Use of azathioprine for graft-vs-host disease is the major risk for development of secondary malignancies after haematopoietic stem cell transplantation: a nationwide population-based study.

BACKGROUND: As more patients are treated by haematopoietic stem cell transplantation (HSCT), development of secondary malignancy (SM) becomes an increasingly common issue in long-term survivors. METHODS: We conducted a nationwide population-based study of the Taiwanese population to analyse patients who received HSCT between January 1997 and December 2010. Standardised incidence ratios (SIRs) were used to compare the risk of SM in HSCT patients and the general population. Multivariate analysis was performed to identify independent predictors of SM. RESULTS: Patients receiving HSCT had a significantly greater risk of developing SM (SIR 2.00; 95% confidence interval (CI) 1.45-2.69; P<0.001). Specifically, the incidence increased for cancers of the oral cavity (SIR 14.18) and oesophagus (SIR 14.75) after allogeneic HSCT. Multivariate analysis revealed an increased SIR for cancer in patients who received the immunosuppressant azathioprine. The risk of SM also increased with greater cumulative doses of azathioprine. CONCLUSIONS: This study demonstrates an increased incidence of SM in Taiwanese patients who received allogeneic HSCT, especially for cancers of the oral cavity and oesophagus. This finding is different from results in populations of Western countries. Physicians should be cautious about azathioprine use for graft-vs-host disease after HSCT.

Increased cancer risk in patients with haemophilia A: a nationwide population-based 14-year study in Taiwan.

Haemostasis is associated with the development and dissemination of cancer. Whether cancer incidence is increased in haemophiliacs remains uncertain; thus, we aimed to further examine this issue. By using data from the National Health Insurance Research Database in Taiwan, we obtained a cohort of 683 patients with haemophilia A, and compared the incidence rate ratio (IRR) of cancer in this cohort with an age- and sex-matched control of 6830 patients. The log-rank test was used to compare Kaplan-Meier curve of the cumulative cancer incidence between two cohorts. Cox regressions were used to identify independent risk factors of cancer in the study patients. The cancer incidence of patients with haemophilia A was significantly higher compared to the control group (IRR 1.95, 95% CI 1.18-3.09, P = 0.008) during the 14-year follow-up period. The non-lymphoma and non-liver cancer incidence in the haemophilia A cohort remained higher than that of the matched control (P = 0.050 by the log-rank test). The multivariate Cox proportional hazards analysis indicated that age (per year, HR 1.09, 95% CI 1.06-1.12, P < 0.001) was the only significant risk factor for cancer development in haemophilia patients. Patients with haemophilia A had higher cancer incidence than the age- and sex-matched patients, especially for the elderly. With increasing life expectancy for haemophiliacs, physicians should be aware of their cancer development.

Adult T-cell leukaemia/lymphoma can mimic other lymphomas in a non-endemic area: dilemmas in diagnosis and treatment.

BACKGROUND: The diagnosis of Adult T-cell leukaemia/lymphoma (ATL) in non-endemic regions is challenging. AIM: This study analyses the clinicopathologic features and diagnostic processes of ATL patients in Taiwan. METHODS: ATL patients diagnosed and treated at Taipei Veterans General Hospital from 1998 through 2010 were retrospectively identified. The diagnosis of ATL was confirmed by in situ detection of human T-cell leukaemia virus type 1 (HTLV-1) when necessary. Patients' data were reviewed and analysed. RESULTS: Fourteen ATL patients were identified, among whom six (42.9%) had an antecedent diagnosis of other malignant lymphomas before the ATL diagnosis, including two diagnosed with Hodgkin disease (HD), one with peripheral T-cell lymphoma, two with chronic lymphocytic leukaemia and one with angioimmunoblastic T-cell lymphoma. Of the 14 patients, eight (57%) were subclassified as the acute type, three (21.4%) as the lymphoma type, and three (21.4%) as the chronic type ATL. Five of six (83.3%) patients with initial non-ATL misdiagnosis were diagnosed with non-acute type ATL. In particular, a patient with an antecedent diagnosis of HD presented with typical Reed-Sternberg (RS)-like cells harbouring Epstein-Barr virus genomes in affected lymph nodes. The patient progressed to acute type ATL 3 years after the initial diagnosis, and HTLV-1 genomes were identified in the previous RS-like cells. CONCLUSION: In non-endemic areas, such as Taiwan, ATL, particularly the non-acute type, may mimic other lymphomas and easily be misdiagnosed. HTLV-1 serology should be routinely screened in all malignant lymphoma patients. In situ detection of HTLV-1 is helpful in cases with diagnostic dilemmas.

