Any biochemical reaction underlying drug metabolism depends on individual gene–drug interactions and on groups of genes interacting together. Based on a high‐throughput genetic approach, we sought to identify a set of covariant single‐nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable‐selection strategy to reinforce the stability of the variable‐selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0per dose with a maximum of 44 gene variants (p‐value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug‐resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort. In this study, the authors perform high‐throughput screening to identify a set of covariant single nucleotide polymorphisms predictive of interindividual tacrolimus dose requirement variability in a population of kidney transplant patients. See further discussion in the letters on pages 1144and 1146.

Any biochemical reaction underlying drug metabolism depends on individual gene–drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort.

Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5genotype is associated with improved achievement of target trough concentration (C0), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long‐term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0was within target range (10–15 ng/mL) at day 10. Our results indicate that the incidence of biopsy‐proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes. This study of the long‐term clinical impact of the adaptation of tacrolimus dosing according to CYP3A5genotype suggests that optimization of the initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes after kidney transplantation.

Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5genotype is associated with improved achievement of target trough concentration (C0), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0was within target range (10–15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0target ranges earlier. Patients’ death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.

This study demonstrates that kidney transplant recipients who carry the CYP3A4*22allelic variant and are low expressors of the cytochrome P450 3A4 in the liver have an increased risk of tacrolimus overexposure and need doses that are 30% lower than individuals who express the cytochrome P450 3A4.

CYP3A4*22is an allelic variant of the cytochrome P450 3A4 associated with a decreased activity. Carriers of this polymorphism may require reduced tacrolimus (Tac) doses to reach the target residual concentrations (Co). We tested this hypothesis in a population of kidney transplant recipients extracted from a multicenter, prospective and randomized study. Among the 186 kidney transplant recipients included, 9.3% (18 patients) were heterozygous for the CYP3A4*22genotype and none were homozygous (allele frequency of 4.8%). Ten days after transplantation (3 days after starting treatment with Tac), 11% of the CYP3A4*22carriers were within the target range of Tac Co (10–15 ng/mL), whereas among the CYP3A4*1/*1carriers, 40% were within the target range (p = 0.02, OR = 0.19 [0.03; 0.69]). The mean Tac Co at day 10 in the CYP3A4*1/*22group was 23.5 ng/mL (16.6–30.9) compared with 15.1 ng/mL (14–16.3) in the CYP3A4*1/*1group, p < 0.001. The Tac Co/dose significantly depended on the CYP3A4genotype during the follow-up (random effects model, p < 0.001) with the corresponding equivalent dose for patients heterozygous for CYP3A4*22being 0.67 [0.54; 0.84] times the dose for CYP3A4*1/*1carriers. In conclusion, the CYP3A4*22allelic variant is associated with a significantly altered Tac metabolism and carriers of this polymorphism often reach supratherapeutic concentrations.

Calcineurin inhibitors improve acute rejection rates and short‐term graft survival in renal transplantation, but their continuous use may be deleterious. We evaluated the 5‐year outcomes of sirolimus (SRL) versus cyclosporine (CsA) immunosuppressive treatment. This observational study was an extension of the SPIESSER study where deceased donor kidney transplant recipients were randomized before transplantation to a SRL‐ or CsA‐based regimen and followed up 1 year. Data from 131 (63 SRL, 68 CsA) out of 133 patients living with a functional graft at 1 year were collected retrospectively at 5 years posttransplant. Seventy percent of CsA patients versus 54% of SRL patients were still on the allocated treatment at 5 years (p = 0.091), most discontinuations in each group being due to safety issues. In intent‐to‐treat, mean MDRD eGFR was higher with SRL: 54.2 versus 45.3 mL/min with CsA (p = 0.019); SRL advantage was greater in on‐treatment analyses. There were no differences for patient survival (p = 0.873), graft survival (p = 0.121) and acute rejection (p = 0.284). Adverse events were more frequent with SRL (80% vs. 60%, p = 0.015). Results confirmed the high SRL discontinuation rate due to adverse events. Nevertheless, a benefit was evidenced on renal function in patients (more than 50%) still on treatment at 5 years.

