Cih En Huang

Frequencies, clinical characteristics, and outcome of somatic CALR mutations in JAK2-unmutated essential thrombocythemia

Calreticulin (CALR) mutations were recently identified in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) devoid of JAK2 and MPL mutations. We evaluated the clinical, laboratory, and molecular features of a Taiwanese population of patients with ET. Among 147 ET patients, CALR mutations were detected in 33 (22.5xa0%), JAK2V617F in 94 (63.9xa0%), and MPL mutations in 4 (2.7xa0%). Sixteen (10.9xa0%) patients were negative for all three mutations (CALR, JAK2V617F, and MPL; triple negative). Interestingly, one patient with the type 2 CALR mutation also harbored a low allele burden (0.025xa0%) of JAK2V617F mutation. Furthermore, we found a novel CALR mutation, with the resultant protein sharing an identical amino acid sequence to the type 6 CALR mutant. Compared to those with JAK2 mutation, CALR-mutated ET patients were characterized by younger age, lower leukocyte count, higher platelet count, and decreased risk of thrombosis. CARL mutations had a favorable impact on thrombosis-free survival (TFS) for ET patients, whereas the respective TFS outcomes were similarly poorer in JAK2-mutated ET and PV patients. Multivariate analysis confirmed that younger age (<60xa0years), presence of CALR mutations, and a lower platelet count (<1,000u2009×u2009109/L) were independently associated with a longer TFS in ET patients. The current study demonstrates that CALR mutations characterize a special group of ET patients with unique phenotypes that are not discrepant from those seen in Western countries.

The incidence and risk of developing a second primary esophageal cancer in patients with oral and pharyngeal carcinoma: a population-based study in Taiwan over a 25 year period

BackgroundThe incidence of oral and pharyngeal (including oral cavity, oropharynx and hypopharynx) carcinoma increases rapidly in Asia and South Pacific because of betel quid chewing. Thus far, large-scale epidemiological studies are not available yet to stratify these patients by their risks of developing a second primary cancer in the digestive tract including esophagus, stomach, colon, and rectum.MethodsA population-based study was conducted using the database from the Taiwan National Cancer Registry for the period 1979-2003. We quantified standardized incidence ratios (SIRs) and cumulative incidence of second primary cancers among 33,787 patients with initial diagnoses of oral and pharyngeal carcinoma.ResultsAmong these four digestive tract organs, the esophagus was the only site of second cancer with excess risk in patients with oral and pharyngeal carcinoma. The incidence and risk of developing a second primary esophageal cancer differed by the site of the primary index tumor, most frequently seen in hypopharyngeal cancer (71/4,218 = 1.68%, SIR = 22.76, 95% CI 17.77-28.70), followed by oropharyngeal cancer (30/3,403 = 0.88%, SIR = 14.29, 95% CI 9.64-20.39) and the least in oral cavity cancer (99/26,166 = 0.38%, SIR = 5.57, 95% CI 4.53-6.78). In addition, the risk was extraordinarily high for patients with a follow-up interval ≤ 1 year and those with first primary cancer diagnosed at age ≤50. These patients may justify more close surveillance.ConclusionThe present study represents the first population-based study in Asia attempting to stratify the patients of oral and pharyngeal carcinoma by their risk of developing a second esophageal cancer. It helps identify patients at high risk and tailor the application of intense follow-up surveillance to the estimated risk in each individual case.

