Clinical features of patients with infections caused by Candida guilliermondii and Candida fermentati and antifungal susceptibility of the isolates at a medical centre in Taiwan, 2001-10.

OBJECTIVES: This study was intended to analyse the clinical characteristics and outcomes of patients with infections due to Candida guilliermondii complex and evaluate in vitro susceptibilities of the isolates. METHODS: We searched the Mycology Database of the National Taiwan University Hospital and identified patients with infections due to C. guilliermondii complex from 2001 to 2010. Isolates were identified to species level by two yeast identification systems and restriction fragment length polymorphism of the riboflavin synthetase gene. MICs of nine antifungal agents were determined using the Sensititre YeastOne system (Trek Diagnostic Systems) and were interpreted by breakpoints (BPs) for three echinocandins and epidemiological cut-off values (ECVs) for the other agents. RESULTS: Fifty-two patients with infections due to C. guilliermondii complex were evaluated. The majority (90%, n = 47) of the isolates were C. guilliermondii, followed by Candida fermentati (10%, n = 5). Among them, 42 (81%) were isolated from blood cultures. Among the 52 patients, 27 (52%) had underlying malignancy and 15 (29%) had undergone abdominal surgery. The 30 day mortality rates among patients with C. guilliermondii and C. fermentati infections were 45% and 60%, respectively. Among C. guilliermondii isolates, 98%, 100% and 98% were susceptible to caspofungin, micafungin and anidulafungin, respectively, by BPs. Nearly all (96%-100%) C. guilliermondii isolates belonged to wild-type for the other agents by ECVs. All five C. fermentati were susceptible to three echinocandins and belonged to wild-type for the other agents. CONCLUSIONS: The currently used antifungal agents exhibited good in vitro activities against C. guilliermondii complex isolates.

Clinical and microbiological characteristics of perianal infections in adult patients with acute leukemia.

BACKGROUND: Perianal infection is a common problem for patients with acute leukemia. However, neutropenia and bleeding tendency are relatively contraindicated to surgical intervention. The epidemiology, microbiology, clinical manifestations and outcomes of perianal infection in leukemic patients are also rarely discussed. METHOD: The medical records of 1102 adult patients with acute leukemia at a tertiary medical center in Taiwan between 2001 and 2010 were retrospectively reviewed and analyzed. RESULT: The prevalence of perianal infection was 6.7% (74 of 1102) in adult patients with acute leukemia. Twenty-three (31%) of the 74 patients had recurrent episodes of perianal infections. Patients with acute myeloid leukemia had higher recurrent rates than acute lymphoblastic leukemia patients (p = 0.028). More than half (n = 61, 53%) of the perianal infections were caused by gram-negative bacilli, followed by gram-positive cocci (n = 36, 31%), anaerobes (n = 18, 15%) and Candida (n = 1, 1%) from pus culture. Eighteen patients experienced bacteremia (n = 24) or candidemia (n = 1). Overall 41 (68%) of 60 patients had polymicrobial infection. Escherichia coli (25%) was the most common micro-organism isolated, followed by Enterococcus species (22%), Klebsiella pneumoniae (13%), and Bacteroides species (11%). Twenty-five (34%) of 74 patients received surgical intervention. Acute leukemia patients with surgically managed anal fistulas tended to have fewer recurrences (p = 0.067). Four (5%) patients died within 30 days after diagnosis of perianal infection. Univariate analysis of 30-day survival revealed the elderly (≧ 65 years) (p = 0.015) and patients with shock (p<0.001) had worse outcome. Multivariate analysis showed septic shock to be the independent predictive factor of 30-day crude mortality of perianal infections (p = 0.016). CONCLUSION: Perianal infections were common and had high recurrence rate in adult patients with acute leukemia. Empirical broad-spectrum antibiotics with anaerobic coverage should be considered. Shock independently predicted 30-day crude mortality. Surgical intervention for perianal infection remains challenging in patients with acute leukemia.

Clinical characteristics of candidaemia in adults with haematological malignancy, and antimicrobial susceptibilities of the isolates at a medical centre in Taiwan, 2001-2010.