A case of myeloid neoplasm associated with eosinophilia and KIAA1509-PDGFRß responsive to combination treatment with imatinib mesylate and prednisolone.

A 41-year-old woman presented with dyspnoea, persistent leucocytosis and eosinophilia for 8 months. High-resolution computed tomography scan and pathology of bronchoalveolar lavage confirmed the diagnosis of hypereosinophilic pneumonitis. The patient was treated with prednisolone (0·5-1 mg/kg/day) for more than 20 weeks under the impression of hypereosinophilic syndrome, but without improvement of leucocytosis and eosinophilia. The bone marrow aspiration smear disclosed hypercellular marrow with myeloid hyperplasia and eosinophilia. The fusion gene detection was positive for KIAA1509-PDGFRß. Myeloid neoplasm associated with eosinophilia and abnormality of PDGFRß was then diagnosed (Tefferi A, Vardiman JW, Leukemia, 22, 2008, 14). The tyrosine kinase inhibitor, imatinib mesylate (Glivec; 200 mg/day), was administered along with prednisolone (0·25-1 mg/kg/day). White blood cell (WBC) count decreased from 49,500/µL to 17,200/µL, and eosinophil count decreased from 1932/µL to 35/µL, which represent percentage dropped from 7·7%> to 0·2%. Withdrawal of prednisolone was done to avoid adverse events. However, absolute eosinophil count increased progressively despite the continue administration of imatinib and negative detection PDGFRß fusion gene. The patient then received combination therapy of imatinib and prednisolone again. WBC and absolute eosinophil were normalized subsequently. We had discontinued the prednisolone one more time, and rebound of eosinophilia was seen again. The phenomenon of rebounding of eosinophilia was observed in two subsequent withdrawals of prednisolone. Either steroid or imatinib mesylate alone failed to achieve complete haematological response. A synergistic effect of imatinib and steroid is postulated.

Hepatitis B infection in haematopoietic stem cell transplantation: still unresolved.

Impact of hepatitis B virus (HBV) infection on haematopoietic stem cell transplantation (HSCT) was reported earlier since late 1980s. It was shown that changing patterns of HBV serological markers was accompanied by variable severity of hepatitis after transplantation. Recipient's hepatitis B virus surface antigen (HBsAg) positivity was not considered an absolute contra-indication to allogeneic HSCT. However, HBsAg positivity was an important risk factor of reactivation hepatitis after transplantation, especially in allogeneic setting. Managing HBV reactivation in HSCT recipients was not successful till the availability of lamivudine since mid-1990s. For HBsAg-positive recipients, prophylactic lamivudine has been shown to significantly reduce reactivation hepatitis. As for HBsAg-negative recipients, there have been a small number of patients who develop so-called reverse seroconversion, that is, appearance of HBsAg after transplantation. In addition to chronic graft-versus-host disease, the risk was also high in allogeneic HSCT recipients who received fludarabine-antithymocyte globulin-containing conditioning regimens. The HBV is harboured earlier in the recipients before transplantation rather than transmitted via transfusion. At present, the optimal duration of lamivudine prophylaxis is not well-defined, and there are several fatal cases associated with early withdrawal and resistant HBV mutants. In conclusion, in HBV-endemic areas, the war between HBV and HSCT recipients continued even though several anti-HBV agents and molecular detection techniques are available. It deserves additional effort to overcome and also presents a chance to elucidate underlying mechanisms of HBV immunity, which are not easily studied in non-HSCT setting.

Hyperphosphorylation of p53 induced by okadaic acid attenuates its transcriptional activation function.