Second primary esophageal or lung cancer in patients with head and neck carcinoma in Taiwan: incidence and risk in relation to primary index tumor site

BackgroundSecond primary cancer is prevalent in patients with head and neck cancer (HNC), for which esophagus and lung are the most usual sites, associated with an extremely poor prognosis. However, information regarding the actual risk of second primary esophageal or lung cancer in South-east Asia, the betel-quid chewing area, has been restricted to data from single-institutions. We have therefore conducted a population-based study to evaluate the incidence, risk, and developmental time of second esophageal or lung cancer in HNC patients.MethodsStandardized incidence ratios (SIRs) and cumulative incidences were calculated for second primary esophageal or lung cancer using a database from the Taiwan Cancer Registry that included 63,720 cases having an initial diagnosis of HNC.ResultsThe risk of second esophageal cancer was increased in patients with oral/pharyngeal (SIRxa0=xa08.71, 95% CI 7.55–10.01) and laryngeal (SIRxa0=xa04.65, 95% CI 3.37–6.27) cancers, whereas second lung risk was increased in patients with laryngeal (SIRxa0=xa02.05, 95% CI 1.69–2.45) and oral/pharyngeal (SIRxa0=xa01.56, 95% CI 1.34–1.80) cancers. The risk excess was prominent for patients with a follow-up intervalxa0<5xa0years and a first primary cancer diagnosed at agexa0<50. Nevertheless, patients with nasopharyngeal carcinoma were not associated with an excess risk in second esophageal or lung cancer.ConclusionsThe present dataset provides definite evidence that there is a substantial excess risk of second primary esophageal or lung cancer for the index tumors of oral cavity, pharynx and larynx. The absence of risk excess found in nasopharyngeal carcinoma is also compatible with the existing knowledge that it might have an entirely distinctive etiology.

Incidence and Patterns of Second Primary Malignancies Following Oral Cavity Cancers in a Prevalent Area of Betel-nut Chewing: A Population-based Cohort of 26 166 Patients in Taiwan

OBJECTIVEnThe incidence of oral cavity cancers is increasing rapidly in South-East Asia, which may be attributable to tobacco smoking, alcohol and betel-nut chewing. However, the actual incidence and risk of second primary malignancies after oral cavity cancers have not been well established in this region. A population-based study was therefore conducted.nnnMETHODSnStandardized incidence ratios and cumulative incidences were calculated for second primary cancers using the Taiwan Cancer Registry database for the period 1979-2003, which included 26 166 cases having an initial diagnosis of oral cavity cancers.nnnRESULTSnA 3.11-fold increase in risk for second cancer at all sites was observed after oral cavity cancers compared with the general population (standardized incidence ratio = 3.11, 95% confidence interval: 2.97-3.25). Of nine sites with excess risks of developing a second cancer, the frequency was highest in the oral/pharynx (60%), followed by lung (7.2%) and esophagus (5.5%). Second esophageal and lung cancers had a greater impact on survival compared with other types of second cancer. Notably, the risk excess was more prominent for patients with a follow-up interval of ≤ 1 year and a first primary cancer diagnosed at age of ≤ 40. These patients may justify closer surveillance.nnnCONCLUSIONSnThis is the largest population-based study with a homogeneous patient population focusing on oral cavity cancers within a high-incidence area. We found that oral cavity cancers are associated with an increased risk of nine second malignancies, which had a negative impact on survival.

Incidence and risk factors for central venous access port-related infection in Chinese cancer patients

BACKGROUND/PURPOSEnCytotoxic chemotherapy via central venous access ports is an important part of the standard treatment for most cancers, but it is accompanied with the risk of infections. This study aimed to analyze the incidence and risk factors for central venous access port-related infection (CPI) among Chinese patients receiving cytotoxic chemotherapy.nnnMETHODSnBetween January 1, 2002 and December 31, 2005 a total of 1391 cancer patients with 1449 totally implantable central venous access ports were evaluated. The log-rank test and Cox proportional hazards model were used for the analyses of risk factors.nnnRESULTSnThe overall CPI incidence rate was 0.21 per 1000 catheter-days. Hematological malignancies and head and neck cancer were associated with an increased risk of CPI (hazard ratio 4.00 and 4.11, respectively, both pxa0<xa00.001) and less infection-free catheter longevity (pxa0<xa00.001) compared with other cancer types. Chemotherapy in an adjuvant setting was associated with a lower risk of infection than for patients in a nonadjuvant setting (pxa0<xa00.001). The most common pathogens isolated from CPI were Pseudomonas aeruginosa and Candida.nnnCONCLUSIONnInfection remains to be a challenging issue for totally implantable central venous ports. Implementation of an insertion bundle for the prevention of central line-associated bloodstream infections is warranted, especially for those patients with hematological and head and neck cancers, as well as for patients receiving chemotherapy in the metastatic settings.

