Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI.

Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort.

Relevance of KIR gene matching in unrelated hematopoietic stem cell transplantations.

The aim of this collaborative study was to evaluate the impact of killer cell immunoglobulin-like receptor (KIR) gene disparities on unrelated hematopoietic stem cell transplantations (HSCT) outcome. To address this question, we have determined the presence or absence of 14 functional KIR genes in HLA-matched (n= 164) or HLA-mismatched (n= 100) donor/recipient pairs and investigated whether KIR gene disparities had an impact on both the occurrence of acute graft-vs-host-disease incidence and overall survival. In a univariate analysis, our preliminary results suggest a detrimental effect of a few KIR gene disparities on patient survival that should be avoided in unrelated HSCT.

Devic disease and thymoma with anti-central nervous system and antithymus antibodies.

A patient with myasthenia gravis and thymoma developed neuromyelitis optica (NMO) and necrotizing myositis 4 months after treatment of the tumor. Antibodies reacting with the CNS and thymic epithelial cells were detected in the serum during the acute phase of NMO, suggesting that the NMO was linked to the thymoma.

Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy.

Subacute sensory neuronopathy with anti-Hu antibodies is the best-characterized paraneoplastic peripheral neuropathy associated with carcinoma. Anti-CV2 antibodies, another group of paraneoplastic antibodies, react with a 66-kd brain protein belonging to the family of Ulip/CRMP proteins. The manifestations associated with anti-CV2 antibodies include cerebellar degeneration, uveitis, and peripheral neuropathy. Some of these patients also have anti-Hu antibodies. We have compared the clinical, electrophysiological, and pathological characteristics of the peripheral neuropathy in 9 patients with anti-CV2 antibodies (3 of whom also had anti-Hu antibodies) and 12 patients with only anti-Hu antibodies. Data for patients with anti-Hu antibodies alone indicated subacute sensory neuronopathy. Patients with anti-CV2 antibodies had a mixed axonal and demyelinating sensory motor neuropathy that was sometimes superimposed on subacute sensory neuronopathy when both anti-CV2 and anti-Hu antibodies were present. Unlike anti-Hu antibodies, anti-CV2 antibodies reacted with peripheral nerve antigens, as shown by their ability to bind to a 66-kd protein in human and rat nerve on Western blot analysis and to immunolabel peripheral nerve axons and sensory neurons on immunohistochemical study.

[Thrombocytopenia due to materno-fetal allo-immunization. Report of a familial case]. / Thrombocytopénie par allo-immunisation materno-foetale. A propos d'une observation familiale.

The diagnosis of fetomaternal alloimmune thrombocytopenia (FMAT) was made in a newborn with thrombocytopenia and intracranial hemorrhage. The first child of the family was severely affected with neurodevelopmental sequelae secondary to intracranial hemorrhage. According to the maternal HPA phenotype, close to 100% of subsequent pregnancies could be expected to be affected as the homozygous state was observed in both platelet systems. Another infant was born after a poorly followed pregnancy and was affected as was his elder brother. Prednisolone was given during another pregnancy. A thrombocytic newborn without intracranial hemorrhage was delivered by prudent cesarian section. The infant received platelet transfusion (maternal platelets). We present case histories of FMAT, and stress the conditions for prenatal diagnosis and management.

Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies.

