Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

Effectiveness of Image-Guided Radiotherapy in Adjuvant Radiotherapy on Survival for Localized Breast Cancer: A Population-Based Analysis.

PURPOSE: Image-guided radiotherapy (IGRT) is an advanced radiotherapy technique to improve the radiotherapy delivery. We aimed to compare the overall survival (OS) for localized breast cancer (LBC) patient treated with adjuvant conventional fractionated radiotherapy (CFRT) using IGRT vs those without IGRT via a population-based analysis. PATIENTS AND METHODS: Eligible LBC patients diagnosed between 2011 and 2013 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders between groups. The hazard ratio (HR) of death and other outcomes were compared between IGRT and non-IGRT. We also evaluated OS in various supplementary analyses. RESULTS: Our primary analysis included 6490 patients in whom covariates were well balanced after PS weighing. The HR for death when IGRT was compared with non-IGRT was 1.02 (95% confidence interval 0.80-1.31, P = 0.86). There were also no significant differences in the supplementary analyses. CONCLUSION: We found that OS of LBC patients treated with adjuvant CFRT was not statistically different between those treated with IGRT versus without IGRT. This was the first study in this regard to our knowledge but randomized controlled trials were needed to confirm our finding.

Effectiveness of Intensity-Modulated Radiotherapy for Rectal Cancer Patients Treated With Neoadjuvant Concurrent Chemoradiotherapy: A Population-based Propensity Score-matched Analysis.

BACKGROUND/AIM: Neoadjuvant concurrent chemoradiotherapy (nCCRT) is the standard of care for locally advanced rectal cancer (LARC) patients treated with neoadjuvant concurrent chemoradiotherapy (nCCRT). The aim of this study was to compare intensity-modulated radiotherapy (IMRT) to 3D conformal radiotherapy (3DCRT) in nCCRT patients. PATIENTS AND METHODS: We identified LARC patients diagnosed from 2007 to 2015 through the Taiwan cancer registry (TCR) and we constructed a propensity score matched cohort to compare IMRT to 3DCRT after balancing observable potential confounders. We compared the hazard ratio (HR) of death as well as other endpoints between the IMRT and 3DCRT. We performed supplementary analysis (SA) when additional potential confounders were considered. RESULTS: Our study population consisted of 696 patients. There was no statistical difference when IMRT was compared to 3DCRT (HR for death=1.01, 95%confidence interval(CI)=0.76-1.35, p=0.93). There were also no statistical differences for the other endpoints or SA. CONCLUSION: For LARC patients treated with nCCRT, the treatment outcome has no statistically significant benefit between those treated with IMRT or 3DCRT.

Risk of cancer among HIV-infected patients from a population-based nested case-control study: implications for cancer prevention.

BACKGROUND: The burden of cancer is likely to increase among the human immunodeficiency virus (HIV)-positive population as it ages due to successful antiretroviral therapy (ART). The purpose of this study was to determine the risk of cancer in HIV-infected patients. METHODS: This study was a matched nested case-control study. It was performed using the National Health Insurance Research Database of Taiwan. The control group included non-HIV-infected patients matched by sex, age, and year of enrollment. Logistic regression analyses were performed and simultaneously adjusted for potential confounders (income, urbanization, and Charslon index of comorbidity to evaluate HIV infection as an independent risk of cancer. We calculated the overall and sex-specific standardized incidence ratios (SIR) to investigate the pattern of cancer risk and overall cancer risk in the patients with HIV infection. RESULTS: Of the 1,115 HIV-infected patients, 104 (9.33%) developed cancer during the 11-year follow-up period. The risk of cancer for patients with HIV infection was significant (adjusted odds ratio = 3.89, 95% confidence interval [CI] = 2.92-5.19) after adjustment for potential confounders. There was a significantly increased risk of developing non-Hodgkin lymphoma (SIR = 25.73, 95% CI = 6.83-90.85), cervical cancer (SIR = 4.01, 95% CI = 1.0-16.06), lymphoma (SIR = 20.26, 95% CI = 5.86-70.10), and respiratory and intrathoracic cancer (SIR = 20.09, 95% CI = 2.34-172.09) compared with the control group. In addition, HIV-infected patients were at significant risk for renal, oral, breast, liver, skin, and colorectal cancer. CONCLUSIONS: Patients with HIV infection are at increased risk for several specific cancers. Our results support the implementation of an active and accelerated cancer screening schedule for patients with HIV infection to increase their life span.

