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.

Health inequality: a longitudinal study on geographic variations in lung cancer incidence and mortality in Taiwan.

BACKGROUND: This study is aimed toward an analysis of the variations in lung cancer incidence and mortality, adjusted by population factors (age, gender, and year), between administrative areas. METHODS: This is a retrospective study, using 2005-2014 data in each administrative area from the Taiwan Cancer Registry database organized by the Health Promotion Administration. The yearly age-standardized (overall) and crude (stratified by gender and age) incidence/mortality (and their growth rates) for each administrative area were collected and calculated. We used a mixed model to analyze the repeated measurements of yearly incidence and mortality rates and used general linear regression to analyze their growth rates. RESULTS: It was found that male and elderly populations had significantly higher lung cancer incidence and mortality in Taiwan. After adjusting for gender, age, and calendar year, there were no significant variations in incidence among the administrative areas, while the mortality in Yilan County was significantly higher than that in Taipei City (the capital city of Taiwan). On the other hand, the incidence in the female and younger population and mortality growth rates were higher. The incidence growth rate in Keelung City was significantly lower than that in Taipei City, while there were no significant variations in mortality growth rate among administrative areas. CONCLUSIONS: This study found an inequality in the lung cancer burden among cities in Taiwan, which can serve as the basis for future resource allocations for lung cancer prevention and treatment in Taiwan.

BRCA1 and BRCA2 Gene Mutations and Lung Cancer Sisk: A Meta-Analysis.

Background and objective: BRCA1 and BRCA2 are associated with many cancer types in addition to hereditary breast and ovarian cancers. However, their relation to lung cancer remains to be explored. Materials and Methods: Observation studies were systematically reviewed to explore the association of BRCA1 or BRCA2 with lung cancer. PubMed, MEDLINE [EBSCOhost], and relevant articles published up to 7 January 2020 were searched. Odd ratio (OR), standardized morbidity rate (SMR), and cancer-specific standardized incidence ratios (SIRs) were pooled together as relative risk (RR) estimates (95% confidence interval [CI], 0.66-1.40). Results: Thirteen studies were included for analysis. Results showed that the RR of BRCA2 is 0.76 (95% CI, 0.48-1.19), the overall RR is 0.96 (95% CI, 0.66-1.40), and that of BRCA1 is 0.66 (95% CI, 0.41-1.05), indicating that it was not associated with lung cancer. Conclusion: With the limitation of the retrospective study design and severe heterogeneity, these results inform clinicians and relevant families that BRCA1 and BRCA2 mutation carriers have no increased risk of lung cancer.

Bevacizumab and Atezolizumab for Unresectable Hepatocellular Carcinoma: Real-world Data in Taiwan-Tainan Medical Oncology Group H01 Trial.

BACKGROUND/AIM: The combination of bevacizumab and atezolizumab (Bev-Ate) has been established as a standard first-line systemic treatment option for unresectable hepatocellular carcinoma (HCC) since 2020. This study examined the outcomes of HCC patients who received the combination in southern Taiwan. PATIENTS AND METHODS: All patients were enrolled from four hospitals in Taiwan. They received Bev-Ate therapy for unresectable HCC. RESULTS: Thirty-five patients were included; 28 (80%) had Barcelona Clinic Liver Cancer stage C disease. Hepatitis etiology was chronic hepatitis B and C in 63% and 17% of patients, respectively. Eleven (31%) patients had received prior systemic treatment for unresectable HCC. The response rate was 51%, and the disease control rate was 72% for all patients. The median progression-free survival (PFS) and overall survival (OS) was 5.2 and 22.2 months, respectively. For patients who received prior systemic treatment, the efficacy of Bev-Ate in terms of response rates was similar compared with those without prior systemic treatment. Patients who received lower doses of bevacizumab (<15 mg/kg per dose) had non-inferior PFS and OS compared with those receiving a standard dose of bevacizumab. The incidence of proteinuria of all grades (15.8%) was less common when lower doses of bevacizumab were used. CONCLUSION: Real world data from HCC patients in southern Taiwan disclosed that the efficacy outcomes of Bev-Ate treatment were generally consistent with those of clinical trials in other countries. In patients who were exposed to prior systemic treatment or who received lower doses of bevacizumab, the Bev-Ate regimen retained its clinical efficacy.

