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  1. Fadilah, S.A.W., Shanty, V., Goh, AS
    Medicine & Health, 2007;2(1):99-102.
    MyJurnal
    Kimura’s disease (KD) is a rare, benign chronic inflammatory disease of unknown aetiology, typically presents in the Orientals as subcutaneous masses in the head and neck region that could be easily misdiagnosed as a malignant tumour, leading to unnecessary radical surgery or intensive cytotoxic therapy. It has been mainly reported in the Chinese and Japanese literature. It is difficult to diagnose before tissue biopsy and fine needle aspiration cytology (FNAC) has limited value. Hence, unless the pathologists are aware of this entity, it might be mistaken as a malignant lesion. We encountered a case of KD in a Malay patient presenting as a parotid mass that was initially diagnosed as Hodgkin’s lymphoma (HL). This disorder should be suspected in young male Asian patients presenting with a painless unilateral mass in the head and neck region with associated hypereosinophilia. 
  2. Teoh CS, Goh AS
    Case Rep Transplant, 2021;2021:8831125.
    PMID: 33552611 DOI: 10.1155/2021/8831125
    A middle-aged gentleman who was diagnosed with high-risk chronic lymphocytic leukaemia (CLL), Rai stage IV, Binet C with del(17p) and del(13q) underwent allogeneic haematopoeitic stem cell transplantation (allo-HSCT) from a human leukocyte antigen (HLA) identical sister. The patient developed extensive skin, oral, and liver chronic graft versus host disease (GVHD) required tacrolimus, mycophenolate mofetil (MMF), and prednisolone. At seventh month after allo-HSCT, the patient presented with systemic symptoms, right cervical lymphadenopathy, splenomegaly, marked pancytopaenia, and elevated lactate dehydrogenase (LDH). Bone marrow study, immunophenotyping (IP), chromosome analysis, and PET-CT scan confirmed relapsed CLL with no evidence of Richter's transformation or posttransplant lymphoproliferative disease (PTLD). Withdrawal of immunosuppressant (IS) worsened cutaneous and liver GVHD. Chemotherapy was not a suitable treatment option in view of immunodeficiency. The patient underwent extracorporeal photopheresis (ECP) therapy eventually for extensive chronic GVHD, and the IS were gradually tapered to the minimal effective dose. The relapsed CLL was treated successfully with oral venetoclax accessible via a compassionate drug program. This case highlights challenges in managing relapsed CLL and loss of graft-versus-leukaemia (GVL) effect despite extensive chronic GVHD. Venetoclax is an effective and well-tolerated oral novel agent for relapsed CLL after allo-HSCT.
  3. Lee KT, Lim SL, Goh AS
    Med J Malaysia, 2020 01;75(1):33-37.
    PMID: 32008017
    INTRODUCTION: Frequent blood transfusions results in iron overload and lead to multiple endocrine complications. In spite of improvements in iron chelation therapy, a significant number of transfusion dependent thalassaemia (TDT) patients still develop endocrine complications. The aim of this study is to evaluate the prevalence of various endocrine complications in our adult TDT patients and to study the correlation with serum ferritin and liver iron concentration (LIC).

    METHODS: A retrospective review of all TDT patients treated in Haematology Unit, Hospital Pulau Pinang (HPP) was conducted.

    RESULTS: Of the 45 adult TDT patients, 22 were males and 23 were females with mean age of 28.8±6.9 years old. Majority of TDT in HPP were beta thalassemia major (71.1%), followed by E-Beta thalassemia (24.4%) and HbH-Constant Spring (4.4%). Frequency of transfusion was 3-4 weekly. 40.0% of adult TDT suffered from at least one endocrine complication. Among the adult TDT patients with endocrine complication, 50% have one endocrinopathy, 38.9% with two types of endocrinopathies and 11.1% of them have three or more types of endocrinopathies. Hypogonadism (22.2%) was the commonest endocrine complication, followed by osteoporosis (20%), hypothyroidism (13.3%), diabetes mellitus (6.7%) and hypocortisolism (4.4%). Patients with endocrine complications were significantly older. Mean serum ferritin level and LIC was higher among patients with endocrine complications but both were not statistically significant.

