Long term follow‐up of allogeneic stem cell transplantation in patients with myelodysplastic syndromes using busulfan,cytosine arabinoside,and cyclophosphamide

We report here the 10‐year follow‐up of 86 patients who underwent allogeneic stem cell transplantation (ASCT) for myelodysplastic syndrome (MDS). All patients received the busulfan, cytosine arabinoside, and cyclophosphamide (BAC) preparative regimen which consisted of busulfan 16 mg/kg, cytosine arabinoside 8 g/m² IV, and cyclophosphamide 120 mg/kg IV. Fifty‐nine patients (69%) had de novo MDS; 26 (30%) had secondary MDS (treatment related), and one had a preceding aplastic anemia which progressed to MDS before transplant. Cytogenetics (80 patients) was classified as good (34%), intermediate (17%), or poor (42%). With a median follow‐up for survivors of 124 months, the 10‐year Kaplan‐Meier estimates for overall survival (OS) was 43% (95% confidence interval [CI]: 31–53%). Cumulative nonrelapse mortality (NRM) and relapse was 43% (95% CI: 32–54%) and 19% (95% CI: 11–27%), respectively. No patient relapsed after 2 years. In patients with RAEB‐T/AML, 10‐year relapse‐free survival (RFS), relapse, and NRM was 36%, 36%, and 27%, respectively. Younger age (P = 0.05), human leukocyte antigen (HLA) match (P = 0.002), good risk cytogenetics (P = 0.008), and having a related donor (P = 0.03) significantly improved overall and RFS in the multivariable analysis. The long‐term follow‐up of patients receiving the BAC regimen with ASCT in this study indicated durable relapse‐free and OS with acceptable toxicity in this group of patients with high‐risk features. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Zoonotic filariasis in the Arabian Peninsula: autochthonous onchocerciasis and dirofilariasis

We describe zoonotic filariasis in two patients from Kuwait; one with Onchocerca spp. and one with Dirofilaria spp. Case 1, a 12-year-old Kuwaiti woman who had visited Saudi Arabia, initially reported ocular symptoms. She later reported a nodule that appeared in the suprapubic area, which was resected. A coiled worm was observed in histologic sections and was identified as an Onchocerca spp., but could not be definitively identified. This patient represents the 15th reported case of zoonotic onchocerciasis in a country that is not endemic for human onchocerciasis. Case 2, a 34-year-old Indian woman from Kuwait City, reported a moving object in her left eye. A live worm was extracted and tentatively identified as an immature female Dirofilaria (Nochtiella) repens. These two cases bring to four the number of reports of zoonotic filariasis in the Arabian Peninsula and suggest that zoonotic filariasis is not uncommon in the Arabian Gulf region.     

Emergency hospitalization in the elderly in a French university hospital: medical and social conditions and crisis factors precipitating admissions and outcome at discharge

Emergency admissions of elderly patients constitute a major management issue due to the complexity of their problems. The aim of this retrospective observational study was to identify medical and social characteristics and crisis factors for emergency department (ED) hospitalization in elderly patients, and to evaluate the influence of these factors on the length of stay and outcome at discharge. During a 4-month period, 396 patients aged 70 years and older were referred to the ED of a University Hospital (H?pital Edouard Herriot) in Lyon, France. A questionnaire specifically designed for the study was completed for each patient using the information in the patients' files previously filled in by the "Rapid Geriatric Assessment Team" of the ED. We described civil and marital status, living conditions, reason for admission to ED and other associated pathologies according to the ICM-9, crisis factors, length of stay (LOS) and outcome at discharge. The mean age was 81.9 years (SD 6.5); two thirds (66.7%) of the study subjects were female, and 46.7% were widowed; the majority (68.7%) lived in their own homes. The main reasons for admission were cardiopulmonary diseases in 31.6% of cases, followed by neuropsychiatric disorders in 28.2%, and falls in 8.3%; a final category (31.8%) included subjects admitted for general, non-specific symptoms. Among the crisis factors observed, 49.4% presented an acute episode of a chronic illness, 33.6% lived alone, and 20.9% had been hospitalized during the 6-month period preceding the study. The average LOS was 3.15 days. The multivariate model showed that falls increase LOS by 74%, dementia by 65%, and depression by 21%. Upon discharge, 13% returned to their residence before hospitalization, 55% were transferred to a medical speciality ward, and 4% to other facilities, whereas only 19% were transferred to a geriatric ward, and 9% died during their stay in the ED. The multinomial model showed that outcome at discharge was influenced by functional dependency, dementia, depression, and acute episodes of a chronic illness. For many elderly, the ED remains a critical point of access to more complete managed care. This elderly population is comprised of polypathological, frail persons whose morbid state requires multidisciplinary management in geriatric units. The findings of this study suggest that interventions of multidisciplinary networks, such as home health care programs aimed at detecting crisis factors and establishing early prevention of crisis states, may improve unfavorable medical and social conditions and reduce hospitalization in geriatric patients.     

