Prevalence and Survival of Cancer After Pancreas-Kidney Transplantation.

BACKGROUND: Malignancy is an important cause of mortality in solid organ transplantation. There have been few studies of de novo solid organ malignancy (NSOM) after pancreas-kidney transplantation (PKT). The aim of this study was analyze the prevalence of NSOM and transplant outcomes. METHODS: We studied the development of NSOM after PKT in our center from May 1990 to February 2017. We analyzed demographic characteristics, prevalence of cancer, and survival after cancer diagnosis. We excluded nonmelanoma skin cancer and patients with history of malignancy before transplantation. RESULTS: We included 194 patients who received 206 PKTs (184 simultaneous PKTs and 22 pancreas after kidney transplants) with triple immunosuppressive therapy and basiliximab in more than 95%. The mean age at transplantation was 39 ± 7 years and 74% were male patients. Twelve patients developed malignancies (6.1%). Median time from transplant to NSOM was 6.6 (interquartile range [IQR] 0.2-11.7) years. The malignancies were 2 cecal appendix tumors, 2 hematologic tumors, 2 breast tumors, 1 melanoma, 1 native kidney tumor, 1 brain tumor, 1 bladder tumor, 1 prostate tumor, and 1 leiomyosarcoma. Thirty-five of the 194 patients of the whole cohort died throughout the follow-up, 4 of whom died after NSOM diagnosis (11.4%). Patient and grafts survivals were lower in recipients with tumor compared with recipients without tumor, but the difference was not statistically significant: renal graft survival was 80% vs 90% at 10 years (P = .86); and pancreatic graft survival was 45% vs 70% at 10 years (P = .15), respectively. The mean patient survival time from the diagnosis of cancer was 36.6 (IQR 18-54) months. Patient survival after NSOM diagnosis was 90% at 1 year and 50% at 5 years. CONCLUSION: The prevalence of NSOM in our PKT recipients is low, despite the scarce series of published data for comparison. Also hematologic tumors rate is very low, possibly influenced by age and type of induction.

Oxygen Sensing by Arterial Chemoreceptors Depends on Mitochondrial Complex I Signaling.

O2 sensing is essential for mammalian homeostasis. Peripheral chemoreceptors such as the carotid body (CB) contain cells with O2-sensitive K(+) channels, which are inhibited by hypoxia to trigger fast adaptive cardiorespiratory reflexes. How variations of O2 tension (PO2) are detected and the mechanisms whereby these changes are conveyed to membrane ion channels have remained elusive. We have studied acute O2 sensing in conditional knockout mice lacking mitochondrial complex I (MCI) genes. We inactivated Ndufs2, which encodes a protein that participates in ubiquinone binding. Ndufs2-null mice lose the hyperventilatory response to hypoxia, although they respond to hypercapnia. Ndufs2-deficient CB cells have normal functions and ATP content but are insensitive to changes in PO2. Our data suggest that chemoreceptor cells have a specialized succinate-dependent metabolism that induces an MCI state during hypoxia, characterized by the production of reactive oxygen species and accumulation of reduced pyridine nucleotides, which signal neighboring K(+) channels.

Recurrent membranoproliferative glomerulonephritis after second renal graft treated with plasmapheresis and rituximab.

We present a case of a 45-year-old man who suffered from idiopatic membranoproliferative glomerulonephritis (MPGN) in the native kidney that relapsed after his first and second renal grafts. The patient was diagnosed in 1990 with lobular MPGN type I, receiving his first renal graft in 1996. In 2001, a biopsy showed recurrence of MPGN type I (rMPGN). He underwent a second renal graft in 2008. In January 2010, he experienced increased proteinuria and creatinine. Upon electron microscopy of a renal graft biopsy we diagnosed a new rMPGN. At the time of the biopsy, complement levels were normal, although C3 and C4 decreased further. We administered 12 plasmapheresis (PP) sessions and four doses of rituximab. Due to persistent renal impairment, we performed a new biopsy 3 months later, showing less severity of the acute lessions. He received a new cycle of treatment (PP+rituximab). One year later, his renal function was stable with a creatinine ranging between 2 and 2.5 mg/dL and a protein/creatinine ratio less than 1 mg/mg. We concluded that the treatment stopped the disease progression.

Long-term survival of simultaneous pancreas-kidney transplantation: influence of early posttransplantation complications.

