Postremission therapy with repeated courses of high-dose cytarabine, idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia.

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.

Dissection of partial 21q monosomy in different phenotypes: clinical and molecular characterization of five cases and review of the literature.

BACKGROUND: Partial deletion of chromosome 21q is a very rare chromosomal abnormality associated with highly variable phenotypes, such as facial dysmorphic features, heart defects, seizures, psychomotor delay, and severe to mild intellectual disability, depending on the location and size of deletions. So far, three broad deletion regions of 21q have been correlated with the clinical phenotype. RESULTS: We described the clinical and genetic features of three family members (father and two siblings) and other two unrelated patients with very wide range in age of diagnosis. All of them showed intellectual disability with very variable symptoms, from mild to severe, and carried 21q interstitial deletions with different sizes and position, as detected by conventional karyotype and array-CGH. CONCLUSIONS: Our study provided additional cases of partial 21q deletions, allowing to better delineate the genotype-phenotype correlations. In contrast to previous observations, we showed that deletions of the 21q proximal region are not necessarily associated with severe phenotypes and, therefore, that mild phenotypes are not exclusively related to distal deletions. To the best of our knowledge, this is the first report showing 21q deletions in adult patients associated with mild phenotypes, mainly consisting of neurobehavioral abnormalities, such as obsessive-compulsive disorders, poor social interactions and vulnerability to psychosis.

Lenalidomide in patients with red blood cell transfusion-dependent myelodysplastic syndrome and del(5q): a single-centre "real-world" experience.

"Real life" data are needed to complement published trials on the efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) and del(5q) and on the risk of inducing acute myeloid leukemia (AML) progression. Here, we present results of lenalidomide treatment in a consecutive, population-based series of 21 red blood cell (RBC) transfusion-dependent elderly patients with multiple comorbidities. Of 18 evaluable patients (median follow-up: 22 months), 17 achieved an erythroid hematologic response (HI-E) and 16 an RBC transfusion independence. Cytogenetic response (CyR) rate was 80%, median overall survival was 48 months (range 3-164), and 5-year leukemia-free survival was 84%. Three patients progressed to AML; one, with baseline TP53 mutation, achieved HI-E, partial CyR, and did not progress to AML. Eighteen patients experienced hematological adverse events. Overall, lenalidomide was very effective and well tolerated even in unselected elderly patients with multiple comorbidities and did not appear to increase the risk of AML.

BDNF Val66Met polymorphism and protein levels in amniotic fluid.

BACKGROUND: Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin which plays survival- and growth-promoting activity in neuronal cells and it is involved in cellular plasticity mechanisms as it controls activity dependent synaptic transmission. A functional polymorphism (Val66Met) in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF has been associated with memory and cognitive deficits as well as to an increased susceptibility for several psychiatric disorders especially those with a neurodevelopmental origin. To date, no study has evaluated the influence of the Val66Met polymorphism on BDNF levels in a peripheral system that may reflect fetal neurodevelopment. Therefore we investigated in amniotic fluids (AF) obtained from 139 healthy women during 15-17 week of pregnancy, BDNF protein levels in correlation with the Val66Met polymorphism. RESULTS: Interestingly we found a significant BDNF protein levels reduction in 55 Met carriers (Val/Met and Met/Met) (p = 0.002) as compared to 84 non carriers (Val/Val), and no effect of fetus gender, maternal age or gestation week on BDNF levels has been observed. CONCLUSION: These results, although explorative, indicate that during fetal life the Val66Met genotype might influences BDNF protein levels in AF supporting the involvement of this polymorphism in behavioral and functional brain individual differences in the adulthood.

De novo balanced chromosome rearrangements in prenatal diagnosis.

