Glutathione S-Transferase T1 Mismatch Is a Risk Factor for Chronic Ductopenic Rejection of Liver Allografts.

The underlying causes of chronic rejection (CR) after liver transplantation (LT) are not completely known. The main aim of this study was to explore the involvement of the minor histocompatibility antigen glutathione S-transferase T1 (GSTT1) in CR. We retrospectively studied 611 patients who underwent LTs at University Hospital Virgen del Rocío between 2003 and 2016 with a median follow-up of 7.4 ± 4.2 years. The GSTT1 genotype was determined by polymerase chain reaction. We defined GSTT1 mismatch as a specific donor/recipient combination in which a recipient who was homozygous for the deletion allele received a transplant from a positive donor. The prevalence of CR in our whole cohort was 11.6% (71/611), and the prevalence in the GSTT1-mismatched group was 18.8% (16/85) versus 10.5% (55/526) in the GSTT1-matched group. In the cyclosporine A (CsA) group, the prevalence was 26.3% (26/99), much higher than the 8.8% (45/512) observed in the tacrolimus (Tac) group. For statistical analysis, the patients were distributed into 2 groups: group 1, regarded as GSTT1 mismatched, which included the donor (D)+/recipient (R)- allelic combination; and group 2, regarded as GSTT1 matched, which included the other allelic combinations of D+/R+, D-/R-, and D-/R+. All relevant clinical information was collected, and a diagnosis of CR was always confirmed by liver biopsy. GSTT1 mismatch (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.08-3.66; P = 0.03) and use of CsA/Tac (P < 0.001) were independent risk factors for CR. CR increased the risk of mortality (HR, 2; 95% CI, 1.2-3.6; P = 0.01). Out of the 71 CR patients, 12 (16.9%) needed retransplantation. In conclusion, the GSTT1 D+/R- allelic mismatch is an independent risk factor for CR. A long follow-up of LT patients is recommended because the incidence of CR in adults seems to be underestimated.

Identification of the cellular components involved in de novo immune hepatitis: a quantitative immunohistochemical analysis.

BACKGROUND: Diagnosis of de novo immune hepatitis (dnIH) after liver transplantation relies on biopsy findings, with an abundance of plasma cells (PCs) in the inflammatory infiltrates a hallmark of the disease. Very little is known about what other types of immune cells exist in the infiltrates mainly located in the portal areas of the liver tissue. METHODS: We analyzed the composition of T cells, B cells, PCs, and macrophages in the liver biopsies of 12 patients with dnIH, 9 of them obtained at the time of diagnosis. For comparison, biopsies from 9 patients with chronic rejection (CR) were included in the study. The results were analyzed by a computer-assisted stereology quantification method. RESULTS: The major components of the infiltrates in the portal areas were CD3+ T lymphocytes in both groups, with 36.6% in the dnIH group versus 49.4% in the CR group. CD20+ B lymphocytes represented 14.9% in the dnIH group and 29.1% in the CR group. Macrophage levels were very similar in the dnIH and CR group (19.7% versus 16.8%, respectively). PCs were much less represented in CR biopsies than those from the dnIH group (mean value of 4.7% versus 28.8%). CONCLUSION: In conclusion, the determination of a characteristic cellular profile could be an important tool for a more reliable diagnosis of dnIH, in support of the histological evaluation made by the pathologist, which in most cases is challenging. Recognition of this condition is crucial because it leads to graft failure if left untreated.

IgG subclass profile among anti-Glutathione S-transferase T1 antibodies in post-transplant de novo immune hepatitis.

