Publications by authors named "Udomsak Bunworasate"

31 Publications

Isolated Extramedullary Relapse After Human Leukocyte Antigen-Matched Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia Patients: Case Reports and Literature Review.

Transplant Proc 2021 May 4. Epub 2021 May 4.

Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Research Unit in Translational Hematology, Chulalongkorn University, Bangkok, Thailand. Electronic address:

Isolated extramedullary relapse (iEMR) of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare and has a dismal prognosis. Among 67 patients with AML after allo-HSCT, iEMR and bone marrow relapse occurred in 6% and 20.9%, respectively, with a median time to relapse of 11.5 and 6.5 months, respectively. Here, we presented 4 iEMR-AML cases. Common relapse locations occurred in the central nervous system, skin, and lymph nodes. We also report a rare case of cardiac iEMR that responded to chemoradiotherapy. Two cases responded to local/systemic treatments, which resulted in prolonged survival. Another case had iEMR in the presence of chronic graft-versus-host disease. Bone marrow relapse occurring after iEMR was typical and found in three-fourths of the cases. In conclusion, iEMR-AML occurrence after allo-HSCT is not rare in Thai patients. Its unpredictability and lack of graft-versus-leukemia effect highlight the importance of monitoring EMR carefully and promptly providing treatments once it is detected.
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http://dx.doi.org/10.1016/j.transproceed.2021.02.030DOI Listing
May 2021

Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin.

Blood Adv 2020 12;4(24):6098-6105

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept "preemptive" treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.
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http://dx.doi.org/10.1182/bloodadvances.2020003336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756981PMC
December 2020

Frequent mutations in HLA and related genes in extranodal NK/T cell lymphomas.

Leuk Lymphoma 2021 01 23;62(1):95-103. Epub 2020 Sep 23.

Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.

Extranodal NK/T cell lymphomas (ENKTCLs) are aggressive Epstein-Barr virus-associated T/NK neoplasms that predominantly affect Asians. To explore the causative somatic events, we conducted a comprehensive genetic analysis of 19 ENKTCL patients by whole-genome ( = 2), whole-exome ( = 16), and targeted sequencing ( = 15). Commonly deregulated gene pathways in ENKTCLs included epigenetic modifiers (58%, 11/19) followed by human leukocyte antigens (HLAs) and related genes including , , and (32%, 6/19), and JAK-STAT pathway (26%, 5/19). Conspicuously, loss-of-function mutations in were recurrently identified in ENKTCLs (16%, 3/19). HLA protein expression was examined by immunohistochemistry in 16 patients and lower expression was associated with advanced stages at presentation ( = .007). In conclusion, the defective antigen presenting pathway is common and related to disease progression, suggesting immune escape as a pathogenic mechanism of ENKTCLs.
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http://dx.doi.org/10.1080/10428194.2020.1821011DOI Listing
January 2021

Event-free survival at 12 months is a strong surrogate endpoint for stage 1 diffuse large B cell lymphoma: a report from Nation Wide Registry Thai Lymphoma Study Group.

Leuk Lymphoma 2020 11 23;61(11):2614-2621. Epub 2020 Jun 23.

Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Event-free survival at 12 months (EFS12) is a surrogate endpoint for long-term outcomes in many histologic lymphoma subtypes. However, most reports have primarily investigated the implication of EFS12 in advanced-stage non-Hodgkin lymphoma (NHL). There are limited data regarding the significance of EFS12 in early-stage NHL. Herein, we evaluated the prognostic significance of EFS12 in patients with stage 1 diffuse large B-cell lymphoma (DLBCL). Out of 282 patients with stage 1 DLBCL who received intensive therapy, 227 (80.5%) achieved EFS12. The 4-year overall survival (OS) was 91.4% and 4.0% for patients who achieved and failed to achieve EFS12, respectively. Multivariable analyses demonstrated response to treatment and achievement of EFS12 as independent predictors for OS. In conclusion, our study demonstrated EFS12 as a powerful prognostic factor for stage 1 DLBCL. Further validation in more extensive prospective studies is warranted.
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http://dx.doi.org/10.1080/10428194.2020.1780586DOI Listing
November 2020

Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE).

Br J Haematol 2020 04 3;189(2):303-312. Epub 2020 Feb 3.

Seoul St. Mary's Hematology Hospital, Leukemia Research Institute, The Catholic University of Korea, Seoul, South Korea.

In the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice-daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once-daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months' follow-up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR-ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR ) were achieved within 48 months by more radotinib-treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib-treated patients (71% and 44%, respectively). Estimated overall and progression-free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment-free remission may be attainable.
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http://dx.doi.org/10.1111/bjh.16381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187446PMC
April 2020

Novel DDX41 variants in Thai patients with myeloid neoplasms.

Int J Hematol 2020 Feb 11;111(2):241-246. Epub 2019 Nov 11.

