Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival.

BACKGROUND: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. RESULTS: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. CONCLUSIONS: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.

Effects of the adenosine A 2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide.

Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A(2A) antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. The motor test employed was tremulous jaw movements, which is used as a model of parkinsonian tremor. In addition, c-Fos expression in the ventrolateral neostriatum, which is the striatal area most associated with tremulous jaw movements, was used as a marker of striatal cell activity in animals that were tested in the behavioral experiments. Repeated administration of 1.0 mg/kg pimozide induced tremulous jaw movements and increased ventrolateral striatal c-Fos expression, while administration of 20.0 mg/kg of the atypical antipsychotic quetiapine did not. The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A(2A) antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A(2A) antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.

Results of treatment of subtrochanteric femoral fractures with the AO/ASIF Long Trochanteric Fixation Nail (LTFN).

PURPOSE OF THE STUDY: This retrospective study reports on the clinical results of a group of 23 patients with subtrochanteric femoral fractures using the Long Trochanteric Fixation Nail (LTFN). MATERIAL: Between January 2005 and January 2008, 23 patients (20 women, 3 men; average age: 64.8 years old) with subtrochanteric femoral fractures were treated surgically. According to the AO/ASIF Classification, the most frequent fracture type was an 32-A1. They were also classified regarding the Seinsheimer Classification, in which the commonest type was the IIB. Of the 23 fractures, 14 of them had been the result of an unexpected fall, 2 were the result of a high-energy trauma and 7 consisted of pathologic fractures. METHODS: All the patients were treated using the LTFN device and they all received clinical and radiological follow-ups at least until their fractures were consolidated. The average surgery time, average decrease in haemoglobin in the first 24 hours post- surgery, average need for red blood cell transfusion, postoperative mortality at a 6th month follow-up, time to autonomous deambulation, most frequent destination at the time of discharge, average time for consolidation of the fracture and average follow-up time were reported. Intraoperative and postoperative complications were also recorded. RESULTS: The average surgery time from cut to stitch was 97.45 minutes with the decrease in haemoglobin averaging 26.45 g/L and, on average, the need for red blood cell transfusion was 1.12 concentrates. In the first postoperative week, 57.1% of the total number patients were capable of deambulation. The time to hospital discharge was 12.9 days. After an average follow-up of 13.9 months, total weightbearing was achieved in the 64.7% of the patients. The average consolidation time was 21.6 weeks and none of the patients developed pseudoarthrosis. Technical failures were seen in 4.3% of the cases: 1 patient suffered a migration of the distal locking screw. There were no cases of deep infection, cut-out, bending/breaking of the implant, malrotation or fracture of the femoral shaft at the tip of the implant. DISCUSSION: From a mechanical point of view the use of a long intramedullary nail in combination with a blade or a screw seems to be the most appropriate treatment for subtrochanteric fractures of the femur. Despite the improvement of implants and surgical techniques, failures due to complications are still considerable. The low distal shaft diameter of the LTFN, in combination with an extremely precise positioning of the blade in the middle of the femoral head, can prevent mechanical complications. Open reduction and cerclage cabling may be required so as to obtain a correct alignment of the fracture. CONCLUSION: We conclude that the LTFN is a safe and reliable intramedullary device for the treatment of subtrochanteric fractures of the femur. Deambulation within the first postoperative surgery is possible when positioned properly. Its implantation requires more surgical time than the standard nails.

Reduction in the anxiolytic effects of ethanol by centrally formed acetaldehyde: the role of catalase inhibitors and acetaldehyde-sequestering agents.

RATIONALE: Considerable evidence indicates that brain ethanol metabolism mediated by catalase is involved in modulating some of the behavioral and physiological effects of this drug, which suggests that the first metabolite of ethanol, acetaldehyde, may have central actions. Previous results have shown that acetaldehyde administered into the lateral ventricles produced anxiolysis in a novel open arena in rats. OBJECTIVES: The present studies investigate the effects of centrally formed acetaldehyde on ethanol-induced anxiolysis. MATERIALS AND METHODS: The effects of the catalase inhibitor sodium azide (SA; 0 or 10 mg/kg, IP) on ethanol-induced anxiolysis (0.0, 0.5, or 1.0 g/kg, IP) were evaluated in CD1 mice in two anxiety paradigms, the elevated plus maze and the dark/light box. Additional studies assessed the effect of the noncompetitive catalase inhibitor 3-amino-1,2,4-triazole (AT; 0.5 g/kg, IP) and the acetaldehyde inactivation agent D: -penicillamine (50 mg/kg, IP) on the plus maze. RESULTS: SA reduced the anxiolytic effects of ethanol on several parameters evaluated in the elevated plus maze and in the dark/light box. In the plus maze, AT completely blocked and D-penicillamine significantly reduced the anxiolytic properties of ethanol. CONCLUSIONS: Thus, when cerebral metabolism of ethanol into acetaldehyde is blocked by catalase inhibitors, or acetaldehyde is inactivated, there is a suppressive effect on the anxiolytic actions of ethanol. These data provide further support for the idea that centrally formed or administered acetaldehyde can contribute to some of the psychopharmacological actions of ethanol, including its anxiolytic properties.

