Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study

Treatment options for patients suffering from indolent forms of mastocytosis remain inadequate with the hyperactivation of mast cells responsible for many of the disease's systemic manifestations. Masitinib is a potent and highly selective oral tyrosine kinase inhibitor. A combined inhibition of c-Kit and Lyn make it particularly efficient in controlling the activity of mast cells and therefore, of potential therapeutic benefit in mastocytosis. Masitinib was administered to 25 patients diagnosed as having systemic or cutaneous mastocytosis with related handicap (i.e., disabilities associated with flushes, depression, pruritus and quality-of-life) at the initial dose levels of 3 or 6 mg/kg/day over 12 weeks. In accordance with the AFIRMM study, response was based upon change of clinical symptoms associated with patient handicap at week 12 relative to baseline, regardless of disease subtype. Improvement was observed in all primary endpoints at week 12 including a reduction of flushes, Hamilton rating, and pruritus as compared with baseline by 64% (P = 0.0005), 43% (P = 0.0049), and 36% (P = 0.0077), respectively. An overall clinical response was observed in 14/25 patients (56%; [95%CI = 37%-75%]), with sustainable improvement observed throughout an extension phase (>60 weeks). Common adverse events were edema (44%), nausea (44%), muscle spasms (28%), and rash (28%), the majority of which were of mild or moderate severity with a significant decline in frequency observed after 12 weeks of treatment. One patient experienced a serious adverse event of reversible agranulocytosis. Masitinib is a promising treatment for indolent forms of mastocytosis with handicap and indicates acceptable tolerability for long-term treatment regimens.     

Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with the strength of responsiveness to interleukin-15

Immunologic memory is a critical feature of the adaptive immune system to fight recurrent infections. However, the mechanisms that shape the composition and function of the human memory T-cell pool remain incompletely understood. We here demonstrate that post-thymic human T-cell differentiation was associated with the downregulation, but not loss, of the inhibitory molecule CD5. The sensitivity of human CD8(+) and CD4(+) memory T cells to interleukin (IL)-15 was inversely associated with the level of CD5 expression. CD5 expression was downregulated by IL-15-mediated signaling in vitro and CD5(lo) memory T cells accumulated in the bone marrow. Persistent antigenic stimulation, as in the case of cytomegalovirus infection and rheumatoid arthritis (RA), was also associated with an increased number of CD5(lo) memory T cells. In conclusion, CD5 may be a useful marker to identify memory T-cell subsets with distinct responsiveness to the homeostatic cytokine IL-15.     

Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity

The neuronal circuits involved in the regulation of feeding behavior and energy expenditure are soft-wired, reflecting the relative activity of the postsynaptic neuronal system, including the anorexigenic proopiomelanocortin (POMC)-expressing cells of the arcuate nucleus. We analyzed the synaptic input organization of the melanocortin system in lean rats that were vulnerable (DIO) or resistant (DR) to diet-induced obesity. We found a distinct difference in the quantitative and qualitative synaptology of POMC cells between DIO and DR animals, with a significantly greater number of inhibitory inputs in the POMC neurons in DIO rats compared with DR rats. When exposed to a high-fat diet (HFD), the POMC cells of DIO animals lost synapses, whereas those of DR rats recruited connections. In both DIO rats and mice, the HFD-triggered loss of synapses on POMC neurons was associated with increased glial ensheathment of the POMC perikarya. The altered synaptic organization of HFD-fed animals promoted increased POMC tone and a decrease in the stimulatory connections onto the neighboring neuropeptide Y (NPY) cells. Exposure to HFD was associated with reactive gliosis, and this affected the structure of the blood-brain barrier such that the POMC and NPY cell bodies and dendrites became less accessible to blood vessels. Taken together, these data suggest that consumption of an HFD has a major impact on the cytoarchitecture of the arcuate nucleus in vulnerable subjects, with changes that might be irreversible due to reactive gliosis.     