Although the pathogenic pathways leading to de novo immune hepatitis (IH) are not completely understood, we have shown strong evidences of an antidonor response against Glutathione S-transferase T1 (GSTT1), an antigen exclusively expressed in the donor liver. The first sign of this process is the production of GSTT1 antibodies that, in 25% of the cases, will precede de novo IH. Because the presence of the antibodies is not sufficient to trigger the disease, we aimed to study GSTT1 IgG subclasses in a group of 18 liver transplant patients, 12 that developed de novo IH and 6 that remained free of disease. Surprisingly, the predominant subclasses were IgG1-GSTT 1 and IgG4-GSTT 1. The presence of IgG4-expressing plasma cells was also investigated in 10 available liver biopsies. Six biopsies coinciding with diagnosis showed a mean value of 32.8 IgG4+ plasma cells/hpf vs. 5.55 in patients without the disease. We have not found a distinctive GSTT1-IgG profile in patients with de novo IH, but the ratio IgG1-GSTT 1 /IgG4-GSTT 1 in samples from close to the time of diagnosis seemed to be important. The novel finding of abundant IgG4-GSTT 1 in liver transplantation is intriguing, but their possible role in pathogenesis of de novo IH remains unknown.

Mismatch on glutathione S-transferase T1 increases the risk of graft-versus-host disease and mortality after allogeneic stem cell transplantation.

Several drug-metabolizing enzymes, preferentially expressed in the liver, have the potential to act as minor histocompatibility antigens. In the present study, we analyzed the impact of glutathione S-transferase T1 (GSTT1), glutathione S-transferase M1, glutathione S-transferase P1, and UDP glucuronosyl transferase 2B17 (UGT2B17) disparities on the outcome of 125 patients undergoing allogeneic hematopoietic stem cell transplantation. Grades 2 to 4 acute graft-versus-host disease (aGVHD) developed in 56.2% versus 73.3% of GSTT1-matched versus mismatched patients (P = .048). Remarkably, 8.6% GSTT1-matched patients developed grades 2 to 4 liver aGVHD, compared with 36.8% among GSTT1-mismatched recipients (P < .001). Regarding chronic graft-versus-host disease (cGVHD), 34.8% versus 70.7% matched versus mismatched patients developed overall cGVHD (P = .038) and 16.3% versus 48% developed hepatic cGVHD (P = .006). We also found a strong association between the UGT2B17 mismatch and the risk of severe aGVHD (P = .001), especially with gut involvement (P < .001). Most striking was the influence of the GSTT1 mismatch on nonrelapse mortality (26.8% versus 52.6%, P = .031) and overall survival (62% versus 36.9%, P = .045). In summary, UGT2B17 and GSTT1 mismatch are risk factors for the development of GVHD and the latter also influences on mortality and survival after allogeneic transplantation from HLA-identical donors.

Pancreatic tuberculosis mimicking a neoplastic mass in an immunosuppressed patient who also presented adenopathy syndrome: Case report.

Introduction: Pancreatic tuberculosis is unusual, with an incidence reported to be less than 4,7 % worldwide. Case report: We report the case of a 32-year-old man recently diagnosed with HIV whose adenopathy syndrome was understudy. Lymph node cervical and bone marrow biopsies were performed without evidence of neoplastic infiltration, fungal infection, or tuberculosis. He arrived at the emergency room for acute band abdominal pain radiating to the back. Results: Contrast-enhanced abdominal computed tomography revealed a mass in the head of the pancreas which generates intra- and extrahepatic bile duct dilation. Serial sputum, PPD, Genexpert, bronchoscopy and ultrasound fine needle aspiration biopsy were negative for tuberculosis, with no evidence of microorganisms or malignancy; cultures results pending. A second biopsy was requested using a No. 19 needle reporting a necrotizing process with acid-fast bacilli, compatible with tuberculosis, and the pending cultures results were positive for the mycobacterium tuberculosis complex, confirming the diagnosis. Conclusion: Clinical awareness of pancreatic tuberculosis in immunosuppressed patients in our country, may lead to faster and accurate diagnosis study and management, using minimally invasive techniques as diagnostic tools.

Complement component 4d immunostaining in liver allografts of patients with de novo immune hepatitis.