Thalidomide for the treatment of myelodysplastic syndrome in Taiwan: results of a phase II trial.

BACKGROUND: Thalidomide inhibits angiogenesis and exerts complex immunomodulatory activities. This phase II study aimed to examine the efficacy of thalidomide in Taiwanese patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Sixty patients [intention to treat group (ITT)] with MDS were treated with thalidomide (100 mg/day, increased by 100 mg/day weekly to a maximum of 400 mg/day) for 12 weeks. Forty-two patients of the ITT group were considered as comprising the evaluable population (EP). RESULTS: Thalidomide resulted in hematological improvement (HI) in 28% of ITT analysis and in HI in 40% of the EP. Thalidomide was more effective for MDS patients with low to intermediate-1 International Prognostic Score System scores. The response rates were 7% for ITT and 10% for EP patients. Only two patients exhibited a cytogenetic response. Net reduced levels of vascular endothelial growth factor and basic fibroblast growth factor cytokines were observed in the peripheral blood and the bone marrow of thalidomide-treated patients. CONCLUSION: Low-dose thalidomide is an effective and safe treatment for patients with low-risk MDS.

Efficacy and safety of tramadol/acetaminophen in the treatment of breakthrough pain in cancer patients.

OBJECTIVE: We evaluated the analgesic efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg combination tablet, for the treatment of breakthrough pain in cancer patients. METHODS: This study was conducted at Changhua Christian Hospital, Changhua, Taiwan from January 2006 to February 2007. The single-center and open-label study enrolled 59 opioid-treated cancer patients with at least moderate breakthrough pain (visual analog scale [VAS] score ≥40mm on a 100-mm scale). The efficacy measures included VAS scores and adverse effect assessment 10, 30, and 60 minutes after the administration of tramadol/acetaminophen. Visual analog scale score at time of pain relief was reported. RESULTS: The mean VAS score when the breakthrough pain episode began (0 minute) was 77.8. Analysis showed significant better mean pain VAS scores at 10, 30, and 60 minutes after the administration of tramadol/acetaminophen (p≤0.001 versus 0 min for all 3 time points). The mean time to pain relief was 597.2 seconds and the mean VAS score at time of relief was 43.4. The effective rates, defined by more than 30% reduction of the VAS score, after 10 minutes of administration was 74.6%, 30 minutes 86.4%, and one hour 94.9% (p≤0.001 versus 0 minute for all 3 time points). Two cases of drowsiness were reported. CONCLUSION: Tramadol/acetaminophen might be efficacious and safe in the treatment of breakthrough pain in cancer.

Photoelectrochemical properties of N/C-codoped TiO2 film electrodes prepared by reactive DC magnetron sputtering.

This paper aims to characterize the photoelectrochemical properties of the visible-light enabling titanium dioxide (TiO2) film electrodes prepared by codoping nitrogen (N) and a presputtered carbon film (C-film) onto indium tin oxide (ITO) glass substrates using a direct current (DC) magnetron sputtering technique. To improve its photoelectrochemical properties, different amount of C-doping sources, 2 h and 4 h C-film, are chose to prepare the N/C-codoped TiO2 film electrodes. Under visible-light (420 < lambda < 610 nm) illumination, a remarkable photocurrent density of 22 microA/cm2 is obtained for the N/C-TiO2 film electrode prepared with a 4 h C-film (NC(4)-T) at an applied potential of +1.2 V versus SCE. Under ultraviolet (lambda approximately 365 nm) illumination, the NC(4)-T film electrode also exhibits the highest photocurrent density of 0.23 mA/cm2 among all samples tested. A more negative flat band potential of NC(4)-T film electrode is attributed to the synergistic effect of N/C codoping. The XRD spectrum of the NC(4)-T film electrode shows mainly the well-crystallized anatase TiO2 phase and an extremely intense (211) plane. Thus, photoelectrochemical activity of the NC(4)-T film electrode can be ascribed to the well-crystallized columnar crystals with pores at its grain boundary, open surface morphology, which are revealed by SEM and TEM images, and a more negative flat band potential. The visible-light induced activity is mostly enhanced as a result of the synergistic effects of N/C-codoping into the TiO2 crystals. A potential application to photocatalytic splitting of water for hydrogen evolution using solar light is practically possible.