Calcineurin inhibitors improve acute rejection rates and short-term graft survival in renal transplantation, but their continuous use may be deleterious. We evaluated the 5-year outcomes of sirolimus (SRL) versus cyclosporine (CsA) immunosuppressive treatment. This observational study was an extension of the SPIESSER study where deceased donor kidney transplant recipients were randomized before transplantation to a SRL- or CsA-based regimen and followed up 1 year. Data from 131 (63 SRL, 68 CsA) out of 133 patients living with a functional graft at 1 year were collected retrospectively at 5 years posttransplant. Seventy percent of CsA patients versus 54% of SRL patients were still on the allocated treatment at 5 years (p = 0.091), most discontinuations in each group being due to safety issues. In intent-to-treat, mean MDRD eGFR was higher with SRL: 54.2 versus 45.3 mL/min with CsA (p = 0.019); SRL advantage was greater in on-treatment analyses. There were no differences for patient survival (p = 0.873), graft survival (p = 0.121) and acute rejection (p = 0.284). Adverse events were more frequent with SRL (80% vs. 60%, p = 0.015). Results confirmed the high SRL discontinuation rate due to adverse events. Nevertheless, a benefit was evidenced on renal function in patients (more than 50%) still on treatment at 5 years.

Although end‐stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5‐ and 10‐year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5‐ and 10‐ year graft survival censored for death between two groups. AA amyloidosis‐transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1‐year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

Introduction: Esophagectomy with reconstruction by collar anastomosis has an impact on the patients' quality of life (QOL). The aim of this study was to explore a potential difference in QOL between elective and emergency esophagectomy with collar reconstruction.Patients and Methods: Quality of life questionnaires were evaluated in 17 patients prior to esophagectomy, shortly after surgery, hospital discharge, and at least > 9 months after surgery using the EORTC QLQ C30 and EORTC OES 18 forms. In all patients reconstruction was performed by high collar anastomosis. Patients in group A received elective esophageal resection. In group B emergency esophagectomy was performed because of esophageal perforation for various reasons apart from cancer. In this group, delayed reconstruction was performed in a second operation 3–6 months after esophagectomy.Results: There was a temporary decrease of postoperative QOL in both groups, which returned to preoperative values in the follow-up except for physical functioning, which remained decreased in group A (p < 0,05). There were no persisting differences in QOL after elective and emergency esophagectomy in the follow-up.Discussion: Patients with elective and emergency esophagectomy and reconstruction by high collar anastomosis gained a good long-term QOL in our cohort of patients. This gives evidence that the observed QOL after elective resection of esophageal cancer is not only caused by a relief of cancer burden, but also due to a surgical procedure which is able to provide a good long-term QOL.

Transplant glomerulopathy (TGP) appears to be a pathogenic feature of chronic antibody-mediated rejection, but the pathogenesis of this histologic entity is still poorly understood. Previous studies suggest the involvement of lymphocytes but the phenotypes of these cells have never been analyzed. Here, we report the first study of mRNAs for specific markers of CD4+ T cells including Th1 (T-bet and INFγ), Th2 (IL4 and GATA3), Treg (Foxp3) and Th17 (IL-17 and RORγt) subsets, cytotoxic CD8 T cells (Granzyme B) and B-cell markers (CD20) in renal biopsies from renal transplant recipients suffering interstitial fibrosis and tubular atrophy (IF/TA) with or without TGP but with a similar inflammatory score and controls including transplant recipients with normal renal function. Only INFγ, T-bet (both functionally defined markers of Th1 CD4 T cells) and granzyme B (a CD8 cytotoxic marker) were significantly more strongly expressed in patients with TGP than in patients without TGP and normal controls. These results indicate a role of an active T-mediated inflammatory and cytotoxic process in the pathogenesis of TGP.

