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.

[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.

Cell death and optic fiber penetration in the optic stalk of the chick.

The role of dying cells in the optic stalk in relation to retinal fiber migration was investigated in the chick embryo. Cell death was analysed at various stages of development by counting pycnotic nuclei and also by the Gomori acid phosphatase reaction, while nerve fibers were visualised by the Bodian method. A wave of cell death, beginning in the neural retina at stage 18 and advancing with time through the stalk towards the diencephalon, occurred simultaneously or slightly prior to differentiation and migration of ganglion cell axons. Cell death stopped and gliogenesis occurred in the stalk after penetration by retinal fibers. Cell death occurred in the stalk even when fiber penetration was prevented by optic cup ablation. In this case, necrosis ensued until almost complete degeneration of the stalk, usually within three days after the operation, and gliogenesis did not occur. As the stalk degenerated, its cells became heavily pigmented. These observations suggest that the onset of cell death in the optic stalk is determined prior to and independently of retinal fiber penetration. On the other hand, cessation of cell death and subsequent gliogenesis occur only in the presence of ingrowing optic fibers.

Experimental approach to the pathogenesis of the anomalies of amniotic disease.

By intra-adnexal injection of glucose in the rabbit embryo, we were able to stimulate all the anomalies associated with "Amniotic Disease". Since we were even able to obtain amniotic bands, this study provides an excellent experimental model of this disease. Resulting lesions occur early in development, corresponding to the first trimester of human gestation. All of the anomalies can ultimately be explained by the destruction of the most superficial cells: epiblastic cells of the embryo and the amnion, subjacent mesenchyme, and endothelial cells. The subsequent lack of interaction between these cells and the importance of the anatomical localizations of resulting hematomas can lead to the pathogenetic approach to this disease. In light of the present study, the disease appears to be caused by an external factor within the amniotic fluid. The exact nature of the destructive agent(s) remains a mystery in man.

[Morphologic acrosomal changes in a man exposed to heat]. / Modifications morphologiques de l'acrosome chez un homme exposé à la chaleur.

In view of a case of primary sterility with heat professional exposure and abuse of warm baths, we have studied the spermatozoa ultrastructural morphology. Same type of acrosomal malformations were observed in spermatozoa following experimental scrotal heating. These abnormalities appears to produce sterility in this case.

[Relation between spermatozoids and reducing sugars (glucose and fructose) in human seminal fluid]. / Etude des relations entre spermatozoïdes et sucres réducteurs (glucose et fructose) dans le liquide séminal humain.

The prostatic fraction of seminal plasma contains components that are involved in the process of transforming fructose into glucose. If a positive correlation can be found between the slope of the decrease of fructose (estimated to be between 30 minutes and 5 hours) and the sperm count, with at the same time the maintenance of a relatively constant glucose level, then we have been able to demonstrate that glucose is more efficient than fructose to keep spermatozoa mobile. The enzyme process involved in transforming fructose into glucose may thus act to maintain definite glyspermia with a maximum value of 1.8 g/l. Aspermia in some circumstances then can be related to the absence or poor function of the transformation process and thus with the absence or decrease in prostatic secretion.

[The interpretation of athenospermia as a function of the parameters in a spermogram (author's transl)]. / Interprétation des asthénospermies en fonction des paramètres du spermogramme.

The study of spermiograms, conducted on patients consulting for sterility, showed relationships between motility and other variable factors of the sperm. Testicular and prostatic factors are involved in immediate asthenospermia, whereas factors are involved in secondary asthenospermia.

[Lipid composition of peritoneal and follicular ovulatory fluid from patients participating in an in vitro fertilization protocol]. / Etude de la composition lipidique du liquide péritonéal et folliculaire ovulatoire chez des patientes incluses dans un protocole de fécondation in vitro.

The aim of this work is to study and compare lipid composition of peritoneal and ovulatory follicular fluid of women. The studied patients are involved in a FIV protocol. We have studied 53 peritoneal fluids and 90 follicular fluids from 33 patients. On each sample the following parameters are estimated: cholesterol, triglycerides, phospholipids, non esterified fatty acids (A.G.N.E.), HDL and LDL cholesterol, HDL and LDL phospholipids. Lipid composition of follicular and peritoneal fluids differ from these of blood plasma. The two mediums studies show no differences with regard to their lipid composition. In both cholesterol is only found as HDL cholesterol. Cholesterol arising from spermatozoa membranes may be implicated in capacitation phenomenon. HDL Cholesterol, the only form found in the studied mediums, may act as a cholesterol acceptor. Theses two points partially explain the fact that follicular and peritoneal fluids are good mediums for capacitation and survival of spermatozoa.

[Comparative study of the lipid composition of seminal fluid and ovulatory peritoneal fluid in humans]. / Etude comparative de la composition lipidique du liquide séminal et du liquide péritonéal ovulatoire dans l'espèce humaine.

Sperm capacitation is accompanied by changes in the lipid composition of the sperm membrane. The purpose of this study is to compare the lipid composition of the semen with that of peritoneal fluid. These two media have opposite effects on sperm capacitation. Cholesterol, triglyceride and phospholipids were measured in seminal fluid (15 specimens) obtained by sperm centrifugation immediately after liquefaction and in the peritoneal fluid at ovulation (15 specimens) obtained through transvaginal puncture. The lipid composition of these two media is different from that of serum. Seminal fluid is characterized by a high level of phospholipids, 14.79 +/- 3.67 g/l as against 0.53 +/- 0.12 g/l in peritoneal fluid. The level of cholesterol is identical in the two media. The cholesterol/phospholipid ratio is therefore lower in seminal fluid than in peritoneal fluid (0.022/0.79). Lecithins are raised in peritoneal fluid as are sphingomyelins and the phosphatidylethanolamines, which are the most important phospholipids in seminal fluid. It therefore can be postulated that the cholesterol/phospholipid ratio, which is low in seminal fluid, and its richness in sphingomyelin brings about stabilization of the membrane cover which corresponds to a decapacitated state, whereas the cholesterol/phospholipid ratio, which is higher in peritoneal fluid, makes for greater fluidity, and this corresponds to the state of capacitation. These preliminary results obtained from human material do not in any way contradict those obtained from animal studies.

[Effects of an extract of the bark of Pygeum africanum (V.1326) on prostatic secretions in the rat and in man]. / Effets d'un extrait d'écorce de Pygeum africanum (V.1326) sur les sécrétions prostatiques du rat et de l'homme.

Treatment with V.1326 in the rat induces an increase in prostatic secretion. In men with insufficient prostatic secretion, this treatment also induces an increased secretion.

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.