    CONCLUSION: Endocrinopathy is still prevalent in 40% of adult TDT patients. This leads to higher health-care resource utilization, cost and significant morbidities among patients with TDT. Therefore, regular monitoring and early detection with intensification of chelation therapy is essential.

  4. Seow CE, Goh AS, Lim SL
    Med J Malaysia, 2021 Nov;76(6):799-803.
    PMID: 34806663
    INTRODUCTION: Thalassemia is the most common heritable haematological disorder in Malaysia. Hypothyroidism is one of the complications of the transfusion dependent thalassemia (TDT) patients as a result of iron overload.

    MATERIALS AND METHODS: All registered TDT patients attending Haematology day care, Hospital Pulau Pinang from January 2019 to January 2020 were included in the study. Hypothyroidism was defined according to TSH and FT4, or based on the history of treatment for diagnosed hypothyroidism.

    RESULTS: There were 51 TDT patients, with 24 (47%) males and 27 (53%) females. Most of the patients were Malays (27, 53%) followed with Chinese (23, 45%) and Indonesian (1, 2%). Beta thalassemia major and HbE beta thalassaemia accounted for 35 (68.8%) and 14 (27.5%) TDT patients respectively, while two (3.9%) were HbH Constant Spring. Eleven (21.6%) had hypothyroidism; of which seven (63.6%) had central hypothyroidism, three (27.3%) had subclinical hypothyroidism, the remaining one (9.1%) had primary hypothyroidism. Three (27.3%) had concomitant hypogonadism, one (9.1%) had hypocortisolism and another (9.1%) had both diabetes mellitus and hypogonadism. There was no statistical relationship between the prevalence of hypothyroidism and age, serum ferritin, splenectomy history and iron chelation therapy.

    CONCLUSION: High prevalence of central hypothyroidism is reported. Measurement of both TSH and FT4 is recommended as initial screening for thyroid dysfunction among patient with TDT.

  5. Lee KT, Tan SK, Goh AS
    Med J Malaysia, 2024 Mar;79(2):170-175.
    PMID: 38553922
    INTRODUCTION: Haemophilia is one of the commonest inherited bleeding disorders which may lead to long term disabilities if not treated properly. Our aim of study is to understand the clinical characteristic, treatment and complications of adult haemophilia patients in our centre.

    MATERIALS AND METHODS: A retrospective cross-sectional review of all adult haemophilia A (HA) or haemophilia B (HB) patients who received treatment in Hospital Pulau Pinang from January 2021 to December 2022 was conducted. Data was retrieved from patients' medical records.

    RESULTS: A total of 75 haemophilia patients (64 HA and 11 HB) were included in this study with median age of 37 years (range 19 70). 42 of them had severe haemophilia (50% of HA, 91% of HB). All HB and 93.8% of severe HA patients were on prophylaxis. Six severe and one mild HA patients developed inhibitor with four of them currently on non-factor prophylaxis. 24 patients (32%) had prior hepatitis C infection and all of them have been successfully treated. The mean annual bleeding rate for severe haemophilia patients were 1.77 (SD ±3.6). Target joints were observed in 9.3% of patients with ankle joint (71.4%) being the most affected joint. More than one quarter (26.7%) of our patients have comorbidities with majority of them having hypertension (17/20), followed by diabetes mellitus (5/20) and ischemic heart disease (5/20).

    CONCLUSION: Our study showed that a significant number of adult patients with haemophilia have comorbidities. Apart from optimising factor replacement therapy, future planning should include improvement in screening, risk modification and prevention of cardiovascular disease.

