Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II 'proof-of-concept' iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network.

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal centre B-cell subtype, with unmet medical needs. This study aimed to evaluate the efficacy and toxicity of ibrutinib in DLBCL-PCNSL PATIENTS AND METHODS: This prospective, multicentre, phase II study involved patients with relapse or refractory(R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma. The treatment consisted of ibrutinib (560 mg/day) until disease progression or unacceptable toxicity occurred. The primary outcome was the disease control (DC) rate after two months of treatment (P0 < 10%; P1 > 30%). RESULTS: Fifty-two patients were recruited. Forty-four patients were evaluable for response. After 2 months of treatment, the DC was 70% in evaluable patients and 62% in the intent-to-treat analysis, including 10 complete responses (19%), 17 partial responses (33%) and 5 stable diseases (10%). With a median follow-up of 25.7 months (range, 0.7-30.5), the median progression-free and overall survivals were 4.8 months (95% confidence interval [CI]; 2.8-12.7) and 19.2 months (95% CI; 7.2-NR), respectively. Thirteen patients received ibrutinib for more than 12 months. Two patients experienced pulmonary aspergillosis with a favourable (n = 1) or fatal outcome (n = 1). Ibrutinib was detectable in the cerebrospinal fluid (CSF). The clinical response to ibrutinib seemed independent of the gene mutations in the BCR pathway. CONCLUSION: Ibrutinib showed clinical activity in the brain, the CSF and the intraocular compartment and was tolerated in R/R PCNSL. The addition of ibrutinib to standard methotrexate-base induction chemotherapy will be further evaluated in the first-line treatment. CLINICAL TRIAL NUMBER: NCT02542514.

Allo-SCT for Philadelphia-negative myeloproliferative neoplasms in blast phase: a study from the Societe Française de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC).

Progression of Philadelphia-negative myeloproliferative (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) to acute myeloid leukemia (AML) is an adverse event in the course of the disease. Although allogeneic hematopoietic SCT (allo-SCT) is considered as the only curative therapy, few data exist on the outcome of patients with Philadelphia-negative MPN or MDS/MPN in blast phase who received an allo-SCT. Sixty patients were included in this retrospective study. AML was secondary to an MPN in 43 cases, whereas AML evolved from an MDS/MPN in 17 cases. Patients received allo-SCT in CR or advanced disease in 26 cases and 34 cases, respectively. With a median follow-up of 31 months (range, 25-44), OS and leukemia-free survival (LFS) were, respectively, 18% and 9% at 3 years. CR at transplant was associated with an improved LFS in univariate and multivariate analysis. The 3-year LFS was 18% for patients undergoing allo-SCT in CR versus 3% in advanced disease (P=0.008). Absence of thrombosis and an intermediate or favorable AML karyotype were associated with an improved outcome for patients who received allo-SCT in CR. New strategies are needed to improve the outcome of patients with MPN-MDS/MPN in blast phase.

Escalated lymphodepletion followed by donor lymphocyte infusion can induce a graft-versus-host response without overwhelming toxicity.

Treatment of relapse of hematological malignancies following allogeneic hematopoietic SCT (allo-HSCT) remains very challenging and relies usually on the readministration of chemotherapy combined with donor lymphocyte infusion (DLI). To enhance DLI effectiveness, lymphodepletion (LD) with fludarabine (Flu) and/or CY before the injection of lymphocytes is an attractive modality to modify the immune environment, leading possibly to suppression of regulatory T cells (T(reg)) and exposing the patient to cytokine activation. However, LD before DLI may lead to induction of deleterious GVHD. To avoid inducing overwhelming toxicity, we proceeded by escalating doses of both LD and DLI. Eighteen patients with various non-CML hematological malignancies who relapsed following allo-HSCT were treated with chemotherapy and LD-DLI or LD-DLI upfront. T-cell subpopulation and DC levels as well as cytokine plasma levels (IL-7, IL-15) were measured before and following LD-DLI. Cumulative incidence of acute grade II-IV GVHD was 29.4% similar to that reported in patients receiving DLI without LD. In addition, Flu alone with low dose of DLI was not associated with severe GHVD. CY/Flu at the respective doses of 600 mg/m(2) on day 1 and Flu 25 mg/m(2)/day on days 1-3 did not result in a marked decrease of T(reg) cells, nor in endogenous IL-7 and IL-15 production. However, a peripheral expansion of DCs was observed. These findings suggest that the escalated dose procedure appears safe and prevent overwhelming toxicity. A dose-limiting toxicity has not yet been reached.

[Primary ciliary dyskinesia. Clinical presentation and diagnosis]. / La dyskinésie ciliaire primitive. Etude clinique et diagnostic.