Department of Medicine, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand.

Germline DDX41 mutations were recently reported to cause MDS/AML and donor-derived leukemia after transplantation. While previously described in Western countries, DDX41 variants have not been reported in a Southeast Asian population. We performed targeted sequencing of blood or bone marrow samples from 109 Thai patients with myeloid malignancies. Among the 109 patients (75 MDS, 8 MPN, 11 MDS/MPN and 15 AML), the most frequent mutations were in ASXL1 (17.4%), TET2 (16.5%) and SRSF2 (12.8%), respectively. DDX41 variants were detectable in six (5.5%) cases. Four patients exhibited three presumable germline DDX41 mutations: p.S21fs (n = 2), p.F235fs (n = 1), and p.R339H (n = 1). While p.S21fs was previously reported in myeloid neoplasm, the latter two variants have not been described. Two of these cases harbored concomitant probable germline/somatic DDX41 mutations (p.S21fs/p.R525H and p.R339H/p.K494T), while the other two patients carried only somatic mutations (p.R525H and p.F438L). The p.K494T and p.F438L variants have not been previously reported. In patients with DDX41 alterations, the diagnoses were MDS with excess blasts (4), secondary AML (1) and low-risk MDS (1). In conclusion, we identified DDX41 variants in Thai patients with myeloid malignancies in which these variants could be used to assess predisposition to MDS in Southeast Asia.
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http://dx.doi.org/10.1007/s12185-019-02770-3DOI Listing
February 2020

Event free survival at 24 months is a strong surrogate prognostic endpoint of peripheral T cell lymphoma.

Hematol Oncol 2019 Dec 12;37(5):578-585. Epub 2019 Nov 12.

Department of Internal Medicine, Chulalongkorn University, Bangkok, Thailand.

Event free survival at 24 months (EFS24) has been described as a powerful predictor for outcome in several subtypes of B cell lymphoma. However, it was limitedly described in T cell lymphoma. We explored the implication of EFS24 as a predictor marker for peripheral T cell lymphoma (PTCL). We reviewed 293 systemic PTCL patients at 13 nationwide major university hospitals in Thailand from 2007 to 2014. The median event free survival (EFS) and overall survival (OS) of PTCL patients in our cohort was 16.3 and 27.7 months with corresponding 2-year EFS and 2-year OS of 45.8% and 51.9%, respectively. A total of 118 patients achieved EFS24 (no events during the first 24 mo). Patients who achieved EFS24 had better OS than patients who did not (2-y OS 92% vs 18.8%; HR, 0.1; P < .001). The standardized mortality ratio of patients achieving EFS24 was 18.7 (95% CI, 14.6-22.8). Multivariable analysis demonstrated performance status, histologic subtype, remission status, and EFS24 achievement as independent predictors for OS. Our study affirmed the value of EFS24 as a powerful prognostic factor for PTCL. Further validation in prospective study setting is warranted.
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http://dx.doi.org/10.1002/hon.2687DOI Listing
December 2019

Programmed Cell Death 1 and Programmed Cell Death Ligands in Extranodal Natural Killer/T Cell Lymphoma: Expression Pattern and Potential Prognostic Relevance.

Acta Haematol 2020 22;143(1):78-88. Epub 2019 Jul 22.

Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand,

The programmed cell death 1/programmed cell death ligands (PD-1/PD-Ls) axis is a potential immune escape mechanism of cancers. However, data on the PD-1/PD-Ls pathway in EBV-associated extranodal natural killer/T cell lymphoma (ENKTL) and its clinical implication are limited. Herein, we characterized PD-1/PD-L expression and its prognosis relevance in 49 ENKTL patients in Thailand. PD-L1 was expressed frequently on both lymphoma cells (61.2%) and stroma (77.5%), whereas PD-L2 expression was more common on lymphoma (63.2%) than stromal cells. PD-1 was positive in 20.5% of stroma, but undetectable on lymphoma cells. There was no association between baseline clinical characteristics and the expression PD-1/PD-Ls. The survival of patients with PD-Ls on tumor cells was poor. For PD-L1-positive versus negative cases, the 2-year event-free survival (EFS) was 42.2 versus 71.8% (p = 0.03) and 2-year overall survival (OS) was 45.4 versus 78.9% (p = 0.02), respectively. Comparing between patients with PD-L2-positive and PD-L2-negative lymphoma, the 2-year EFS was 37.1 versus 82.4% (p = 0.02) and 2-year OS was 45.2 versus 82.4% (p = 0.03), respectively. Neither PD-1 nor PD-Ls expression in the stroma predicted outcomes. In conclusion, PD-Ls were frequently expressed on ENKTL cells and associated with inferior outcomes. Therefore, PD-Ls are potential prognostic biomarkers and the roles of immune checkpoint blockade therapy in ENKTL deserve further investigation.
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http://dx.doi.org/10.1159/000500974DOI Listing
April 2020

Advances in hematopoietic stem cell transplantation in the Asia-Pacific region: the second report from APBMT 2005-2015.