Sirolimus (SRL) allows to minimize the use of cyclosporine (CsA), but de novoadministration after transplantation is associated with various complications. We report a prospective, open-label, multicenter randomized study to evaluate conversion from a CsA- based regimen to a SRL-based regimen 3 months after transplantation. One hundred ninety-two of a total of 237 patients were eligible at 3 months to be converted to SRL (n = 95) or to continue CsA (n = 97). All patients were also given mycophenolate mofetil (MMF) and oral steroids, planned to be discontinued at month 8. The primary endpoint, the clearance estimated according to Cockcroft and Gault at week 52, was significantly better in the SRL group (68.9 vs. 64.4 mL/min, p = 0.017). Patient and graft survival were not statistically different. The incidence of acute rejection episodes, mainly occurring after withdrawal of steroids, was numerically but not statistically higher in the SRL group (17% vs. 8%, p = 0.071). Sixteen patients discontinued SRL, mainly for adverse events (n = 11), and seven patients discontinued CsA for renal failure or acute rejection. Significantly, more patients in the SRL group reported aphthous, diarrhea, acne and high triglyceride levels. Conversion CsA to SRL 3 months after transplantation combined with MMF is associated with improvement in renal function.

Transplant glomerulopathy (TGP) appears to be a pathogenic feature of chronic antibody-mediated rejection, but the pathogenesis of this histologic entity is still poorly understood. Previous studies suggest the involvement of lymphocytes but the phenotypes of these cells have never been analyzed. Here, we report the first study of mRNAs for specific markers of CD4 T cells including Th1 (T-bet and INF?), Th2 (IL4 and GATA3), Treg (Foxp3) and Th17 (IL-17 and ROR?t) subsets, cytotoxic CD8 T cells (Granzyme B) and B-cell markers (CD20) in renal biopsies from renal transplant recipients suffering interstitial fibrosis and tubular atrophy (IFTA) with or without TGP but with a similar inflammatory score and controls including transplant recipients with normal renal function. Only INF?, T-bet (both functionally defined markers of Th1 CD4 T cells) and granzyme B (a CD8 cytotoxic marker) were significantly more strongly expressed in patients with TGP than in patients without TGP and normal controls. These results indicate a role of an active T-mediated inflammatory and cytotoxic process in the pathogenesis of TGP.

Sirolimus (SRL) allows to minimize the use of cyclosporine (CsA), but de novoadministration after transplantation is associated with various complications. We report a prospective, open-label, multicenter randomized study to evaluate conversion from a CsA-based regimen to a SRL-based regimen 3 months after transplantation. One hundred ninety-two of a total of 237 patients were eligible at 3 months to be converted to SRL (n 95) or to continue CsA (n 97). All patients were also given mycophenolate mofetil (MMF) and oral steroids, planned to be discontinued at month 8. The primary endpoint, the clearance estimated according to Cockcroft and Gault at week 52, was significantly better in the SRL group (68.9 vs. 64.4 mLmin, p 0.017). Patient and graft survival were not statistically different. The incidence of acute rejection episodes, mainly occurring after withdrawal of steroids, was numerically but not statistically higher in the SRL group (17 vs. 8, p 0.071). Sixteen patients discontinued SRL, mainly for adverse events (n 11), and seven patients discontinued CsA for renal failure or acute rejection. Significantly, more patients in the SRL group reported aphthous, diarrhea, acne and high triglyceride levels. Conversion CsA to SRL 3 months after transplantation combined with MMF is associated with improvement in renal function.