De novo immune hepatitis (DNIH) is a form of late graft dysfunction after liver transplantation. The fine mechanisms leading to the development of DNIH are not known, and whether this hepatitis is a form of rejection or a result of an auto/alloimmune injury has not been established. In our patients, DNIH was always preceded by the production of donor-specific antibodies against the glutathione S-transferase T1 (GSTT1) enzyme because of a genetic mismatch in which the donors carried the wild-type gene and the recipients displayed the null genotype. Complement component 4d (C4d) immunopositivity in 12 paraffin-embedded liver biopsy samples from 8 patients diagnosed with DNIH associated with anti-GSTT1 antibodies was retrospectively evaluated. Six patients with a diagnosis of chronic rejection (CR) and 7 patients with hepatitis C virus recurrence were included as control groups. Among the patients with DNIH, 7 showed C4d-positive immunostaining localized in the portal tracts, whereas in the tested biopsy samples of the 2 control groups, this staining pattern was absent. Four biopsy samples of the CR group showed C4d-positive sinusoidal staining. This study confirms the activation of the complement pathway in the presence of donor-specific antibodies, which was shown by the deposition of C4d elements in liver biopsy samples of patients with DNIH. The use of C4d as a marker of antibody-mediated rejection in liver allografts in the presence of antidonor antibodies is discussed, and it may contribute to improved differential diagnoses based on biopsy findings.

Choice of calcineurin inhibitor may influence the development of de novo immune hepatitis associated with anti-GSTT1 antibodies after liver transplantation.

In 2004, we defined the genetic mismatch in the glutathione S-transferase T1 (GSTT1) gene positive donor/null recipient as a risk factor to develop de novo immune hepatitis (IH) after liver transplant (LT), which is always associated with production of donor-specific anti-GSTT1 antibodies. However, there are several unresolved questions, such as why some of these patients produce antibodies, why others do not and why not all of the patients with antibodies develop the disease. The aim of this study was to evaluate the influence of several variables in the production of anti-GSTT1 antibodies and/or de novo IH. The study group included 35 liver-transplanted patients. The number of patients not producing antibodies was significantly higher in the group treated with Tac-based immunosuppression compared with the CsA-based group (94.1% vs. 5.9%, p = 0.001). Additionally, a protective effect of the Tac-based therapy vs. the CsA-based therapy was observed with regard to development of de novo IH (80.8% vs. 19.2%, p = 0.003). In conclusion, the choice of calcineurin inhibitor may influence the development of de novo IH mediated by anti-GSTT1 antibodies.

Epicardial fat tissue, coronary arterial calcification and mortality in patients with advanced chronic kidney disease and hemodialysis.

INTRODUCTION AND OBJECTIVES: Epicardial and mediastinal adipose tissue (EAT, MAT) are linked to metabolic syndrome and coronary artery disease. Patients with chronic kidney disease (CKD) have thicker EAT. We assessed if EAT and MAT could be associated with increased mortality and cardiovascular events in patients with advanced CKD and haemodialysis therapy. METHODS: A post-hoc study was performed. We analyzed a prospective series of 104 cases. EAT thickness was quantified by a multislice synchronized computed tomography (MSCT). RESULTS: The follow-up period was 112.68 (109.94-115.42) months. The optimal cut-off point of EAT for prediction of total mortality was 11.45 mm (92.86% and 43.75%). EAT thickness was associated with serum albumin levels, serum triglyceride levels, phosphorus and calcium phosphate product. The EAT was greater in haemodialysis patients compared to those with advanced CKD (P < .001). Patients with diabetes mellitus had greater EAT and MAT thickness (P = .018). At the end of follow up, the survival average time of patients with EAT thickness <11.45 mm was 97.48 months vs. 76.65 months for thickness > 11.45 mm (P = .007). CONCLUSIONS: A higher EAT and MAT thickness was associated with increased mortality. Furthermore, EAT was associated with lower free survival time to fatal and non-fatal cardiovascular events. The measurement of EAT and MAT by MSCT could be a prognostic tool to predict cardiovascular events and mortality risk in advanced CKD patients.

Epicardial fat tissue, coronary arterial calcification and mortality in patients with advanced chronic kidney disease and hemodialysis. / Tejido graso epicárdico, calcificación arterial coronaria y mortalidad en pacientes con enfermedad renal crónica avanzada y hemodiálisis.