The tumor suppressor and transcriptional factor p53 is a phosphorylated protein. Its phosphorylation states are regulated by several protein kinases and phosphatases. In this study, the wild-type p53 was transfected and expressed in chronic myelogenous leukemia K-562 cells. Incubation of the transfected cells with okadaic acid, an inhibitor of serine phosphatases 2A and 1, induced hyperphosphorylation of p53 protein. The treatment also increased the steady state level of p53 protein in the cells. However, the hyperphosphorylated p53 protein was less active in promoting transcription mediated by two p53-binding DNA elements, the ribosomal gene cluster and the p53 consensus DNA-binding sequence. Nevertheless, the decreased transcription activation was not due to decreased binding of p53 to these elements, as analyzed by mobility shift DNA-binding assays. In addition, the treatment did not induce a conformational change in p53, as assayed by two conformation-specific anti-p53 monoclonal antibodies, PAb240 and PAb1620. These results suggest that the phosphorylation induced by okadaic acid may selectively modulate the transcription activation function of p53. Consequently, phosphorylation may represent a mechanism of p53 inactivation in tumor cells that harbor the wild-type p53.

Favorable clinical outcome and unique characteristics in association with Twist1 overexpression in de novo acute myeloid leukemia.

Epithelial-mesenchymal transition (EMT) is a critical process for inducing stem-like properties of epithelial cancer cells. However, the role of EMT inducers in hematological malignancies is unknown. Twist1, an EMT inducer necessary for cell migration, has recently been found to have transcriptionally regulatory activity on the expression of Bmi1, and these two are capable of promoting tumorigenesis in a synergized manner. Knowing that Bmi1 expression is essential for maintenance of leukemic stem cells, we speculate that Twist1 might govern the pathogenesis of acute myeloid leukemia (AML) development as well. We found that upregulated Twist1 increased Bmi1 expression in AML and endued leukemic cells a higher proliferative potential and increased resistance to apoptosis. In primary AML samples, there was strong positive correlation between the expression levels of Twist1 and Bmi1. AML patients whose leukemic blasts harbored overexpressed Twist1 had a more aggressive clinical phenotype, but they were more likely to have a better clinical outcome after standard therapy. In vitro studies confirmed that Twist1-overexpressing leukemic cells were more susceptible to cytarabine, but not daunorubicin, cytotoxicity. Our findings suggest that, in a subset of AML patients, Twist1 has a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

DAE (daunorubicin, Ara-C, and etoposide) and intermediate dose Ara-C for remission induction and consolidation treatment of adult patients with acute myeloid leukemia.

Fifty-one patients (age 18-73 years) with acute myeloid leukemia were treated with daunorubicin, cytarabine, and etoposide in an age-adjusted protocol, with patients older than 50 receiving fewer days of therapy. Complete remission (CR) occurred in 66% of the patients (34 of 51 patients). Patients 50 years of age and younger achieved a 74% CR rate (23 of 31 patients) compared to a 55% CR rate (11 of 20 patients) in older patients. Of the 34 complete responders, 11 (32%) refused consolidation therapy and received traditional Chinese herbal medicine. All of these 11 patients relapsed after a short remission duration (median, 3.8 months) and died. The median remission duration and median overall survival of 23 complete responders receiving at least two courses of consolidation therapy were 10.1 and 19.8 months, respectively. The actuarial 3-year disease-free survival for these 23 complete responders was 21 +/- 9%. Myelosuppression was the major toxicity, and nonhematological side effects were acceptable. The regimen appeared to have acceptable toxicity, and its efficacy was comparable with that of standard regimens with long-term maintenance therapy.

Intensive postremission chemotherapy in Taiwanese adults with acute myelogenous leukemia.

Intensive postremission chemotherapy has produced disease-free survival comparable to that of bone marrow transplantation in patients with acute myelogenous leukemia (AML), but its efficacy was unknown in Taiwan. We assessed the efficacy of intensive postremission chemotherapy, consisting of high-dose arabinoside-C (HiDAC) with or without transplantation of peripheral blood stem cells, in 33 AML patients from a single institute in Taiwan. Toxic reactions, treatment outcome, prognostic factors, and the size of the peripheral blood stem-cell harvest after HiDAC were analyzed. After a median follow-up of 21 months, 18 patients remained in continuous complete remission. The actuarial leukemia-free survival at 4 years was 51%. Relapse occurred in 12 patients, at a median of 12 months after initial diagnosis. All 6 patients with acute promyelocytic leukemia remained disease free after HiDAC therapy. Age, sex, and number of remission-induction or intensive consolidation chemotherapy courses had no effect on the risk of relapse. Intensive postremission chemotherapy can effectively prolong the duration of remission in young (< 60 years of age) adults with AML.