La pandémie de Covid-19 a frappé le monde de la transplantation en mars 2020. Rapidement, les équipes se sont organisées pour optimiser la prise en charge de leurs patients immunodéprimés et progresser dans la connaissance de cette nouvelle maladie. Pour ce faire, un registre français regroupant tous les patients transplantés d’organes solides ayant développé une infection à SARS Cov2 ont été recensés. De nombreux travaux réalisés à partir de ces données nous ont permis de décrire la maladie chez le transplanté, de caractériser ses facteurs de gravité clinique et biologique et d’en définir son pronostic. La mortalité des patients transplantés hospitalisés pour Covid-19 est de 23 % à 60jours et l’insuffisance rénale participe grandement au mauvais pronostic en sus des facteurs de risque classiques décrits dans la population générale. L’arrivée de la vaccination a été un grand soulagement mais les patients transplantés ont développé une moins bonne réponse vaccinale que les sujets immunocompétents les maintenant dans une situation à risque de maladie grave après un schéma vaccinal adapté. Des stratégies spécifiques ont dû être adoptées dans cette population particulièrement fragile (augmentation du nombre de doses de vaccin, injection d’anticorps monoclonaux). La collaboration des centres de transplantation français sous l’impulsion de la Société francophone de transplantation nous a permis de mener de nombreux projets collaboratifs qui ont été d’une grande utilité pour la prise en charge des patients.

Mutations in one or more genes encoding complement-regulatory proteins predispose to atypical hemolytic uremic syndrome (aHUS) and its recurrence following kidney transplantation. We evaluated plasma complement level and performed a screening for mutations in genes encoding complement Factors H and I (CFH, CFI) and membrane cofactor protein (MCP) in 24 kidney transplant recipients experiencing de novothrombotic microangiopathy (TMA). Six patients presented with low C3 andor low Factor B levels suggestive complement alternative pathway. A mutation in the CFH or CFI gene was found in 724 patients (29), two of whom had a mutation in both genes. On the contrary, no mutation was identified in a control kidney transplant patients group (n 25) without TMA. Patients with or without mutations were similar with regard to clinical features. Eight out of 24 patients lost their graft within 1 year of posttransplantation including six patients with a CFH mutation or a decrease of C3 or CFB in plasma. To conclude, kidney transplant patients with de novoTMA exhibit an unexpectedly high frequency of CFH and CFI mutations. These results suggest that genetic abnormalities may represent risk factors for de novoTMA after kidney transplantation and raise the question of the best therapeutic strategy.

Mutations in one or more genes encoding complement-regulatory proteins predispose to atypical hemolytic uremic syndrome (aHUS) and its recurrence following kidney transplantation. We evaluated plasma complement level and performed a screening for mutations in genes encoding complement Factors H and I (CFH, CFI) and membrane cofactor protein (MCP) in 24 kidney transplant recipients experiencing de novo thrombotic microangiopathy (TMA). Six patients presented with low C3 and/or low Factor B levels suggestive complement alternative pathway. A mutation in the CFH or CFI gene was found in 7/24 patients (29%), two of whom had a mutation in both genes. On the contrary, no mutation was identified in a control kidney transplant patients group (n = 25) without TMA. Patients with or without mutations were similar with regard to clinical features. Eight out of 24 patients lost their graft within 1 year of posttransplantation including six patients with a CFH mutation or a decrease of C3 or CFB in plasma. To conclude, kidney transplant patients with de novo TMA exhibit an unexpectedly high frequency of CFH and CFI mutations. These results suggest that genetic abnormalities may represent risk factors for de novo TMA after kidney transplantation and raise the question of the best therapeutic strategy.

Background: Microalbuminuria and macroalbuminuria constitute risk factors for ESRD and death in non-transplanted populations. Whether microalbuminuria (especially in non-proteinuric patients) and macroalbuminuria constitute risk factors for graft loss and death is presently unknown in renal transplantation.

Pancreatic cancer has a very poor prognosis, largely due to its propensity for early local and distant spread. Histopathologically, most pancreatic cancers are characterized by a prominent stromal/fibrous reaction in and around tumor tissue. The aims of this study were to determine whether (1) the cells responsible for the formation of the stromal reaction in human pancreatic cancers are activated pancreatic stellate cells (PSCs) and (2) an interaction exists between pancreatic cancer cells and PSCs that may facilitate local and distant invasion of tumor.

