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.

Lipopolysaccharide suppresses IgE-mast cell-mediated reactions.

BACKGROUND: Clinical and experimental analyses have identified a central role for IgE/FcεRI/mast cells in promoting IgE-mediated anaphylaxis. Recent data from human studies suggest that bacterial infections can alter susceptibility to anaphylaxis. OBJECTIVE: We examined the effect of LPS exposure on the induction of IgE-mast cell (MC) mediated reactions in mice. METHODS: C57BL/6 WT, tlr4-/- and IL10-/- mice were exposed to LPS, and serum cytokines (TNF and IL-10) were measured. Mice were subsequently treated with anti-IgE, and the symptoms of passive IgE-mediated anaphylaxis, MC activation, Ca2+ -mobilization and the expression of FcεRI on peritoneal MCs were quantitated. RESULTS: We show that LPS exposure of C57BL/6 WT mice constraints IgE-MC-mediated reactions. LPS-induced suppression of IgE-MC-mediated responses was TLR-4-dependent and associated with increased systemic IL-10 levels, decreased surface expression of FcεRI on MCs and loss of sensitivity to IgE activation. Notably, LPS-induced desensitization of MCs was short term with MC sensitivity to IgE reconstituted within 48 hours, which was associated with recapitulation of FcεRI expression on the MCs. Mechanistic analyses revealed a requirement for IL-10 in LPS-mediated decrease in MC FcεRI surface expression. CONCLUSIONS & CLINICAL RELEVANCE: Collectively, these studies suggest that LPS-induced IL-10 promotes the down-regulation of MC surface FcεRI expression and leads to desensitization of mice to IgE-mediated reactions. These studies indicate that targeting of the LPS-TLR-4-IL-10 pathway may be used as a therapeutic approach to prevent adverse IgE-mediated reactions.

Arthrocentesis followed by intra-articular autologous blood injection for the treatment of recurrent temporomandibular joint dislocation.

Temporomandibular joint (TMJ) dislocation is an excessive forward movement of the condyle beyond the articular eminence with complete separation of the articular surfaces and fixation in that position. This study was conducted to assess autologous blood injection to the TMJ for the treatment of chronic recurrent TMJ dislocation. Fifteen patients with bilateral chronic recurrent condylar dislocation were included in the study. Bilateral TMJ arthrocentesis was performed on each patient, followed by the injection of 2ml of autologous blood into the superior joint compartment and 1ml onto the outer surface of the joint capsule. Preoperative and postoperative assessment included a thorough history and physical examination to determine the maximal mouth opening, presence of pain and sounds, frequency of luxation, recurrence rate, and presence of facial nerve paralysis. Eighty percent of the subjects (12 patients) had a successful outcome with no further episodes of dislocation and required no further treatment at their 1-year follow-up, whereas three patients had recurrent dislocation as early as 2 weeks after treatment. Autologous blood injection is a safe, simple, and cost-effective treatment for chronic recurrent TMJ dislocation.

Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS.

BACKGROUND: There is no consensual first-line chemotherapy for elderly patients with mantle cell lymphoma (MCL). The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang) group previously developed the (R)VAD+C regimen (rituximab, vincristine, doxorubicin, dexamethasone and chlorambucil), which appeared as efficient as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone) while less toxic. Based on this protocol, we now added bortezomib (RiPAD+C: rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil) given its efficacy in relapsed/refractory MCL patients. The goal of the current phase II trial was to evaluate the feasibility and efficacy of the RiPAD+C regimen as frontline therapy for elderly patients with MCL. PATIENTS AND METHODS: Patients between 65 and 80 years of age with newly diagnosed MCL received up to six cycles of RiPAD+C. RESULTS: Thirty-nine patients were enrolled. Median age was 72 years (65-80). After four cycles of RiPAD+C, the overall response rate was 79%, including 51% complete responses (CRs). After six cycles, CR rate increased up to 59%. After a 27-month follow-up, median progression-free survival (PFS) is 26 months and median overall survival has not been reached. Four patients (10%) discontinued the treatment because of a severe toxicity and seven patients (18%) experienced grade 3 neurotoxicity. CONCLUSION: The bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.

The role of angiogenesis in a murine tibial model of distraction osteogenesis.