A method for investigating the temporal dynamics of local neuroretinal responses

Visual sensitivity improves with prolonged exposure to light. Global neuroretinal responses increase, but little is known about the dynamics of local retinal responses over brief time intervals after changes in light level. This study applies the time-slice multifocal electroretinogram (TS mfERG) paradigm for the measurement of local electrical responses of the human eye over brief time intervals. Sixty-one, localised retinal areas were assessed over 25 degrees of the visual field. Cone-mediated contributions to the time-slice waveform were established. The time-slice mfERG waveforms were similar in shape and timing for pre- and post-photopigment bleach conditions after saturation of rod-mediated responses, suggesting there was no rod-mediated intrusion in the waveform. The temporal dynamics of the mfERG components show that N1P1 amplitudes decrease with each successive time-slice probe, with larger amplitude responses in the central retina compared to nasal and temporal retina. The time-slice mfERG waveform is a technique for assessing the temporal dynamics of cone-generated neural responses over time. The data are interpreted in terms of the vascular supplies and lower-level visual adaptation mechanisms.     

Study of HHV-8 DNA sequences in archival biopsies from lesional skin of Kaposi's sarcoma,various mesenchymal tumors and related reactive conditions

Background: HHV-8 has been identified as the causative agent of Kaposi's sarcoma (KS) and some lymphoproliferative disorders. In addition, there are anecdotal reports on the presence of HHV-8 in other tumors, especially cutaneous epithelial and mesenchymal neoplasms. The aim of the study was to ascertain the value of identification of HHV-8 viral DNA sequences in routinely processed, formalin-fixed, paraffin-embedded tissues for the diagnosis of Kaposi's sarcoma and other mesenchymal tumors.
Methods: The presence of HHV-8 sequences in archival material was studied by nested PCR using specific primers for amplification of a 233-bp long fragment of HHV-8 (ORF 26).
Results: Thirty-three patients with KS (18 classic/sporadic, six post-transplant and nine AIDS-related) and various mesenchymal tumors and related conditions (n = 76) were studied. HHV-8 DNA sequences were detected in 29 of the 33 cases of KS and in one case of multiple eruptive dermatofibroma (MEDF).
Conclusions: Identification of HHV-8 DNA sequences in routinely processed tissue is a useful diagnostic marker for KS. Although other mesenchymal tumors are usually not associated with HHV-8, its presence is not fully specific for KS since HHV-8 sequences were also found in one case of MEDF. Therefore, PCR analysis for the detection of HHV-8 should only be used as an additional diagnostic marker for KS and in the context of other tools such as routine histology.     

Spontaneous fat necrosis of the falciform ligament: Tale of the unexpected

Abdominal pain has a myriad of causes. Advances in technology have improved accuracy in diagnosis and management. Despite this, there are still cases that defy all diagnostic tests, showing themselves only at operation to the amazement of the surgeon. We report one such case, perhaps the second of its kind, as a literature search has shown.     

Neue Forschungsergebnisse über die Wirkung von Ganzvirus- und Subunit-Influenza-Impfstoffen auf das Immunsystem

Ohne Zusammenfassung     

High-Dose Cyclophosphamide, Adriamycin, And Vlncrlstlne (Hd-Cav) In Children with Recurrent Solid Tumor

A dose-intensive regimen of cyclophosphamide (140 mg/kg over 2 days), doxorubicin (Adriamycin, 75 mg/m² over 3 days), and vincristine (1 mg/m² on days 1,2, and 3 and 1.5 mg/m² on day 9) was tested in 18 children and adolescents with poor-prognosis recurrent or refractory solid tumors. Nine were affected by neuroblastoma, 3 by Ewing's tumors, 2 by rhabdomyosarcoma, 2 by synovial sarcoma, 1 by hepatocellular carcinoma, and 1 by osteogenic sarcoma. All enrolled patients were heavily pretreated, including 2 patients after bone marrow transplantation. Forty courses were applied (median, 2). The overall response rate was 33% (2 complete remissions and 4 partial remissions). Responses were obtained in children with neuroblastoma, Ewing's tumors, and hepatocellular carcinoma. Myelosuppression [World Health Organization (WHO) grade IV after all courses] and cardiac toxicity (3 WHO grade I,5 WHO grade III, and 3 WHO grade IV) were the main side effects. Nephrotoxicity and hepatoxicity were not obserued. With further therapy consisting of surgery, radiotherapy, and high-dose chemotherapy [cisplatin, carboplatin/etoposide (VP16), or ifosfaamide/VP16 with or without autologous stem cell reinfusion after conditioning with melphalan/VP16/carboplatin], 3 complete remissions and 5 very good partial remissions were obtained. Ten of 18 Patients are alive after a median follow-up of 16 months.