The lack of antiplatelet effect of crude extracts from ganoderma lucidum on HIV-positive hemophiliacs.

Effects of the extracts from Ganoderm lucidum (GL-P) to influence immune status of the hemophiliacs with positive HIV antibody and reversed helper/suppressor T-lymphocyte ratio were studied. Since the extracts from G. lucidum have been reported to contain high levels of adenosine, the untoward antiplatelet effect of the extracts on hemophiliacs were highly concerned. Five patients of hemophilia A voluntarily received the extracts which has been analyzed to contain 150 mg of adenosine in 100 gm of the extracts. Patients were estimated to take 1.35 mg of the adenosine daily. Platelet aggregation tests before and after the trial of the extracts showed no significant change. Our crude extracts of the Ganoderma lucidum was considered not to have untoward antiplatelet effect in vivo despite the high contents of adenosine.

How to predict the outcome in mature T and NK cell lymphoma by currently used prognostic models?

To select an appropriate prognostic model in the treatment of mature T- and natural killer (NK) -cell lymphoma (peripheral T-cell lymphoma (PTCL) and NK-/T-cell lymphoma (NKTCL)) is crucial. This study investigated the usefulness of Ann Arbor staging classification International prognostic index (IPI), prognostic index for T-cell lymphoma (PIT) and International peripheral T-cell lymphoma Project score (IPTCLP). Between 2000 and 2009, 176 patients (122 males) with PTCL and NKTCL were diagnosed and treated from a single institute in Taiwan. The correlation between complete response (CR) rate, 3-year overall survival (OS), early mortality rate and four prognostic models was analyzed. Thirty-one patients received hematopoietic stem cell transplantation (HSCT) and were analyzed separately. Three-year OS rate was 34.7%, and anaplastic large-cell lymphoma harbored better outcome than others. IPI score had the lowest Akaike information criterion value (1081.197) and was the best score in predicting OS and early mortality (P=0.009). Ann Arbor stage classification can predict CR rate more precisely (P=0.006). OS was significantly better in patients who received HSCT, even in patients with unfavorable features compared with chemotherapy alone. All prognostic models were useful to evaluate the outcome of patients with PTCL and NKTCL but IPI score did best in predicting OS in PTCL and PIT score in NKTCL. This study also supported the role of HSCT in patients with high-risk or refractory PTCL or NKTCL.

Impact of bloodstream infections on outcome and the influence of prophylactic oral antibiotic regimens in allogeneic hematopoietic SCT recipients.

This study aimed to determine the impact of blood stream infections (BSIs) on outcome of allogeneic hematopoietic SCT (HSCT), and to examine the influence of old (non-levofloxacin-containing) and new (levofloxacin-based) prophylactic antibiotic protocols on the pattern of BSIs. We retrospectively enrolled 246 allogeneic HSCT recipients between January 1999 and June 2006, dividing patients into BSI (within 6 months post-HSCT, n=61) and non-BSI groups (n=185). We found that Gram-negative bacteria (GNB) predominated BSI pathogens (54%). Multivariate analyses showed that patients with a BSI, compared with those without, had a significantly greater 6-month mortality (hazard ratio, 1.75; 95% confidence interval, 1.09-2.82; P=0.021) and a significantly increased length of hospital (LOH) stay (70.8 vs 55.2 days, P=0.014). Moreover, recipients of old and new protocols did not have a significantly different 6-month mortality and time-to-occurrence of BSIs. However, there were significantly more resistant GNB to third-generation cephalosporins and carbapenem in recipients of levofloxacin-based prophylaxis. Our data suggest that BSIs occur substantially and impact negatively on the outcome and LOH stay after allogeneic HSCT despite antibiotic prophylaxis. Levofloxacin-based prophylaxis, albeit providing similar efficacy to non-levofloxacin-containing regimens, may be associated with increased antimicrobial resistance.

High incidence of oral squamous cell carcinoma independent of HPV infection after allogeneic hematopoietic SCT in Taiwan.