Superwarfarin intoxication: hematuria is a major clinical manifestation.

Since superwarfarin is popular and readily available in stores, it may cause intoxication or overexposure, which can result in coagulopathy or abnormal bleeding in humans and, thus, is an important public health problem. We report our clinical experience with superwarfarin intoxication. Nine patients, including eight patients who had histories of ingesting superwarfarin, were studied. Of the patients, hematuria occurred in eight. Laboratory tests among the nine patients showed extremely prolonged prothrombin times and activated partial thromboplastin times, which could be corrected to normal by mixing 1:1 with normal pooled plasma; they also had very low functional levels of factor II, VII, IX, X, and proteins C and S, but normal functional levels of factors V, VIII, fibrinogen, and anti-thrombin III. Large doses of vitamin K1 were needed for 3 months or more to treat and correct the coagulopathy among the patients. The majority of the patients presented with gross hematuria, suggesting that hematuria is probably a major clinical manifestation of superwarfarin intoxication. Prolonged use of large doses of vitamin K1 is needed for the treatment of superwarfarin intoxication.

Phase II study of oxaliplatin in combination with continuous infusion of 5-fluorouracil/leucovorin as first-line chemotherapy in patients with advanced gastric cancer.

This study was designed to determine the efficacy and safety of biweekly oxaliplatin in combination with infusional 5-fluouracil (5-FU) and leucovorin in patients with advanced gastric cancer (AGC). Fifty-five eligible patients with measurable or assessable M/AGC (median age 62 and 90% of patients presented with metastasis) received oxaliplatin (85 mg/m2) intravenous infusion for 2 h, followed by intravenous infusion of 5-FU (3000 mg/m2) and leucovorin (100 mg/m2) for 46 h every 14 days until the patient's disease was either in progression, unacceptable toxicity, patient's withdrawal or the investigators' decision to discontinue treatment. Of the 55 enrolled patients, 48 were evaluable for response. Three patients (5.4%) showed complete remission and 20 patients (36.4%) achieved partial response. The overall response rate was 47.9%. Nineteen patients (34.5%) had stable disease and six patients (10.9%) showed progressive disease. The median time to progression was 5.6 months and the median overall survival was 10.8 months. Grade 3/4 toxicities included leucopenia (12.7%), thrombocytopenia (5.4%), diarrhoea (3.6%) and vomiting (9.1%). Peripheral neuropathy was noted in 61.8% of the patients (grade 1/2: 54.5%; grade 3: 7.3%). Our study confirmed that the combination of oxaliplatin and continuous infusion of 5-FU/leucoverin without bolus 5-FU as first-line chemotherapy is active for patients with AGC and relatively safe with lower haematological toxicity.

High efficacy of erlotinib in Taiwanese NSCLC patients in an expanded access program study previously treated with chemotherapy.

