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.

Epidemiology of multiple myeloma in Taiwan: increasing incidence for the past 25 years and higher prevalence of extramedullary myeloma in patients younger than 55 years.

BACKGROUND: The incidence of multiple myeloma (MM) is lower in Asia than in western countries. However, no data are available on descriptive epidemiology of MM in Chinese. METHODS: From 1979 to 2003, 3602 MM patients were registered in the Taiwan National Cancer Registry. The annual incidence and mortality were calculated and age-standardized to the world standard population in the year 2000. Age-period-cohort effects on incidence were analyzed. The salient clinical data of 526 MM patients in a single institute were also investigated. RESULTS: From 1979 to 2003, the average age-adjusted incidence per 100,000 population was 0.75. The incidence increased with age to a peak of 5.2 in those aged 75-79 years. In addition to age, remarkable period and birth cohort effects were found to contribute to increased incidence of MM. The age-adjusted mortality also increased, which accounted for an average of 0.59 per 100,000 deaths; however, the fatality rate was steady at 80%. Clinical and laboratory characteristics and treatment outcomes of the 526 MM patients were similar to those reported elsewhere. Remarkably, extramedullary myeloma (extra-MM) at diagnosis was more common in patients younger than 55 years of age than in others (43% vs 13%, P < .001). CONCLUSIONS: Incidence of MM in Taiwan has dramatically increased in recent years and is associated with a birth-cohort effect. There are no apparent differences in treatment outcome between MM patients in Taiwan and in other countries. However, prevalence of extra-MM is higher in patients younger than 55 years of age.

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.

Increased serum high-density lipoprotein cholesterol level is associated with a reduction in peripheral monocyte count in normal individuals.

BACKGROUND AND PURPOSE: Monocytes and high-density lipoprotein cholesterol (HDL-C) both play important roles in the process of atherosclerosis. This retrospective study investigated whether an increase in serum HDL-C level would be followed by a reduction in monocyte count. METHODS: A total of 781 participants in a health check program in 1996 who had received a second health check in 1997, 1998, or 1999 were included. Based on the change in HDL-C at the second health check, the subjects were divided into the following 3 groups: 1) increase in HDL-C of >or= 5% (n = 426); 2) change of HDL-C of < 5% (n = 162); and 3) decrease of HDL-C of >or= 5% (n = 193). The relations between the change in HDL-C and the change in monocyte count were analyzed. RESULTS: A significant inverse relation between the change in HDL-C level and the change in monocyte count was found among the 3 study groups by 1-way analysis of variance (p = 0.002). Subjects with increased HDL-C had significantly decreased monocyte count at the second check while subjects with decreased HDL-C had increased monocyte count. Multivariate regression analysis of data from all subjects revealed that the change of HDL-C was independently associated with a significant inverse change in monocyte count (p = 0.007). CONCLUSIONS: In view of the documented inflammatory nature of atherosclerosis, the inverse relation between the change of HDL-C level and the change of monocyte count may partly explain why a higher serum HDL-C level can protect arteries against atherosclerosis.

Trends and antimicrobial resistance of pathogens causing bloodstream infections among febrile neutropenic adults with hematological malignancy.

BACKGROUND AND PURPOSE: The microbiological spectrum in cancer patients with febrile neutropenia has changed over the past several decades in western countries. The growing incidence of antimicrobial resistance is an inevitable consequence of the widespread use of antibiotics in medical settings. The aim of this study was to clarify the trends and antimicrobial resistance among pathogens causing bloodstream infections in febrile neutropenic adults with hematological malignancies. METHODS: The characteristics of pathogens causing bloodstream infection isolated from patients with febrile neutropenia who were treated at National Taiwan University Hospital from 1996 to 2001 were reviewed. A total of 1174 pathogens were isolated from 3093 admissions to a hematological ward during this period. Among them, 738 isolates were recovered from patients with febrile neutropenia. RESULTS: The majority (93%) of these neutropenic febrile patients had underlying acute leukemia or lymphoma. Gram-negative bacteria accounted for 57% of isolated pathogens, followed by Gram-positive bacteria (32%), fungi (7%), and anaerobes (3%). In decreasing frequency, Escherichia coli (13%), Klebsiella pneumoniae (12%), Enterobacter cloacae (7%), Pseudomonas aeruginosa (6%), and Acinetobacter baumannii (5%) were the predominant Gram-negative bacteria, while coagulase-negative staphylococci (13%), viridans group streptococci (4%), and Staphylococcus aureus (4%) were the major Gram-positive pathogens. Two-thirds (20/30) of S. aureus isolates were resistant to oxacillin. No vancomycin-resistant enterococci were isolated. Resistance to cefotaxime was found in 63% of E. cloacae, 13% of K. pneumoniae and 10% of E. coli. Overall, 33% of E. coli and 13% of K. pneumoniae were resistant to ciprofloxacin. CONCLUSIONS: This study indicates that the microbiological spectrum of microorganisms causing bloodstream infections in neutropenic febrile patients with hematological malignancies at National Taiwan University Hospital is different from western countries in that Gram-negative bacteria remain the predominant pathogens. Antimicrobial resistance among these pathogens is high and E. coli and K. pneumoniae isolates with resistance to third-generation cephalosporins and ciprofloxacin are increasing.