Bone Marrow Transplant 2019 12 14;54(12):1973-1986. Epub 2019 May 14.

Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT), Nagoya, Japan.

Between 2005 and 2015, 138,165 hematopoietic stem cell transplantation (HSCT) were reported in 18 countries/regions in the Asia-Pacific region. In this report, we describe current trends in HSCT throughout the Asia-Pacific region and differences among nations in this region and various global registries. Since 2008, more than 10,000 HSCTs have been recorded each year by the Asia-Pacific Blood and Marrow Transplantation Group Data Center. Between 2005 and 2015, the greatest increase in the number of HSCTs was observed in Vietnam. Allogeneic HSCT was performed more frequently than autologous HSCT, and a majority of cases involved related donors. Regarding allogeneic HSCT, the use of cord blood has remained steady, especially in Japan, and the number of cases involving related HLA non-identical donors has increased rapidly, particularly in China. The incidence of hemoglobinopathy, a main indication for allogeneic HSCT in India, China, Iran, and Pakistan, increased nearly six-fold over the last decade. Among the 18 participating countries/regions, the transplant rate per population varied widely according to the absolute number of HSCTs and the national/regional population size. We believe that this report will not only benefit the AP region but will also provide information about HSCT to other regions worldwide.
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http://dx.doi.org/10.1038/s41409-019-0554-9DOI Listing
December 2019

Characteristics, treatment patterns, prognostic determinants and outcome of peripheral T cell lymphoma and natural killer/T cell non-Hodgkin Lymphoma in older patients: The result of the nationwide multi-institutional registry Thai Lymphoma Study Group.

J Geriatr Oncol 2020 01 30;11(1):62-68. Epub 2019 Mar 30.

Department of Internal Medicine, Chulalongkorn University, Bangkok, Thailand.

Introduction: Peripheral T cell NHL (PTCL) and natural killer/T cell NHL (NKTCL) are relatively rare disorders. Data on clinical presentation, treatment and outcome are limited especially in older age groups.

Methods: We identified 127 patients with PTCL and NKTCL, excluding cutaneous T/NK cell lymphoma, aged over 60 years old from Thailand nationwide multicenter registry.

Results: Of 127 patients, median age of diagnosis was 67 years old. Patients aged older than 75 years old had similar characteristics to younger (60-74 years old) but higher comorbidity index. Seventy-nine patients (62.2%) received intensive/definite multi-agent chemotherapy, however, the proportion was significant lower in older patients (70.4% vs 34.5%, p < .001). After a median follow up duration of 17.3 months, 2-year progression free survival and overall survival were 38.1% and 48.5%. Univariate and multivariable analysis demonstrated older age, poor performance status and absence of definite multi-agent chemotherapy were associated with inferior survival. Definite multi-agent lymphoma specific chemotherapy was an independent factor for overall survival after adjustment for age, comorbidity index, performance status and prognostic index for T cell lymphoma.

Conclusion: Despite overall poor prognosis of PTCL and NKTCL in older adults, chemotherapy could result in objective response and long-term survival in selected patients of this vulnerable age group thus emphasizing the importance of comprehensive geriatric evaluation.
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http://dx.doi.org/10.1016/j.jgo.2019.03.016DOI Listing
January 2020

Frequent germline mutations of in sporadic subcutaneous panniculitis-like T-cell lymphoma.

Blood Adv 2019 02;3(4):588-595

Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in , encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable-like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations.
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http://dx.doi.org/10.1182/bloodadvances.2018028340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391671PMC
February 2019

Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802.

Blood Adv 2018 08;2(15):1882-1888

National Marrow Donor Program, Minneapolis, MN.

Amphiregulin (AREG) is an epidermal growth factor receptor ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously reported that circulating AREG is elevated in late-onset aGVHD (occurring after 100 days posttransplant), but its clinical relevance in the context of aGVHD risk is unknown. We measured AREG in 251 aGVHD onset blood samples from Blood and Marrow Clinical Trials Network (BMT CTN) primary treatment trials and determined their association with GVHD severity, day 28 complete or partial response (CR/PR) to first-line therapy, overall survival (OS), and nonrelapse mortality (NRM). Every doubling of plasma AREG was associated with a 33% decrease in the odds of day 28 CR/PR (odds ratio [OR], 0.67; < .01). An AREG threshold of 33 pg/mL or greater divided patients with Minnesota standard-risk (SR) aGVHD into a distinct group with a significantly lower likelihood of: day 28 CR/PR (72% vs 85%; = .02); greater 2-year NRM (42% vs 15%; < .01); and inferior OS (40% vs 66%; < .01). High AREG ≥ 33 pg/mL also stratified patients with Minnesota high-risk (HR) aGVHD: day 28 CR/PR (54% vs 83%; = .03) and 2-year NRM (53% vs 11%; < .01), with a trend toward inferior 2-year OS (37% vs 60%; = .09). High-circulating AREG (≥33 pg/mL) reclassifies patients into HR subgroups and thereby further refines the Minnesota aGVHD clinical risk score.
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http://dx.doi.org/10.1182/bloodadvances.2018017343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093743PMC
August 2018