PURPOSE: Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) which has demonstrated a survival benefit in non-small-cell lung cancer (NSCLC) patients. An open label phase II study was conducted in Taiwanese patients with NSCLC to evaluate its efficacy. METHODS: Patients with proven stage IIIB/IV NSCLC who had received at least one line of standard chemotherapy or radiotherapy were enrolled into this study. All patients were given oral erlotinib, 150mg/day till disease progression. RESULTS: From May 2005 to July 2006, 300 patients were entered from 14 hospitals in Taiwan. This analysis was based on 299 patients who received at least one dose of erlotinib. The best response rates were a 29% partial response and 44% stable disease in 273 patients who had response data available. Non-smoking (p=0.033), adenocarcinoma/BAC (p=0.0027), female (p=0.0013), aged less than 65 years (p=0.0115), stage IV (p=0.0492), patients with skin rash (p=0.0216), and a higher grade of skin rash (p=0.003) were significantly correlated with response to treatment. Skin rash was a common adverse event (any grade: 84%, Gr 3-4: 16%). The median time to disease progression was 5.6 months. Cox regression model for progression free survival showed patients most at risk of early progression were males of low performance status having squamous cell carcinoma. CONCLUSIONS: This was the largest multicenter prospective clinical study of NSCLC in Taiwan. The results demonstrated the excellent response rates, time-to-progression and overall survival of erlotinib in a large population of Taiwanese NSCLC patients who had been previously treated with chemotherapy or radiotherapy.

Prognostic factors in extrapulmonary small cell carcinomas. A large retrospective study.

BACKGROUND: Extrapulmonary small cell carcinoma (EPSCC) is a heterogeneous group of cancers. The clinicopathological features of EPSCC remain poorly defined. PATIENTS AND METHODS: Patients with the clinicopathological features of EPSCC, treated at three major medical centers in Taiwan, were included. Histologic and clinical diagnoses, smoking history, staging, clinical course and treatment outcome were reviewed and analyzed. RESULTS: A total of 90 patients, treated between 1995 and 2005, were eligible for analysis. Forty-nine patients had limited disease and 41 extensive disease. Ten, 18, 17 and 45 patients received no treatment, local treatment, chemotherapy alone or combined modality treatment, respectively; the median survival for these four groups was 1.1, 13.8, 6.7 and 24.9 months. The origin of cancer was head and neck in 17, gastrointestinal in 27, genitourinary in 10, gynecologic in 27 and unknown in 9 patients; the median survival time was 34.2, 6.4, 9.1, 23.7 and 9.2 months, respectively. Ten out of 90 patients were long-term survivors, and 9 of them had tumors of head-and-neck and gynecologic origin. There was no statistically significant difference in survival between smokers and non-smokers. Factors associated with survival in univariate analysis included age < or =60, female gender, limited disease, head-and-neck and gynecologic origin, as well as combined modality treatment. However, in multivariate analysis, only female gender, limited disease and combined modality treatment were independent predictors of survival. CONCLUSIONS: Female gender, limited disease and combined modality treatment are favorable prognostic factors for patients with EPSCC. Prolonged survival is more likely in patients with tumors of head-and-neck and gynecologic origin.

Hyperhomocysteinemia, deep vein thrombosis and vitamin B12 deficiency in a metformin-treated diabetic patient.

Vitamin B12 deficiency may be induced by long-term use of metformin, which may in turn lead to hyperhomocysteinemia. Thus, hyperhomocysteinemia may increase the risk of vascular thrombosis in diabetic patients, when metformin is used and a homozygous methylenetetrahydrofolate reductase (MTHFR) C677T mutation is present. We report a 65-year-old Taiwanese diabetic woman who was treated with metformin for 6 years and who had suffered from swelling of the left lower extremity for 3 months. Ascending venography confirmed the diagnosis of proximal deep vein thrombosis, while hyperhomocysteinemia, megaloblastic anemia caused by vitamin B12 deficiency, and a homozygous C677T mutation of the MTHFR gene were also found. She had no identifiable venous thrombotic risk factors other than hyperhomocysteinemia, which seemed to be caused by both MTHFR C677T homozygous mutation and vitamin B12 deficiency. With the substitution of insulin injection for metformin, short-term supplement of vitamin B12, and anticoagulant therapy for the deep vein thrombosis, her anemia and hyperhomocysteinemia recovered rapidly. The deep vein thrombosis also responded well. Our findings highly suggested the role of metformin in causing vitamin B12 deficiency, which may serve as an additional risk factor for venous thrombosis in diabetic patients. Our report also highlights the need to check vitamin B12 levels during metformin treatment.

