IntroductionExtranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare and severe malignancy. It is more frequent in Asia and Central/South America than in Europe and North America. It is thought to arise from NK cells or, occasionally, from a subset of ␥␦ or ␣␤ cytotoxic T cells, and shows a tight association with Epstein-Barr virus (EBV). It is classically characterized by a cytoplasmic CD3 ⑀ phenotype, with no surface CD3 or T-cell receptor expression, no T-cell receptor gene rearrangements, an activated cytotoxic profile with perforin, granzyme B, and TIA-1 expression, and frequent CD56 expression. [1][2][3] Extranodal NK/T-cell lymphoma is usually diagnosed in adults, with a median age in the fifth decade. The nasal cavity or other parts of the upper aerodigestive tract are primarily involved, but some cases occur at extranasal sites. The term "nasal-type" is used in the World Health Organization classification to describe forms arising both in the nasal cavity and in extranasal sites. 3,4 Because disease incidence is rare even in prevalent areas, there has been no randomized controlled trial, and most treatment protocols are consensus-guided. 5 Localized NK/T-cell lymphomas often respond to radiotherapy 6,7 or to concurrent radiation and chemotherapy, 8 but relapse is common. Chemotherapy protocols used for lymphomas of other histologic subtypes are poorly effective, at least in part, because of frequent multidrug resistance gene expression by tumor cells. 9 Patients with disseminated or relapsing disease have a very poor outcome, 4,10,11 and there is no standard management for relapsed or refractory disease. We and others, in small retrospective studies, 12-16 have observed very good response and survival rates in patients treated with L-asparaginase, a drug with an original antitumoral mechanism not affected by MDR. NK cells lack asparagine synthase activity, and asparaginase has been shown to induce apoptosis of tumoral NK cells in vitro. 17 These findings provided the rationale for this open-label phase 2 study of an L-asparaginase-containing regimen for patients with relapsed and/or refractory extranodal NK/T-cell lymphoma. We chose to combine L-asparaginase with methotrexate, a drug insensitive to the multidrug resistance pathway, because of its well-known synergistic effect with asparaginase in acute lymphoblastic leukemia and its ability to prevent central nervous system involvement. Dexamethasone was added because T-cell lymphomas are usually sensitive to corticosteroids and dexamethasone For personal use only. on May 12, 2018. by guest www.bloodjournal.org From seems to be associated with a lower risk of thrombosis when given with L-asparaginase. 18 Methods PatientsThe patients were at least 18 years of age, with relapsed or refractory extranodal NK/T-cell lymphoma. Eligibility criteria included biopsyproven diagnosis of NK/T-cell lymphoma, nasal-type, irrespective of the anatomic site. Malignant cells in all cases had a CD3⑀ ϩ , CD20 Ϫ phenotype, a cytotoxic profile, and evidence of E...

The data collected in ten patients with mRCC indicate that repeated infusions of Innacell gammadelta at different dose levels (up to 8 x 10(9) total cells), either alone or with IL-2 is well tolerated. These results are in favor of the therapeutic value of cell therapy with Innacell gammadelta for the treatment of cancers.

Alpha 1-antitrypsin (alpha 1-AT) is the major inhibitor of proteinase 3 (PR3), the main target antigen of antineutrophil cytoplasm antibodies (ANCA) in Wegener's granulomatosis. alpha 1-AT is encoded by a polymorphic gene, with over 75 alleles, defining severely, medium and non-deficient protease inhibitor (PI) phenotypes. We describe the association of severely and medium deficient PI phenotypes with anti-PR3 positive systemic vasculitis, and postulate a pathogenetic role for alpha 1-AT deficiency and the occurrence of ANCA, with specificity for PR3 in a subgroup of patients with Wegener's granulomatosis.

IPH1101 in combination with SC low-dose IL-2 is safe, well tolerated and induces a potent gammadelta T lymphocyte expansion in patients. Its clinical activity will be evaluated in phase II clinical trials.

BackgroundDendritic cells (DC) and regulatory cells (Treg) play pivotal roles in controlling both normal and autoimmune adaptive immune responses. DC are the main antigen-presenting cells to T cells, and they also control Treg functions. In this study, we examined the frequency and phenotype of DC subsets, and the frequency and function of Treg from patients with ANCA-associated vasculitis (AAV).Methodology/Principal FindingsBlood samples from 19 untreated patients with AAV during flares and before any immunosuppressive treatment were analyzed, along with 15 AAV patients in remission and 18 age-matched healthy controls. DC and Treg numbers, and phenotypes were assessed by flow cytometry, and in vitro suppressive function of Treg was determined by co-culture assay. When compared to healthy volunteers, absolute numbers of conventional and plasmacytoid DC were decreased in AAV patients. During the acute phase this decrease was significantly more pronounced and was associated with an increased DC expression of CD62L. Absolute numbers of Treg (CD4+CD25highCD127low/− Tcells) were moderately decreased in patients. FOXP3 and CD39 were expressed at similar levels on Treg from patients as compared to controls. The suppressive function of Treg from AAV patients was dramatically decreased as compared to controls, and this defect was more pronounced during flares than remission. This Treg functional deficiency occurred in the absence of obvious Th17 deviation.ConclusionIn conclusion, these data show that AAV flares are associated with both a decrease number and altered phenotype of circulating DC and point to a role for Treg functional deficiency in the pathogenesis of AAV.

The severity of anti-PL12 ASS varied because of the constant pulmonary involvement. ILD was the predominant prognosis factor, which was notable in cases associated with pulmonary hypertension.

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International audienceSevere chronic primary neutropenia (CPN) is a rare entity, and long-term outcome and risk factors for infections in severe CPN adults have not been described to date. We report the characteristics and outcomes of 108 severe adult CPN patients enrolled in a multi-institutional observational study. Severe CPN adults were mostly female (78%), and median age at diagnosis was 28.3 years. Diagnosis was fortuitous in 62% of cases. The median absolute neutrophil count (ANC) at diagnosis was 0.4 × 109/L, and median ANC without granulocyte colony-stimulating factor (G-CSF) during follow-up was 0.5 × 109/L. Twenty-three of 66 (34.8%) evaluable patients had neutrophil autoantibodies, and 6 of 47 (12.8%) a T-cell clone. The presence of neutrophil autoantibodies or T-cell clone was not associated with any specific clinical or biological characteristics. No death or hematologic malignancies occurred, and 44 severe bacterial infections were reported in 27 patients with a median follow-up of 8.3 years. Fifty patients received G-CSF either sporadically (n = 24) or continuously (n = 26) and responded (96%). Nineteen patients received immunosuppressive therapies: overall response (OR) was 41%, and median duration of response was 3 months. At diagnosis, the only predictive factor for the occurrence of severe bacterial infections was an ANC count below 0.2 × 109/L (OR, 0.76). Severe CPN in adults is characterized by a female predominance and a benign outcome with a low rate of severe bacterial infections and no secondary malignancies. G-CSF is efficient and well tolerated but is not required in a majority of patient