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.

In vivo growth suppression of CT-26 mouse colorectal cancer cells by adenovirus-expressed small hairpin RNA specifically targeting thymosin beta-4 mRNA.

Thymosin beta-4 (Tß4) is known to be involved in tumorigenesis. Overexpression of this polypeptide has been observed in a wide variety of cancers, including colorectal carcinoma (CRC). Accordingly, Tß4 has been proposed to be a novel therapeutic target for CRC, especially in its metastatic form. Although in vitro tumor-suppressive effects of Tß4 gene silencing mediated by small hairpin RNA (shRNA) have already been demonstrated, the in vivo efficacy of such an approach has not yet been reported. Herein, we demonstrated that infection with recombinant adenovirus expressing an shRNA targeting Tß4 markedly reduced the growth of and robustly induced apoptosis in CT-26 mouse CRC cells in culture. Additionally, tumors grown in nude mice from the CT-26 cells whose Tß4 expression already been downregulated by virus infection were also drastically reduced. Most importantly, significant growth arrest of tumors derived from the parental CT-26 cells was observed after multiple intratumoral injections of these viruses. Together, our results show for the first time that in vivo silencing of Tß4 expression by its shRNA generated after adenoviral infection can suppress CRC growth. These results further demonstrate the feasibility of treating CRC by a Tß4 knockdown gene therapeutic approach.

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.

Tuberculosis in myasthenia gravis.

SETTING: The relationship between myasthenia gravis (MG) and tuberculosis (TB) has not been determined. OBJECTIVE: To evaluate the relationship between MG and TB. DESIGN: A national survey conducted between 2000 and 2006 included 2317 patients with MG identified from the Taiwan National Health Insurance database. The incidence rate ratio of TB in these patients was compared with those in 23 170 randomly selected age-, sex- and comorbidity-matched controls without MG. RESULTS: The risk of TB was higher in the MG cohort (adjusted hazard ratio [aHR] 1.96, 95% confidence interval [CI] 1.22-3.16, P = 0.005), mainly due to an excess risk of pulmonary TB (aHR 2.10, 95%CI 1.27-3.47, P = 0.004). Age ≥60 years (HR 4.99, 95%CI 2.06-12.10, P < 0.001) and the use of corticosteroids (HR 1.12, 95%CI 1.07-1.17, P < 0.001) were risk factors for developing TB in the MG cohort. Patients with MG who developed TB had a lower 5-year survival rate than those who did not (89.4% vs. 96.0%, P = 0.032). CONCLUSION: The incidence of pulmonary TB is significantly higher in patients with MG. Careful screening strategies for TB should be considered among high-risk patients with MG.

Impact of Port-A-Cath device management in cancer patients with candidaemia.

This study investigated the impact of management of a totally implantable central venous access port device, Port-A-Cath (Smith Medical, St. Paul, MN, USA), on the outcome of 98 cancer patients with candidaemia. Port-A-Cath retention was found to be significantly associated with poorer outcome, independent of other significant adverse factors [breakthrough candidaemia, Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥ 21, and worse Eastern Cooperative Oncology Group (ECOG) performance score (3-4)]. However, retention of Port-A-Cath devices could be considered in patients who do not have definite catheter-related candidaemia, are not using total parenteral nutrition, do not have poor ECOG performance scores or APACHE II scores, and do not have septic shock.

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 pulmonary and extrapulmonary tuberculosis infection in kidney transplantation: a nationwide population-based study in Taiwan.

BACKGROUND: Tuberculosis (TB) has been reported to increase morbidity after kidney transplantation and pose a therapeutic challenge. However, population-based research, specifically focused on the association between kidney transplantation and subsequent pulmonary or extrapulmonary TB, is lacking. METHODS: A nationwide population-based study was conducted using Taiwan's National Health Insurance Research Database, which provided claims data belonging to kidney transplant recipients during 1997-2006. Multivariate analysis was used to identify independent risk factors for TB after kidney transplantation. Kaplan-Meier survival analysis was used to assess the outcome of patients with TB. RESULTS: Among 4554 kidney transplant recipients over the 10-year period, 109 (2.4%) patients with newly diagnosed TB were identified: 75 patients with only pulmonary involvement, and 34 with extrapulmonary spread. The incidence of kidney transplant recipients developing TB was 638 per 100,000 person-years. The independent risk factors for post-transplant TB included cyclosporine-based immunosuppressant agents during the first year after kidney transplantation (odds ratio [OR]: 1.98, P = 0.001), hepatitis C infection (OR: 1.79, P = 0.024), and chronic obstructive pulmonary disease (OR: 1.50, P = 0.041). Kidney transplant recipients who developed TB had a lower 5-year survival rate than those who did not (78.6% vs. 93.4%, P = 0.001). CONCLUSIONS: Kidney transplant recipients in Taiwan did have a high risk of TB infection, with high proportion of extrapulmonary spread. Physicians need to be vigilant in surveying for TB in kidney transplantation, especially in high-risk patients.