Efficacy and safety of frontline rituximab, cyclophosphamide, doxorubicin and prednisone plus bortezomib (VR-CAP) or vincristine (R-CHOP) in a subset of newly diagnosed mantle cell lymphoma patients medically eligible for transplantation in the randomized, phase 3 LYM-3002 study.

Leuk Lymphoma 2018 04 17;59(4):896-903. Epub 2018 Jan 17.

q Oncology Institute of Southern Switzerland Ospedale San Giovanni , Bellinzona , Switzerland.

This post-hoc subanalysis of the LYM-3002 phase 3 study assessed the efficacy and safety of substituting vincristine in rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHOP; n = 42) for bortezomib (VR-CAP; n = 38) in a subgroup of 80 mantle cell lymphoma (MCL) patients aged <60 years who did not receive stem cell transplantation (SCT) despite medical eligibility. Complete response (CR)/unconfirmed CR (CRu) rates were 67 vs. 39% (odds ratio 3.69 [95% CI(confidence interval): 1.31, 10.41]; p = .012). After 40 months median follow-up, median progression-free survival by independent radiology committee with VR-CAP vs. R-CHOP was 32.6 vs. 12.0 months (hazard ratio (HR) 0.59 [95% CI: 0.31, 1.13]; p = .108); median overall survival was not reached vs. 47.3 months (HR 0.81 [95% CI: 0.33, 1.96]; p = .634). Adverse events included neutropenia (92/76%), thrombocytopenia (70/10%) and leukopenia (65/50%). VR-CAP represents a potential alternative to R-CHOP in combined and/or alternating regimens for younger, SCT-eligible MCL patients.
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http://dx.doi.org/10.1080/10428194.2017.1365855DOI Listing
April 2018

Phase III Clinical Trial (RERISE study) Results of Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia.

Clin Cancer Res 2017 Dec 22;23(23):7180-7188. Epub 2017 Sep 22.

Seoul St. Mary's Hospital, Leukemia Research Institute, The Catholic University of Korea, Seoul, South Korea.

Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months. Two hundred forty-one patients were randomized to receive radotinib 300 mg ( = 79) or 400 mg twice-daily ( = 81), or imatinib 400 mg daily ( = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; = 0.0044 and = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome-positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289 .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0957DOI Listing
December 2017

Non-Hodgkin lymphoma in South East Asia: An analysis of the histopathology, clinical features, and survival from Thailand.

Hematol Oncol 2018 Feb 23;36(1):28-36. Epub 2017 Mar 23.

Departmentof Pathology, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand.

Systemic reports on the descriptive epidemiology of non-Hodgkin lymphoma (NHL) from Southeast Asia are scarce. A nationwide multi-institutional registry was conducted to compare the histopathology, clinical features, and survival of Thai adult patients with NHL using large registries, especially those from Far East Asia (FEA). Using a web-based registry system, 13 major medical centers from the 4 geographic regions of Thailand prospectively collected, from 2007 to 2014, the diagnostic pathology, according to the World Health Organization classification, 2008, clinical features and survival of 4056 patients who were newly diagnosed with NHL. The median age of the patients was 56 years (range, 16-99 years). The male-to-female ratio was 1.3:1. From the total of 4056 patients, T/NK-cell lymphoma (TNKCL) accounted for 12.6% of cases, and 5.1% had human immunodeficiency virus-associated lymphoma. The four leading histological subtypes were diffuse large B-cell lymphoma, not otherwise specified (58.1%); follicular lymphoma (5.6%); extranodal mucosa-associated lymphoid tissue lymphoma (5.2%); and peripheral T-cell lymphoma, not otherwise specified (4.0%). With a median follow-up duration of 46.1 months, the median overall survival of B-cell NHL was significantly longer than that of patients with TNKCL (76.5 vs 28.8 months, P = .0001). Compared to FEA, the Thai registry had an approximately one-half lower relative frequency of TNKCL; the prevalence of extranodal mucosa-associated lymphoid tissue lymphoma was much lower than in Korea, and the frequency of extranodal TNKCL, nasal type, was strikingly low compared to China. It is concluded that while the median age of Thai patients with NHL was approximately a decade younger than for Caucasians, the long-term survival rates for most histological subtypes were comparable. While the histological distribution generally complied with the characteristic Asian features, some differences from FEA were observed.
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http://dx.doi.org/10.1002/hon.2392DOI Listing
February 2018

An early-biomarker algorithm predicts lethal graft-versus-host disease and survival.