INTRODUCTION AND OBJECTIVES: Epicardial and mediastinal adipose tissue (EAT, MAT) are linked to metabolic syndrome and coronary artery disease. Patients with chronic kidney disease (CKD) have thicker EAT. We assessed if EAT and MAT could be associated with increased mortality and cardiovascular events in patients with advanced CKD and haemodialysis therapy. METHODS: A post-hoc study was performed. We analyzed a prospective series of 104 cases. EAT thickness was quantified by a multislice synchronized computed tomography (MSCT). RESULTS: The follow-up period was 112.68 (109.94 -115.42) months. The optimal cut-off point of EAT for prediction of total mortality was 11.45mm (92.86% and 43.75%). EAT thickness was associated with serum albumin levels, serum triglyceride levels, phosphorus and calcium phosphate product. The EAT was greater in haemodialysis patients compared to those with advanced CKD (P<.001). Patients with diabetes mellitus had greater EAT and MAT thickness (P=.018). At the end of follow up, the survival average time of patients with EAT thickness <11.45mm was 97.48 months vs. 76.65 months for thickness > 11.45mm (P=.007). CONCLUSIONS: A higher EAT and MAT thickness was associated with increased mortality. Furthermore, EAT was associated with lower free survival time to fatal and non-fatal cardiovascular events. The measurement of EAT and MAT by MSCT could be a prognostic tool to predict cardiovascular events and mortality risk in advanced CKD patients.

Computer-Assisted Definition of the Inflammatory Infiltrates in Patients With Different Categories of Banff Kidney Allograft Rejection.

Currently, the diagnosis of kidney allograft rejection relies on individual histological assessments made by expert pathologists according to the Banff classification. In this study, we applied new Computer-Assisted System Technology (newCAST™) by Visiopharm® with the aim of identifying and quantifying the immune cells in inflammatory infiltrates. We searched for distinctive cellular profiles that could be assigned to each rejection category of the Banff schema: antibody-mediated rejection (active and chronic active), borderline, T cell-mediated rejection (TCMR), and mixed rejection. This study was performed with 49 biopsy samples, 42 from patients with rejection and 7 from patients with clinical signs of dysfunction but an absence of histological findings of rejection. Plasma cells, B and T lymphocytes, natural killer cells, and macrophages, with a special focus on the M1 and M2 subsets, were studied. A major difference among the Banff rejection groups was in the total amount of cells/mm2 tissue. Principal component analysis identified some distinctive associations. The borderline category grouped with CD4+ lymphocytes and M1 macrophages, and active antibody-mediated rejection (aAMR) clustered with natural killer cells. Despite these findings, the search for characteristic profiles linked to the rejection types proved to be a very difficult task since the cellular composition varied significantly among individuals within the same diagnostic category. The results of this study will be analyzed from the perspective of reconciling the classic way of diagnosing rejection and the immune situation "in situ" at the time of diagnosis.

Positive association of anticytoskeletal endothelial cell antibodies and cardiac allograft rejection.

Using an indirect immunofluorescence method on human umbilical vein endothelial cells (HUVEC), we investigated the presence of antiendothelial cell antibodies (AECA) in 136 pre- and posttransplant serum samples sequentially collected from 31 patients during the first year after cardiac transplantation. A healthy control group was also included (n = 87). Colocalization studies demonstrated a positive staining pattern of different cytoskeletal components (cytoskeletal-antiendothelial cell antibodies, CSK-AECA) including antivimentin, antiactin, antitubulin, and anticytokeratin among heart transplanted patients. Frequency of CSK-AECA in the control group and at day 0 in the transplant group was 18.3 and 22.5%, respectively (p = NS). A progressive increase in the frequency of CSK-AECA was observed after cardiac transplantation: 13.3% at day 15; 22.2% at day 30; 53.8% at day 90, and 58% at day 360. Interestingly, rejection episodes within the first year after transplantation occurred in 83.3% of CSK-AECA-positive and in 30.7% of CSK-AECA-negative patients (p = 0.0045). The presence of antibodies was detected prior to the rejection event and was associated with a poor clinical outcome: rejection episodes occurred at a mean of 36.14 +/- 17 days after transplantation in patients with preexisting AECA and 174.25 +/- 51.9 days after de novo antibody appearance in patients with no antibodies at day 0 (p = 0.029). In conclusion, a progressive increase in the frequency of CSK-AECA was observed following cardiac transplantation; the presence of these antibodies is strongly associated and precedes the rejection episodes. Thus, CSK-AECA could be a good marker for acute graft rejection.