Real-World Effectiveness of Sorafenib versus Lenvatinib Combined with PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICIs) combined with multitarget tyrosine kinase inhibitors (MTKIs) exert a synergistic effect and are effective in unresectable hepatocellular carcinoma (uHCC). However, precise data regarding the real-world clinical applications of these combination therapies in uHCC are lacking. This study compared the treatment efficacy of sorafenib versus lenvatinib in combination with programmed cell death protein-1 (PD-1) inhibitors in patients with uHCC in a clinical setting. Among 208 patients with uHCC treated with PD-1 inhibitors, 88 were administered with ICIs in combination with sorafenib or lenvatinib. The treatment response and survival outcomes were evaluated. Predictors of survival were assessed by multivariate analysis. A total of 49 patients were treated with PD-1 inhibitors combined with sorafenib, and 39 patients were treated with PD-1 inhibitors combined with lenvatinib. The lenvatinib group exhibited a stronger objective response rate (ORR) (20.51% vs. 16.33%) and had a higher disease control rate (41.03% vs. 28.57%) than did the sorafenib group. The median overall survival was longer in the lenvatinib group than the sorafenib group (13.1 vs. 7.8 months; hazard ratio = 0.39, p = 0.017). The incidence of treatment-related adverse events was similar. PD-1 inhibitors combined with lenvatinib can be a feasible treatment strategy for HCC patients receiving MTKI-based combination therapy. PD-1 inhibitors combined with lenvatinib resulted in more favorable survival outcomes without increased toxic effects compared with PD-1 inhibitors with sorafenib. Additional larger-scale and prospective studies should be conducted to verify the study results.

STAT3 Inactivation and Induction of Apoptosis Associate With Fluoxetine-inhibited Epithelial-mesenchymal Transition and Growth of Triple-negative Breast Cancer In Vivo.

BACKGROUND/AIM: Breast cancer (BC) is the most common cancer and second leading cause of death in women worldwide. Triple-negative breast cancer (TNBC) is the most aggressive type of BC, while the treatment option is limited and has long been considered as a major unmet need. Meta-analysis indicated the anti-tumor potential of anti-depressants, especially selective serotonin-reuptake inhibitors (SSRIs). The SSRI fluoxetine has been shown to suppress BC and ovarian cancer cell growth; however, whether it suppresses tumor progression in vivo is unclear. MATERIALS AND METHODS: We established an 4T1 bearing animal model, an orthotopic TNBC model, to identify the mechanism and therapeutic efficacy of fluoxetine. RESULTS: Tumor growth evaluated by caliper and computed tomography scan demonstrated the inhibition effect by fluoxetine treatment. Immunohistochemistry showed that the expression of STAT3-mediated epithelial-to-mesenchymal transition (EMT) proteins and apoptosis-related proteins was decreased. CONCLUSION: Fluoxetine may induce an anti-TNBC effect via inactivating STAT3 signaling transduction and triggering the caspase-mediated apoptotic pathway.

Magnolol Induces Apoptosis Through Extrinsic/intrinsic Pathways and Attenuates NF-κB/STAT3 Signaling in Non-small-cell Lung Cancer Cells.