OBJECTIVE: When to suspect a paraneoplastic disorder is a puzzling problem that has not recently been studied in a large series of patients referred for peripheral neuropathy. METHODS: From 422 consecutive patients with peripheral neuropathy, 26 were analysed who concomitantly had carcinoma but no tumorous infiltration, drug toxicity, or cachexia. Their clinical, pathological, and electrophysiological data were analysed according to the presence of anti-onconeural antibodies, the latency between presentation and cancer diagnosis, and the incidence of carcinoma in the corresponding types of neuropathy of the population of 422 patients. RESULTS: Seven patients (group I) had anti-onconeural antibodies (six anti-Hu, one anti-CV2) and 19 did not (groups IIA and B). In group I, subacute sensory neuropathy (SSN) was the most frequent but other neuropathies including demyelinating neuropathies were present. Patients in group II A had a short latency (mean 7.88 months), and a rapidly and usually severe neuropathy which corresponded in 11/14 to an established inflammatory disorder including neuropathy with encephalomyelitis, mononeuritis multiplex, and acute or chronic inflammatory demyelinating polyneuropathy (CIDP). Patients in group IIB had a long latency (mean 8.4 years) and a very chronic disorder corresponding in four of five to an axonal non-inflammatory polyneuropathy. In this population, the incidence of carcinoma occurring with a short latency was 47% in sensory neuronopathy, 1.7% in Guillain-Barré syndrome, 10% in mononeuritis multiplex and CIDP, and 4.5% in axonal polyneuropathy. CONCLUSIONS: Paraneoplastic neuropathies associated with carcinoma are heterogeneous disorders. Neuropathies occurring with a long latency with tumours probably resulted from a coincidental association. Neuropathies which occurred within a few years of the tumour evolved rapidly and corresponded mostly to inflammatory disorders. As dysimmune neuropathies are probably paraneoplastic in a limited number of cases, patients with these disorders should probably not be investigated systematically for carcinoma in the absence of anti-onconeural antibodies, except when the neuropathy is associated with encephalomyelitis and probably with vasculitis. Questions remain concerning CIDP.

Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors.

BACKGROUND: Antiamphiphysin antibodies react with a 128-kd protein found in synaptic vesicles. They were first described in patients with paraneoplastic stiff-man syndrome and breast cancer, but studies suggest that they can also occur in patients with other tumors and neurological disorders. OBJECTIVE: To determine if antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. PATIENTS AND METHODS: Of 2800 serum samples tested by routine immunohistochemical procedures on sections of paraformaldehyde-fixed rat brain for the detection of autoantibodies associated with paraneoplastic neurological syndromes, 5 were selected because of labeling suggestive of antiamphiphysin antibodies and subsequently confirmed by the results of Western blot analysis using recombinant amphiphysin protein. Controls consisted of 40 patients with various nonparaneoplastic neurological diseases; 101 patients with cancer but without paraneoplastic neurological syndrome; 9 patients with small cell lung cancer, anti-Hu antibodies, and paraneoplastic neurological syndrome; 3 patients with M2-type antimitochondrial antibodies but no neurological disorder; and 30 normal subjects. RESULTS: Of the 5 patients with antiamphiphysin antibodies, patient 1 had sensory neuronopathy, encephalomyelitis, and breast cancer; patient 2 had limbic encephalitis, and small cell lung cancer was detected in the mediastinum after 24 months of follow-up; patient 3 had encephalomyelitis and ovarian carcinoma; and patients 4 and 5 had Lambert-Eaton myasthenic syndrome and small cell lung cancer (patient 4 subsequently developed cerebellar degeneration). None of the 5 had stiffness. Two patients (Nos. 2 and 4) had antimitochondrial antibodies. The two patients (Nos. 4 and 5) with Lambert-Eaton myasthenic syndrome had antibodies directed against the voltage-gated calcium channel, and patient 2 subsequently developed anti-Hu antibodies. In the controls, antiamphiphysin antibodies were detected by Western blot analysis in 3 of 8 patients with anti-Hu antibodies, but in none of the other groups. CONCLUSIONS: These data indicate that antiamphiphysin antibodies are not specific for one type of tumor or one neurological syndrome and can be associated with other neural and nonneural antibodies. The simultaneous association of several antibodies in some patients suggests multimodal autoantibody production.

Paraneoplastic demyelinating neuropathy, subacute sensory neuropathy, and anti-Hu antibodies: clinicopathological study of an autopsy case.

