Myeloid malignancies with translocation t(4;12)(q11-13;p13): molecular landscape, clonal hierarchy and clinical outcomes.

Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.

Prospective evaluation of the effect of deferasirox on hematologic response in transfusion-dependent patients with low-risk MDS and iron overload.

OBJECTIVES: To assess the reduction of transfusions rate in transfusion-dependent patients with low-risk myelodysplastic syndrome (MDS) with iron overload treated with deferasirox. METHODS: Prospective observational study. Primary endpoint was reduction in transfusion requirements (RTR) at 3 months, (assessed on 8-week period). Secondary endpoints were hematologic improvement according to International Working Group (IWG) 2006 criteria at 3, 6, and 12 months. RESULTS: Fifty-seven patients were evaluable. After 3 months of chelation, no effect was seen on transfusion requirement (5.9 packed red blood cells (PRBC) vs 5.8 before chelation). According to the Kaplan-Meier analysis, the probability of RTR at 3, 6, and 12 months was assessed as 3.5%, 9.1%, and 18.7%, respectively. Median duration of RTR was 182 days. However, during the 12-month follow-up after deferasirox initiation, 17 patients (31.5%) achieved minor erythroid response [HI-E] according to IWG criteria, 10 of whom having achieved Hb improvement at month 12. CONCLUSION: After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused patients with low-risk MDS. However, deferasirox could induce 31% of erythroid response during the 12-month follow-up period thus suggesting that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a subset of patients with MDS and iron overload.

[Neurobiological, psychological and sociological approach to sexual desire and sexual satisfaction]. / Une approche neurobiologique, psychologique et sociologique du désir sexuel et de la satisfaction sexuelle.

In the last years, University Fund Maurice Chalumeau (FUMC) launched a dynamic of research designed to promote scientific excellence and the development of Sexology with particular interest regarding sexual desire. The FUMC has supported a research project entitled "Neurobiological, psychological and sociological approach to sexual desire and sexual satisfaction". This project, sampled on 600 people (300 men and 300 women) aged between 25 and 46 years, was structured around three studies: a broad sociological study and two more specific ones, focused on some psychological mechanisms and neurobiological factors involved in sexual desire. The results show how the secondary socialization, personal expectations, beliefs and values in sexuality, sexual motivations, body image, as well as the neurobiological foundations and visual patterns, are of vital importance in the dynamics of sexual desire.

Chronic sinusitis in a patient with selective IgG4 subclass deficiency controlled with enriched immunoglobulins.

A 71-year-old female patient with no major history of infection had presented with recurrent chronic purulent sinusitis over the past 3 years. These recurrent infections started in 2000 with otolaryngologists' support before diagnosis of IgG4 deficiency be asked. The patient was treated with increasingly extensive courses of antibiotics and underwent several maxillary and sphenoidal sinus washouts. She continued to present with purulent nasal discharge containing Staphylococcus epidermidis. The blood and immune work-ups were normal. Her antinuclear antibody count was 1/320, with no unusual types. The total immunoglobulin (Ig)E, serology, CD4 count, and lymphocyte B phenotype results were all normal. No humoral immune deficiency was detected. The analyses confirmed an underlying specific IgG4 deficiency with values of 3-4 mg/L over 4 months. The patient was treated in March 2011 with prophylactic antibiotic therapy, sinus drainage, and IV infusions of enriched immunoglobulins (IVIg 10%) administered at the outpatient clinic every 4 weeks for 3 months. The IgIV treatment was not interrupted. Her general condition improved within a few months, with her IgG4 levels rising to 44 mg/L. The IVIg infusions were well tolerated. The purulent nasal discharge was controlled, and the antibiotics were stopped. The follow-up visits at 2 and 9 months after introduction of IVIg showed that her IgG4 level had improved, rising to 15 and 11 mg/L, respectively, although it had not yet returned to normal. The infusions were then given every 3 weeks. At her last visit, the patient's clinical condition had substantially improved. She was able to start using the subcutaneous Ig concentrate form (20% SCIg), 15 g every 2 weeks, leading to a clear improvement in her clinical condition, with stabilization of her otolaryngologists' symptoms and signs. The complete blood count was normal, IgG4 were stable at 40 mg/L, and the other immunoglobulins and IgG subclasses were normal. It was then possible to reduce the SCIg dose to 10 g every 3 weeks, while continuing to monitor her clinical condition and laboratory test results. This is one of the rare cases of selective IgG4 subclass deficiency treated with immunoglobulins. Treatment resulted in a significant improvement in IgG4 levels versus pretreatment levels. The first improvement noted was the stabilization otolaryngologists' infections particularly purulent nasal discharge.

Clinicopathological and genetic study of early-onset demyelinating neuropathy.

Autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4), Dejerine-Sottas disease and congenital hypomyelinating neuropathy are variants of hereditary demyelinating neuropathy of infancy, a genetically heterogeneous group of disorders. To explore the spectrum of early-onset demyelinating neuropathies further, we studied the clinicopathological and genetic aspects of 20 patients born to unaffected parents. In 19 families out of 20, consanguinity between the parents or presence of an affected sib suggested autosomal recessive transmission. Screening of various genes known to be involved in CMT4 revealed six mutations of which five are novel. Four of these novel mutations occurred in the homozygous state and include: one in GDAP1, one in MTMR2, one in PRX and one in KIAA1985. One patient was heterozygous for a novel MTMR2 mutation and still another was homozygous for the founder mutation, R148X, in NDRG1. All patients tested negative for mutations in EGR2. Histopathological examination of nerve biopsy specimens showed a severe, chronic demyelinating neuropathy, with onion bulb formation, extensive demyelination of isolated fibres and axon loss. We did not discern a specific pattern of histopathology that could be correlated to mutations in a particular gene.

Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease.

Mutations in the ganglioside-induced differentiation-associated protein 1 gene cause either autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4A or autosomal recessive axonal Charcot-Marie-Tooth disease with vocal cord paresis. We sequenced the ganglioside-induced differentiation-associated protein 1 gene in 138 patients from 119 unrelated families diagnosed with either demyelinating or axonal autosomal recessive Charcot-Marie-Tooth disease. We detected six distinct mutant alleles in four families, four of which are novel. Electrophysiological studies show severely slowed motor nerve conduction velocities with severely reduced compound muscle action potentials. However, one patient had a normal conduction velocity in the ulnar nerve. Based on the electrophysiological tests, patients with ganglioside-induced differentiation-associated protein 1 mutations will therefore be classified as either axonal or demyelinating Charcot-Marie-Tooth disease. The neuropathological aspect shows a divergent pattern; nerve biopsies taken from two siblings at the same age and sharing the same ganglioside-induced differentiation-associated protein 1 gene mutation showed a dissimilar severity stage.