There have been very few population pharmacokinetic (PopPK) studies and Bayesian forecasting methods dealing with cyclosporin (CsA) so far, probably because of the difficulty of modeling the particular absorption profiles of CsA. The present study was conducted in stable renal transplant patients treated with Neoral®and employed the NONMEM program. Its goals were (1) to develop a population pharmacokinetic model for CsA based on an Erlang frequency distribution (which describes asymmetric S-shaped absorption profiles) combined with a 2-compartment model; (2) to compare this model with models combining a time-lag parameter and either a zero-order or first-order rate constant and with a model based on a Weibull distribution; and (3) to develop a PK Bayesian estimator for full AUC estimation based on that “Erlang model.” The PopPK model was developed in an index set of 70 patients, and then individual PK parameters and AUC were estimated in 10 other patients using Bayesian estimation. The “Erlang” model best described the data, with mean absorption time (MAT), apparent clearance (CL/F), and apparent volume of the central compartment (Vc/F) of 0.78 hours, 26.3 L/h, and 76 L, respectively (interindividual variability CV 33, 30, and 48). Bayesian estimation allowed accurate prediction of systemic exposure using only 3 samples collected at 0, 1, and 3 hours. Regression analysis found no significant difference between the predicted and observed concentrations (10 per patient), and AUC0–12were estimated with a nonsignificant bias (0.6 to 8.7) and good precision (RMSE 5.3). In conclusion, the Erlang distribution best described CsA absorption profiles, and a Bayesian estimator developed using this model and a mixed-effect PK modeling program provided accurate estimates of CsA systemic exposure using only 3 blood samples.

The etiology of inflammation, edema, and smoothmuscle contraction characteristic of inflammatory boweldisease is not clearly understood. There is evidencethat several neuropeptides, including substance P (SP), may play a role. In this study weevaluated the ability of a SP-antagonist (SR140333) tomodify the course of experimental colitis induced in therat by trinitrobenzene sulfonic acid (TNB). Colitis was induced in 24 rats using TNB applied byintrarectal enema. Twelve TNB-treated rats receivedSR140333, 0.1 mg/kg intraperitoneally, 30 min before theadministration of TNB and every 48 hr until death. Twelve rats receiving only intrarectal 0.9%saline served as controls. Rats of each group werekilled after 14 days. At day 14, the control groupshowed no signs of inflammation whereas the TNB-treated rats without SR140333 treatment exhibited awell-established colitis. The TNB-treated group had ahigher level of inflammation, as seen histologically andby the significantly greater weight of colon strips, compared to the controls (0.30 ± 0.09 gvs 0.13 ± 0.03 g, P < 0.001) and to theSR140333-treated rats (0.30 ± 0.09 g vs 0.14± 0.05 g, P < 0.001). In addition, smoothmuscle contractility was significantly reduced in the inflamedcolons of TNB-treated rats when compared with thecontrols (carbachol: 42.7 ± 20.3 vs 254.2± 69.78 mg/mm2± 10.02 vs 89.45± 23.17 mg/mm211.4 ± 2.2 vs 98.32 ± 33.57mg/mm21). However, SR140333-treated ratsshowed a recovery from inflammation and motoralterations caused by TNB (carbachol: 150.9 ±46.1 mg/mm21; SP: 32.5 ± 9.4 mg/mm25; KCl:125.7 ± 36.1 mg/mm21). In conclusion,treatment with SP antagonist SR140333 reduces theseverity of colitis and has beneficial effects on theconcomitant alterations of contractility. Thus, theblockade of substance P may represent a possibility inthe treatment of intestinal inflammation.