Anti-glutathione S-transferase T1 antibody-mediated rejection in C4d-positive renal allograft recipients.

BACKGROUND: Chronic humoral rejection is a progressive form of graft injury, with defined diagnostic criteria, the crucial one being the evidence of circulating anti-donor antibodies. These antibodies are mainly directed against human leucocyte antigens (HLA), but other targets have also been described. We previously reported that antibodies against the Glutathione S-transferase T1 (GSTT1) enzyme appear in recipients without the GSTT1 gene who receive a graft from a GSTT1-positive donor. The primary aim of this study was to analyse the role of GSTT1 in cases of antibody-mediated rejection (AMR) in the absence of anti-HLA antibodies. A second objective was to describe the distribution of the GSTT1 enzyme in the human kidney. METHODS: Four renal biopsies from four renal transplanted patients with declined renal function and circulating anti-donor GSTT1 antibodies were studied for C4d deposits in sections of paraffin-embedded tissue samples. Anti-donor-specific HLA and MICA antibody detection was done with the Luminex platform and anti-GSTT1 antibodies were tested by indirect immunofluorescence on rat tissues and ELISA assay. DNA of the patients was extracted for GSTT1 genotyping. RESULTS: Four patients with the GSTT1 donor/recipient mismatch developed anti-GSTT1 antibodies 32, 42, 48 and 60 months after the transplant. One patient also had donor-specific anti-HLA antibodies. Their biopsies showed pathologic lesions compatible with chronic antibody-mediated rejection (CAMR), along with positive C4d deposition in peritubular capillaries in three of them, being no valuable in the other case. CONCLUSION: This is the first study reporting an association between the appearance of chronic antibody-mediated renal allograft rejection and the occurrence of de novo production of anti-GSTT1 antibodies, in the absence of anti-HLA donor-specific antibodies. This fact suggests a potential role of the GSTT1 system in anti-graft immune response.

Rethinking de novo immune hepatitis, an old concept for liver allograft rejection: Relevance of glutathione S-transferase T1 mismatch.

Antibody-mediated rejection (AMR) in liver transplantation has long been underestimated. The concept of the liver as an organ susceptible to AMR has emerged in recent years, not only in the context of the major histocompatibility complex with the presence of HLA donor-specific antibodies, but also with antigens regarded as "minor", whose role in AMR has been demonstrated. Among them, antibodies against glutathione S-transferase T1 have been found in 100% of patients with de novo autoimmune hepatitis (dnAIH) when studied. In its latest update, the Banff Working Group for liver allograft pathology proposed replacing the term dnAIH with plasma cell (PC)-rich rejection. Antibodies to glutathione S-transferase T1 (GSTT1) in null recipients of GSTT1 positive donors have been included as a contributory but nonessential feature of the diagnosis of PC-rich rejection. Also in this update, non-organ-specific anti-nuclear or smooth muscle autoantibodies are no longer included as diagnostic criteria. Although initially found in a proportion of patients with PC-rich rejection, the presence of autoantibodies is misleading since they are not disease-specific and appear in many different contexts as bystanders. The cellular types and proportions of the inflammatory infiltrates in diagnostic biopsies have been studied in detail very recently. PC-rich rejection biopsies present a characteristic cellular profile with a predominance of T lymphocytes and a high proportion of PCs, close to 30%, of which 16.48% are IgG4+. New data on the relevance of GSTT1-specific T lymphocytes to PC-rich rejection will be discussed in this review.

De novo recipient-specific Glutathione S-transferase T1 antibody development after HLA-identical hematopoietic cell transplantation.