Risk of extrathymic cancer in patients with myasthenia gravis in Taiwan: a nationwide population-based study.

BACKGROUND AND PURPOSE: The relationship between myasthenia gravis (MG) and extrathymic malignancies has not been determined. This study aimed to explore the risk of extrathymic malignancy in patients with MG based on a nationwide population-based dataset. METHODS: We identified 2614 patients with MG from the Taiwan National Health Insurance database between 1997 and 2005 and compared the incidence rates of extrathymic malignancies with 15, 684 randomly selected age-, sex-, and comorbidity-matched subjects without MG. Both cohorts were followed until the end of 2009. Cox proportional hazard model was used to evaluate the predictors of extrathymic malignancy in the MG cohort, including age, sex, comorbidities, and prescription drugs. RESULTS: After an average follow-up of 8 years, the MG cohort had a higher risk of extrathymic cancers with an incidence rate ratio (IRR) of 1.38 (95% CI 1.12-1.68, P = 0.002) than the control cohort. Although breast cancer was the most common cancer found, no statistically significant relationship between MG and any specific malignancy was observed. Cox multivariate proportional hazards analysis showed that only age (HR = 1.05, 95% CI 1.04-1.06, P < 0.001) and liver cirrhosis (IRR = 3.85, 95% CI 1.22-12.14, P = 0.021) were predictors of extrathymic cancers in the MG cohort. CONCLUSIONS: Our study showed that patients with MG had an increased risk of extrathymic malignancy in a follow-up of 8 years, but no specific susceptibility to certain malignancies was found.

VEGF -460T → C polymorphism and its association with VEGF expression and outcome to FOLFOX-4 treatment in patients with colorectal carcinoma.

The -460T → C polymorphism of vascular endothelial growth factor (VEGF) gene significantly increases its promoter activity. A pilot study was conducted to assess the influence of this polymorphism on clinicopathological features of patients with colorectal carcinoma. In total, 228 patients were enrolled, including 100 with stage II/III colorectal carcinoma receiving curative surgery and 128 with metastatic disease. An excellent correlation in VEGF -460 genotypes based on white blood cells and tumor tissues existed, but there was no between-group difference in patients with or without colorectal carcinoma. A marked increase in intratumor and circulating VEGF levels were observed in patients with the T/C or C/C genotypes (P < 0.01), which was associated with increased extent of invasion, nodal involvement, poor histological differentiation, subsequent metastasis and shorter survival in stage II/III patients treated with curative surgery (P < 0.01). For patients with metastatic disease, this polymorphism was associated with a lower response rate to FOLFOX-4 (P = 0.03) and shorter survival (P < 0.001). By multivariate analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). These data suggest that -460T → C polymorphism of VEGF gene, by increasing VEGF expression and subsequent angiogenesis, could be a key determinant for increased tumor recurrence and a poor prognosis of patients with colorectal carcinoma. However, this study is exploratory and is not adjusted for multiple comparisons, requiring independent replication.

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.

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.

Haematopoietic stem cell transplantation in Taiwan: past, present, and future.