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.

SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia.

The proliferation and differentiation of hematopoietic precursor cells depend on various cytokines. The suppressor of cytokine signaling-1 (SOCS1) down-regulates Janus kinases/signal transducers and activators of transcription (JAK/STAT) pathway activity and inhibits the biological effects of cytokines. SOCS1 has been shown to have tumor-suppressor activity, and methylation of this gene, resulting in transcriptional silencing, has been found in 65% of hepatocellular carcinoma and has been suggested to play an important role in the development of the cancer. The methylation status of the SOCS1 gene in acute myeloid leukemia (AML) has not been reported before. In this study, we analyzed SOCS1 methylation in 89 patients with newly diagnosed AML and correlated the result with immunophenotypes, cytogenetics, clinical features, and treatment outcome. SOCS1 methylation was found in the leukemic cells from 53 patients (60%). Thirteen (76%) of the 17 patients with t(15;17) had SOCS1 methylation, whereas this gene was methylated in only one (11%) of the nine patients with t(8;21). The frequencies of SOCS1 methylation among various cytogenetic subgroups differed significantly (P = 0.014). Other clinical and laboratory parameters and the disease-free survival and overall survival were similar between patients with and without SOCS1 methylation. In conclusion, SOCS1 methylation occurs in more than half of AML cases, correlates with cytogenetic abnormalities, and may play an important role in the development of subsets of AML.

Peripheral differential leukocyte counts and subsequent mortality from all diseases, cancers, and cardiovascular diseases in Taiwanese.

BACKGROUND AND PURPOSE: A higher total leukocyte count has been reported to predict all-cause mortality in men, but data are limited for this relation in women and for the relation between differential leukocyte counts and all-cause mortality in both men and women. This study was designed to analyze these relationships in Taiwanese. METHODS: A total of 8447 subjects were enrolled from participants in a physical check-up program at National Taiwan University Hospital from 1995 to 1997. Information on mortality was obtained from a national mortality databank that was updated to the end of 2001. Data were analyzed by Student's t test and Cox regression analysis. RESULTS: Among the 245 deaths, 88 were due to cancer and 62 were due to cardiovascular diseases. Cox regression analysis revealed an inverse association between lymphocyte count and all-cause mortality in the study group as a whole (all subjects, p < 0.01, hazard ratio = 0.73). This inverse association was mainly due to an inverse association between lymphocyte count and cancer mortality (p < 0.05, hazard ratio = 0.64), especially the mortality from hepatoma (p = 0.010, hazard ratio = 0.29). The latter hazard ratio of 0.29 indicates that, in all subjects, every decrease of 1.0 x 10(9)/L in lymphocyte count increased the risk of mortality from hepatoma by 3.45-fold during an average follow-up period of 65.5 months. There was a positive association between total leukocyte count and all-cause mortality in men (p < 0.05, hazard ratio = 1.10), mainly due to both the neutrophil and monocyte counts having positive associations with the cardiovascular mortality (both p < 0.05, hazard ratio = 1.23 and 1.22, respectively). The latter hazard ratio of 1.22 indicates that, in men, every increase of 0.1 x 10(9)/L in monocyte count increased the risk of cardiovascular mortality by 1.22-fold. CONCLUSIONS: In Taiwanese adults of both genders, a lower lymphocyte count is associated with cancer mortality, especially mortality from hepatoma. In Taiwanese men, higher neutrophil and monocyte counts are associated with cardiovascular mortality.

Additional chromosomal abnormalities and variability of BCR breakpoints in Philadelphia chromosome/BCR-ABL-positive acute lymphoblastic leukemia in Taiwan.