  6. Yong ASM, Goh AS, Rahman M, Menon J, Purushothaman V
    Med J Malaysia, 1998 Mar;53(1):59-62.
    PMID: 10968139
    Aplastic anaemia is a rare disease which is more prevalent in the Far East. In Malaysia, it appears to be unusually common in the state of Sabah. A retrospective analysis of all cases of aplastic anaemia diagnosed between January 1993 and March 1996 was undertaken. The criteria of the International Aplastic Anaemia and Agranulocytosis Study (IAAAS) was used. In this 39 month period, 31 cases were confirmed by marrow trephine biopsy to be aplastic anaemia. The male-to-female ratio was 3.4. Median age of diagnosis was 23 years. There were 24 patients (77%) who were from the Kadazan-Dusun ethnic group, which forms 18% of the population of Sabah. The incidence of aplastic anaemia in Sabah appears to be higher than that reported elsewhere in the Far East, at 4.8 per million population per year. Peak incidence is in the elderly group at 8.6 per million followed by a second peak in young people aged 15 to 24 (7.9 per million). The aplastic anaemia to total acute leukaemia ratio is 0.37. The marked male preponderance and apparent susceptibility of the Kadazan-Dusun people are also notable. A further prospective study to address the true incidence of aplastic anaemia and possible aetiologic factors accounting for these observations is necessary.
  7. Lee KT, Teoh CS, Chew TK, Goh AS
    J R Coll Physicians Edinb, 2020 Jun;50(2):144-147.
    PMID: 32568285 DOI: 10.4997/JRCPE.2020.213
    Vitamin B12 deficiency and folate deficiency are common causes of macrocytic anaemia and both are important for many cellular processes. These deficiencies could be due to inadequate dietary intake, impaired absorption or drug ingestion. We present a case of a 47-year-old male with a history of diffuse large B-cell lymphoma (DLBCL) who was admitted for fatigue, persistent frontal headache and left upper-quadrant abdominal pain. Further investigation showed that he had pancytopenia with microangiopathic haemolytic anaemia (MAHA) and intracranial bleeding (ICB). Serum vitamin B12 and folate were later found to be low and a diagnosis of combined vitamin B12 and folate deficiency mimicking thrombotic thrombocytopenic purpura (TTP) was made. The patient responded well to vitamin B12 and folate replacement.
  8. Au A, Aziz Baba A, Goh AS, Wahid Fadilah SA, Teh A, Rosline H, et al.
    Biomed Pharmacother, 2014 Apr;68(3):343-9.
    PMID: 24581936 DOI: 10.1016/j.biopha.2014.01.009
    The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.
  9. Ong CK, Lim SL, Tan WC, Ong EE, Goh AS
    Med J Malaysia, 2008 Jun;63(2):109-12.
    PMID: 18942294 MyJurnal
    Frequent blood transfusions can lead to iron overload which may result in several endocrine complications especially in the absence of adequate chelation therapy. The objectives of this study are to determine the prevalence of endocrine complications in transfusion dependent thalassaemia patients and the correlation of endocrine complications with the degree of iron chelation. This retrospective study looked at cases of adult patients with transfusion dependent thalassaemia treated in the Haematology Unit, Penang Hospital. Of the 25 transfusion dependent thalassaemia patients, there were 10 male and 15 female patients respectively with almost equal number of Malay and Chinese patients (13 and 12 patients respectively). Short stature was seen in 36.0% of our patients. In our cohort, 12 patients had delayed puberty (male 70.0% and female 33.3%). Prevalence of osteoporosis was 36.0%. Hypogonadism was noted in 40.0% of males and 46.7% of females. 53.4% of the female population had menstrual abnormalities with prevalence of primary and secondary amenorrhoea at 26.7% each. The prevalence of other endocrinopathies was much lower: 8.0% had diabetes mellitus and only one patient had hypocortisolism. Iron chelation appeared insufficient in our study population. The high frequency of endocrine complications noted in our study supports the rationale for regular follow-up of transfusion dependent thalassaemic patients to ensure early detection and timely treatment of associated complications.
  10. Tan JA, Kho SL, Ngim CF, Chua KH, Goh AS, Yeoh SL, et al.
    Sci Rep, 2016 06 08;6:26994.
    PMID: 27271331 DOI: 10.1038/srep26994
    Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional α-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable α-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7 kb gene deletion (-α(3.7)), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional α-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (α(codon 59)α/α(CS)α) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (α(codon 59)α/α(Paksé)α) after nine years of being misdiagnosis with Hb Adana and HbCS (α(codon 59)α/α(CS)α). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations.
  11. Teoh CS, Lee SY, Chiang SK, Chew TK, Goh AS
    Asian Pac J Cancer Prev, 2018 May 26;19(5):1229-1236.
    PMID: 29801406
    Background: Diffuse large B-cell lymphoma (DLBCL) with double expression of c-MYC and BCL2 protein is
    associated with dismal outcome after treatment with R-CHOP. Local data on disease burden and survival outcome in
    DLBCL is limited. We investigated the prognostic values of c-MYC/BCL2 protein co-expression and cell of origin
    subtypes using immunohistochemistry (IHC) and to determine their associations with multiethnic groups under
    resource limited setting. Methods: This was a retrospective study which recruited 104 patients in between June 2012
    and December 2015 for IHC review and analysis. Result: We demonstrated that patients with high International
    Prognostic Index (IPI) (score 3-5) and co-expression of c-MYC/BCL2 protein had significant inferior overall survival
    (OS) and event free survival (EFS) respectively (P<0.05). c-MYC/BCL2 protein co-expression was more common in
    non-germinal center B-cell (non-GCB) (P=0.048) and contributed to adverse prognosis in this group of patients (OS,
    P=0.004; EFS, P=0.005). In multivariate analysis, double-protein co-expression was a significant independent predictor
    of inferior outcome after adjusted for IPI and cell of origin subtypes (OS hazard ratio [HR], 2.11; 95% CI, 1.01 to 4.04;
    P=0.048; EFS HR, 2.31; 95% CI, 1.05 to 5.04; P=0.036). In addition, non-GCB subtype was more common than GCB
    in Malays (60% vs 40%, P=0.106) and Chinese (81.2% vs 18.8%, P=0.042). Indians had more DLBCL without c-MYC/
    BCL2 protein co-expression compared to double-protein positive cases (66.7% vs 33.3%, P=0.414). Otherwise, the
    prognostic impact of ethnicity on survival outcome was insignificant (P=0.961). Conclusion: c-MYC/BCL2 protein
    co-expression in non-GCB subtype constituted a unique group with extremely inferior outcome regardless of ethnicity.
    Gene expression profile (GEP) may possibly provide insights into the cause of discrepancies in DLBCL subtypes and
    protein expression among the multiethnic groups.
  12. Foong WC, Chean KY, Rahim FF, Goh AS, Yeoh SL, Yeoh AAC
    Health Qual Life Outcomes, 2022 Jan 08;20(1):2.
    PMID: 34998406 DOI: 10.1186/s12955-021-01897-4
    BACKGROUND: Improvement in medical management has enabled transfusion dependent thalassaemia (TDT) patients to survive beyond childhood, building families, and contributing to the labour force and society. Knowledge about their adult life would provide guidance on how to support their needs. This study aims to explore the general well-being of adults with TDT, their employment status and challenges.