UNLABELLED: Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. OBJECTIVE: We analyzed the main clinical features and test results of PCD in order to evaluate their usefulness for diagnosis. PATIENTS AND METHODS: Retrospective study of 35 cases of PCD evaluated by the same team, with nasal brushings in all cases (special light microscopy) and electron microscopy and/or by isotopic mucociliary clearance study in some. RESULTS: In a cohort of 145 patients with suspected PCD, the diagnosis of PCD was established in 35 cases using a combination of compatible clinical features coupled with the study of nasal brushings: 13 females and 22 males, average age at time of diagnosis 25 years, situs inversus in 12 patients (34%). CONCLUSION: In the absence of consensus in the literature for diagnosis of PCD, we propose the association of the following diagnostic criteria: upper airway and bronchopulmonary infections beginning often early in the life, more inconstantly situs inversus, familial cases of PCD, consanguinity, infertility and permanent and ubiquitous abnormalities of ciliary structure/function. Nasal brushing with ciliary study (special light microscopy) seems to be an easy and reliable diagnostic criterion. Electron microscopy is necessary for proving ultrastructural abnormalities.

Effects of pesticide exposure on time to pregnancy: results of a multicenter study in France and Denmark. ASCLEPIOS Study Group.

The aim of this study was to determine whether there was a relation between male exposure to pesticides and the amount of time needed to conceive (time to pregnancy) for farmers and agricultural workers in France and Denmark. The authors used retrospective studies to compare the time to pregnancy of couples in which the man was exposed to pesticides during the year before the birth of their youngest child with that of couples in which the man was not exposed. In 1995 and 1996, the authors studied 362 French rural workers (142 exposed to pesticides and 220 not exposed), 449 Danish farmers (326 conventional farmers exposed to pesticides and 123 nonexposed organic farmers), and 121 Danish greenhouse workers exposed to pesticides. The fecundability ratio for exposure to pesticides (Cox model, before and after adjustment for confounding factors) did not differ from 1 in any of the three populations. In France, the adjusted fecundability ratio was 1.17 (95% confidence interval (CI) 0.89-1.55) for exposed and nonexposed agricultural workers. In Denmark, it was 1.09 (95% CI 0.82-1.43) for exposed and nonexposed farmers and 0.83 (95% CI 0.69-1.18) for greenhouse workers and nonexposed farmers. Thus, this study found no relation between fertility (time to pregnancy) and male exposure to pesticides.

[Inflammatory proteins of the seminal fluid]. / Les protéines inflammatoires du plasma séminal.

If the clinical asymptomatic infection of the genital tract is a very frequent diagnosis of the hypofertility, it's quite important to know if the infection is evolutive or not. The assessment of inflammatory proteins of the seminal plasma as albumin IgA, gamma-globulins, lysozyme allows to do the differential diagnosis. So, an increase of such proteins is the expression of an evolutive infection.

[Seminal fluid, bacteria, and spermatozoa ]. / Plasma séminal, bactéries et spermatozoïdes.

The antibacterial function of the seminal plasma is subdivided in: inhibition of the bacterial proliferation; inhibition of the bacterial adherence; reduction of the concentration of coiled tail spermatozoas. The reduction of the antibacterial activity of the seminal plasma can explain the high frequency of the genital tract reinfection.

Alterations in the lipid composition of seminal plasma in patients with a chronic infection of the urogenital tract.

The lipid composition of seminal plasma was studied in 15 control subjects and 21 patients consulting for hypofertility and showing a chronic infection of the urogenital tract. In the infected patients a significant reduction in total cholesterol, HDL cholesterol and total phospholipids was noted. Moreover, there is a significant correlation between the rates of total cholesterol and prostatic acid phosphatases and the rates of phospholipids and proteins in seminal plasma. Knowing the role of lipids in the phenomena of maturation and capacitation of spermatozoa, such modifications enable us to understand better the functional anomalies of sperm observed in patients with chronic infection of the urogenital tract and also enable us to explain the effects of the infection on fertility.

On the glandular origin of seminal plasma lipids in man.

The aim of this study is to examine the glandular origin of seminal fluid lipids in man. The triglycerides, the total cholesterol, the non-esterified fatty acid and the total phospholipids were measured in seminal plasma of vasectomized patients (n = 8) and control subjects (n = 15). The same parameters were measured in seminal plasma collected in three fractions from split ejaculates (n = 10). The total cholesterol and the non-esterified fatty acid are principally prostatic in origin. The phospholipids are secreted by the epididymis but also by the prostate. The origin of the triglycerides seems to be very varied.

Antispermatozoal autoantibodies and genital infection.

The aim of this study was to evaluate why high levels of antispermatozoa autoantibodies (SPZAA) in seminal fluid represent a particularly detrimental factor in male fertility. We studied a population of 219 patients consulting us on conjugal sterility associated with an initial asthenospermia. We looked in each case for the presence of SPZAA at the surface of spermatozoa in the seminal fluid and in the serum. We found 31 patients positive for surface SPZAA, 26 of whom had urogenital infections. We also demonstrated statistically significant correlations between high levels of SPZAA in seminal fluid and both a reduction in ejaculate volume and a tendency to oligospermia. A similar correlation was found between the reduction in ejaculate volume and oligospermia. These results suggest that urogenital infection is at present the main cause of SPZAA production, that testicular damage is frequently associated with apparently isolated glandular damage, and above all that a high level of SPZAA in seminal fluid has a more detrimental effect on male fertility due to more severe genital (glandular and testicular) damage.