OBJECTIVE: We surveyed the datasheets of 29 laboratories concerning prenatal diagnosis of de novo apparently balanced chromosome rearrangements to assess the involvement of specific chromosomes, the breakpoints distribution and the impact on the pregnancy outcome. METHOD: By means of a questionnaire, data on 269.371 analyses performed from 1983 to 2006 on amniotic fluid, chorionic villus and fetal blood samples were collected. RESULTS: A total of 246 balanced anomalies were detected at frequencies of 72% for reciprocal translocations, 18% for Robertsonian translocations, 7% for inversions and 3% for complex chromosome rearrangements. The total frequencies of balanced rearrangements were 0.09%, 0.08% and 0.05% on amniotic fluid, chorionic villus and fetal blood samples. CONCLUSION: A preferential involvement of chromosomes 22, 7, 21, 3, 9 and 11 and a less involvement of chromosomes X, 19, 12, 6 and 1 was observed. A nonrandom distribution of the breakpoints across chromosomes was noticed. Association in the location of recurrent breakpoints and fragile sites was observed for chromosomes 11, 7, 10 and 22, while it was not recorded for chromosome 3. The rate of pregnancy termination was about 20%, with frequencies decreasing from complex chromosomal rearrangements (33%), reciprocal translocations (24%) to inversions (11%) and Robertsonian translocations (3%).

Recombinant granulocyte-colony stimulating factor as treatment for poor prognosis oligoblastic acute myeloid leukemia in elderly patients.

Twenty-five elderly patients with oligoblastic acute myeloid leukemia (AML) received subcutaneous granulocyte colony-stimulating factor (filgrastim) in addition to supportive care. Ninety-two percent of the patients had multilineage dysplasia, 17% hypoplasia, and 48% a high-risk karyotype. During filgrastim treatment neutrophil and platelet counts increased significantly (p<0.0001 and (p=0.042), respectively) and 3/13 patients (23%) no longer required transfusions. A complete peripheral hematologic response (CHR) was obtained in eight (32%) and marrow blast cell clearance (<5%) in five patients (20%), lasting 12 and 10 months, respectively. Filgrastim caused osteomyalgia and fever in 20% of cases. The median survival was 8 months overall, and 15 months in patients who achieved a CHR. Filgrastim may be a useful adjunct to supportive care in elderly patients with poor-risk AML.

Unexpected identification of two interstitial deletions in a patient with a pericentric inversion of a chromosome 4 and an abnormal phenotype.

Interstitial deletions and pericentric inversions of chromosome 4 appear to be unusual phenomena. Here, we report the case of a 14-year-old boy with severe psychomotor retardation with a de novo 46,XY,der(4)del(p15.2p15.31)inv(4)(p15.2q13.3)del(4)(q13.2q13.2) karyotype. We used FISH analysis with YAC and BAC clones to characterise the inversion's breakpoints. A complex event with six breakpoints was found, characterised by a pericentric inversion and two deletions, the first on the short arm of chromosome 4 (4p) and the second on the long arm of chromosome 4 (4q). The deletion events had removed two segments, one of approximately 5 Mb, from 4p, outside the inversion, and the other 2 Mb from 4q, inside the inversion. These rearrangements were not found in the parents. Microsatellite marker analysis showed that the inversion carrying chromosome 4 was derived from the father. Bioinformatic analysis of the human genome sequence allowed us to identify several hemizygotic genes in the patient, which might be involved in the pathogenesis of this clinical phenotype.

Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories.

PURPOSE: We evaluated the experiences of 19 Italian laboratories concerning 241 small supernumerary marker chromosomes (sSMCs) with the aim of answering questions arising from their origin from any chromosome, their variable size and genetic content, and their impact on the carrier's phenotype. METHODS: Conventional protocols were used to set up the cultures and chromosome preparations. Both commercial and homemade probes were used for the fluorescent in situ hybridization analyses. RESULTS: A total of 113 of the 241 sSMCs were detected antenatally, and 128 were detected postnatally. There were 52 inherited and 172 de novo cases. Abnormal phenotype was present in 137 cases (57%), 38 of which were antenatally diagnosed. A mosaic condition was observed in 87 cases (36%). In terms of morphology, monocentric and dicentric bisatellited marker chromosomes were the most common, followed by monocentric rings and short-arm isochromosomes. The chromosomes generating the sSMCs were acrocentric in 132 cases (69%) and non-acrocentric chromosomes in 60 cases (31%); a neocentromere was hypothesized in three cases involving chromosomes 6, 8, and 15. CONCLUSION: The presented and published data still do not allow any definite conclusions to be drawn concerning karyotype-phenotype correlations. Only concerted efforts to characterize molecularly the sSMCs associated or not with a clinical phenotype can yield results suitable for addressing karyotype-phenotype correlations in support of genetic counseling.