    METHODS: This study recruited 450 people with TDT, aged 18 and above, of both genders through all regional Thalassaemia societies in Malaysia and from the two participating hospitals, over five months in year 2016. A self-administered questionnaire including 'Healthy Days Core Module', WHOQOL-BREF and employment measurements was used. Multiple linear regression models were fitted with associations adjusted for several potential confounders.

    RESULTS: A total of 196 adults with TDT responded to the survey (43.6% response rate). Almost half (45%) had comorbidities and 9% suffered multiple complications: bone-related (13%), hormonal (12%), cardiac (3%) and infections (2%), resulting in 23% seeking treatment more than twice monthly. Within a month, they suffered from at least three days with poor physical and or mental health and their normal daily activities were disrupted up to three days. 36% were jobless and 38% of those with a job were receiving salaries below RM1000. The mean WHOQOL-BREF score (mean (SD)) was: physical health 62.6 (15.5), psychological health 64.7 (15.7), social relationship 64 (15.9), environmental health 60.8 (16.7). Having days with mental issues, financial status, education level, ethnic and marital status were main factors affecting QOL scores. Open questions showed dissatisfaction with health service provision, conflicting judgement in prioritising between health and job, and poor public empathy.

    CONCLUSION: The adults with TDT perceived their health as good and had less unhealthy days when compared with people with other chronic diseases. However, some perceived themselves to be facing more life disruption in a rather non-supportive community and that health services do not meet their needs. Future qualitative studies are needed to focus on their perceived needs and to look for more tailored supportive approaches.