BACKGROUND: Complications that develop in the early posttransplantation period after simultaneous pancreas-kidney transplantation (SPKT) can contribute to poor long-term survival of grafts and patients. PATIENTS AND METHODS: We studied 86 SPKTs that were performed between 2000 and 2010 in our hospital, analyzing all complications in the early posttransplantation period and their impact on long-term survival in patients and grafts. RESULTS: The mean age of the patients was 38.77 ± 7.13 years (79.1% male). Of the 86 SPKT patients, 22.1% were on peritoneal dialysis (PD) before transplantation, 68.6% were on hemodialysis (HD), and 9.3% had not received any substitutive renal therapy. The immunosuppressive regimens consisted of induction with basiliximab followed by tacrolimus, mycophenolate mofetil, and steroid therapy. More than 75% of patients experienced an infection in the early posttransplantation period: bacteremia (37.2%), central catheter infection (7%), wound infection (4.7%), urinary tract (14%) and positive abdominal drain culture (45.3%). Approximately one third (31.4%) of patients underwent a reoperation, primarily due to bleeding (21.95%) or infection (19.51%). One fifth of patients (19.8%) experienced an acute rejection episode. The 3-year survival of the pancreas was lower among PD patients (82%) compared with patients who did not undergo dialysis before SPKT (100%). The 5-year survival rate of both grafts was lower among patients who underwent a reoperation than those who did not: pancreas survival rates, were 70% versus 93%, respectively (P = .015) and kidney graft survival rates were 75% versus 96%, respectively (P = .0017). Five-year patient survival rates were also lower among reoperated patients than those who were not (85% vs 97%, respectively), although the difference was not significant (P = .27). CONCLUSIONS: Complications in the early posttransplantation period after SPKT were frequent, increasing morbidity and inpatient stay. One third of our patients underwent a reoperation, which had a negative impact on graft survival.

Impact of recurrent glomerulonephritis on renal graft survival.

BACKGROUND: Glomerular disease causes graft loss in the intermediate and long term, especially recurrent primary renal disease, negatively impacting graft survival. Thus, it must be considered a differential diagnosis in the evaluation of chronic graft dysfunction. METHODS: The objectives of our study were to compare the impacts of primary glomerular disease on graft survival and association with interstitial fibrosis/tubular atrophy (IFTA) or transplant glomerulopathy. We examined the influence of the relapse of glomerulonephritis (GN) on renal graft survival in a retrospective study of 1057 patients undergoing renal transplantations between March 1981 and October 2009. Among this group, 128 patients were diagnosed with pretransplant GN by renal biopsy. We examined graft survival on recurrence compared with IFTA and transplant glomerulopathy using Kaplan-Meier analysis. RESULTS: We analyzed a cohort of 128 patients who were diagnosed with pretransplant GN by renal biopsy, including 28.9% (37) of whom were males. The mean age was 42.04 ± 13.82 years. The most frequent type was immunoglobulin A GN (IgAGN; 31.3%), followed by membranoproliferative GN (MPGN; 28.9%), rapidly progressive GN (RPGN; 16.4%), focal-segmental GN (FSGN; 13.3%), membranous GN (9.4%), and minimal change GN; (0.8%). Among the 16 cases (12.5%) of GN recurrence; MPGN was associated most frequently (n = 10, 28.9%), followed by FSGN (n = 4, 23.5%), RPGN (n = 1, 4.8%), and IgAGN (n = 1, 2.5%). We noted that 11.8% of subjects to be positive for hepatitis C virus; while 3.9% were hepatitis B virus(HBV)-positive. We observed no differences in hepatic serology between patients who experienced recurrence (HBV 6.3% vs hepatitis C virus [HCV] 18.8%) compared with IFTA (HBV 3.1% vs HCV 9.4%). Fifty-one patients (39.8%) were biopsied after transplantation due to impaired renal function: there were recurrences of GN in 12.5% (n = 16), IFTA in 25% (n = 32), and transplant glomerulopathy in 2.3% (n = 3) cases. The average graft survival in our cohort was 8.36 ± 0.59 years. The median patient survival among those who experienced a recurrence was 8.36 ± 1.79 years; 7.19 ± 1.01 years in IFTA patients; and 3.31 ± 0.91 years in patients with transplant glomerulopathy (log-rank P = .06). Upon multivariate analysis, recurrence of GN was not an independent predictor of renal loss. CONCLUSIONS: MPGN was the type of GN that recurred most frequently followed by FSGN. No differences in graft survival were noted between long-term recurrence of GN and other causes of chronic graft dysfunction. The recurrence of primary disease did not worsen the renal graft prognosis versus other causes of chronic graft dysfunction.

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.

OBJECTIVE: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. METHODS: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. RESULTS: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert-Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. INTERPRETATION: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

Cancer incidence and survival in kidney transplant patients.