We sought to identify characteristics of pancreatic nerves that were altered in chronic pancreatitis. Pancreatic tissue removed from patients with chronic pancreatitis was analyzed for the number and size of nerves, their association with inflammatory infiltrates, and their fine structure. The mean diameter of nerves in these patients was significantly greater than in controls, whereas the mean area of tissue served per nerve was significantly less than in controls. Foci of inflammatory cells, prominent in some specimens, sometimes were associated with nerves and ganglia, but inflammatory foci and neural elements also existed separately. Invasion of nerve tissue by inflammatory cells was observed but was not massive. Ultrastructural changes were detected in nerves. Individual nerve fibers showed evidence of damage, and there was evidence of edema in the nerve bundle. The perineurial sheath was altered so that it no longer provided a barrier between the surrounding connective tissue and the internal neural components. The results of this study indicate that nerves are preferentially retained while parenchyma degenerates and is replaced by fibrosis during chronic pancreatitis, but that they are retained in an altered condition. Increased mean diameters of nerves in chronic pancreatitis argues against pain being caused by constriction due to fibrosis. It is likely that both sensory and motor nerve fibers are affected by this alteration.

Background: Little is known about exocrine pancreatic function during human acute pancreatitis. We aimed to evaluate interdigestive exocrine pancreatic secretion and pancreatic polypeptide (PP) release during the early phase of acute pancreatitis in humans. Methods: Eight patients with acute pancreatitis (six biliary, one alcoholic, and one idiopathic acute pancreatitis) were studied within 72 h from the onset of symptoms. Four patients had necrotizing and four had edematous acute pancreatitis. Normal values were obtained from 26 normal subjects matched by sex and age. Interdigestive pancreatic secretion was studied by a duodenal intubation perfusion technique. Enzyme output was calculated for consecutive 15-min periods over 3-4 h and expressed as units per hour within a secretion cycle and units per hour around a secretion peak. Plasma PP concentrations were measured by radioimmunoassay in 15-min intervals. Results: All variables studied were similar in patients with acute pancreatitis and in controls. PP release in acute pancreatitis was maintained in a normal cyclical pattern closely related to the secretory cycles. Conclusions: Interdigestive exocrine pancreatic secretion in the early phase of mild to moderate acute pancreatitis in humans remains within the normal range. This finding provides a rational basis for early therapeutic inhibition of pancreatic secretion in human acute pancreatitis.

Octreotide (SMS 201–999, a long-acting somatostatin analogue, has been shown to decelerate growth of human pancreatic cancer in vitro and in vivo. We analyzed the efficacy of octreotide treatment in 22 patients (14 men, 8 women) with histologically verified ductal pancreatic cancer. All patients had advanced tumor stages (stage 111: 13 patients; stage IV: 9 patients). Octreotide was given by self-administered subcutaneous injection (3 × 100 kg/day). When there was evidence of tumor progression, the dose of octreotide was increased to 3 × 200 μg/day. A monthly follow-up, including clinical status, CT scan or ultrasonography, and tumor marker carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19–9 determination was carried out. There were no severe side effects apart from slight burning sensation at the injection site. No partial or complete remission was seen. Eighteen patients showed tumor progression with a median survival time of 17 weeks (range 3–42 weeks). In three patients a “no change” evaluation with a median survival time of 46 weeks (range 40–68 weeks) was registered. In these three patients the serum tumor markers CA 19–9 and CEA did not show an increase to more than twice the baseline value during this time. One patient discontinued the octreotide treatment because of tumor progression. The results of the analysis indicate that lowdose octreotide treatment is not effective in patients suffering from advanced tumor stages of pancreatic cancer.