An outbreak of Plasmodium falciparum malaria due to Anopheles minimus in central Assam, India

Epidemiological investigations were conducted in Nellie subcentre, PHC Jhargaon, under Morigaon district (Assam). The results of fever cases revealed 68 per cent slide positivity rate (SPR) and 40 per cent slide falciparum rate (SfR). The Pf proportion was > 87 per cent and remaining cases were P. vivax infections. An. minimus was incriminated as a malaria vector during the study period. The sporozoite rate was 3.08 per cent. The indoor man mosquito contact was 35 per bait/night as against 23 in outdoors. Results of susceptibility test revealed that the vector was still susceptible to both DDT and malathion at discriminating dosages. The study revealed that inadequate surveillance and vector control measures were contributing factors for malaria outbreak. In view of this, insecticide treated nets may be introduced to provide cost-effective control of malaria.     

Diagnosis of imported malaria by Plasmodium lactate dehydrogenase (pLDH) and histidine-rich protein 2 (PfHRP-2)-based immunocapture assays.

This study was conducted to evaluate the performance of two rapid non-microscopic assays: Plasmodium lactate dehydrogenase (pLDH) assay (OptiMAL) and Plasmodium falciparum histidine-rich protein 2 (PfHRP-2) assay (ICT Malaria). The assays were used to detect malaria infection in 515 immigrants living in Kuwait. The performance of both assays was compared to that of microscopy of Giemsa-stained thick blood films and to each other. Of the 515 patients tested, 163 were positive for malaria parasites by microscopy of thick blood film. Of these, 87 were infected with Plasmodium vivax parasites, 63 with P. falciparum, 1 with Plasmodium malariae, and 12 had mixed infections of P. falciparum and P. vivax. The PfHRP-2 assay detected 53 P. falciparum infections and, as expected, failed to detect all but one case of P. vivax. Three cases of mixed infections were also not detected by this assay. The pLDH assay detected 56 P. falciparum cases and 77 P. vivax infections but failed to detect 4 cases of mixed infections. Compared to microscopy, the performance of both the assays to diagnose P. falciparum infection was comparable. The sensitivity for the PfHRP-2 assay was 82% with a specificity of 99.0% and for the pLDH assay the sensitivity was 89% with a specificity of 99.5%. The PfHRP-2 assay detected 4 false positive cases, 2 of which were also detected by the pLDH assay. These patients reported treatment with chloroquine in the last 2-5 weeks. Though the immunocapture diagnostic assays may be helpful in certain situations, microscopy of thick blood film is still the method of choice in diagnosing imported malaria.     

Chemoembolization in hepatocellular carcinoma: multivariate analysis of survival prognostic factors after the first session

AIM: The aim of the study was to determine whether simple routine parameters evaluating the first session of transarterial chemoembolization (variation in alfa-fetoprotein concentration, tumor lipiodol uptake, and post-embolization syndrome) can predict survival of patients treated for hepatocellular carcinoma. METHODS: Seventy-two patients treated with transarterial chemoembolization and evaluated one month after the first sessions with CT scan were included. Transarterial chemoembolization session included hepatic arteriography, lipiodol and doxorubicin (50 mg) emulsion injection, followed by gelatin sponge embolization. The following variables were studied in univariate and multivariate analysis: 6 recorded at the first session (age, cirrhosis etiology, Child-Pugh class, tumor number, largest lesion size, and alpha-fetoprotein concentration), and 5 recorded after the first session (variation in alfa-fetoprotein concentration, tumor lipiodol uptake, post-embolization syndrome, mean interval between each session, and associated treatment). RESULTS: Mean follow-up was 22.7 months (4-106). Mean survival was 30.4 months (95% CI: 23. 3-37.5). Actuarial survival at 1, 2, 3 and 5 years was respectively 65.5%, 44%, 29.5%, and 18%. The only independent prognostic factors in multivariate analysis were the Child Pugh class and the mean interval between sessions (P<0.001 and<0.01 respectively). None of our criteria evaluating the first TACE session significantly influenced survival. CONCLUSION: The 3 parameters (variation in alpha-fetoprotein concentration, tumor lipiodol uptake and post-embolization syndrome) after the first transarterial chemoembolization did not predict survival. They could not be used to determine which patient could benefit from repeated transarterial chemoembolization sessions.     

Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B

We have analyzed the molecular dynamics of emergence of drug-resistant strains in patients receiving lamivudine therapy for chronic hepatitis B. Twenty consecutive patients with lamivudine resistance were studied (13 hepatitis B e antigen [HBeAg]-positive patients and 7 HBe antibody [anti-HBe]-positive patients). Determination of viral genotype, precore mutants, and polymerase gene mutants (L528M, M552V, M552I) was performed using the research version of Lipa-HBV. Quantitative analysis of HBV DNA was performed using both branched DNA (bDNA) and polymerase chain reaction (PCR) assays. Polymerase mutants (genotypic resistance) were found in 16 of 20 patients. Genotypic resistance was detected earlier than the phenotypic resistance (P =.004). Quantitative PCR allowed detection of viral DNA throughout the entire study period in 16 of 20 patients. Analysis of pretreatment variables showed that high alanine transaminase (ALT) levels (>3 x the upper limit of normal [ULN]) was associated with a more rapid selection of drug-resistant mutants (P =.027) and a high hepatitis B virus (HBV) DNA level (>1,497 Meq/mL, bDNA) with a more rapid occurrence of phenotypic resistance (P =.04). At the time of viral breakthrough, the mean serum HBV-DNA values were not different from the pretreatment values (P =.37). ALT levels were higher in anti-HBe-positive patients compared with pretreatment values and to HBeAg-positive patients (P =.01). In 8 patients, antiviral therapy was modified after viral breakthrough, with the introduction of famciclovir and/or interferon alfa. Viral DNA became undetectable by bDNA in 3 patients who received interferon. Our results suggest that genotypic assays for polymerase mutant detection and quantitative determination of viremia with highly sensitive assay are warranted for an optimal monitoring of antiviral therapy of chronic hepatitis B.     

Next-Generation Sequencing Based Approach to Identify Underlying Genetic Defects of Glanzmann Thrombasthenia

Glanzmann thrombasthenia (GT) is an autosomal recessive platelet function disorder characterized by mucocutaneous bleeding as the most common clinical phenotype. Patients with GT have normal platelet counts, platelet morphology but reduced platelet aggregation in response to various agonists. Homozygosity or compound heterozygosity for variants in the ITGA2B/ITGB3 genes is the genetic basis for GT. Establishing a molecular diagnosis is definitive and is important for predictive testing. Using multi-gene panels is an accurate, faster, and cost-effective mode as compared to Sanger sequencing in large genes. We used a targeted resequencing based approach to identify pathogenic variants in eight cases in seven families. These variants were validated using Sanger sequencing in patients as well as family members and were predicted probably pathogenic using in-silico prediction tools. The variants include three missense (3/7 = 43%) (ITGA2B:c.1028 T > C, ITGA2B:c.1186G > A, ITGB3:c.1388G > C), two deletions (ITGA2B:c.559delG, ITGA2B:c.3092delT), one duplication (ITGA2B:c.1424_1427dupAGGT) and nonsense variant (ITGA2B:c.2578C > T, p.Gln860Ter). Except for one case which was compound heterozygous, the rest of the cases were homozygous. We found two novel variants that are reported for the first time in GT. The targeted resequencing based approach revealed varied genetic variants in North Indian patients, including two novels ones. The high yield of our panel indicates its suitability for usage in larger cohorts for the genetic diagnosis of GT patients. This approach is cost-effective and less cumbersome as compared to Sanger sequencing for these large size genes with multiple exons. The information so obtained is helpful in prenatal testing, carrier analysis, and genetic counseling.     

Vasostatin,a Calreticulin Fragment,Inhibits Angiogenesis and Suppresses Tumor Growth

An endothelial cell inhibitor was purified from supernatant of an Epstein-Barr virus–immortalized cell line and identified as fragments of calreticulin. The purified recombinant NH₂-terminal domain of calreticulin (amino acids 1–180) inhibited the proliferation of endothelial cells, but not cells of other lineages, and suppressed angiogenesis in vivo. We have named this NH₂-terminal domain of calreticulin vasostatin. When inoculated into athymic mice, vasostatin significantly reduced growth of human Burkitt lymphoma and human colon carcinoma. Compared with other inhibitors of angiogenesis, vasostatin is a small, soluble, and stable molecule that is easy to produce and deliver. As an angiogenesis inhibitor that specifically targets proliferating endothelial cells, vasostatin has a unique potential for cancer treatment.