BACKGROUND/AIM: Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer worldwide, and treatment outcomes are still poor. Magnolol, a hydroxylated biphenyl isolated from Magnolia officinalis, was found to be effective against hepatocellular carcinoma via inactivating nuclear-factor-kappa B (NF-B) signaling. However, whether magnolol targets not only NF-B but also other factors in NSCLC and may contribute to the suppression of tumor progression is unclear. MATERIALS AND METHODS: Cell viability, flow cytometry, and western blotting assays were used to identify the mechanism of magnolol action in human lung adenocarcinoma cell lines A549 and CL1-5-F4. RESULTS: Our results indicated that magnolol induced cytotoxicity through extrinsic/intrinsic apoptosis signaling and suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3)/NF-B and expression of their downstream proteins. CONCLUSION: Magnolol not only induced extrinsic and intrinsic apoptosis signaling but also inactivated STAT3/NF-B and attenuated their signaling of epithelial-mesenchymal transition and metastasis-related protein expression in NSCLC.

Real-World Comparative Effectiveness of Nivolumab versus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma.

PURPOSE: Immune checkpoint inhibitors are effective therapies for advanced hepatocellular carcinoma (HCC); however, comparisons of the clinical efficacy and safety profile for these drugs are still scarce. Thus, the aims of this study were to investigate the differences in efficacy and safety between nivolumab and pembrolizumab in unresectable HCC patients in a real-world setting. PATIENTS AND METHODS: A total of 115 patients who received treatment with nivolumab (n = 73) or pembrolizumab (n = 42) in combination with or without tyrosine kinase inhibitors was enrolled. Therapeutic response, survival outcomes, and safety profiles were compared among these groups. Multivariate analysis of survival response was performed using Cox proportional hazards regression. RESULTS: Patients treated with pembrolizumab demonstrated a significantly higher objective response rate than those with nivolumab (38.1% vs. 15.1%; odds ratio 4.18, p = 0.005) regardless of the combination strategies. In addition, pembrolizumab performed a better overall survival (OS) than nivolumab, (34.9 vs. 9.5 months; hazard ratio (HR) = 0.39, p = 0.004). In subgroup analysis, pembrolizumab exhibited favorable OS than nivolumab for monotherapy (HR = 0.16, p = 0.001) or combination therapy (HR = 0.33, p = 0.006) as second-line or later-line (HR = 0.19, p = 0.001) therapy and those with (HR = 0.31, p = 0.006) or without (HR = 0.15, p = 0.004) well-compensated liver disease. The incidence of adverse events was comparable for both treatments. CONCLUSION: Both pembrolizumab and nivolumab had significant effects for HCC therapy, and pembrolizumab had a significant survival benefit as compared with nivolumab.

Lung cancer survival and mortality in Taiwan following the initial launch of targeted therapies: an interrupted time series study.

OBJECTIVES: Two oral targeted therapies, gefitinib and erlotinib, were first approved and then launched into the market for treatment of late-stage non-small cell lung cancer (NSCLC) in Taiwan in 2003 and 2006, respectively. The aim of this study were to determine the trends in lung cancer burden and examine changes in lung cancer-related survival rates and mortality following the launch of these new drugs. SETTING: Yearly lung cancer-related data (1994-2013), including incidence, number of newly diagnosed patients, survival rate and mortality, were retrieved from the Taiwan Cancer Registry Database. DESIGN AND OUTCOME MEASURES: Using a time series design with autoregressive integrated moving average model, we investigated and projected trends in the incidence and early diagnosis of lung cancer in Taiwan. We also estimated the changes in survival rates and mortality following the launch of targeted therapies using interrupted time series and segmented regression models. RESULTS: The age-standardised incidence of lung cancer increased from 22.53 per 100 000 people in 1994 to 34.09 in 2013, and it was projected to reach 38.98 by 2020. The rate of early-stage NSCLC at diagnosis increased from 12.63% in 2004 to 23.99% in 2013, and it was projected to reach 32.95% by 2020. The 2-year lung cancer survival increased by 19.81% (95% CI 14.90% to 24.71%) 3 years following the launch of gefitinib. Lung cancer mortality declined by 5.97% (95% CI -8.20% to -3.73%) 3 years following the launch of gefitinib. CONCLUSIONS: Lung cancer survival rate increased and mortality decreased significantly following the launch of gefitinib and erlotinib in Taiwan.