Validation of an enhanced International Prognostic Index (NCCN-IPI) in an Asian cohort of patients with diffuse large B cell lymphoma.

To the EditorFor more than 20 years, the International Prognostic Index(IPI) has been used as the standard for risk stratification inpatientswithdiffuselargeB celllymphoma(DLBCL)receiv-ing chemotherapy with CHOP regimen (cyclophosphamide,doxorubicin, vincristine, and prednisone [1].The advent of rituximab (R) changes the landscape oftreatment for the disease and significantly improves theclinical outcome [2, 3], but it also deduces the power ofimpacts of IPI on the prognostic prediction in these pa-tients [4]. There are pressing needs for newer strategiesto better subcategorize DLBCL patients in the rituximabera. Recently, collaborators from North America exploredtheir database containing DLBCL patients treated withR-CHOP and proposed a new prognostic model [5].The new National Comprehensive Cancer Network(NCCN) IPI was developed based on the clinical charac-teristics of 1650 patients from the USA. Validation wasdone using another independent cohort of more than1100 patients from the British Columbia. Reports usingthe same prognostic stratification from various geograph-ic regions have been published since [6, 7],yetitre-mains unclear if these results can be extrapolated to dif-ferent ethnic populations.We reviewed our database and identified 100 DLBCLpatients who received R-CHOP-like chemotherapy at ourinstitute during the last decade. Baseline characteristicswere collected, and the survival outcome analysis wasperformed using the old IPI model and the new NCCN-IPI model, respectively. The mean age was 63.8 years(standard deviation, 15.9 years). There were 56 male pa-tients. Forty-six patients had stage 3 or 4 disease.Extranodal involvement in major organs (bone marrow,CNS, liver/GI tract, or lung) was seen in 44 patients.Fifty-three patients had elevated levels of lactatedehydrogenase.According to the old IPI risk categorization, therewere 35, 28, 20, and 17 patients each in the four dif-ferent risk subgroups (low-, low-intermediate [LI], high-intermediate [HI], and high). The respective numberswere 11, 43, 32, and 14 in the NCCN-IPI model. TheKaplan–Meier curves for progression-free survival (PFS)and overall survival (OS) were plotted with subgroupstratification based on IPI and NCCN-IPI, respectively(Fig. 1). With regard to PFS, patients in the fourNCCN-IPI groups showed a distinctive clinical outcome(Fig. 1b), whereas patients subcategorized by the old IPIexhibited a less discriminative survival pattern,

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

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

Clinical characteristics and treatment outcome in a Taiwanese population of patients with Epstein-Barr virus-positive diffuse large B-cell lymphoma.