JCI Insight 2017 02 9;2(3):e89798. Epub 2017 Feb 9.

Blood and Marrow Transplantation Program, University of Regensburg, Regensburg, Germany.

No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set ( = 309) and validation set ( = 358). A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group ( < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, < 0.001) and the multicenter validation set (26% vs. 10%, < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.
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http://dx.doi.org/10.1172/jci.insight.89798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291735PMC
February 2017

Secondary central nervous system relapse in diffuse large B cell lymphoma in a resource limited country: result from the Thailand nationwide multi-institutional registry.

Ann Hematol 2017 Jan 18;96(1):57-64. Epub 2016 Oct 18.

Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, 1873 Rama IV road Pathumwan, Bangkok, Thailand.

Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p < 0.001). Univariate analysis demonstrated advance stage disease, poor performance status, elevated lactate dehydrogenase, presence of B symptoms, more than one extranodal organ involvement, high IPI, and high CNS-IPI group as predictive factors for SCNS relapse. Rituximab exposure and intrathecal chemoprophylaxis offered no protective effect against SCNS relapse. At the time of analysis, six patients were alive. Median OS in SCNS relapsed patients was significantly shorter than relapsed patients without CNS involvement (13.2 vs 22.6 months) (p < 0.001). Primary causes of death were progressive disease (n = 35, 63.6 %) and infection (n = 9, 16.7 %). In conclusion, although the incidence of SCNS relapse in our cohort was low, the prognosis was dismal. Prophylaxis for SCNS involvement was underused even in high-risk patients. Novel approaches for SCNS relapse prophylaxis and managements are warranted.
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http://dx.doi.org/10.1007/s00277-016-2848-yDOI Listing
January 2017

Correlation of FcγRIIIa Polymorphisms to the Response of Rituximab in Thai Patients with Diffuse Large B-Cell Lymphoma.

J Med Assoc Thai 2015 Dec;98(12):1215-21

Background: Rituximab is an anti-CD20 chimeric antibody widely used in combination with CHOP regimen for the treatment of diffuse large B-cell lymphoma (DLBCL). It is suggested that this antibody destroys B lymphoma cells mainly by antibody dependent cellular cytotoxicity (ADCC) mechanism via the binding of the drug to FC gamma IIIa receptor (FcγRIIIa) on natural killer (NK) cells, affected to kill cancer cells. The FcγRIIIa has genetic polymorphism at nucleotide position 559 (G559T or V158F or rs396991) have shown influence on the binding and efficacy of rituximab.

Objective: We identified the distribution of FcγRIIIa polymorphism in Thai patients with DLBCL and investigated the correlation between FcγRIIIa polymorphisms and the clinical outcomes in Thai DLBCL patients who were treated with rituximab plus CHOP chemotherapy regimen.

Material And Method: The Taqman SNP real-time PCR assay was used to identify the FcγRIIIa polymorphism in the present study and the clinical outcomes of these patients were evaluated and correlated between FcγRIIIa polymorphism.

Results: The distribution of FcγRIIIa genotype in patients were 54.17% homozygous V/V 10.41% homozygous F/F and 35.42% heterozygous V/F and there was no differences in clinical response among these patients (p-value = 0.31). Complete response was assessed in V/V 84.62%, V/F 88.24%, and F/F 80.00%. Partial response was in V/V 7.68% and F/F 20.00%. Stable disease was in V/F 11.76%, progressive disease in V/V 7.72%.

Conclusion: The correlation could not be found between FcγRIIIa polymorphisms to the response of rituximab in Thai patients with diffuse large B-cell lymphoma.
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December 2015

International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium.

Biol Blood Marrow Transplant 2016 Jan 16;22(1):4-10. Epub 2015 Sep 16.

Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Blood and Marrow Transplantation Program, The Icahn School of Medicine at Mount Sinai Hospital, New York, New York. Electronic address:

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation.
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http://dx.doi.org/10.1016/j.bbmt.2015.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706482PMC
January 2016

Successful peripheral blood stem cell mobilization using pegfilgrastim in allogeneic stem cell transplantation.

Int J Hematol 2014 Mar 29;99(3):318-22. Epub 2014 Jan 29.

Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, 10330, Thailand,

Pegfilgrastim is produced by binding a 20,000-dalton polyethylene glycol molecule to granulocyte colony-stimulating factor (G-CSF), increasing the mass of the compound, and resulting in a longer-lasting form of G-CSF. This makes it more convenient to use pegfilgrastim as a single-day injection. This study was a prospective phase II single-center trial. Fifteen normal related donors received pegfilgrastim 12 mg subcutaneously to mobilize peripheral blood stem cells (PBSC) for allogeneic stem cell transplantation. Leukapheresis was planned to start 3 days after injection. All harvests were successful. Median number of leukapheresis was 2 days (range 1-3 days). There were 7/15 donors who only required single leukapheresis. The maximum concentration of white blood cells (WBC) and circulating CD34 cells occurred 3 days after pegfilgrastim injection (WBC: median 62,200/μl; CD34: median 69.76/μl). The median yield of CD34 cells was 6.78 × 10(6)/kg recipient weight. The median CD3 cells was 1.89 × 10(8)/kg recipient weight. The main adverse events were bone pain and headache. Median neutrophil and platelet engraftments in the recipients occurred on day 12 and day 13, respectively, after transplantation. PBSC mobilization with single-day injection of pegfilgrastim in normal donor is feasible. Further comparisons of this protocol to standard G-CSF for allogeneic stem cell mobilization should be conducted in future.
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http://dx.doi.org/10.1007/s12185-014-1507-0DOI Listing
March 2014

Cost utility analysis of reduced intensity hematopoietic stem cell transplantation in adolescence and young adult with severe thalassemia compared to hypertransfusion and iron chelation program.

BMC Health Serv Res 2013 Feb 5;13:45. Epub 2013 Feb 5.

Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand.

Background: Hematopoieticic stem cell transplantation is the only therapeutic option that can cure thalassemia disease. Reduced intensity hematopoietic stem cell transplantation (RI-HSCT) has demonstrated a high cure rate with minimal complications compared to other options. Because RI-HSCT is very costly, economic justification for its value is needed. This study aimed to estimate the cost-utility of RI-HSCT compared with blood transfusions combined with iron chelating therapy (BT-ICT) for adolescent and young adult with severe thalassemia in Thailand.

Methods: A Markov model was used to estimate the relevant costs and health outcomes over the patients' lifetimes using a societal perspective. All future costs and outcomes were discounted at a rate of 3% per annum. The efficacy of RI-HSCT was based a clinical trial including a total of 18 thalassemia patients. Utility values were derived directly from all patients using EQ-5D and SF-6D. Primary outcomes of interest were lifetime costs, quality adjusted life-years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) in US ($) per QALY gained. One-way and probabilistic sensitivity analyses (PSA) were conducted to investigate the effect of parameter uncertainty.

Results: In base case analysis, the RI-HSCT group had a better clinical outcomes and higher lifetime costs. The incremental cost per QALY gained was US $3,236 per QALY. The acceptability curve showed that the probability of RI-HSCT being cost-effective was 71% at the willingness to pay of 1 time of Thai Gross domestic product per capita (GDP per capita), approximately US $4,210 per QALY gained. The most sensitive parameter was utility of severe thalassemia patients without cardiac complication patients.

Conclusion: At a societal willingness to pay of 1 GDP per capita, RI-HSCT was a cost-effective treatment for adolescent and young adult with severe thalassemia in Thailand compared to BT-ICT.
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http://dx.doi.org/10.1186/1472-6963-13-45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583808PMC
February 2013

Inferior progression-free survival for Thai patients with diffuse large B-cell lymphoma treated under Universal Coverage Scheme: the impact of rituximab inaccessability.

Leuk Lymphoma 2013 Jan 9;54(1):83-9. Epub 2012 Jul 9.

Division of Hematology, Department of Medicine, Chulalongkorn University, Bangkok, Thailand.

The impact of health insurance with inequitable rituximab coverage on the survival of patients with diffuse large B-cell lymphoma (DLBCL) has never been reported. We conducted a nationwide multicenter analysis on the outcome of 553 adult patients consecutively diagnosed with DLBCL between July 2003 and June 2006, in whom treatment cost was reimbursed under the Civil Servant Medical Benefit Scheme (CSMBS) (n =201) or the Universal Coverage Scheme (UCS) (n =352). The international prognostic index was comparable between the two payment groups. Rituximab-based therapy was administered in 45.3% and 3.1% of CSMBS and UCS patients, respectively (p <0.001). With a median follow-up of 24.6 months, the 6-year progression-free survival (PFS) was superior for CSMBS patients (34.2 vs. 23.2%, p =0.005). "Not treated with rituximab-based therapy" was the strongest adverse prognostic feature indicating a short PFS (hazard ratio 2.1, p <0.001). It is concluded that lack of access to rituximab is the principal factor accounting for the inferior PFS observed in Thai patients with DLBCL who are treated under the UCS.
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http://dx.doi.org/10.3109/10428194.2012.698739DOI Listing
January 2013

Extranodal NK/T-cell lymphoma, nasal type, includes cases of natural killer cell and αβ, γδ, and αβ/γδ T-cell origin: a comprehensive clinicopathologic and phenotypic study.