Immunosuppression after organ transplantation is associated with a markedly increased risk of nonmelanoma skin cancer (NMSC) and malignancies, including posttransplant lymphoproliferative disorder (PTLD) and solid organ cancer. This study sought to investigate the incidence of malignancies and the clinical characteristics and risk factors of the renal transplant patients with solid organ tumors and NMSC. We included 1017 patients who received a kidney transplant in our hospital from 1979 to 2007. Results were contrasted with a cohort of patients from the same center without malignancies. The mean follow-up of patients in our series was 10 years. The mean age at presentation of the malignancy was 61 +/- 5 years. The malignancy and NMSC incidences were 6% and 5%, respectively. Patients with malignancy had a longer posttransplant time and greater recipient and donor age. In the multivariate analysis, independent risk factors for developing NMSC were: male sex (hazard ratio [HR] 3.1, P = .004); greater patient age (HR 1.09, P < .001), longer posttransplant time (HR 1.2, P = .004) and tacrolimus treatment (HR 4.4, P = .001). Risk factors associated with developing any malignancy were: patient age (HR 1.06, P < .001), number of grafts (HR 3.2, P = .019), tacrolimus treatment (HR 2.5, P = .035), and time posttransplantation (HR 1.2, P = .011). The mean times to development of an NMSC, solid organ malignancy, on PTLD were 7.5, 6.1, or 3.9 years, respectively. The mean survival time from the diagnosis of any malignancy was 9.6 months (95% confidence interval, 0.12-30) for solid organ malignancies and 1 month (95% confidence interval, 0.24-1.87) for PTLD.

Whipple's disease: report of cases diagnosed in our hospital.

We present here a retrospective study of nine patients diagnosed with Whipple's disease (WD) in our hospital. This report em-phasises clinical presentation, diagnostic methods, treatment and response to treatment. In our study, the disease was more frequent in males, and the most frequent presenting symptoms were arthralgia, diarrhoea and weight loss. Since the intestine is almost always affected, oral endoscopy is a useful technique for the diagnosis of WD because it shows the typical miliary pattern and aids in obtaining biopsies to show the presence of PAS-positive macrophages (a suggestive though not diagnostic finding), to show bacilli using electron microscopy, or to detect genetic material using PCR. Our patients responded well to treatment. The most frequently used antibiotic was oral trimethoprim-sulfamethoxazole for at least one year. Treatment with penicillin G and IM streptomycin for 14 days was reserved for severe cases or cases that responded poorly to treatment.

Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): coexistence with Ulip2/CRMP2 in Sema3a- sensitive oligodendrocytes.

The Unc-33-like phosphoprotein/collapsin response mediator protein (Ulip/CRMP) family consists of four homologous phosphoproteins considered crucial for brain development. Autoantibodies produced against member(s) of this family by patients with paraneoplastic neurological diseases have made it possible to clone a fifth human Ulip/CRMP and characterize its cellular and anatomical distribution in developing brain. This protein, referred to as Ulip6/CRMP5, is highly expressed during rat brain development in postmitotic neural precursors and in the fasciculi of fibers, suggesting its involvement in neuronal migration/differentiation and axonal growth. In the adult, Ulip6/CRMP5 is still expressed in some neurons, namely in areas that retain neurogenesis and in oligodendrocytes in the midbrain, hindbrain, and spinal cord. Ulip2/CRMP2 and Ulip6/CRMP5 are coexpressed in postmitotic neural precursors at certain times during development and in oligodendrocytes in the adult. Because Ulip2/CRMP2 has been reported to mediate semaphorin-3A (Sema3A) signal in developing neurons, in studies to understand the function of Ulip6/CRMP5 and Ulip2/CRMP2 in the adult, purified adult rat brain oligodendrocytes were cultured in a Sema3A-conditioned medium. Oligodendrocytes were found to have Sema3A binding sites and to express neuropilin-1, the major Sema3A receptor component. In the presence of Sema3A, these oligodendrocytes displayed a dramatic reduction in process extension, which was reversed by removal of Sema3A and prevented by anti-neuropilin-1, anti-Ulip6/CRMP5, anti-Ulip2/CRMP2 antibodies, or VEGF-165, another neuropilin-1 ligand. These results indicate the existence in the adult brain of a Sema3A signaling pathway that modulates oligodendrocyte process extension mediated by neuropilin-1, Ulip6/CRMP5, and Ulip2/CRMP2, and they open new fields of investigation of neuron/oligodendrocyte interactions in the normal and pathological brain.

Ulip/CRMP proteins are recognized by autoantibodies in paraneoplastic neurological syndromes.