Over the years, experience has shown that the cornerstone for improved survival in patients with infected pancreatic necrosis is an early, precise diagnosis followed by adequate drainage combined with modern intensive care management. In experienced hands, this goal can be achieved with different surgical approaches, provided that all septic collections are thoroughly removed and that reexploration is performed promptly if there is evidence of ongoing sepsis. If there is any concept preferable, and under what conditions, future large-scale randomized trials with precise and comparable patient stratification will have to demonstrate it. En tenant compte des données cliniques, morphologiques, radiologiques et bactériologiques, la pancréatite peut évoluer de manière très variable, allant d’un inconfort modéré, spontanément résolutif à une maladie grave avec décès. Des progrès dans la compréhension des facteurs physiopathologiques de la pancréatite aiguë ont amené à la conclusion que l’infection de la nécrose pancréatique est la complication désastreuse la plus importante dans l’évolution de la maladie. L’incidence de l’infection dans la pancréatite aiguë est fortement corrélée avec la présence de nécrose pancréatique ou extra-pancréatique. Le taux global d’infection dans la pancréatite aiguë ne dépasse pas 10%. Cependant, la nécrose infectée peut se voir jusque chez 70% des patients ayant une pancréatite nécrosante, et elle est responsable d’une mortalité élevée et d’un taux important de morbidité majeure. Actuellement, plus de 80% des décès en rapport avec la pancréatite aiguë sont liés à une complication septique secondaire à l’infection bactérienne. De nos jours, et le médecin et le chirurgien en sont convaincus, le traitement initial de la pancréatite doit être conservateur, en dehors d’une indication précise d’intervention. Alors qu’il existe peu de discussion en ce quie concerne l’indication opératoire en cas de nécrose pancréatique infectée, le type de chirurgie à effectuer reste problématique et controversé. L’introduction de la nécrosectomie pancréatique et péripancréatique, suivie d’un procédé permettant l’élimination et le drainage efficaces de la loge pancréatique ont considérablement réduit la mortalité de la nécrose infectée. Según las manifestaciones clínicas, anatomopatológicas, radiologicas y bacteriológicas, la pancreatitis aguda es una enfermedad de gravedad variable, que va desde una leve molestia autolimitante hasta una enfermedad severa con desenlace fatal. El avance en la comprensión de los factores fisiopatológicos de la pancreatitis aguda ha llevado a la conclusión de que la infectión de la necrosis pancreática es la complicatión principal y la más devastadora en el curso de esta enfermedad. La incidencia de infectión en la pancreatitis aguda aparece fuertemente correlacionada con la presencia de necrosis intra o pancreática. Las tasas globales de infectión en la pancreatitis aguda no exceden 10%; sin embargo, la necrosis pancreática ocurre hasta en 70% de los pacientes con pancreatitis necrotizante (1, 4, 5, 7–10) y se acompaña de elevadas tasas de mortalidad y de alarmante incidencia de morbilidad. En la actualidad más del 80% de las muertes en la pancreatitis aguda son debidas a complicaciones sépticas consecuentes a infectión bacteriana. En la época presente tanto los internistas como los cirujanos consideran que el tratamiento inicial de la pancreatitis aguda es de tipo conservador a menos que se presente una indicatión específica para interventión quirúrgica. En tanto que existe mínimo desacuerdo en cuanto a la necesidad absoluta de interventión quirúrgica en los pacientes con infectión comprobada de la necrosis pancreática, la modalidad técnica de la interventión operatoria es motivo de aguda controversia. La introductión de una amplia y formal necrosectomía pancreática y peripancreática con un procedimiento para el manejo del espacio peripancreático que permita el continuado drenaje y la desbridación, ha resultado en una notoria disminución de la mortalidad por necrosis infectada.