Incidence of congenital hypothyroidism and congenital adrenal hyperplasia at Flushing Hospital Medical Center

BACKGROUND: Newborn screening (NBS) program is a simple and inexpensive method for early detection and treatment of over forty conditions as of 2005. Most cases of congenital hypothyroidism (CH) are sporadic and occurs in 1 in 3500 live births. Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that occurs in 1 in 1600 live births. The detection of CH is determined by either low T4 and/or elevated TSH and the detection of CAH is determined by elevated 17OH progesterone on Guthrie filter paper. Infants who meet the above criteria on NBS for either condition must undergo confirmatory testing. OBJECTIVE: Is the incidence of CH and CAH at FHMC, a community hospital in northern Queens, New York serving a multiethnic population different from theincidence of CH and CAH in New York State (NYS)? DESIGN/METHODS: We reviewed records of the infants recalled and confirmed to have CH and CAH for 2000, 2001 and 2004 and compared with reported incidence of the same conditions in NYS. RESULTS: The total number of live births in NYS was 760,112 and in FHMC 6348 for the three years studied, accounting for 0.7 to 0.8of total NYS live births. The population served by FHMC included 43White, 35Asian, 16Hispanic, 3Afro-American and 3other. A total of 5 patients were identified to have CH in the three years studied, accounting for an incidence of 0.12 (p > 0.05). Three patients were identified to have CAH in 2004 or an incidence of 1.4 (p < 0.05). [Table 1]. CONCLUSIONS: The incidence rate of CH was similar to that of NYS. However, the incidence rate of CAH at FHMC was greater than that reported by NYS. This difference in incidence rate for CAH may be related to the ethnic composition of the population that FHMC serves. Pediatricians and pediatric endocrinologists must be cognizant of the signs and symptoms of CAH in certain populations known to have higher incidence for this condition. Further follow up of incidence rate for CAH at FHMC is indicated since CAH was added to the NBS in 2003.

Exposure to non-arsenic pesticides is associated with lymphoma among farmers in Spain.

OBJECTIVES: To estimate the risk of lymphoma among farmers in Spain. METHODS: This is a multicentre case control study conducted in Spain. Cases were subjects diagnosed with lymphoma according to the World Health Organization (WHO) classification in four hospitals between 1998-2002. Hospital controls were frequency matched to the cases by sex, age, and centre. All subjects were interviewed about jobs ever held in lifetime for at least one year and the exposures in those jobs were recorded. The risk of lymphomas among subjects ever having had a job as a farmer was compared with all other occupations. Farmers were analysed according to the type of farming job performed: crop farming, animal farming, and general farming. Occupational exposure was summarised into 15 main categories: organic dust, radiation, contact with animals, PAH, non-arsenic pesticides (carbamates, organophosphates, chlorinated hydrocarbons, triazines and triazoles, phenoxy herbicides, chlorophenols, dibenzodioxin, and dibenzofuran), arsenic pesticides, contact with meat, contact with children, solvents, asbestos, soldering fumes, organic colourants, polychlorinated biphenyls, ethylene oxide, and hair dyes. RESULTS: Although farmers were not at an increased risk of lymphoma as compared with all other occupations, farmers exposed to non-arsenic pesticides were found to be at increased risk of lymphoma (OR = 1.8, 95% CI 1.1 to 2). This increased risk was observed among farmers working exclusively either as crop farmers or as animal farmers (OR = 2.8, 95% CI 1.3 to 5.8). Risk was highest for exposure to non-arsenic pesticides for over nine years (OR = 2.4, 95% CI 1.2 to 2.8). CONCLUSIONS: Long term exposure to non-arsenic pesticides may induce lymphomagenesis among farmers.

Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

Increased conventional chemotherapy does not improve survival in multiple myeloma: long-term results of two PETHEMA trials including 914 patients.

