Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes.

This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, -2-30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P<0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival.

Severe weight loss in 3 months after allogeneic hematopoietic SCT was associated with an increased risk of subsequent non-relapse mortality.

Patients after allogeneic hematopoietic SCT (HSCT) are at risk of malnutrition. To assess the impact of malnutrition after allogeneic HSCT on transplant outcomes, we conducted a retrospective study. Adult patients who received allogeneic HSCT from 2000 to 2009 for standard-risk leukemia and achieved disease-free survival up to 3 months after allogeneic HSCT were included. From participating centers, 145 patients were enrolled. Median age was 46 years (19-68). Patients were classified based on weight loss during 3 months after allogeneic HSCT as follows: normal group (weight loss <5%, n=53), mild malnutrition group (5%⩽weight loss<10%, n=47), severe malnutrition group (10% ⩽weight loss, n=45). The cumulative incidences of 2-year nonrelapse mortality (NRM) were 3.8% in the normal group, 8.5% in the mild malnutrition group and 27.3% in the severe malnutrition group. The probabilities of a 2-year OS were 73.2% in the normal group, 74.5% in the mild malnutrition group and 55.3% in the severe malnutrition group. In multivariate analysis, severe malnutrition was associated with an increased risk of NRM and a worse OS. In conclusion, weight loss ⩾10% was associated with a worse clinical outcome. Prospective studies that identify patients at risk of malnutrition and intervention by a nutritional support team are warranted.

Prospective study of dental intervention for hematopoietic malignancy.

Various chemotherapeutic agents used in patients with hematopoietic malignancy cause serious side effects, including myelosuppression and immunosuppression. Immunosuppression makes patients more susceptible to infection, resulting in an increased risk of infectious complications, including the development of severe septicemia that may be life-threatening. It is necessary for dental staff to be familiar with an appropriate protocol in such cases and to share information about the chemotherapy with a hematologist. To verify the effectiveness of our dental intervention protocol, we conducted a prospective study on the incidence of complications for each myelosuppressive grade of chemotherapy in patients with hematopoietic malignancy. We compared the incidence of complications between treatment P (patients who finished all the dental treatments according to the protocol) and treatment Q (patients who did not) per grade (A, B, C, D) and incidence of systemic or oral findings. We also compared the incidence of oral complication related to the residual teeth between first chemo (patients who were undergoing chemotherapy for the first time) and prior chemo (not the first time). There were significant differences in inflammatory complications between treatment P and treatment Q. We found that both systemic and oral inflammatory complications increased with higher-grade myelosuppressive chemotherapy. Additionally, there was a significant difference between the incidence of oral complications related to the residual teeth between first chemo and prior chemo. Complete implementation of the dental intervention protocol was associated with fewer oral and systemic infectious and inflammatory complications in patients with hematopoietic malignancies undergoing chemotherapy. The incidence of oral and systemic complications also increased with grade of chemotherapy. These results support the validity of our dental intervention protocol. We should pay close attention to the oral state of de novo hematopoietic malignancy patients.

Recent decrease in non-relapse mortality due to GVHD and infection after allogeneic hematopoietic cell transplantation in non-remission acute leukemia.

Although recent improvements have been indicated in the outcome after allogeneic hematopoietic cell transplantation (allo-HCT), little information is available on how changes in transplant modalities have affected the outcomes after allo-HCT in non-remission, based on patient age, donor source and disease type. We compared the incidence and causes of non-relapse mortality (NRM) after allo-HCT in non-remission among three consecutive four-year periods using a nationwide transplant outcome registry database. A total of 3308 patients with acute leukemia in non-remission were analyzed. The risk of NRM decreased over the three periods, and the hazard ratios (HRs) in 2001-2004 and 2005-2008 compared with 1997-2000 were 0.86 (95% CI, 0.70-1.06; P=0.16) and 0.65 (95% CI, 0.53-0.80; P<0.01), respectively. A significant decrease in the HR for overall mortality was also observed in 2005-2008 (HR 0.85; 95% CI, 0.75-0.97; P=0.02). We found that a decrease in the incidences of death due to GVHD and infection contributed to the reduction in NRM, to which high-resolution donor-recipient HLA matching and other improvements may have contributed. As none of the subgroups showed improved survival without a reduction in NRM, the effective prevention of transplant-related complications appears to be necessary for improving outcomes after allo-HCT in non-remission.

Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry.

The outcomes for allogeneic hematopoietic cell transplantation (allo-HCT) are heavily influenced by non-relapse mortality (NRM). We retrospectively assessed the changes in the incidence and causes of NRM after allo-HCT over the past 12 years. NRM, relapse rate and OS were analyzed using the Japan transplant outcome database of 6501 adult patients with acute leukemia or myelodysplastic syndrome who received their first allo-HCT in remission from 1997 through 2008. In multivariate analysis in patients aged 16-49 years, the adjusted hazard ratios (HRs) for NRM for 2001-2004 and 2005-2008 were 0.78 (95% confidence interval, 0.65-0.93) and 0.64 (0.54-0.78), respectively, compared with 1997-2000. The HR for overall mortality in 2005-2008 was 0.81 (0.70-0.93) compared with 1997-2000. In patients aged 50-70 years, the HRs for NRM and overall mortality in 2005-2008 were 0.56 (0.46-0.68) and 0.66 (0.47-0.93), respectively, compared with those in 2001-2004. We found that causes of death that contributed to the changes in NRM varied among subgroups. In conclusion, our study indicated that the incidence of NRM after allo-HCT has significantly decreased over the past 12 years, which has led to an improvement of OS, and also showed reductions in NRM in subgroups consisting of older patients and those who received unrelated cord blood transplantation.

Early full donor myeloid chimerism after reduced-intensity stem cell transplantation using a combination of fludarabine and busulfan.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate lineage-specific chimerism reconstitution after reduced-intensity allogeneic stem cell transplantation (RIST) using a combination of fludarabine (30 mg/m2 for 6 days) and busulfan (4 mg/kg for 2 days). DESIGN AND METHODS: We prospectively enrolled 8 consecutive patients with hematologic malignancies who were not candidates for conventional transplantation because of either high age or organ dysfunction. Host-donor chimerism was evaluated using polymerase chain reaction-based amplification of a polymorphic short tandem repeat region. RESULTS: All of our patients achieved engraftment within a median of 11 days after transplantation. On day 30, full donor myeloid cell chimerism (>90%) was achieved in 7 patients whereas full donor T-cell chimerism was achieved in only one patient. Thus, in contrast to other reported results, full donor chimerism was achieved earlier in the myeloid lineage than the T-cell lineage. On day 60, however, T-cell chimerism caught up with myeloid chimerism. Two patients developed grade II-IV acute graft-versus-host disease (GVHD) before the detection of full donor T-cell chimerism. INTERPRETATION AND CONCLUSIONS: Our findings suggest that the kinetics of lineage-specific chimerism depend on the agents used in the conditioning regimen, and may provide insight into the chimerism kinetics and pathogenesis of GVHD. Thus, the strategy for controlling immunosuppression after RIST should be modified according to the type of conditioning regimen applied.

T-cell receptor gammadelta T-cell leukemia with the morphology of T-cell prolymphocytic leukemia and a postthymic immunophenotype.

T-cell prolymphocytic leukemia (T-PLL) is a postthymic T-cell neoplasm with a characteristic morphology and heterogeneous immunophenotype. Most cases of T-PLL express membrane T-cell receptors (TCRs) of the alphabeta phenotype. We experienced a 30-year-old man suffering from TCRgammadelta T-cell leukemia with morphology compatible to T-PLL with a postthymic phenotype. He was admitted with skin eruption and pancytopenia. Peripheral blood and bone marrow were occupied with medium-sized lymphocytes, which had moderately condensed chromatin with a single nucleolus and sparse, nongranular basophilic cytoplasm. The immunophenotype was CD1a-, CD2-, CD3+, CD4-, CD5+, CD7+, CD8-, and terminal deoxynucleotidyl transferase negative. Hepatosplenomegaly was absent. He was diagnosed as having T-PLL and was treated with combination chemotherapy. Six months later the leukemic cell became chemoresistant. Although the patient showed transient improvement in response to pentostatin, he died 13 months after the diagnosis. To our knowledge, this is the first case of T-PLL with a TCRgammadelta phenotype.

Synthesis of slagenins A, B, and C.