Anti-CV2 autoantibodies have recently been discovered in patients with paraneoplastic neurological diseases (PND). These disorders are associated with neuronal degeneration, mediated by autoimmune processes, in patients with systemic cancer. Anti-CV2 autoantibodies recognize a brain protein of 66 kDa developmentally regulated and specifically expressed by a subpopulation of oligodendrocytes in the adult brain. Here, we demonstrate that anti-CV2 sera recognize several post-translationally modified forms of Ulip4/CRMP3, a member of a protein family related to the axonal guidance and homologous to the Unc-33 gene product in Caenorhabditis elegans. The sequence of the human Ulip4/CRMP3 was determined and the gene localized to chromosome 10q25.2-q26, a region mutated in glioblastomas and containing tumour suppressor genes. The identification of the Ulip/CRMP proteins as recognized by anti-CV2 sera should provide new insights into the role of Ulip/CRMPs in oligodendrocytes and into pathophysiology of PND.

POP66, a paraneoplastic encephalomyelitis-related antigen, is a marker of adult oligodendrocytes.

Paraneoplastic neurological diseases are disorders of the central nervous system, associated with neuronal degeneration in patients with systemic cancer, but are not a direct result of the tumor mass or metastasis. The biological diagnosis of these syndromes is based mainly on the detection, in the patient's serum and cerebrospinal fluid, of autoantibodies (anti-Hu, anti-Yo, for example), suggesting an autoimmune origin for these disorders. Recently, we described novel autoantibodies (anti-CV2 autoantibodies) associated with paraneoplastic neurological disease, which recognize a 66 kDa brain protein. We named this antigen POP66, for Paraneoplastic Oligodendrocyte Protein of 66 kDa molecular weight, as in the adult human, rat, and mouse brain, it is specifically expressed by a subpopulation of oligodendrocytes. This cell type specificity was surprising given the fact that the cell loss in the brains of patients with anti-CV2 autoantibodies is neuronal. POP66-expressing oligodendrocytes are distributed along the longitudinal axis of the brain according to an increasing rostro-caudal gradient, with no positive oligodendrocytes being found in the forebrain and the greatest number found in the spinal cord. In addition, in transverse sections of the spinal cord, the distribution of POP66-positive oligodendrocytes follows an increasing dorsal-to-ventral gradient, which may be related to different oligodendrocyte precursor pools. In addition, the neuronal loss without demyelination seen in the brains of patients with anti-CV2 autoantibodies, together with the exclusive oligodendroglial expression of POP66 in the adult brain, raises the question of the possible involvement of POP66 in neuron survival via neuron/oligodendrocyte interactions.

Immunohistochemical, ultrastructural, biochemical and in vitro studies of a pineocytoma.

Using both tumor specimen and cultured tumor cells, we have studied the differentiation of a pineocytoma by light and electron microscopy (EM) and immunohistochemical demonstration of glial, neuronal and neuroendocrine markers. Only interstitial cells were labeled with anti-glial fibrillary acidic protein and anti-S100 protein antibodies. Synaptophysin, neurofilaments and tau labeling was found in cells forming the pineocytomatous rosettes. Some cells also bound the anti-tryptophan hydroxylase antibody (TPOH), but no staining was seen after application of anti-chromogranin A or S-antigen antibodies. EM provided evidence for neurosensory differentiation demonstrating the presence of vesicle-crowned rodlets, cilia (9+0) and fibrous filaments. In culture, tumor cells proliferated slowly and showed positive immunolabeling for vimentin and TPOH. Expression of mRNA coding for TPOH, serotonin N-acetyltransferase, hydroxyindole-O-methyl-transferase and c-myc was found in the tumor using reverse transcriptase-polymerase chain reaction. These results demonstrate neuronal differentiation of this pineocytoma and suggest that the neoplastic pineal cells are capable of synthesizing serotonin and melatonin.