BACKGROUND: Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the last 30 years. Combination chemotherapy at conventional doses has not shown a significant prolongation of survival when compared to MP. There are few data comparing conventional chemotherapy at standard doses with conventional treatment at higher doses. We present the long-term outcome of 914 patients from two randomized trials comparing three different dose intensity regimens. METHODS: From 1 January, 1985 to 31 December, 1989, 487 patients were randomized between MP (melphalan 9 mg/m(2) p.o. and prednisone 60 mg/m(2) days 1-4) and alternating VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m(2) i.v. on day 1, melphalan 6 mg/m(2) p.o. on days 1-4, and prednisone 60 mg/m(2) on days 1-4) and VBAP (vincristine 1 mg i.v. on day 1, BCNU and doxorubicin 30 mg/m(2) i.v. each on day 1, and prednisone 60 mg/m(2) on days 1-4). From 1 January, 1990 to 31 May, 1994, 427 patients were randomized between VCMP/VBAP at the above detailed doses (VCMP/VBAP 'SD') and the same regimen increasing the doses of cyclophosphamide and doxorubicin from 500 to 1200 mg/m(2) and from 30 to 50 mg/m(2), respectively (VCMP/VBAP 'HD'). RESULTS: Increasing dose intensity produced a significantly higher partial response rate (31% vs 45% vs 51% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P < 0.01). However, a significantly early death rate was observed in the HD arm (7.7, 7.5 and 12.1% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = 0.05). Median duration of response (20 vs 18 vs 19 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) and median survival (25 vs 31 vs 29 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) were similar in the three groups. MP produced a higher degree of thrombocytopenia than combination chemotherapy at standard (P = 0.002) or high dose (P = 0.01), this leading to a significantly higher dose reduction in the MP arm (P < 0.001 and P = 0.003 for VCMP/VBAP 'SD' and VCMP/VBAP 'HD', respectively). CONCLUSION: In these trials the response rate significantly correlated with the regimen intensity. However, no significant differences in response duration and survival were found. This highlights the limited role of conventional chemotherapy in MM and the need for further trials, aimed at determining the impact of new treatment approaches such as high-dose therapy/autotransplantation.

Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. The Spanish Erythropathology Group.

BACKGROUND AND OBJECTIVE: Anemia leading to transfusion is probably the most important problem in patients with myelodysplastic syndromes (MDS). Human recombinant erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) have been used to treat patients with anemia of MDS, but fewer than 50% respond. The aim of this work was to evaluate the benefit of rHuEpo +/- G-CSF treatment and to isolate the response predictive variables in a group of selected patients with MDS. DESIGN AND METHODS: A non-randomized multicenter trial was carried out in 32 patients with MDS. The inclusion criteria were age >= 18 years, refractory anemia (RA) or refractory anemia with ringed sideroblasts, Hb <= 100 g/L or receiving transfusions and serum erythropoietin <= 250 U/L. These patients were treated with subcutaneous rHuEpo (300 U/kg) three times a week for 8 weeks. In the case of partial response (PR) or no response (NR) subcutaneosly administered G-CSF (1 microg/kg) three times a week was added to the rHuEpo for 8 more weeks. If the patient achieved complete response (CR) or PR in the second phase, he was included in a follow-up phase of 24 weeks in which the dose of growth factors was tapered down. Several variables, including the score published by the Scandinavian-American group, were used as possible predictive variables. RESULTS: An erythroid response was observed in 16 patients (50%); in 12 it was a CR and in 4 it was a PR. During the period of rHuEpo administration, 7 CR and 4 PR (34.4%) were documented. Of the 14 patients in whom G-CSF was added to rHuEpo, 7 (50%) responded (3 CR and 4 PR). No major side-effects associated with growth factors were observed. The multivariate analysis showed that of the different variables evaluated only the Scandinavian-American response score was significant with a relative probability of response of 11.8 (95% confident intervals: 2.5-53) when this score was > +1 (77% of cases responded). In contrast, when this score was <= 1 only 15 % of the cases responded. INTERPRETATION AND CONCLUSIONS: Use of the Scandinavian-American response score is to be recommended in a patient-oriented approach to treating MDS cases with the Epo and G-CSF. Treatment with rHuEpo and G-CSF is safe, its main drawback being its cost. However, a long-term study evaluating the regimen's cost-benefit ratio is warranted.

Contribution of cosmic ray heavy ions to the radiation hazard in manned space flights.