Hematopoietic SCT (HSCT) is a well-recognized therapeutic procedure to prolong life and cure patients with life-threatening hematological malignancies; however, the risk of developing secondary carcinoma may increase in long-term survivors. The objective of this study was to determine the incidence and risk factors for secondary squamous carcinoma after HSCT. Between 1984 and 2004, 170 allogeneic HSCT recipients aged >15 years, who had survived for >5 years were enrolled. Demographic data and the characteristics of secondary carcinoma were collected and analyzed for the determination of the incidence and risk of developing secondary carcinoma. Eight patients developed secondary carcinoma, including five oral squamous cell carcinomas, one esophageal, one gastric and one ovarian carcinoma, but no cutaneous carcinomas were detected at a median follow-up of 14.1 years (range, 5.1-23.3 years) after HSCT. The accrual 10-year cumulative incidence of secondary carcinoma was 2.89%. In univariate and multivariate analyses, chronic GVHD and age >40 years at the time of HSCT were both significant risk factors independently associated with the development of secondary carcinoma. Thus, the occurrence of secondary carcinoma is one of the late complications in patients undergoing HSCT. Oral squamous cell carcinoma was more common in our patients after HSCT, indicating the need for lifelong surveillance of the oral cavity. Moreover, because of the relatively long latency in developing secondary carcinoma, extended follow-up is required for a thorough understanding of the incidence and characteristics of secondary carcinoma after HSCT.

Cost-effectiveness of postremission intensive therapy in patients with acute leukemia.

BACKGROUND: We assessed the cost-effectiveness of high-dose arabinoside (HiDAC)-based and allogeneic stem-cell transplantation (alloSCT)-based therapy in patients with acute leukemia. PATIENTS AND METHODS: We analyzed the outcome, cost and cost-effectiveness of 106 patients treated from January 1994 to January 2002 [94 acute myelogenous leukemia (AML)/12 acute lymphoblastic leukemia (ALL)]. Forty-two young patients at either intermediate or unknown cytogenetic risk received postremission intensive therapy (24 HiDAC-based/18 alloSCT-based therapy). RESULTS: After a median follow-up of 50 months, the estimated 7-year overall survival for the HiDAC-based group showed a tendency to be higher than the alloSCT-based group (48% versus 28%, P = 0.1452). The HiDAC-based group spent a significantly lower total cost ($US51,857 versus 75,474, P = 0.004) than the alloSCT-based group. Cost-effectiveness analysis showed that the mean cost per year of life saved for the HiDAC-based group is considerably less expensive than the alloSCT-based group ($US11,224 versus 21,564). The reduced total cost for the HiDAC-based group originated from lower cost in room fees, medication, laboratory and procedure, but not in blood transfusion and professional manpower fees. CONCLUSION: For the postremission therapy in young AML patients at either intermediate or unknown cytogenetic risk, cost-effectiveness of HiDAC-based therapy compares favorably with that of alloSCT-based therapy, which deserves further clinical trials.

Pretreatment prognostic factors and treatment outcome in elderly patients with de novo acute myeloid leukemia.

BACKGROUND: Elderly patients with acute myeloid leukemia (AML) generally have an unfavorable clinical course and are under-represented in clinical trials. The aim of this study was to analyze the prognosis and treatment outcome of elderly AML patients. PATIENTS AND METHODS: We studied 205 AML patients aged 65 years or older at our hospital. Prior to study initiation, we designated 13 variables to be analyzed for their impact on complete remission (CR) rate and overall survival (OS). RESULTS: Induction regimen (standard chemotherapy) and good performance status (PS) (Eastern Cooperative Oncology Group PS 0-1) independently influenced the achievement of CR. Multivariate analysis also determined five poor prognostic factors for OS: poor PS (score 2-4), presence of comorbidities, elevated serum lactate dehydrogenase level (> or =2x upper normal limit), extreme leukocytosis (> or =100 x 10(9)/l) and marked thrombocytopenia (< or =20 x 10(9)/l). Age was not an independent contributing factor in terms of either CR attainment or OS duration. Low-risk patients, who possessed one or less non-leukocytosis poor prognostic factor, had significantly longer disease-free survival and OS than their high-risk counterparts. CONCLUSIONS: Elderly AML patients should be risk-stratified at diagnosis. Anthracycline-based induction chemotherapy would be the best therapeutic option for such patients.