Distraction osteogenesis (DO) is one of the most dramatic in vivo applications of mechanical stimulation as a means of inducing bone regeneration. A simple and reproducible murine model of tibia distraction osteogenesis was developed using a monolateral fixator. Bone formation was assessed histologically over a 35-day time course. The steady state expression of a broad family of angiogenesis-associated genes was assessed by microarray hybridization analyses over the same time course, while the immediate gene response that was induced during each cycle of distraction was assessed at 30 min and 8 h after the first and last rounds of activation of the fixator. Distraction osteogenesis promoted new bone formation primarily through an intramembranous process with maximal osteogenesis during the active distraction period. Histological analysis also showed that dense cortical bone continued to be formed, during the consolidation phase, for 2 weeks after distraction ended. The analysis of steady state mRNA expression levels over the time course of DO showed that VEGF-A and neuropilin, an alternate receptor for VEGF-A, both angiopoietin (Ang) 1 and 2 factors, and the Ang receptor Tie2 were the critical angiogenic factors during DO. A key transcriptional regulator of many of the angiogenic factors, hypoxia-induced factor1alpha (Hif-1a), the FGF binding protein pleiotropin/OSF1, and multiple MMP(s), were also induced during the active distraction period. Examination of the expression of angiogenic factors that were induced after each cycle of activation, demonstrated that Hif-1a, Nrp1, and VEGF-A were all cyclically induced after each increment of distraction. These results suggest that these factors are early mediators that are produced by distraction and contribute toward the processes that promote bone formation. These experiments represent the first step in defining the molecular mechanisms that regulate skeletal regeneration and the functional relationship between angiogenesis and osteogenesis during distraction osteogenesis.

Trypanothione as a target in the design of antitrypanosomal and antileishmanial agents.

Trypanothione is the key molecule in the defence mechanism of Trypanosoma and Leishmania against oxidative stress. The uniqueness of trypanothione makes the metabolism of this molecule an attractive target in antitrypanosomal and antileishmanial drug design. It became clear that this antioxidant cascade can be considered as the "Achilles heel" of these parasites. The following targets and their respective inhibitors will be discussed: biosynthesis of trypanothione with glutathionylspermidine synthetase and trypanothione synthetase; biosynthesis of glutathione with gamma-glutamylcysteine synthetase; biosynthesis of spermidine with ornithine decarboxylase; trypanothione hydroperoxide metabolism with tryparedoxine peroxidase, tryparedoxine and trypanothione reductase.

Abnormal collagen fibrils in nanophthalmos: a clinical and histologic study.

PURPOSE: To report the successful treatment of choroidal detachment in a patient with nanophthalmos and to report histopathologic findings in this patient's sclera. METHODS: Choroidal detachment, secondary angle closure, and nanophthalmos were diagnosed using biomicroscopy, indirect ophthalmoscopy, and echography. Full-thickness sclerectomies in four quadrants were made on the right eye. Sclerae from these sclerectomies were studied ultrastructurally. RESULTS: Best-corrected visual acuity improved to RE, 20/60 from 20/100 preoperatively; the anterior chamber deepened, and the choroidal detachment resolved. Histopathologic studies of each of the three scleral layers disclosed abnormal collagen fibrils that were frayed, split, and contained lightly stained cores. CONCLUSION: New findings include the identification of collagen with lightly stained centers and identification of differences in collagen morphology in different areas of the sclera in a nanophthalmic eye.

[Percutaneous cholecystostomy. A study of 30 patients]. / Cholécystostomie percutanée. Une étude chez 30 malades.

OBJECTIVE AND METHODS: The treatment of acute cholecystitis or angiocholitis is often difficult in elderly or very ill patients. The aim of this retrospective study was to assess the efficacy and the results of ultrasound guided percutaneous cholecystostomy in patients with acute cholecystitis or biliary tract obstruction and anesthetic or surgical contraindications. RESULTS: Thirty patients (25-93 years, 16 men and 14 women) were included in this study. Ultrasound guided percutaneous cholecystostomy was successful on the septic syndrome in 27 patients; endoscopic sphincterotomy was performed in 6 patients after clinical improvement. A failure of the procedure on sepsis was observed in 3 patients: cholecystectomy was performed after cardiac improvement in one patient, and 2 patients died. Two other patients died of extradigestive diseases. No serious complication related to cholecystostomy was observed. CONCLUSION: Ultrasound guided percutaneous cholecystostomy is a safe and simple procedure. It can be done at bedside and has low morbidity and mortality. It can be considered as a definitive treatment, or a temporary one with secondary surgical or endoscopic management.

Culture of human retinal pigment epithelial cells from peripheral scleral flap biopsies.