Primary cosmic radiation arriving near the Earth may be classified into two general categories: the gamma component and the hadronic component. The hadronic component contains mainly protons, a small amount of alpha particles and a smaller amount of heavier charged nuclei (ions). Although the fluxes of these heavier ions are very small in comparison to those of protons, they are able to originate a huge linear energy transfer (LET). This work studies the contribution of heavy ions from cosmic rays to the radiation hazard to which the crew of a manned long duration space flight might be exposed. The geometry of the energy deposition by a heavy ion is studied, and it is found that energies of the order of up to 10(23) J kg-1 are deposited.

Variable clinical and biochemical presentation of seven Spanish cases with glutaryl-CoA-dehydrogenase deficiency.

In this report, we describe seven new patients with a severe deficiency of glutaryl-CoA dehydrogenase in cultured skin fibroblasts. Three of the patients studied excreted high levels of glutaric acid. The remaining four patients presented a lack of significant glutaric aciduria. However, glutaric acid was found in increased levels in CSF. In both groups of patients, the urine glutaric acid levels were not related to their metabolic condition at the time of sampling. Hypocarnitinemia was a common finding. Some patients also showed defects on respiratory chain complexes in muscle biopsy. Only one patient has a normal psychomotor development. The other six patients are severely handicapped despite the attempts of different therapies. In patients with progressive neurological deterioration with dystonia and cerebellar signs associated with temporal lobe atrophy and bilateral basal ganglia damage on MRI, a glutaric aciduria type I (GA I) should always be investigated. The presence of glutaric acid in body fluids, especially in CSF, as well as plasma carnitine levels, should be determined. These procedures can lead to the diagnosis of glutaric aciduria type I.

[Monocytoid B-cell lymphoma: clinico-pathologic study of 2 cases]. / Linfoma B monocitoide: estudio clínico-patológico de dos casos.

Monocytoid B-cell lymphoma, considered as a low-grade lymphoma, is seen most frequently in persons of advanced age, chiefly women. It is often diagnosed in lymph-node phase, in low stages (I-II), and peripheral blood, bone-marrow or spleen are seldom involved. The morphologic and immunohistochemical study of two patients with monocytoid B-cell lymphoma is presented. The characteristic cell morphology, with homogeneous nuclei, low number of mitoses, and clear, wide cytoplasm, was present in both. Tumour cells expressed CD45, CD20, HLA-DR and monoclonal IgM-lambda and lambda chains, respectively. Case no. 1 had more irregular nuclei, protruding nucleoli, advanced stage at diagnosis and shorter clinical course. An epithelioid granulomatous reaction was present in case no. 2, which delayed the diagnosis until relapse. The diverse forms of clinical onset of monocytoid B-cell lymphoma, as well as its possibly aggressive course, association with other types of lymphoma and the difficulties for an adequate morphologic identification are commented.

Drug-induced agranulocytosis: prognostic factors in a series of 168 episodes.

The prognostic value of 36 clinical and analytical parameters at diagnosis in patients with drug-induced agranulocytosis was analysed in an adult population. This multicentre, retrospective study examined possible prognostic factors by multiple logistic regression analysis in a series of 168 clinical episodes. The overall mortality was 16%. Renal insufficiency at diagnosis and the development of bacteraemia were associated with a poor prognosis. Advanced age, decreased leucocyte count, lymphocytopenia, bone marrow myeloid hypoplasia, increased percentage of bone marrow plasma cells and shock were found to be associated with a poor prognosis only in the univariate analysis. An independent analysis of the myeloid cellularity at diagnosis showed an inverse correlation with the time to recovery of the granulocyte counts (r = -0.43; P = 0.001). Our data indicate that despite some important clinical differences (higher incidence of infections of the oropharynx, shorter period of neutropenia and almost exclusive presence of gram-negative organisms), the infections complicating the treatment of cancer patients have the same prognostic features than those seen in patients with acute agranulocytosis. Therefore the established therapeutic guidelines for neutropenia after cancer chemotherapeutic agents are applicable to patients with acute agranulocytosis.

5-Fluorouracil and recombinant interferon alfa-2a: review of activity and toxicity in advanced colorectal carcinomas.

Improved response rates in metastatic colorectal carcinoma recently have been observed for the combination of 5-fluorouracil (5-FU) and recombinant interferon alfa-2a (rIFN), compared to those obtained in historical trials of single-agent 5-FU. The mechanism of interaction between these agents has not been explored adequately but may relate to biochemical modulation of 5-FU by rIFN. Toxicities resulting from this combination have included fever, chills, myalgias, granulocytopenia, mucositis, diarrhea, skin rash, neurological symptoms, and hand-foot syndrome. Future studies of 5-FU with rIFN should investigate schedules aimed at reducing toxicity without compromising efficacy and also should explore mechanisms of enhanced activity.