  13. Taher AT, Origa R, Perrotta S, Kourakli A, Ruffo GB, Kattamis A, et al.
    Am J Hematol, 2017 May;92(5):420-428.
    PMID: 28142202 DOI: 10.1002/ajh.24668
    Once-daily deferasirox dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater patient adherence, satisfaction, and quality of life. However, barriers still exist to optimal adherence, including gastrointestinal tolerability and palatability, leading to development of a new film-coated tablet (FCT) formulation that can be swallowed with a light meal, without the need to disperse into a suspension prior to consumption. The randomized, open-label, phase II ECLIPSE study evaluated the safety of deferasirox DT and FCT formulations over 24 weeks in chelation-naïve or pre-treated patients aged ≥10 years, with transfusion-dependent thalassemia or IPSS-R very-low-, low-, or intermediate-risk myelodysplastic syndromes. One hundred seventy-three patients were randomized 1:1 to DT (n = 86) or FCT (n = 87). Adverse events (overall), consistent with the known deferasirox safety profile, were reported in similar proportions of patients for each formulation (DT 89.5%; FCT 89.7%), with a lower frequency of severe events observed in patients receiving FCT (19.5% vs. 25.6% DT). Laboratory parameters (serum creatinine, creatinine clearance, alanine aminotransferase, aspartate aminotransferase and urine protein/creatinine ratio) generally remained stable throughout the study. Patient-reported outcomes showed greater adherence and satisfaction, better palatability and fewer concerns with FCT than DT. Treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%). This analysis suggests deferasirox FCT offers an improved formulation with enhanced patient satisfaction, which may improve adherence, thereby reducing frequency and severity of iron overload-related complications.
  14. Walewski J, Hellmann A, Siritanaratkul N, Ozsan GH, Ozcan M, Chuncharunee S, et al.
    Br J Haematol, 2018 11;183(3):400-410.
    PMID: 30168134 DOI: 10.1111/bjh.15539
    Some patients with relapsed/refractory Hodgkin lymphoma (HL) are not considered suitable for stem cell transplant (SCT) and have a poor prognosis. This phase IV study (NCT01990534) evaluated brentuximab vedotin (1·8 mg/kg intravenously once every 3 weeks) in 60 patients (aged ≥18 years) with CD30-positive relapsed/refractory HL, a history of ≥1 prior systemic chemotherapy regimen, who were considered unsuitable for SCT/multi-agent chemotherapy. Primary endpoint was overall response rate (ORR) per independent review facility (IRF). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) per IRF, overall survival (OS), proportion proceeding to SCT and safety. The ORR was 50%, with 12% CR; 47% proceeded to SCT. Median DOR was 4·6 months and median duration of CR was 6·1 months. After a median follow-up of 6·9 and 16·6 months, median PFS and OS were 4·8 months (95% confidence interval, 3·0-5·3) and not reached, respectively; estimated OS rate was 86% at 12 months. Most common adverse events (≥10%) were peripheral neuropathy (35%), pyrexia (18%), diarrhoea and neutropenia (each 10%). Brentuximab vedotin showed notable activity with a safety profile consistent with known toxicities, and may act as a bridge to SCT, enabling high-risk patients who achieve suboptimal response to frontline/salvage chemotherapy/radiotherapy to receive potentially curative SCT.
  15. Taher AT, Origa R, Perrotta S, Kouraklis A, Ruffo GB, Kattamis A, et al.
    Health Qual Life Outcomes, 2018 Nov 19;16(1):216.
    PMID: 30453981 DOI: 10.1186/s12955-018-1041-5
    BACKGROUND: Adherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients ≥2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal.

    METHODS: The open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary.

    RESULTS: One hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations.

    CONCLUSIONS: These findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications.

    TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014.