Expression of CD80 and CD86 costimulatory molecules are potential markers for better survival in nasopharyngeal carcinoma.

BACKGROUND: B7 Costimulatory signal is essential to trigger T-cell activation upon the recognition of tumor antigens. This study examined the expression of B7-1 (CD80) and B7-2 (CD86) costimulatory molecules along with HLA-DR and the presence of infiltrating lymphocytes and dendritic cells to assess their significance in patients with nasopharyngeal carcinoma (NPC). METHODS: Expression of CD80, CD86, HLA-DR, S-100 protein and the presence of infiltrating lymphocytes and follicular dendritic reticulum cells were immunohistochemically examined on the paraffin-embedded tissue blocks from newly diagnosed NPC patients (n = 50). The results were correlated with clinical outcome of patients. RESULTS: CD80 and CD86 were each expressed in 10 of 50 cases in which they co-expressed in 9 cases. Univariate analysis revealed that patients with CD80/CD86 expression had significantly better overall survival than those without it (P = 0.017), but after adjustment for stage, nodal status, and treatment, the expression of CD80/CD86 did not significantly correlate with overall survival. Expression of HLA-DR and the presence of infiltrating lymphocytes and dendritic cells did not appear to have impact on the survival of patients. CONCLUSION: Expression of CD80 and CD86 costimulatory molecules appears to be a marker of better survival in patient with NPC.

Expression of c-kit protooncogene in human hepatocellular carcinoma.

The expression of the c-kit protooncogene in human hepatocellular carcinoma (HCC) was investigated. Immunohistochemical staining (IHC) and RT-PCR were employed to examine the protein and mRNA expression of c-kit protooncogene, respectively. IHC results demonstrated that 22 of 86 (25.6%) HCC tissue sections expressed c-kit protein. The c-kit mRNA transcript was further confirmed in all 22 IHC c-kit positive HCC tissue samples by RT-PCR. Moreover, the relationship between c-kit expression in HCC and prognosis of patients was statistically analyzed and a correlation was established. The group of patients whose HCC specimens showed positive c-kit staining exhibited better survival as compared to those patients with negative c-kit expression (p=0.021). These results suggest that c-kit expression may be a good prognostic indicator for HCC.

Corticosteroid administration depresses circulating dendritic cells in ITP patients.

Idiopathic or immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet count resulting from antibody-mediated destruction of platelets. The production of these IgG anti-platelet autoantibodies is critically governed by T-lymphocytes which can be activated by antigen-presenting cells (APC) such as dendritic cells. We hypothesized that one of the mechanisms by which corticosteroid administration can suppress the immune system is to depress the number of circulating dendritic cells production in ITP patients. Dendritic cell population was measured in peripheral blood of three ITP patients before and after the administration of prednisone. Both counts of myeloid and lymphoid dendritic cells in the blood of ITP patients were greatly reduced after the administration of prednisone. The decrease in circulating dendritic cells is associated with the increase of platelets in circulation with the treatment of prednisone. These results suggest that corticosteroid therapy may decrease the effects of the autoantibody on platelets in ITP patients by reduce the number of circulating dendritic cells.

Successful treatment for multiple cerebral hemorrhage in a newly diagnosed patient with acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is characterized by severe bleeding associated with coagulation abnormalities. High incidence of disseminated intravascular coagulation (DIC) in APL often causes early hemorrhagic death. We report a case of APL with massive cerebral hemorrhage and respiratory failure in a 24-year old woman. A combination of all-trans retinoic acid (ATRA) differential therapy and blood component therapy was given to control DIC and stop bleeding. In order to minimize the severity of DIC during chemotherapy induced acute cytolysis, ATRA was started 8 days before the induction chemotherapy which consisted of idarubicin (IDA) and cytosine arabinoside (Ara-C). Complete clinical remission was achieved in this APL patient despite of the severity of the hemorrhage.