A patient with anti-Hu antibodies, small-cell lung carcinoma, and autopsy-proven subacute sensory neuropathy had early slowing of motor and sensory conduction velocities. In the peripheral nerves, chronic demyelinating and remyelinating lesions with axonal degeneration were associated with an inflammatory reaction consisting of CD8+ T cells and CD68+ macrophages. On immunohistochemical testing, the patient's serum did not react with normal nerve, suggesting that the Hu proteins were not the target of the inflammatory reaction in the nerve.

[Can one graft with a positive cross-match?]. / Peut-on greffer avec un cross-match positif?

Differential cross-matches have been proposed to allow immunised patients to be grafted, whereas the dogma of a global positive cross-match discarded them from renal transplantation. We report our one-center experience considering current T positive cross-match as the only contra-indication to grafting, as well as patients whose sera comprise specific anti-donor antibodies. A comprehensive characterization of the antibodies was achieved by identification of auto-antibodies and specification of IgM and IgG isotype, class I and class II specificities, as well as HLA specificities. The differential cross-match comprised an auto and an allo-cross-match, against T and B lymphocytes. Historical and current sera were analysed either untreated or after DTT-treatment, at +4 degrees C and +22 degrees C. We performed 79 renal transplantations across positive cross-matches, which were 20 historical T positive cross-matches, 26 historical B positive cross-matches and 33 current B positive cross-matches. Results and graft survival were strictly identical as those obtained in the transplantations achieved with negative cross-matches throughout the same period, especially in sensitized patients. Current positive B cell cross-matches due to IgG were associated with an increased risk for early graft failure. We conclude that differential cross-match is a safe strategy permitting immunised patients to be grafted.

Chronic inflammatory demyelinating polyneuropathy associated with carcinoma.

The association of chronic inflammatory demyelinating polyneuropathy (CIDP) and carcinoma has rarely been reported and its relevance is debated. Thirty three consecutive patients with probable or definite CIDP (idiopathic or associated with M protein) were investigated. Three patients with definite CIDP had a concomitant carcinoma. One had an IgM paraprotein. Steroids and intravenous immunoglobulins were effective.

[Anticardiolipin antibodies, cerebral ischemia and adrenal hemorrhage in a newborn infant]. / Anticorps anticardiolipine, ischémie cérébrale et hémorragie surrénalienne chez un nouveau-né.

BACKGROUND: Anticardiolipin antibodies, usually associated with vascular thrombosis in systemic lupus erythematosus, have been recently found associated with strokes in childhood, and acute adrenal hemorrhage in the adult. CASE REPORT: A 3 day-old fullterm newborn suffering from cerebrovascular ischemia and bilateral massive hemorrhage was found to have anticardiolipin antibodies detected during the neonatal period and 7 months later. There was no evidence of pathology in the mother or perinatal asphyxia. However, anticardiolipin antibodies were present in the mother 5 and 15 weeks after delivery. CONCLUSION: Association of anticardiolipin antibodies and vascular thrombosis has never been reported in the neonate. Persistence of such antibodies favor the hypothesis that they are not transmitted by the mother; they could represent an early manifestation of primary antiphospholipid syndrome.

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.

[Sneddon syndrome: 9 cases]. / Syndrome de Sneddon: 9 cas.

We observed a series of 9 patients (1 male, 8 females, mean age 49 years) who had experienced cerebral vascular events with livedo racemosa (Sneddon's syndrome). Vascular dementia occurred in 3 patients and in the 6 others there was a single or several acute cerebral ischaemic events. Angiography of the brain revealed multiple distal arterial occlusions in 5 cases and a moya-moya type collateral network in 2. Positivity for anticardiolipid antibodies fluctuated in 4 cases and there was a lupic syndrome in 2. Systemic lupus erythemosus was diagnosed in the last patient. Mitral valve defects were seen in 5 patients, including 3 due to post-rhematitis sequelae which became symptomatic before the appearance of signs of neurocutaneous involvement. Among these three patients, laboratory tests revealed a lupus band in one, anticardilipid antibodies in another and obliterating fibrous endartiritis of the renal arteries in the third. Sneddon's syndrome presents with heterogeneous signs related to its complex pathophysiology.