OBJECTIVEnEpstein-Barr virus-positive diffuse large B-cell lymphoma is a provisional entity in the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues. Reports on the characteristics and clinical outcome of this disease in different geographic regions showed great disparities.nnnMETHODSnTo define the clinical characteristics as well as the prognostic impact of Epstein-Barr virus infection on diffuse large B-cell lymphoma in Taiwan, we retrospectively investigated the Epstein-Barr virus status of 89 patients with newly diagnosed diffuse large B-cell lymphoma in our institute.nnnRESULTSnUsing a cutoff point of positive nuclear staining of Epstein-Barr virus-encoded RNA-1-in situ hybridization in ≥20% of the examined cells, we identified 15 cases (16.9%) of the entire study cohort as Epstein-Barr virus-positive diffuse large B-cell lymphoma. The clinical and laboratory features were not different between Epstein-Barr virus-positive and -negative diffuse large B-cell lymphoma patients. Univariate analysis showed patients with diffuse large B-cell lymphoma that were either Epstein-Barr virus-positive or had activated B-cell-like features had an inferior overall survival. Older age, advanced stage and lymphoma with activated B-cell-like features or Epstein-Barr virus-encoded RNA positivity were independent prognostic factors affecting overall survival on multivariate analysis. Patients with two or three of these adverse-risk factors were considered high risk and fared far worse than patients with no or only one adverse factor.nnnCONCLUSIONSnTaken together, we demonstrated that a higher frequency of Epstein-Barr virus association was detected in a Taiwanese cohort of diffuse large B-cell lymphoma patients, and Epstein-Barr virus-encoded RNA positivity was shown to add important prognostic value in these patients.

The impact of joint range of motion limitations on health‐related quality of life in patients with haemophilia A: a prospective study

In patients with haemophilia A, repeated occurrences of haemarthrosis and synovitis lead to limitations in range of motion (ROM) of major joints. However, the effect of limitations in joint ROM on health‐related quality of life (HRQOL) in these patients has not been studied previously. The aim of this study was to assess the impact of ROM limitations of 10 major joints (bilateral shoulders, elbows, hips, knees and ankles), combined with other possibly influential factors, on HRQOL in patients with haemophilia A. The ROM limitations in 13 movements and pain intensity of the 10 major joints were measured. The socio‐demographic and clinical data were recorded. Short‐Form 36 was used as the HRQOL measurement. Eighteen patients (mean age: 36.9 years) were included. Hip ROM limitations, knee ROM limitations and hip pain intensity predicted physical functioning scale (P < 0.001; adjusted R2 = 0.553). Shoulder ROM limitations and age predicted role limitation were due to emotional problems scale (P < 0.001; adjusted R2 = 0.373). Elbow ROM limitations and haemophilia severity predicted mental health scale (P = 0.001; adjusted R2 = 0.320). Hip ROM limitations predicted social functioning scale (P = 0.041; adjusted R2 = 0.091). Educational level and elbow ROM limitations predicted vitality scale (P < 0.001; adjusted R2 = 0.416). The ROM limitations of hip, knee, shoulder and elbow could be predictors for HRQOL in patients with haemophilia A. Improving ROM of major joints could be an appropriate treatment strategy to enhance HRQOL in these patients.

Clinical efficacy and safety of ruxolitinib in the management of myelofibrosis: A single institution experience in Taiwan.

Objective: Myelofibrosis (MF) is a pathologic entity of myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms that severely affect the quality of life accompanied with the risk of leukemia development. Conventional treatment is usually ineffective and has limited impact on prolongation of survival. Dysregulated Janus kinase (JAK) signaling is common in MPN. In two randomized controlled trials, ruxolitinib, a potent pan-JAK inhibitor, has been shown to be highly effective in patients with intermediate- and high-risk MF. Method: We retrospectively analyzed the therapeutic outcome of 10 MF patients treated with ruxolitinib in our institute. Basic clinical data, JAK2V617F mutational status and Myelofibrosis Symptoms Assessment Form (MF-SAF) to evaluate disease-related symptoms were recorded initially, and at every visit. Result: Among these patients, only half of the patients harbored JAK2V617F mutation. After treatment with ruxolitinib, all patients had reduction of splenic size and reached nadir by week 24. Nine patients had body weight increment, and four of them had body weight increment more than 10%. Seven patients had their total symptom score reduced by more than 50% after therapy. The efficacy of ruxolitinib was irrelevant to JAK2V617F mutational status. Adverse events were mainly hematological and easily manageable. Discussion and conclusion: Ruxolitinib is both safe and efficacious in a cohort of Asian patients with MF. The efficacy of ruxolitinib is irrelevant to the mutational status of JAK2V617F