PURPOSE: We studied various methods for harvesting retinal pigment epithelium (RPE) biopsies from cadaver human eyes of donors over age 60 years. Our goal was to harvest cells for possible autologous RPE cell transplantation in patients with age-related macular degeneration and to test the viability of the RPE after isolation by evaluating explant growth in culture. METHODS: Choroid-RPE biopsies were excised from enucleated human eyes. The RPE was separated from the choroid by treatment with type IV collagenase. RPE patches were cultured. After 100-500 cells had grown out from the explant, the primary cultures were passaged. RESULTS: There was no clear effect of donor age on the ability to establish primary RPE cultures with good morphology from biopsies 2 x 2-10 x 10 mm2 in size. Biopsies 6 x 6 mm2 or larger produced satisfactory primary cultures more than 70% of the time. The number of viable RPE cells (defined as the number of cells adherent to the culture dish 24 h after plating) obtained after enzymatic separation of the RPE and choroid was an important determinant of our ability to establish primary cultures and passage the cells. Primary cultures with good cellular morphology were obtained 100% of the time when RPE explants > 4 mm2 in size were obtained from the biopsy specimen. Seventy-three percent of the biopsies yielding explants > 4 mm2 in size were successfully passaged. CONCLUSIONS: These results suggest that peripheral scleral flap biopsies in aging donors can be used to establish RPE explant primary cultures. These cultures may be suitable as a source for autologous RPE transplantation in patients.

Clinical significance of urinary human tissue non-specific alkaline phosphatase (hTNAP) in pre-eclampsia and eclampsia.

The aim of this work was to determine the levels of urinary human tissue non-specific alkaline phosphatase (hTNAP) in pre-eclampsia and eclampsia in order to assess renal tubular damage. Urine samples were collected from 26 mild pre-eclamptic, 26 were pre-eclamptic, 20 eclamptic patients and 20 healthy pregnant women (controls) in their late third trimester. Urinary hTNAP/creatinine (hTNAP/cr) in severe pre-eclampsia and eclampsia were significantly higher than in controls. Urinary hTNAP/cr was increased in 23%, 77% and 90% of cases of mild pre-eclampsia, severe pre-eclampsia and eclampsia, respectively, indicating that the increase correlates with the severity of the disease. Marked elevation or urinary hTNAP/cr was also associated with bad fetal outcome. These results provide additional evidence for renal tubular damage in pre-eclampsia and eclampsia.

The prevalence of serum antineutrophil cytoplasmic autoantibodies in preeclampsia and eclampsia.

OBJECTIVES: The purpose of this study was to evaluate the prevalence of antineutrophil cytoplasmic autoantibodies (ANCAs) in preeclampsia and eclampsia. METHODS: Blood samples were obtained from 26 mildly preeclamptic, 26 severely preeclamptic, and 20 eclamptic, and 20 normal pregnant women (controls) in the late third trimester for the determination of serum cytoplasmic pattern ANCA (cANCA) and perinuclear pattern ANCA (pANCA) by the corresponding enzyme immunoassay. RESULTS: Significant elevations of serum cANCA and pANCA were found in mild and severe preeclampsia and eclampsia. The extent of rise correlated well with the severity of the disease. Both ANCAs were detected in 80% of eclamptic cases versus 38.5 and 69.3% of mild and severe preeclampsia, respectively. Marked elevations of serum ANCAs were associated with poor fetal outcome. CONCLUSION: ANCAs may be involved in the pathogenesis of glomerulonephritis in preeclampsia and eclampsia and their presence may be attributed to an autoimmune mechanism initiated by autoantibody-mediated activation of neutrophils.

A novel pulse-echo technique for medical three-dimensional imaging.

A new pulse-echo imaging technique for close near-field applications is proposed. Based on the theory developed for the continuous-wave automatic focusing technique (CWAFT), it uses instead, a frequency-domain phase compensation through a convolutional mechanism. In addition, the scanned frequencies of the transmitted CW signals are sent simultaneously in a pulse that is used for the data acquisition and processing. The pulse-echo nature of this technique makes it a candidate for further development and evaluation for ultrasonic three-dimensional (3-D) medical imaging and nondestructive testing. Furthermore, the "spike-like" nature of the back propagator in the frequency domain is used to half the data acquired. This alleviates most of the drawbacks of the CWAFT in data acquisition and processing. Simulation results are presented for both two-dimensional (2-D) and 3-D targets.

Treatment of presumed fungal endophthalmitis with oral fluconazole.

Amphotericin B is the usual treatment for fungal endophthalmitis, but its toxicity and lack of oral bioavailability may limit its use in some patients. The authors report the successful management of two cases of presumed metastatic fungal endophthalmitis with oral fluconazole, a bis-triazole compound with a broad antifungal spectrum.