Donor-specific antibodies against Glutathione S-transferase T1 (GSTT1) have been associated with de novo immune hepatitis after liver transplantation. These antibodies have also been found very early in allo-HCT associated with acute hepatic GvHD but in all the cases the donor cells had experienced previous priming through pregnancies. It remained to be explored whether or not primary recognition of the antigen occurs after HCT and what could be the consequences in the long term outcome. We genotyped a cohort of 68 HCT patients and found 11 with the GSTT1 null donor/positive recipient mismatch. After testing 114 serum samples, we found a unique case of a 33-year-old patient transplanted from his HLA-identical sibling donor in which IgG GSTT1 antibodies were detected for the first time on day +178. After stimulation of peripheral blood mononuclear cells with GSTT1 peptides we could demonstrate that this patient also had GSTT1-specific T lymphocytes that became activated upon exposure to the GSTT1 antigen. In this report, we describe the first case in which simultaneous T and B cell response against GSTT1 is developed in HCT although the clinical consequences in GvHD are still unclear.

T-cell allorecognition of donor glutathione S-transferase T1 in plasma cell-rich rejection.

AIM: To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts. METHODS: The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1 (GSTT1) alleles (don+/rec-), and 4 were matched (don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection (former de novo immune hepatitis). For the detection of specific T lymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ. RESULTS: Activation of CD8+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection (3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides (1.45%-5.18%). Highly unexpected was the finding of a double positive CD4+CD8low T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4+CD8low cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides. CONCLUSION: Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.

Melanoma metastásico a vejiga / Metastatic melanoma to the bladder / Melanoma metastático na bexiga

Introducción. El compromiso tumoral metastásico del melanoma al tracto genitourinario es frecuente, pero, la metástasis a vejiga es rara, constituye menos del 2% de los casos. Sin embargo, en autopsias realizadas a pacientes con melanoma se ha encontrado metástasis en la vejiga en entre un 18% y un 37% de los casos, lo que la convierte en la segunda en incidencia posterior al adenocarcinoma gástrico. La media de supervivencia suele ser entre 6 - 7.5 meses. El objetivo de este trabajo es presentar el caso de un melanoma metastásico a vejiga, entidad poco frecuente y poco diagnosticada por ser la mayoría de las veces asintomática. Presentación del caso. Paciente femenina de 62 años, con antecedente de melanoma al nivel del primer artejo del pie, con manejo quirúrgico y farmacológico. Consultó por hematuria. La cistoscopia evidenció una lesión única sólida, eritematosa, con necrosis y fácil sangrado y se indicó realizar resección transuretral (RTU). La patología demostró compromiso por melanoma ulcerado metastásico. Se inició manejo de segunda línea (Pembrolizumab) y presentó progresión a miembros superiores y recaída a nivel vesical. La paciente falleció un año después. Discusión. Las metástasis de melanoma al tracto genitourinario son frecuentes, pero las metástasis vesicales aisladas son raras. El tratamiento suele ser RTU de la lesión, cistectomía, quimioterapia y radioterapia. La RTU es curativa para las lesiones restringidas al epitelio, aunque la cistectomía radical suele ser la terapia de elección ante un paciente con un tumor localizado. El Pembrolizumab ha demostrado aumentar la supervivencia. El pronóstico depende del tamaño y profundidad de la invasión. Conclusiones. El compromiso vesical metastásico es poco frecuente y diagnosticado, puede estar presente en pacientes con melanoma, síntomas irritativos urinarios no específicos y hematuria. Suele ser de mal pronóstico, y requiere de manejo quirúrgico asociado a manejo sistémico.

