Hui-Chi Hsu

A Comparative Study of Cefepime versus Ceftazidime as Empiric Therapy of Febrile Episodes in Neutropenic Patients

An open-label, randomized comparative study was conducted to evaluate the efficacy and safety of cefepime (2.0 g q. 8 h) and ceftazidime (2.0 g q. 8 h) in the empiric therapy of febrile neutropenic patients. A total of 45 eligible febrile episodes were randomized (1:1) to be treated with the study regimen. Nineteen febrile episodes treated with cefepime and 22 febrile episodes treated with ceftazidime were evaluable for efficacy. The two groups were comparable in terms of age, sex, height, weight, underlying neoplasm, number of pretherapy neutrophil, duration of neutropenia and types of infections. The overall therapeutic success rate of the cefepime group (53%) was comparable to the ceftazidime group (50%). It did not differ significantly (95% confidence interval: –0.28 to 0.34, p = 0.85). Eighty-eight percent of pathogens in each group were bacteriologically eradicated. The safety profile was similar in both groups. No patients in either group discontinued the therapy because of adverse events. None (0%) of the cefepime patients and 2 (9%) of the ceftazidime patients died of infection. The results of this study suggest that cefepime is an effective and safe agent in the empiric therapy of febrile episodes in neutropenic patients.

Low absolute lymphocyte count and addition of rituximab confer high risk for interstitial pneumonia in patients with diffuse large B-cell lymphoma

Several small-scale studies have reported pulmonary toxicity among patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-containing chemotherapy, though whether the use of rituximab predisposes to interstitial pneumonia (IP) remains unclear. This retrospective study was intended to identify the characteristics and risk factors of IP in patients with DLBCL. Between 2000 and 2009, 529 consecutive patients with DLBCL receiving first-line tri-weekly COP- or CHOP-based chemotherapy with or without rituximab were enrolled as subjects. IP was defined as diffuse pulmonary interstitial infiltrates found on computed tomography scans in conjunction with respiratory symptoms. IP was observed in 26 patients (4.9%), six of whom were confirmed with Pneumocystis jirovecii pneumonia. The median number of chemotherapy courses before IP was four cycles. Using multivariate analysis, absolute lymphocyte count less than 1 × 109/l at diagnosis [odds ratio (OR) 2.75, p = 0.014] and the addition of rituximab to chemotherapy (OR 4.56, p = 0.003) were identified as independent risk factors for IP. In conclusion, the incidence of IP is increased in patients with DLBCL receiving rituximab-containing chemotherapy. Specific subgroups with lymphopenia at diagnosis may justify close scrutiny to detect pulmonary complications.

Influence of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, B vitamins and other factors on plasma homocysteine and risk of thromboembolic disease in Chinese

Background: Thromboembolic disease is a major cause of morbidity and mortality in many countries. Our previous study found that Chinese subjects carried the same polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene as described in Western studies. The aim of the present study was to determine the influence of MTHFR polymorphism, B vitamins and other factors on plasma homocysteine (Hcy) levels and risk of thromboembolic disease in Chinese. Methods: One hundred and six subjects were enrolled into the study. They were categorized into 4 groups: healthy individuals (n = 42); those with diabetes mellitus (n = 20); those with deep vein thrombosis (DVT) (n = 11); and those with coronary artery disease (CAD) (n = 33). Plasma levels of folic acid, vitamins B6 and B12, Hcy, and fasting blood sugar were measured; total cholesterol, triglycerides, complete blood count, and 677 C?T mutation in MTHFR were determined. Results: Plasma Hcy was lowest in the healthy subjects, higher in diabetics, followed by patients with DVT, and highest in patients with CAD (p < 0.001, ANOVA). MTHFR C677T polymorphism was the common factor affecting plasma logHcy levels in all 4 groups of subjects. Triglycerides affected plasma logHcy in the CAD patients. For the 4 groups as a whole, MTHFR polymorphism, triglycerides, and vitamin B12 were the most significant factors influencing plasma Hcy. Conclusion: We suggest that high plasma Hcy is an important risk factor for CAD. Other factors including MTHFR polymorphism, vitamin B12, triglycerides, total cholesterol, and gender might affect Hcy levels in different diseases and conditions.