[structure: see text] A short synthesis of the marine sponge metabolites slagenins A (1), B (2), and C (3) is described. The synthetic route features the preparation of beta-hydroxyimidazolone 4 from ornithine and its subsequent oxidative cyclization to the slagenin core.

A facile synthesis of dragmacidin B and 2,5-bis(6'-bromo-3'-indolyl)piperazine.

A short synthesis of dragmacidin B (1), 2,5-bis(6'-bromo-3'-indolyl)piperazine (2), and corresponding didebromo analogues 8 and 9 is described. The key steps involve the dimerization of oxotryptamines 4 and 11 to give bis(indolyl)pyrazines 5 and 12, which upon selective reduction and reductive methylation with sodium cyanoborohydride afforded the requisite piperazine natural products.

A concise synthesis of topsentin A and nortopsentins B and D.

[reaction: see text] A concise synthesis of topsentin A (R(1) = R(2) = H) and nortopsentins B (R(1) = Br, R(2) = H) and D (R(1) = R(2) = H) is described from oxotryptamine 5 via reduction of acyl cyanide 4. Regiospecific bromination of 3-cyanoindole afforded 6-bromo-3-cyanoindole (10) as the major product.

Genetic variation in the promoter region of the beta-fibrinogen gene is associated with ischemic stroke in a Japanese population.

Evidence suggests that an allelic variation in the beta fibrinogen gene may confer an increased risk of coronary artery disease and stroke. The role of the beta fibrinogen gene polymorphism and fibrinogen levels in ischemic stroke has not been determined in Japanese, who are more prone to stroke than to coronary artery disease compared with Caucasians. We investigated the associations between ischemic stroke, plasma fibrinogen level, and a HaeIII restriction fragment length polymorphism (G/A(-455)) located at -455 bp from the start of transcription of the beta fibrinogen gene in 85 hypertensive patients with ischemic stroke (stroke group), 85 hypertensive patients without ischemic stroke (nonstroke group) and in 84 normotensive subjects matched for age, sex, and smoking status recruited at an annual health examination (normotensive group). The frequency of non-cutting allele (designated A(-455) allele) in the control group was 0.07 [95% CI: 0.03-0.11]; this value was significantly lower than that previously reported in Caucasians (0.19-0.26). The A(-455) allele frequency of the nonstroke group and stroke group were 0.08 [95% CI: 0.04-0.12] and 0.15 [95% CI: 0.10-0.21]. A(-455) allele frequency of the stroke group was significantly higher than that of the control group chi2 = 5.63, P= 0.018) and the nonstroke group chi2 = 4.00, P= 0.043). The mean +/- SD fibrinogen level was significantly higher in the stroke group than that in the normotensive group (277 +9/- 64 mg/dl versus 257 +/- 52 mg/dl, P < 0.03), but that of the nonstroke group was not significantly different compared with both normotensive and stroke groups. In conclusion, the positive association between the fibrinogen genotype G/A(-455) and ischemic stroke in hypertensive patients was independent of other risk factors. These results suggest that fibrinogen A(-455) allele may be an independent risk factor for ischemic stroke in the Japanese population.

Factor VII R353Q polymorphism and lacunar stroke in Japanese hypertensive patients and normotensive controls.

Elevated plasma factor VII (FVII) levels are reported to be associated with cardiovascular disease in both Caucasians and Japanese. Recent reports indicate that individuals with the FVII 353Q allele have decreased plasma FVII levels. Thus, we investigated the association between lacunar stroke and the FVII R353Q polymorphism in 137 hypertensive patients with silent or overt lacunar stroke (stroke group), 83 non-stroke hypertensives without any lacunae detected by magnetic resonance imaging (non-stroke group), and 97 normotensive control subjects matched for age, sex, and smoking status recruited at an annual health examination (normotensive control group). The frequency of the FVII 353Q allele was 0.057 in the normotensive control group, 0.051 in the non-stroke group and 0.061 in the stroke group. These frequencies, as well as genotype distribution, were not significantly different from each other, even when we subclassified the ischemic group into silent (n = 54) and clinically overt (n = 64) lacunar stroke subgroups. These results suggest that the FVII 353Q allele is not an important genetic determinant for cerebrovascular disease in Japanese individuals.