In Taiwan, haematopoietic stem cell transplantation (HSCT) has been used to treat patients with haematological diseases since 1983. Thereafter till 2007, there were 2537 patients who had undergone HSCT in more than 15 hospitals. Their diseases included acute myeloid leukaemia in 27.8% of cases, non-Hodgkin's lymphoma 23.3%, acute lymphoblastic leukaemia 12.8%, chronic myeloid leukaemia 11.9%, severe aplastic anaemia 8.7%, and multiple myeloma 4.1%. Most of the cases received myeloablative conditioning regimens. More than 15% of cases received non-myeloablative regimens, and the mean age of these cases was at least 10 years older than those who received myeloablative regimens. The types of graft included peripheral blood (60.4%) and bone marrow (32.0%). A total of 35% of patients received autologous grafts. Of 1557 allogeneic HSCT patients, 338 (21.7%) received grafts from unrelated donors. Cord blood transplantation has been successfully performed in paediatric patients with thalassaemia major and with a large body size, and adult patients. The incidence of acute graft-versus-host disease was relatively low in Taiwan. On the contrary, a relatively higher proportion of hepatitis B carrier in the recipients had led to a higher incidence of reactivation hepatitis, which was markedly decreased following lamivudine prophylaxis. In conclusion, HSCT has become a routine therapy for major medical centres in Taiwan. Our unique experiences in the past decades also contributed to the progress of HSCT. With the establishment of professional association and patient supportive groups, we hope we can fully improve our daily practice and clinical as well as basic research in HSCT.

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.

Microsatellite DNA markers for population-genetic studies of blue mackerel (Scomber australasicus) and cross-specific amplification in S. japonicus.

Blue mackerel (Scomber australasicus) is targeted by large-scale purse-seiners in the western North Pacific, and its stock structure is still contentious. Herein, we described 10 polymorphic microsatellite loci for blue mackerel. The number of alleles among 32 individuals surveyed ranged from five to 27 (average of 16.2 alleles per locus). Departures from Hardy-Weinberg expectation were observed at two loci. Cross-specific amplification in the congener, S. japonicus, was successful, except for one locus, revealed to be diagnostic for these congeners. These microsatellite loci will be useful tools to address queries in population genetic structure, fishery management unit and taxonomic species status in the genus Scomber.

Current status of hematopoietic stem cell transplantation in Taiwan.

In Taiwan, hematopoietic SCT (HSCT) has been used to treat patients with hematological diseases since 1983. Since then, more than 2200 patients have undergone HSCT in 15 large hospitals. The disease entities included acute leukemia in 37% of cases, non-Hodgkin's lymphoma in 26%, CML in 10%, multiple myeloma in 7% and severe aplastic anemia in 6%. The conditioning regimens used were mainly myeloablative (84% of cases). Non-myeloablative regimens were fludarabine-based. The average age of allogeneic recipients was at least 10 years older than those in the era before their application. The grafts of all patients were derived from peripheral blood in 85% of cases, BM in 13% and cord blood (CB) in 2%. Forty percent of HSCT patients received autologous grafts, whereas more than 25% of allogeneic HSCT patients received grafts from unrelated donors, and overall, there were more than 200 Taiwan HSCT recipients. Currently, CB has been used successfully in pediatric patients with thalassemia major and also in adult patients with hematological malignancy. After transplantation, there was a relatively lower prevalence of acute GVHD. However, a relatively higher proportion of hepatitis B carriers in the recipients had led to a higher incidence of viral reactivation and clinical hepatitis, which was dramatically decreased following lamivudine prophylaxis. In conclusion, HSCT has been successfully adapted to routine clinical care in Taiwan. Several important findings contributing to the progress of HSCT in the past two decades have also been noticed on this island.

Hair follicle: a reliable source of recipient origin after allogeneic hematopoietic stem cell transplantation.

Blood, buccal swab and hair follicles are among the most commonly used sources for forensic science, parentage testing and personal identification. A total of 29 patients who have had a sustained engraftment from 15 months to 21.5 years after allogeneic hematopoietic stem cell transplantation (HSCT) without rejection, relapse or chronic GVHD involving oral mucosa were enrolled for a chimerism study. PCR-amplified short tandem repeat analyses were conducted per patient every 3 months for at least three consecutive times. The results for blood were all donor type except one who had a mixed chimerism, 14.5 years after receiving a transplant for lymphoma. As for buccal swab, mixed chimerism ranging from 10 to 96% donor origin was noted for 28 recipients except the one who had mixed chimerism of blood and retained total recipient type. In contrast, hair follicles were 100% recipient type for the entire group. It is concluded that the hair follicle is devoid of adult stem cell plasticity and may serve as a reliable source of recipient's origin when pre-transplant DNA fingerprinting or reference DNA is not available for people who have successfully received allogeneic HSCT while in need of a personal identification.