Background: We investigated the vasopressor hormone response following mesenteric traction (MT) with hypotension due to prostacyclin (PGI2) release in patients undergoing abdominal surgery with a combined general and epidural anesthesia. Methods: In a prospective, randomized, placebo‐controlled study we administered 400 mg ibuprofen (i.v.) in 42 patients scheduled for abdominal surgery. General anesthesia was combined with epidural anesthesia (T4‐L1). Before as well as 5, 15, 30, 45, and 90 min after MT we recorded plasma osmolality, hemodynamics and measured 6‐keto‐PGFlα (stabile metabolite of PGI2), TXB2(stabile metabolite of thromboxane A2) active renin, and arginine vasopressin (AVP) plasma concentrations by radioimmunoassay. Catecholamine levels were assessed by high‐pressure liquid chromatography (HPLC) with electrochemical detection. Results: Following MT, arterial hypotension occurred along with a substantial PGI2release. This was completely abolished by ibuprofen administration. Although plasma levels of 6‐keto‐PGF1α(1133 (708) vs.60 (3) ng/L, median (median absolute deviation), P=0.0001, placebo vs.ibuprofen) remained significantly elevated, blood pressure was restored within 30 min after MT in the placebo group. At the same point in time plasma concentrations of TXB2(164 (87) vs.58 (1) ng/L, P=0.0001), epinephrine (46 (33) vs.14 (6) ng/L, P=0.001), AVP (41 ± (18) vs.12 (7) ng/L, P=0.0004), and active renin (27 (12) vs.12 (4) ng/L, P= 0.001) were significantly higher in placebo‐treated patients. Conclusion: Under combined general and epidural anesthesia arterial hypotension following MT due to endogenous PGI2release is associated with enhanced release of AVP, active renin, epinephrine and thromboxane A2, presumably contributing to hemodynamic stability within 30 min after MT.

BACKGROUND & AIMS: Urokinase plasminogen activator (uPA) regulates plasmin generation from plasminogen. The aim of this study was to analyze the role of the plasminogen activator/plasmin system in chronic pancreatitis (CP). METHODS: Using Northern blot analysis, in situ hybridization, and immunohistochemistry, the expression of uPA, its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and transforming growth factor beta 1 (TGF-beta 1) was studied in 14 patients undergoing pancreatic resection for CP. Normal control pancreatic tissue was obtained through an organ donor program. RESULTS: Eight of 14 CP samples showed concomitant increased expression (P < 0.001) of uPA (5.2-fold), uPAR (5.9-fold), and TGF-beta 1 (8.8-fold) messenger RNA (mRNA) compared with normal controls. PAI-1 mRNA expression was increased (6.5-fold; P < 0.001) in all CP samples. By in situ hybridization, moderate to strong mRNA staining of all four factors was present in acinar cells, some ductal cells, and areas with ductal metaplasia in CP samples. A similar staining pattern was found by immunohistochemistry. Intense mRNA and immunostaining for all of these factors in CP samples was associated with a higher degree of pancreatic damage. CONCLUSIONS: uPA and its receptor may contribute to the lytic damage observed in CP by plasmin generation. Similarly, increased amounts of plasmin may activate latent TGF-beta, thereby leading to the accumulation of fibrotic tissue. (Gastroenterology 1997 Sep;113(3):904-13)

Over the years, experience has shown that the cornerstone for improved survival in patients with infected pancreatic necrosis is an early, precise diagnosis followed by adequate drainage combined with modern intensive care management. In experienced hands, this goal can be achieved with different surgical approaches, provided that all septic collections are thoroughly removed and that reexploration is performed promptly if there is evidence of ongoing sepsis. If there is any concept preferable, and under what conditions, future large-scale randomized trials with precise and comparable patient stratification will have to demonstrate it.

Adjustable gastric banding is a well-established procedure for the treatment of morbid obesity. We present a 62-year-old female who experienced the rare complication of intragastric band perforation due to a gastric adenocarcinoma localized at the site of gastric banding, 10 years after insertion of the band.

Alors que la colonisation fongique des liquides de conservation en transplantation et ses conséquences septiques ont plusieurs fois été décrites, la colonisation bactérienne reste peu abordée, notamment en transplantation rénale. Notre objectif était d’évaluer s’il existe un lien entre la colonisation bactérienne du liquide de conservation des greffons rénaux et l’apparition d’une pyélonéphrite dans l’année suivant la transplantation.