During the period 2001-2010, a total of 154 episodes of candidaemia were noted in 111 of 2574 patients with haematological malignancies at the National Taiwan University Hospital (Taipei, Taiwan). Patients with acute lymphoblastic leukaemia had a significantly higher rate of candidaemia than patients with other haematological malignancies (odds ratio=2.69; P<0.001). Candida tropicalis was the most common Candida species (n=51; 46%), followed by Candida albicans (n=35; 32%), Candida parapsilosis (n=13; 12%), Candida glabrata (n=8; 7%) and Candida krusei (n=4; 4%). Persistent candidaemia was initially identified in 21 patients (18.9%) and was frequently associated with central venous catheter-related infection (52% vs. 24%; P=0.017). Multivariate analysis revealed that shock (P<0.001), allogeneic transplantation (P=0.033) and elderly age (≥60 years) (P=0.041) were independent prognostic factors of 30-day overall survival in patients with haematological malignancy and candidaemia. Minimum inhibitory concentrations (MICs) of a total of 103 non-duplicate blood isolates of Candida spp., including 82 isolates from 82 patients without persistent candidaemia and 21 isolates causing first episodes among 21 patients with persistent candidaemia, to nine antifungal agents were determined using the broth microdilution method. Among the 103 Candida isolates, 53 (51.5%), 94 (91.3%) and 102 (99.0%) were susceptible to itraconazole, fluconazole and voriconazole, respectively. All Candida isolates were susceptible to caspofungin, and 2 (15%) of the 13 C. parapsilosis isolates were not susceptible to micafungin or anidulafungin. The MIC(90) (MIC for 90% of the organisms) of posaconazole was 0.03 mg/L for C. albicans, 0.5 mg/L for C. tropicalis, 0.12 mg/L for C. parapsilosis and 2 mg/L for C. glabrata.

HLA-DR-matched parental donors for allogeneic hematopoietic stem cell transplantation in patients with high-risk acute leukemia.

The immunomodulating effect of human leukocyte antigen (HLA)-DR and the central role of CD4 T cells in alloimmunity provide clues suggesting that HLA-DR-matched, partially mismatched related donors could be feasible alternative donors of allogeneic hematopoietic stem cells for transplantations (allo-HSCT). We describe our experience with allo-HSCT in eight patients with high-risk acute leukemia; donors included one of each of the parents. Among the eight patients, seven were identical HLA-DR matches with the donors. The stem cells were not manipulated in vitro. Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, cyclosporine, and methotrexate. All patients had successful trilineage engraftment. Only one patient had grade 2-4 acute GVHD. Two patients died before day +100 due to complications. At the end of follow-up, four patients had survived for 18-48 months and three are alive and without relapse. Our results suggest that HLA-DR fully-matched parents are feasible alternative donors for allo-HSCT in patients with high-risk acute leukemia under an intensive conditioning regimen.

Clinical characteristics and treatment response of Hodgkin's lymphoma in Taiwan.

BACKGROUND/PURPOSE: Hodgkin's lymphoma (HL) is particularly rare in Asia, including Taiwan. The report concerning its clinical features and treatment outcomes in Asians is limited. An exploration of the characteristics of HL in this area is of importance for future studies. METHODS: In this study, 133 patients with HL diagnosed between January 1985 and December 2004 at National Taiwan University Hospital were analyzed retrospectively. RESULTS: The age distribution revealed a young-adult peak at the age around 20 years. The nodular sclerosis type (NS-HL) was the most common histopathologic subtype (45%), followed by mixed cellularity (29%), lymphocyte predominant (13%), and lymphocyte depleted subtype (2%). The incidence of NS-HL was, however, lower compared with that in the West (around 70%). The male to female ratio was approximately 1:2 in patients with NS-HL, in contrast to the male predominance in patients with other subtypes. Induction therapy led to complete remission (CR) in 87% of patients. At a median follow-up of 78 months, the 10-year overall survival (OS) was 79% in all HL patients and was 90% in those who achieved first CR. In multivariate analysis, the achievement of CR was the only independent factor associated with good OS. CONCLUSION: The treatment response of HL in Taiwan is good and comparable to that in Western countries. The epidemiologic differences between Taiwan and the West mandate further studies.

RUNX1 gene mutation in primary myelodysplastic syndrome--the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome.

Mutations of Runt-related transcription factor 1 (RUNX1) have been detected in patients with myelodysplastic syndrome (MDS). However, the prognostic implication of RUNX1 mutations in primary MDS is limited. The stage of the disease at which the mutations are acquired and whether they persist during the disease course also remain unclear. We analysed mutations of RUNX1 exons 3-8 in 132 patients with primary MDS and correlated the results with clinical features. Serial studies were performed during the follow-up period. Sixteen patients (12%) had RUNX1 mutations at the time of diagnosis. All RUNX1 mutations that were detected at diagnosis remained unchanged during the clinical course. Two other patients acquired RUNX1 mutations at leukaemic transformation 34 months and 35 months after the diagnosis of MDS. Patients with RUNX1 mutations at diagnosis had higher neutrophil counts and higher frequency of -7/7q deletion than those without. Furthermore, RUNX1 mutation was closely associated with a short overall survival (P = 0.039). This is the first report to demonstrate that RUNX1 mutation can not only be detected early at diagnosis but also acquired during disease progression and is associated with poor prognosis in patients with primary MDS. It may play a role in the development and progression of a subset of primary MDS.