Introduction. Metastatic tumor compromise of melanoma to the genitourinary tract is frequent, but metastasis to the bladder is rare, representing less than 2% of cases. However, autopsies performed on patients with melanoma have found metastases in the bladder in 18-37% of cases, making it the second incidence after gastric adenocarcinoma. The median survival is usually 6 to 7.5 months. The objective of this work is to present the case of a metastatic melanoma to the bladder, a rare and underdiagnosed condition because most of the time it is asymptomatic. Case Presentation. 62-year-old female patient, with a history of melanoma at the level of the first toe, with surgical and pharmacological management. The reason for consultation was hematuria. Cystoscopy revealed a single solid, erythematous lesion with necrosis and easy bleeding, and a transurethral resection (TUR) was indicated. The pathology found compromise for metastatic ulcerated melanoma. Second-line treatment (Pembrolizumab) was started and presented progression to the upper limbs and relapse at the bladder level. The patient died a year later. Discussion. Melanoma metastases to the genitourinary tract are common, but isolated bladder metastases are rare. Treatment is usually TUR of the lesion, cystectomy, chemotherapy, and radiation therapy. TUR is curative for lesions restricted to the epithelium, although radical cystectomy is usually the therapy of choice in patients with a localized tumor. Pembrolizumab has been shown to increase survival. The prognosis depends on the size and depth of the invasion. Conclusions. Metastatic bladder compromise is rare and underdiagnosed, it may be present in patients with melanoma, non-specific urinary irritative symptoms, and hematuria. It tends to have a poor prognosis, and requires surgical management associated with systemic management.

Introdução. O comprometimento do tumor metastático do melanoma no trato geniturinário é comum, mas a metástase na bexiga é rara, constituindo menos de 2% dos casos. Entretanto, em autópsias realizadas em pacientes com melanoma, foi encontrada metástase na bexiga entre 18% e 37% dos casos, o que a torna a segunda em incidência após o adenocarcinoma gástrico. A média de sobrevivência é geralmente entre 6 - 7,5 meses. O objetivo deste trabalho é apresentar o caso de um melanoma metastático na bexiga, uma entidade pouco frequente e subdiagnosticada, pois na maioria das vezes é assintomática. Apresentação do caso. Paciente do sexo feminino, 62 anos, com antecedentes de melanoma no nível do hálux, com manejo cirúrgico e farmacológico. Ela consultou por hematúria. A cistoscopia revelou uma única lesão sólida, eritematosa com necrose e sangramento fácil, e foi indicada uma ressecção transuretral (RTU). A patologia mostrou comprometimento de melanoma ulceroso metastático. O tratamento de segunda linha (Pembrolizumab) foi iniciado e a patologia avançou para os membros superiores e uma recaída no nível da bexiga. A paciente morreu um ano depois. Discussão. As metástases de melanoma para o trato geniturinário são frequentes, mas as metástases vesicais isoladas são raras. O tratamento é geralmente RTU da lesão, cistectomia, quimioterapia e radioterapia. A RTU é curativa para lesões restritas ao epitélio, embora a cistectomia radical seja geralmente a terapia de escolha para um paciente com um tumor localizado. O Pembrolizumab demonstrou aumentar a sobrevivência. O prognóstico depende do tamanho e da profundidade da invasão. Conclusões. O comprometimento vesical metastático é raro e subdiagnosticado, pode estar presente em pacientes com melanoma, sintomas irritantes urinários não específicos e hematúria. Geralmente tem um prognóstico negativo e requer manejo cirúrgico em associação com manejo sistêmico.

Alloimmune response against donor glutathione S-transferase T1 antigen in renal transplant recipients.

BACKGROUND: The long-term outcome of kidney transplantation could be influenced by the appearance of antibodies against donor-specific antigens. Glutathione S-transferase T1 (GSTT1) is a protein preferentially expressed in liver and kidney cells. Deletion of the GSTT1 gene results in a complete lack of protein expression, which occurs in 20% of the white population. GSTT1 donor-recipient mismatch has been deleterious in liver transplantation. The purpose of this study is to examine immunologic and clinical consequences of a GSTT1 donor-recipient mismatch in kidney transplantation. METHODS: The presence of anti-GSTT1 antibodies was studied retrospectively in sera from 135 patients who underwent transplantation before 1995. Samples from 89 patients who received a GSTT1-positive kidney graft between December 1998 and May 2001 were collected prospectively. GSTT1 genotypes and anti-GSTT1 antibodies were studied by using standard methods. RESULTS: Seven patients, all with the null genotype, produced anti-GSTT1 antibodies. No transplant recipient with a positive genotype produced these antibodies. Six of 7 patients with antibodies also were positive for hepatitis C virus. Clinical outcomes of these patients did not differ from those of the entire group. CONCLUSION: After kidney transplantation, some patients with the null GSTT1 genotype who received a GSTT1-positive graft developed an immune response, with production of anti-GSTT1 antibodies. The presence of these antibodies did not seem to produce functional impairment in the graft. Hepatitis C virus seems to have a prominent role in this particular allograft immune response.