Pure red cell aplasia after ABO-incompatible allogeneic stem cell transplantation in severe aplastic anemia with response to steroids: a case report and literature review.

Abstract. Pure red cell aplasia (PRCA) is a rare complication after ABO-incompatible allogeneic stem cell transplantation, but its mechanism is still unknown. Here we report on a patient with severe aplastic anemia who developed PRCA after HLA-identical but major ABO-mismatched peripheral blood stem cell transplantation. Erythroid engraftment was successful with primary steroid treatment. We concluded that an adequate dose of steroids can be the first line of therapy for PRCA after ABO-mismatched allogeneic stem cell transplantation.

A novel splicing acceptor mutation of the factor VIII gene producing skipping of exon 25

A gross deletion in the factor VIII (FVIII) mRNA was determined by reverse transcriptase polymerase chain reaction (RT-PCR) for a patient with moderately severe hemophilia A. Sequencing of the RT-PCR product depicted a 177-bp deletion ranging from nucleotide (nt) 6724 to nt 6900 of FVIII cDNA, exactly corresponding to the whole exon 25. Further study of the genomic DNA revealed the presence of a single base pair substitution (G >A) at position –1 of intron 24. The absolute consensus AG doublet of the intron 24 splicing acceptor changed to AA. In the novel splice site mutation, exon 24 was erroneously spliced to exon 26, skipping exon 25. The FVIII antigen level was normal despite the markedly reduced functional activity. Since exon 25 corresponds to part of the C2 domain, we speculate that for this patient the aberrant C2 domain markedly reduces binding affinity of FVIII protein to the phospholipid membrane, thus severely impairing the protein function.

Blockade of JAK2 activity suppressed accumulation of β‐catenin in leukemic cells

The Wnt/β‐catenin pathway has been implicated in leukemogenesis. We found β‐catenin abnormally accumulated in both human acute T cell leukemia Jurkat cells and human erythroleukemia HEL cells. β‐Catenin can be significantly down‐regulated by the Janus kinase 2 specific inhibitor AG490 in these two cells. AG490 also reduces the luciferase activity of a reporter plasmid driven by LEF/β‐catenin promoter. Similar results were observed in HEL cells infected with lentivirus containing shRNA against JAK2 gene. After treatment with 50 µM AG490 or shRNA, the mRNA expression levels of β‐catenin, APC, Axin, β‐Trcp, GSK3α, and GSK3β were up‐regulated within 12–16 h. However, only the protein levels of GSK3β and β‐Trcp were found to have increased relative to untreated cells. Knockdown experiments revealed that the AG490‐induced inhibition of β‐catenin can be attenuated by shRNA targeting β‐TrCP. Taken together; these results suggest that β‐Trcp plays a key role in the cross‐talk between JAK/STAT and Wnt/β‐catenin signaling in leukemia cells. J. Cell. Biochem. 111: 402–411, 2010.

Prevalence of the JAK2‐V617F mutation in Taiwanese patients with chronic myeloproliferative disorders

Background:  The Janus kinase‐2 (JAK‐2) V617F mutation has been recently reported in patients with myeloproliferative disorders (MPD), which is believed to underlie growth factor hypersensitivity displayed by haematopoietic progenitors in these disorders. However, its frequency has been rarely determined in Taiwanese patients.