Fine needle aspiration biopsy cytology of superficial lymph nodes: comparative with histopathology.

Fine needle aspiration biopsy cytology was done in 215 lymph nodes involving cervical, submandibular, supraclavicular, axillary and inguinal regions. One hundred and forty of these were diagnosed by histopathology after excisional biopsy or surgery, including 46 cases of metastatic tumor, 57 of lymphoma (46 were non-Hodgkin's lymphoma and 11 were Hodgkin's disease), and 37 of benign lymphadenopathy. Diagnosis of metastatic malignancy was easily made by aspiration biopsy cytology with a total sensitivity of 95.7% (44/46). The diagnosis of lymphoma was less satisfactory with a total sensitivity of 82.5% (47/57). The specificity for diagnosis of benign lymphadenopathy was 97.3% (36/37) with one false positive. The concordance of cell type in aspiration biopsy cytology and histopathology was 75% (33/44) in metastatic malignancy, and 73.5% (28/38) in lymphoma. Typical Reed-Sternberg giant cells were detected in 4 of 11 cases of Hodgkin's disease by aspiration cytology. Out of the 37 cases of benign lymphadenopathy diagnosed by aspiration cytology, 7 were cases of tuberculous lymphadenitis, of which typical Langhans' giant cells were found in 2, and acid fast stain bacilli in 3 cases. There was no complication or needle tract spreading throughout the procedure. We concluded that aspiration biopsy cytology is a simple, safe, reliable, and quick diagnostic method.

Aplastic anemia in Taiwan and its etiological factors.

Ninety patients with a strict diagnosis of aplastic anemia were observed during a 4-year period. The incidence of aplastic anemia is estimated to be much higher here than in western countries. A disproportionately large number of young males were noted among our patients. Two cases were congenital. One case presented a past history of paroxysmal nocturnal hemoglobinuria. The etiology of 8 cases (8.9%) could be attributed to drugs and/or chemicals. In the remaining 79 cases (87.8%), the causes of the disease were unknown. The carrier rate of the hepatitis B surface antigen in the patients with aplastic anemia was similar to that of the general population, and chronic hepatitis B infection was not considered a major etiological factor. Coexistence of abnormal liver functions at the initial presentation was noted in 21.9% of the patients. Exposure to unknown drugs by self-medication was possibly one of the major causes of the high incidence of aplastic anemia and the associated abnormal liver functions in our patients.

Ketoconazole and high-dose methylprednisolone predisposing to cyclosporine-induced seizures: report of 3 cases.

Three consecutive cases of severe aplastic anemia undergoing immunosuppressive therapy with cyclosporin A (CyA) and high-dose methylprednisolone (HDMP) developed grand mal seizures after receiving ketoconazole treatment. All the seizures were reversed after transient discontinuation of those drugs. To our knowledge, it has not been reported as yet that the combination of ketoconazole and HDMP may considerably increase the risk of CyA-induced seizure. We would advise that ketoconazole and HDMP not be taken concomitantly with CyA treatment, and whenever ketoconazole therapy is needed, CyA be started with as small a dose as possible.

Efficacy of a modified improved technique for detecting red cell haemoglobin H inclusions.

Alpha-thalassaemia is a common disease in Taiwan. A feature useful in diagnosis is the excess of of beta-chains that result from impaired alpha-chain production. These excess chains assemble into beta 4 tetramers (i.e. Hb H) which can be detected by its rapid anodal migration on alkaline electrophoretic media as seen in Hb H disease. However, this technique cannot, and conventional Hb H inclusion staining rarely can visualize alpha-thalassaemic traits due to small quantities of Hb H formed in these patients. The staining for Hb H inclusion bodies uses brilliant cresyl blue (BCB) or methylene blue (MB) as an oxidant to denature Hb H as intracellular inclusions. We have improved the technique of Jones (who modified the original method in order to obtain enriched young red cells) by prolonging the incubation time from 30 min to 3 h. The sensitivity of this modified improved method was 91% for detecting obligatory alpha-thalassaemic traits as shown in table. No false positive results were seen in beta-thalassaemia or in others. We believe this can be used as a confirmatory test in heterozygous alpha 1-thalassaemia and homozygous alpha 2-thalassaemia.