Am J Surg Pathol 2012 Apr;36(4):481-99

Department of Pathology, Division of Hematopathology, University of Pittsburgh School of Medicine, Pittsburgh 15213-2582, USA.

Extranodal NK/T-cell lymphoma (ENKTL), nasal type, may be of NK or T-cell origin; however, the proportion of T-ENKTLs and whether they are of αβ or γδ type remains uncertain. To elucidate the cell of origin and detailed phenotype of ENKTL and assess any clinicopathologic associations, 67 cases of ENKTL from Thailand were investigated, together with 5 γδ enteropathy-associated T-cell lymphomas (EATLs) for comparison. In all, 70% of the ENKTL were T-cell receptor (TCR) β,γ and, in cases tested, δ negative (presumptive NK origin); 5% were TCR γδ, 3% were TCR αβ, 1% were TCR αβ/γδ, and 21% were indeterminate. Out of 17 presumptive NK-ENKTLs tested, 3 had clonal TCR rearrangements. All cases were EBV and TIA-1; >85% were positive for CD3, CD2, granzyme B, pSTAT3, and Lsk/MATK; and all were CD16. Presumptive NK-ENKTLs had significantly more frequent CD56 (83% vs. 33%) and CXCL13 (59% vs. 0%) but less frequent PD-1 (0% vs. 40%) compared with T-ENKTLs. Of the NK-ENKTLs, 38% were Oct-2 compared with 0% of T-ENKTLs, and 54% were IRF4/MUM1 compared with 20% of T-ENKTLs. Only αβ T-ENKTLs were CD5. Intestinal ENKTLs were EBV and had significantly more frequent CD30, pSTAT3, and IRF4/MUM1 expression but less frequent CD16 compared with γδ EATL. Significant adverse prognostic indicators included a primary non-upper aerodigestive tract site, high stage, bone marrow involvement, International Prognostic Index ≥2, lack of radiotherapy, Ki67 >40%, and CD25 expression. The upper aerodigestive tract ENKTLs of T-cell origin compared with those of presumptive NK origin showed a trend for better survival. Thus, at least 11% of evaluable ENKTLs are of T-cell origin. Although T-ENKTLs have phenotypic and some possible clinical differences, they share many similarities with ENKTLs that lack TCR expression and are distinct from intestinal γδ EATL.
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http://dx.doi.org/10.1097/PAS.0b013e31824433d8DOI Listing
April 2012

Intra-coronary bone marrow mononuclear cell transplantation in patients with ST-elevation myocardial infarction: a randomized controlled study.

J Med Assoc Thai 2011 Jun;94(6):657-63

Division of Cardiology, Department of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.

Background: Stem cell transplantation is a potential treatment to improve left ventricular ejection fraction (LVEF) after ST elevation myocardial infarction (STEMI). However, the outcomes still are controversial.

Objective: To determine the 6-month LVEF of the patients who underwent intra-coronary bone marrow mononuclear cell (BMC) transplantation in patients with STEMI compared with controlled subjects.

Material And Method: After successful percutaneous coronary intervention (PCI) in STEMI patients who had LVEF was less than 50% were randomized to intra-coronary BMC transplantation or control. Bone marrow aspiration of 100 cc was performed in the morning. After cellprocessing for three hours, the suspension of BMC about 10 cc were infused to infracted area using standard PCI technique. Balloon occlusion for three minutes was performed during cell infusion. Cardiac magnetic resonance imaging was used to determine LVEF scar volume and LV volume before and six-month follow-up.

Results: Between September 2006 and July 2008, 23patients (11 in BMC group and 12 in control group) were enrolled. Mean BMC count before transplant was 420 x 10(6) cell with 96% viability. At six-month follow-up, New York Heart Association function class significantly improved in both groups (2.3 +/- 0.6 to 1.2 +/- 0. 4 for BMC and 2.3 +/- 0.7 to 1.3 +/- 0.5 for control group) but no difference was seen between groups. However, scar volume, wall motion score index, and LVEF did not show improvement after six months in both groups (33.7 +/- 7.7 to 33.5 +/- 7.6 for BMC and 31.1 +/- 7.1 to 32.6 +/- 8.3 for control group). No complication was observed during the procedure.

Conclusion: BMC transplantation intra-coronary in patients with STEMI in KCMH was feasible and safe but LVEF improvement could not be demonstrated.
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June 2011

Chronic myeloid leukemia in the Asia-Pacific region: current practice, challenges and opportunities in the targeted therapy era.

Leuk Res 2010 Nov;34(11):1459-71

Division of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.