Aula invertida en enseñanzas sanitarias: recomendaciones para su puesta en práctica / Flipped classroom in health teaching: recommendations for its implementation

El aula invertida es un modelo de enseñanza-aprendizaje en el que los alumnos tienen el primer contacto con la información a ser aprendida fuera de clase, mediante documentos (textos y videos) que el docente les hace llegar por medios electrónicos. El tiempo de clase así ahorrado se dedica a actividades de aula que consolidan la asimilación de ese conocimiento y lo aplican a la resolución de cuestiones, casos y problemas. Este modelo de aprendizaje reduce el tiempo de instrucción directa en clase y aumenta el dedicado al aprendizaje activo. Se transfiere al alumno la responsabilidad de esforzarse inicialmente para alcanzar un nivel de comprensión básico y comunicar sus dificultades y dudas al docente. Así, el docente recibe información sobre cuáles son las dificultades y necesidades de sus alumnos y podrá adaptar las actividades que realizará en el aula para resolver las dudas manifestadas por ellos. Denominamos a esta metodología 'aula invertida adaptativa'. El aula invertida logra un mayor grado de implicación de los alumnos con su aprendizaje, mejoras en la valoración de su percepción sobre la docencia recibida y, sobre todo, mejoras en sus resultados académicos. En este artículo también se sopesan los beneficios y los costes del cambio desde la metodología expositiva tradicional al aula invertida adaptativa y, finalmente, se aportan recomendaciones para la puesta en práctica del aula invertida en el contexto de una enseñanza tradicional de las ciencias sanitarias

Flipped classroom means that students have the first exposure to new information to be learned outside the classroom by mean of electronic documents (texts and videos). Next, class time is devoted to class activities which reinforce the assimilation of that knowledge by applying it to answer questions and solving cases and problems. This learning model reduces the class time devoted to direct instruction and increases the time used in active learning. It transfers to the student the responsibility of initially striving to reach a basic understanding and communicate their difficulties and doubts to the teacher. Thus, the teacher receives information about the difficulties and needs of their students and can adapt the activities they will carry out in the classroom to solve the doubts expressed by their students. We named this teaching methodology as adaptive fl ipped classroom. The fl ipped classroom achieves a greater degree of involvement of students with their learning, improvements in academic results and in their assessment of the teaching received. In this report, the benefits and costs of the change are weighed from the traditional expositive methodology to the adaptive flipped classroom and, finally, recommendations are given for the implementation of the flipped classroom in the context of a traditional teaching of health sciences

Clinical relevance of GSTT1 mismatch in solid organ and hematopoietic stem cell transplantation.

Since 2001, year in which Glutathione S-transferase theta class 1 (GSTT1) gene appeared to be related to the occurrence of de novo immune hepatitis after liver transplantation, this gene with two allelic variants, GSTT1(∗)A (wild type copy) and GSTT1(∗)0 (deletion copy), has emerged as a potent histocompatibility antigen. Namely, a donor-recipient liver graft combination of a GSTT1-negative recipient (homozygous for GSTT1(∗)0) and a GSTT1-positive donor results, very frequently, in the appearance of a severe immune-related graft hepatitis with production of IgG anti-GSTT1 antibodies. In kidney transplantation, GSTT1 donor-recipient mismatch is also associated with production of anti-GSTT1 antibodies and antibody-related rejection episodes with C4d deposition in graft biopsy. The more recent discovery of anti-GSTT1 antibodies in hematopoietic stem cell transplantation, clearly confirms a role of GSTT1 as histocompatibility antigen in this setting. Interestingly, the consequences of GSTT1 mismatch might be either rejection or graft-versus-host disease, depending on the GSTT1 mismatch's sense of direction. The involvement of GSTT1 in immunological allo-recognition is unquestionable although there are still many aspects that remain to be explored.