Severe pulmonary complications after initial treatment with Rituximab for the Asian-variant of intravascular lymphoma.

Rituximab improves response to treatment and outcome for patients with CD20+ B-cell lymphoma. Herein, however, we report the occurrence of severe pulmonary complications shortly after rituximab infusion in three patients with the newly diagnosed Asian variant of intravascular lymphoma. It is suggested that patients with this subtype of lymphoma are monitored carefully for possible drug reactions during the use of rituximab.

Clinical implications of SOCS1 methylation in myelodysplastic syndrome.

The suppressor of cytokine signalling-1 (SOCS1) protein is a tumour suppressor. Hypermethylation of SOCS1 gene, resulting in transcriptional silencing, is suggested to play an important role in cancer development. We sought to characterise SOCS1 methylation in primary myelodysplastic syndrome (MDS) and clarify its clinical implications. The methylation status of SOCS1 was analysed by methylation-specific polymerase chain reaction in 114 patients with primary MDS and serial studies were performed in 29 of them. SOCS1 methylation occurred in 54 patients (47.4%), and was more frequent in patients with high-risk MDS than in those with low-risk (52.6% vs. 25.8%, P = 0.011). SOCS1 methylation was closely associated with NRAS mutation (P = 0.010) and inversely associated with good-risk karyotype (P = 0.021). With a median follow-up of 17 months (range: 1-231 months), two patients acquired SOCS1 methylation during disease progression. In two patients, SOCS1 methylation present at diagnosis, disappeared after haematopoietic stem cell transplantation. Patients with SOCS1 methylation had a higher cumulative risk of leukaemic transformation than those without (55.8% vs. 27.7% at 3 years, P = 0.004). This difference remained significant within the subgroup of patients with high-risk MDS (67.3% vs. 45.1% at 3 years, P = 0.045). This is the first report to demonstrate the clinical relevance of SOCS1 methylation in MDS. It may play an important role in the pathogenesis of MDS, especially among patients with high-risk subtypes.

Reduction of leukocyte count is associated with thalidomide response in treatment of multiple myeloma.

Fifty Taiwanese patients with relapsed and/or refractory multiple myeloma (MM) were treated with thalidomide on a dose-escalation schedule, commencing with 100 mg/d nightly and incremented either to the maximally tolerated dose or 800 mg/d. Twenty-two patients (44%) responded, with 10 (45.5%) classified as partial remission and 12 (54.5%) minimal response (MR). Complete response did not occur. Of the 28 non-responders, 14 were progressive disease and 14 stable. The median time from commencement of thalidomide treatment to initial achievement of MR was 29 days (range, 8~155), and the corresponding thalidomide dose was 200 mg/d (range, 100~500). The median tolerated dose of thalidomide for the entire sample was 400 mg/d (range, 100~800), with only two (4%) able to tolerate 800 mg/d. Comparing responsive and non-responsive patients, statistically significant differences were not demonstrated for any characteristics except for CRP level and percentage cytogenetic change, which was slightly higher in the latter group relative to the former. Of particular interest, 18 of the 22 responders experienced transient reduction of leukocyte count preceding the attainment of significant reduction in M-proteins in comparison to only four of the 28 non-responders (82% vs. 14%; p<0.001). The median time from commencement of thalidomide treatment to attainment of minimal leukocyte count was 28 days (range, 7~150), with a mean of 2.19x10(9)/l (range, 0.96~3.35x10(9)/l). Leukopenia was generally transient, with rapid recovery despite subsequent continuation of thalidomide. Levels of other non-hematologically adverse effects attributed solely to thalidomide were generally acceptable. For 25 patients, thalidomide treatment was supplemented with low-dose dexamethasone (4 mg, every other day). Of these, 11 had relapsed from and 14 were primarily refractory to thalidomide treatment. Nine of the 25 dexamethasone-supplemented patients were responders (36%). Of particular note were the unusual events noted with this thalidomide-dexamethasone combination, including vascular thrombosis, acute cholecystitis, idiopathic interstitial lung disease and sudden cardiac death. Our results suggest that thalidomide is also effective for Taiwanese patients with refractory and/or relapsed MM. Importantly, the transient reduction in leukocyte count after commencement of thalidomide treatment may serve as a clinical predictor for response. Adverse effects should be carefully monitored when combining thalidomide and dexamethasone, however.