Chronic hepatitis virus infection in patients with multiple myeloma: clinical characteristics and outcomes

OBJECTIVES: Cytotoxic agents and steroids are used to treat lymphoid malignancies, but these compounds may exacerbate chronic viral hepatitis. For patients with multiple myeloma, the impact of preexisting hepatitis virus infection is unclear. The aim of this study is to explore the characteristics and outcomes of myeloma patients with chronic hepatitis virus infection. METHODS: From 2003 to 2008, 155 myeloma patients were examined to determine their chronic hepatitis virus infection statuses using serologic tests for the hepatitis B (HBV) and C viruses (HCV). Clinical parameters and outcome variables were retrieved via a medical chart review. RESULTS: The estimated prevalences of chronic HBV and HCV infections were 11.0% (n = 17) and 9.0% (n = 14), respectively. The characteristics of patients who were hepatitis virus carriers and those who were not were similar. However, carrier patients had a higher prevalence of conventional cytogenetic abnormalities (64.3% vs. 25.0%). The cumulative incidences of grade 3-4 elevation of the level of alanine transaminase, 30.0% vs. 12.0%, and hyperbilirubinemia, 20.0% vs. 1.6%, were higher in carriers as well. In a Kaplan-Meier analysis, carrier patients had worse overall survival (median: 16.0 vs. 42.4 months). The prognostic value of carrier status was not statistically significant in the multivariate analysis, but an age of more than 65 years old, the presence of cytogenetic abnormalities, a beta-2-microglobulin level of more than 3.5 mg/L, and a serum creatinine level of more than 2 mg/dL were independent factors associated with poor prognosis. CONCLUSION: Myeloma patients with chronic hepatitis virus infections might be a distinct subgroup, and close monitoring of hepatic adverse events should be mandatory.

Assessment of first-year post-graduate residents: Usefulness of multiple tools

Background: Objective Structural Clinical Examination (OSCE) usually needs a large number of stations with long test time, which usually exceeds the resources available in a medical center. We aimed to determine the reliability of a combination of Direct Observation of Procedural Skills (DOPS), Internal Medicine in‐Training Examination (IM‐ITE®) and OSCE, and to verify the correlation between the small‐scale OSCE+DOPS+IM‐ITE®‐composited scores and 360‐degree evaluation scores of first year post‐graduate (PGY1) residents. Methods: Between 2007 January to 2010 January, two hundred and nine internal medicine PGY1 residents completed DOPS, IM‐ITE® and small‐scale OSCE at our hospital. Faculty members completed 12‐item 360‐degree evaluation for each of the PGY1 residents regularly. Results: The small‐scale OSCE scores correlated well with the 360‐degree evaluation scores (r = 0.37, p < 0.021). Interestingly, the addition of DOPS scores to small‐scale OSCE scores [small‐scale OSCE+DOPS‐composited scores] increased its correlation with 360‐degree evaluation scores of PGY1 residents (r = 0.72, p < 0.036). Further, combination of IM‐ITE® score with small‐scale OSCE+DOPS scores [small‐scale OSCE+DOPS+IM‐ITE®‐composited scores] markedly enhanced their correlation with 360‐degree evaluation scores (r = 0.85, p < 0.016). Conclusion: The strong correlations between 360‐degree evaluation and small‐scale OSCE+DOPS+IM‐ITE®‐composited scores suggested that both methods were measuring the same quality. Our results showed that the small‐scale OSCE, when associated with both the DOPS and IM‐ITE®, could be an important assessment method for PGY1 residents.

A core competence-based objective structured clinical examination (OSCE) in evaluation of clinical performance of postgraduate year-1 (PGY1) residents

Background: Clinical competency certifications are important parts of internal medicine residency training. This study aims to evaluate a composite objective structured clinical examination (OSCE) that assesses postgraduate year‐1 (PGY1) residents’ acquisition of the six core competencies defined by the Accreditation council for Graduate Medical Education (ACGME). Methods: Six‐core‐competency‐based OSCE was used as examination of the clinical performance of 192 PGY1 residents during their 3‐month internal medicine training between 2007 January and 2009 December. For each year, the reliability of the entire examination was calculated with Cronbach’s alpha. Results: The reliability of six‐core‐competency‐based OSCE was acceptable, ranging from 0.69 to 0.87 between 2007 and 2009. In comparison with baseline scores, the summary scores and core‐competency subscores all showed significant increase after PGY1 residents finished their 3‐month internal medicine training program. Conclusion: By using a structured development process, the authors were able to create reliable evaluation items for determining PGY1 residents’ acquisition of the ACGME core competencies.