  16. Chow PK, Poon DY, Khin MW, Singh H, Han HS, Goh AS, et al.
    PLoS One, 2014;9(3):e90909.
    PMID: 24614178 DOI: 10.1371/journal.pone.0090909
    The safety and tolerability of sequential radioembolization-sorafenib therapy is unknown. An open-label, single arm, investigator-initiated Phase II study (NCT0071279) was conducted at four Asia-Pacific centers to evaluate the safety and efficacy of sequential radioembolization-sorafenib in patients with hepatocellular carcinoma (HCC) not amenable to curative therapies.
  17. Ting CY, Chang KM, Kuan JW, Sathar J, Chew LP, Wong OJ, et al.
    Int J Med Sci, 2019;16(4):556-566.
    PMID: 31171907 DOI: 10.7150/ijms.27610
    Background: Clinical significance of germinal center B-cell (GCB) and non-GCB sub-categorization, expression of MYC, BCL2, BCL6, CD5 proteins and Epstein Barr virus encoded RNA (EBER) positivity in diffuse large B-cell lymphoma (DLBCL) remain controversial. Could these biomarkers accurately identify high risk DLBCL patients? Are MYC, BCL2 and BCL6 proteins expression feasible as baseline testing to predict c-Myc, BCL2 or BCL6 gene rearrangements? Aims: To investigate prognostic values of GCB/non-GCB sub-categorization, Double Protein Expression Lymphoma (DPL), Triple Protein Expression Lymphoma (TPL), positivity of CD5 protein and EBER in patients with DLBCL disease. To evaluate correlation between BCL2 , c-Myc and BCL6 gene rearrangements with BCL2, MYC and BCL6 proteins expression. Methods: Diagnostic tissue samples of 120 DLBCL patients between January 2012 to December 2013 from four major hospitals in Malaysia were selected. Samples were subjected to immunohistochemical staining, fluorescent in-situ hybridization (FISH) testing, and central pathological review. Pathological data were correlated with clinical characteristics and treatment outcome. Results: A total of 120 cases were analysed. Mean age of diagnosis was 54.1 years ± 14.6, 64 were males, 56 were females, mean follow up period was 25 months (ranged from 1 to 36 months). Of the 120 cases, 74.2% were non-GCB whereas 25.8% were GCB, 6.7% were EBER positive, 6.7% expressed CD5 protein, 13.3% were DPL and 40% were TPL. The prevalence of c-Myc, BCL2, BCL6 gene rearrangements were 5.8%, 5.8%, and 14.2%, respectively; and 1.6% were Double Hit Lymphoma (DHL). EBER positivity, DPL, TPL, c-Myc gene rearrangement, BCL2 gene rearrangement, extra copies of BCL2 gene and BCL6 gene rearrangement were associated with shorter median overall survival (P<0.05). IPI score was the significant determinants of median overall survival in DPL and TPL (P<0.05). CD5 protein expression and GCB/non-GCB sub-categorization did not affect treatment outcome (P>0.05). Overall, c-Myc, BCL2 and BCL6 gene rearrangements showed weak correlation with expression of MYC, BCL2 and BCL6 proteins (P>0.05). Fluorescent in situ hybridization is the preferred technique for prediction of treatment outcome in DLBCL patients. Conclusion:c-Myc, BCL2, and BCL6 gene rearrangements, EBER expression, DHL, TPL and IPI score are reliable risk stratification tools. MYC, BCL2 and BCL6 proteins expression are not applicable as baseline biomarkers to predict c-Myc, BCL2, and BCL6 gene rearrangements.
  18. Yap YY, Law KB, Sathar J, Lau NS, Goh AS, Chew TK, et al.
    Exp Hematol Oncol, 2018;7:31.
    PMID: 30564475 DOI: 10.1186/s40164-018-0124-7
    Background: The evolution of molecular studies in myeloproliferative neoplasms (MPN) has enlightened us the understanding of this complex disease consisting of polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The epidemiology is well described in the western world but not in Asian countries like Malaysia.

    Materials and methods: This retrospective national registry of MPN was conducted from year 2009 to 2015 in Malaysia.

    Results: A total of 1010 patients were registered over a period of 5 years. The mean age was 54 years with male predominance. The ethnic distribution revealed that Chinese had a relatively high weighted incidence proportion (43.2%), followed by Indian (23.8%), Malay (15.8%) and other ethnic groups (17.2%). The types of MPN reported were 40.4% of ET (n = 408), 38.1% of PV (n = 385), 9.2% of PMF (n = 93), 3.1% of hypereosinophilic syndrome (HES) (n = 31) and 7.9% of unclassifiable MPN (MPN-U) (n = 80). Splenomegaly was only palpable clinically in 32.2% of patients. The positive JAK2 V617F mutation was present in 644 patients with 46.6% in PV, 36.0% in ET, 9.0% in PMF, and 7.4% in MPN-U, and had significantly lower haemoglobin (p 

  19. Matsushita T, Shapiro A, Abraham A, Angchaisuksiri P, Castaman G, Cepo K, et al.
    N Engl J Med, 2023 Aug 31;389(9):783-794.
    PMID: 37646676 DOI: 10.1056/NEJMoa2216455
    BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors.

    METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed.

    RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time.

    CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

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