Antibodies to a subpopulation of glial cells and a 66 kDa developmental protein in patients with paraneoplastic neurological syndromes.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are inflammatory disorders that probably depend on autoimmune processes. Several autoantibodies (anti-Hu, anti-Ri, and anti-Yo) have been characterised in PNS and proved to be helpful in the diagnosis. However, these do not account for all the cases and the possibility that other types of antibodies could be detected was investigated. METHODS AND RESULTS: Of 45 patients with PNS whose serum was probed on paraformaldehyde fixed rat brain sections, 11 patients were identified whose serum samples recognised a cytoplasmic antigen in a subpopulation of glial cells in the white matter of adult rat brainstem, cerebellum, and spinal cord that were double labelled with a monoclonal antibody specific for oligodendrocytes. All serum samples reacted with a 66 kDa protein of newborn rat brain on western blot analysis. These antibodies were designated as anti-CV2 antibodies. Only one of the 11 patients had one of the well characterised autoantibodies (anti-Hu). Five patients had cerebellar degeneration, three had limbic encephalitis, two had encephalomyelitis, and one had Lambert-Eaton myasthenic syndrome. The tumours were small cell lung cancer or undifferentiated mediastinal cancer in seven patients, uterine sarcoma in two, and malignant thymoma in two. Among 1061 control serum samples, only two patients had anti-CV2 antibodies. One had small cell lung cancer and the other malignant thymoma. CONCLUSIONS: The detection of anti-CV2 antibodies in patients with neurological disorders should be considered as an indication of the presence of an occult cancer.

Limbic encephalitis and immunological perturbations in two patients with thymoma.

Two patients with clinical and radiological evidence of limbic encephalitis associated with an invasive lymphoepithelial thymoma who improved after thymectomy and radiotherapy are reported. The serum of both patients and the CSF of one of them contained different types of antibodies that immunoreacted with human and rat brain and newborn rat thymus. After treatment of the tumour, the antibody titres decreased. Similar antibodies were not found in various controls. Two out of 16 patients with thymoma, myasthenia gravis, and no CNS involvement had low titres of antibodies reacting with the brain. It is suggested that in some patients with thymoma, an autoimmune reaction involving antigens common to the brain and thymus is possibly misdirected against the CNS.

High resolution two-dimensional polyacrylamide gel electrophoresis using Immobilines. Application to the study of brain proteins.

Cytoplasmic soluble proteins of unknown origin but which could be associated with the development and maturation of the central nervous system are recognized by antibodies found in serum of patients with a paraneoplastic neurological syndrome. The associated antigens are of great interest in understanding these neurological pathologies. To study these antigens we describe and criticize a two dimensional polyacrylamide gel electrophoresis (2D-PAGE), using immobilized pH gradient (IPG) in first dimension. Proteins from brain complex mixtures were separated by this technique in order to identify and characterize (molecular weight, p-isoelectric point, sequencing) a protein of interest. Results prove the high reproducibility and the good resolution of the technique. Without applying enrichment method prior to 2D-PAGE, any proteins are not sequenceable after transblotting to PVDF (polyvinylidene difluoride) membrane and Coomassie blue staining. In these cases the meaning to reach the wanted aim, i.e. sequencing, was discussed.

Posterior uveitis, paraneoplastic encephalomyelitis and auto-antibodies reacting with developmental protein of brain and retina.

We report a 68-year-old woman who presented with posterior uveitis, cerebellar ataxia, dysautonomia, peripheral neuropathy and undifferentiated carcinoma. Autopsy showed slight brain inflammatory changes and severe Purkinje cell degeneration. By immunocytochemistry, the serum and CSF contained antibodies that reacted with the cytoplasm of cells in the brain and retina of rat. Some neurons and glial cells were stained. However, the most labelled cells were immature cells of the subventricular layers of the dentate gyrus, olfactory bulb and lateral ventricles. In rat retina, the plexiform layers and cells of the inner granular layer were stained. E15 rat embryo showed diffuse staining of post-mitotic cells and process in the central and peripheral nervous system. With the patient's IgG, various bands of 45, 60, 70 and 135 kDa apparent molecular weight were demonstrated on immunoblots of adult human, adult and E15 embryonic rat brain and rat and bovine retina. Eluates of tissue bound IgG labelled the same bands.

[Histogenesis of subependymal glioma in Bourneville's tuberous sclerosis]. / Contribution à l'étude de l'histogenèse des gliomes sous-épendymaires de la sclérose tubéreuse de Bourneville.

The phenotypic characteristics of 7 subependymal giant cell astrocytomas (GSECG) (6 of these being associated with tuberous sclerosis) are studied using morphological and immunohistochemical methods with antiserums against vimentine, glial fibrillary acid protein (GFA), S100 protein, and neurofilaments. The glycoproteic secretion of the tumor cells was also analyzed after exposure to Concanavalin A (CON A) by a direct fluorescent method. Our results suggest that some GSECG originate from specialized ependyma (circum-ventricular organs). They have the same location (foramen of Monro), present some common ultrastructural features (cytoplasm with lumen containing cilia), are positive with certain immunohistochemical markers (staining with S100 protein in 4 cases, with vimentin in 3 cases) and show a strong glycoproteic secretion (positive with CON A). Therefore, some GSECG might be considered hamartomas of specialized ependyma, with a reduced evolutivity potential.