From 1986 to 1998, 26 (23%) of 114 adult acute lymphoblastic leukemia (ALL) patients and 11 (4%) of 328 pediatric patients were found to have Philadelphia (Ph) chromosome. In the 30 patients with available data at diagnosis, 18 (60%) had extra-chromosomal abnormalities. They included 1q duplication (5/18, 28%), supernumerary Ph chromosome (4/18, 22%), 9p abnormalities (3/18, 17%), 7q deletion/monosomy 7 (3/18, 17%), trisomy 19 (1/18, 6%), and trisomy 8 (1/18, 6%). Excluding those with specific cytogenetic changes, only one patient had hyperdiploid karyotype with more than 50 chromosomes. The incidence of 1q duplication was higher and that of hyperdiploidy was lower in this study than has been previously reported. There was no prognostic implication of these additional cytogenetic abnormalities. With fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR), 14 (27%) of 53 unselected adult ALL patients and 2 (5%) of 38 unselected pediatric patients were BCR-ABL-positive, including one adult and two children without Ph chromosome. The BCR-ABL fusion genes/transcripts were also present in all other 16 selected Ph-positive ALL patients. The BCR-ABL fusion subtypes were determined in all these 32 patients: 91% (11/12) childhood cases showed m-type fusion gene while 45% (9/20) adult ones did so (P = 0.0083). The clinical outcome was similar between the two groups of patients with m-type and M-type BCR-ABL. In conclusion, both cytogenetic and molecular studies are very helpful for identifying the subgroup of ALL patients with Ph/BCR-ABL. The additional cytogenetic abnormalities and subtypes of BCR-ABL fusion genes/transcripts had no significant implications in this group of patients.

Combination of 13-cis retinoic acid and interferon-alpha in the treatment of recurrent or refractory peripheral T-cell lymphoma.

We previously reported the therapeutic efficacy of 13-cis retinoic acid (13-cRA) in some subtypes of peripheral T-cell lymphoma (PTCL). This study sought to clarify if the addition of interferon-alpha2a (IFN-alpha2a), an agent with synergistic cytotoxicity with 13-cRA in many types of malignant cells, may be more effective in the treatment of PTCL. Eligible patients has histologically proven PTCL, which was recurrent after or refractory to anthracycline-containing systemic chemotherapy. The treatment included oral administration of 13-cRA 1 mg/kg/day, divided into three doses, and intramuscular injection of IFN-alpha2a 4.5 MU/M2, three times per week. From March 1995 to July 2000, a total of 17 patients, 10 men and 7 women, with a median age of 47 years (range, 18-77 years), were recruited. The histologic diagnosis included 7 cases of unspecified PTCL, 6 cases of Ki-1 anaplastic large cell lymphoma (ALCL), 1 case of angioimmunoblastic T-cell lymphoma, and 3 cases of angiocentric nasal NK/T cell lymphoma. They received a median of 1.7 months of treatment (range, 0.4-13.3 months). One patient refused further treatment due to toxicity. The doses of 13-cRA and IFN-alpha2a had to be decreased in 7 and 7 patients, respectively. Grade III/IV hematologic and non-hematologic toxicity developed in 2 and 5 patients, respectively. There were 5 partial responses (Ki-1, 4; unspecified PTCL, 1), with a total response rate of 31.3% (95% CI, 5.7-56.8%). The median duration of response for the responders was 2.5 months (range, 0.8-7.2 months). The median overall survival for the entire group of patients was 3.6 months. In conclusion, a combination of 13-cRA and IFN-alpha2a is a useful salvage treatment for selected patients with recurrent or refractory PTCL, particularly those with the Ki-1 subtype. However, the data does not support that addition of IFN-alpha2a is superior to 13-cRA alone.

High incidence of CD56 expression and relapse rate in acute myeloid leukemia patients with t(8;21) in Taiwan.

BACKGROUND AND PURPOSE: CD56 is a marker of natural killer cells, but can also be found on blast cells in acute myeloid leukemia (AML). The prognostic implications of CD56 expression in AML are not clear. In this study, we evaluated the correlation among CD56 expression, cytogenetic abnormality, and clinical outcome in AML. METHODS: CD56 expression was analyzed in leukemic cells from 94 adults with primary AML in Taiwan and was correlated with clinical and hematologic features, cytogenetics, and immunophenotypes of the leukemia. RESULTS: Thirty patients (32%) showed CD56 expression. CD56+ AML patients had a higher lactate dehydrogenase level than CD56- patients (1.136 vs 730 V/L, p = 0.048). Patients with t(8;21) had a significantly higher incidence (89%, 8/9) of CD56 positivity in leukemic cells than those with normal karyotype or other cytogenetic abnormalities (26%, 22/85, p < 0.001). In general, there was no difference in overall survival time in CD56+ and CD56- AML patients. However, three patients had central nervous system involvement at initial presentation; two of these had concomitant CD56 expression and t(8;21). In addition, five of the seven patients with t(8;21) and CD56 expression who achieved complete remission later relapsed. CONCLUSIONS: The incidence of CD56 expression in AML patients with t(8;21) is very high in Taiwan, and it may imply a poor prognosis in this subgroup of patients.