Chronic myeloid leukemia (CML) management varies across Asia due to disparities in affluence and healthcare provision. We surveyed CML management practice at 33 hospitals in 14 countries/regions to identify treatment challenges and opportunities for harmonization. Patients were generally treated according to international guidelines; however, tyrosine kinase inhibitors (TKIs) and molecular monitoring are inaccessible to many patients not covered by national insurance or eligible for subsidized treatment. Late diagnosis and suboptimal monitoring, often due to cost and accessibility issues, are challenges. Priorities for Asia include: extending accessibility to TKIs; specialist laboratory monitoring; and enriching data to support regional CML management guidelines.
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http://dx.doi.org/10.1016/j.leukres.2010.03.033DOI Listing
November 2010

Feasibility and safety of intra-coronary bone marrow mononuclear cell transplantation in ST elevation myocardial infarction patients.

J Med Assoc Thai 2009 Dec;92(12):1591-6

Division of Cardiovascular Diseases, Department of Medicine, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand.

Background: Stem cell transplantation is a potential treatment to improve left ventricular ejection fraction (LVEF) after ST elevation myocardial infarction (STEMI). However technique and mode of transplantation, type of cells, number of cells, and when to transplant are still unknown.

Objective: To determine the feasibility and safety of bone marrow mononuclear cell (BMC) intra-coronary transplantation and 6-months results in patients with STEMI.

Material And Method: After successful percutaneous coronary intervention (PCI) in STEMI patients who did not have flow re-established within 12 hours and poor LVEF (less than 50%) by echocardiography were enrolled Bone marrow aspiration of 100 cc was performed in the morning. After cell processing for 3 hours, the suspension of BMC about 10 cc were infused to infarcted area using standard PCI technique. Balloon occlusion for 3 minutes was performed during cell infusion. Cardiac magnetic resonance imaging was used to determine LVEF scar volume and LV volume before and 6 months after transplantation.

Results: Five patients were enrolled between May and August 2006. Duration of STEMI before transplantation ranged from 18 days to 14 years. Total amount of BMC ranged from 67 x 10(6) to 335 x 10(6). Number of CD 34 and CD 133+ cells were approximation to be 0.7 x 10(6) to 7.7 x 10(6) and 0.01 x 10(6) to 3.04 x 10(6). LVEF was increased from 36.4 at baseline to 43.3 at 6-month. NT pro-BNP level was decreased from 1105 ng/ml at baseline to 288 pg/ml at 6-month. No complications such as chest pain, no re-flow phenomenon, ventricular arrhythmia, or hypotension was detected during the procedure.

Conclusion: Intra-coronary BMC transplantation in patients with STEMI in our center is feasible and safe. LVEF was slightly improved; however, a randomized controlled study is needed.
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December 2009

Dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient: the first case report.

Infect Dis Rep 2009 Sep 6;1(1):e3. Epub 2009 Nov 6.

Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;

Dengue infection, a mosquito-borne infectious disease in tropical and subtropical areas, has recently become an emerging global disease. The clinical course of dengue infection may be unfavorable in immunocompromised patients. In this report, we present a 16-year old female patient with acute myeloid leukemia who received allogeneic peripheral blood stem cell transplant five months prior to presentation. She was hospitalized at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, due to fever, headache, and myalgia for one day. During hospitalization, she developed capillary leakage syndrome and progressive thrombocytopenia. A diagnosis of dengue hemorrhagic fever was made and confirmed by positive dengue serology and polymerase chain reaction testing. She made a full recovery 14 days after hospitalization. Our case possibly acquired dengue virus from infected mosquitoes while visiting her relatives four days before her present illness. In conclusion, this is the first reported case of dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient. In addition, we review all previous reports of dengue infection in organ transplant recipients.
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http://dx.doi.org/10.4081/idr.2009.e3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892570PMC
September 2009

Bilateral pheochromocytoma during the postpartum period.

Arch Gynecol Obstet 2009 Dec 2;280(6):1055-8. Epub 2009 Apr 2.

Department of Internal Medicine, Chulalongkorn University, Patumwan, Bangkok, Thailand.

Background: Pheochromocytoma manifesting during pregnancy is uncommon but it is responsible for a high maternal and fetal mortality rate, especially when unrecognized. Most cases of pheochromocytoma are sporadic but they can be part of hereditary autosomal dominant syndromes.

Case: We describe a case of bilateral pheochromocytoma in a term-pregnant patient with a previous history of medullary thyroid carcinoma (MTC). Her genetic study revealed a heterozygous mutation, c.1900T>C, in the RET proto-oncogene which confirmed the diagnosis of multiple endocrine neoplasia type 2A (MEN2A). Unrecognized, the tumors caused a crisis with fatal outcome in the mother during the postpartum period. This event might have been prevented if the tumor had been detected previously.

Conclusion: MEN2A affected pregnancy is an unusual condition. This syndrome should be suspected when a pregnant patient has a history of MTC. Early detection and appropriate management can prevent serious maternal and fetal complications. We also reviewed the literature of MEN2A-affected pregnancies.
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http://dx.doi.org/10.1007/s00404-009-1057-5DOI Listing
December 2009