Association between palliative care and end-of-Life care for patients with hematological malignancies: A population-based study.

To date, few studies have examined the end-of-life (EOL) care for patients with hematological malignancies (HMs). We evaluated the effects of palliative care on the quality of EOL care and health care costs for adult patients with HMs in the final month of life.We conducted a population-based study and analyzed data from Taiwan's Longitudinal Health Insurance Database, which contains claims information for patient medical records, health care costs, and insurance system exit dates (our proxy for death) between 2000 and 2011.A total of 724 adult patients who died of HMs were investigated. Of these patients, 43 (5.9%) had received only inpatient palliative care (i-Pal group), and 19 (2.6%) received home palliative care (h-Pal group). The mean health care costs during the final month of life were not significantly different between the non-Pal and Pal groups (p=0.315) and between the non-Pal, i-Pal, and h-Pal groups (p=0.293) either. By the multivariate regression model, the i-Pal group had lower risks of chemotherapy, ICU admission, and receipt of CPR, but higher risks of at least two hospitalizations and dying in hospital after adjustments. The h-Pal group had the similar trends as the i-Pal group but lower risk of dying in hospital after adjustments.Patients with HMs who had received palliative care could benefit from less aggressive EOL cancer care in the final month of life. However, 8.6% patients with HMs received palliative care. The related factors of more hospitalizations and dying in hospital warrant further investigation.

Comprehensive value assessment of drugs using a multi-criteria decision analysis: An example of targeted therapies for metastatic colorectal cancer treatment.

OBJECTIVE: This study is aimed toward establishing a decision-making model with multiple criteria for appraisal and reimbursement to compare the attitudes of different stakeholders toward various dimensions and criteria and to evaluate the five targeted therapies (bevacizumab, cetuximab, panitumumab, aflibercept, and regorafenib) for metastatic colorectal cancer. METHOD: This study is a multi-criteria decision analysis (MCDA) using a model that includes three dimensions and nine criteria. Both the overall and individual scores of the respective targeted therapies in different dimensions and criteria were calculated. A sensitivity analysis was carried out in order to evaluate the robustness of the research results. An interview-based questionnaire survey was applied to obtain the performance information for the targeted therapies and the weights of the dimensions and criteria. RESULTS: Overall, the clinical dimension had the highest weight, followed by the economic dimension, and finally, the social dimension. In the clinical dimension, the "comparative efficacy" criterion had the highest weight; in the economic dimension, the "cost-effectiveness" criterion" was given the greatest importance; in the social dimension, the "social concern and patient needs" criterion was given more emphasis. The overall values ranked from high to low as follows: cetuximab (overall score 3.3666), bevacizumab (3.3043), panitumumab (3.2030), aflibercept (2.8923) and regorafenib (2.8366). CONCLUSIONS: A comprehensive value assessment system combining "multi-dimensional criteria," "multi-perspectives," and an "integrative assessment" is necessary to evaluate the value of medicines. The results showed not only the order of weights of different dimensions or criteria, but also the rankings of the value of the targeted therapies.

Traditional Chinese medicine is associated with a decreased risk of heart failure in breast cancer patients receiving doxorubicin treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiovascular disease is the main concern of breast cancer survivors who received doxorubicin treatment. Traditional Chinese medicine (TCM) provides as a complementary therapy to patients with breast cancer and is an important component of health care in Taiwan. However, the TCM utilization patterns and it's efficacy in breast cancer patients is unknown. MATERIALS AND METHODS: From a sample of claims data collected over the period of 1997-2010 in Taiwan, we identified 24,457 breast cancer patients who received TCM treatments and 24,457 breast cancer patients who did not receive TCM treatments. All enrollment patients had received doxorubicin chemotherapy. These patients were paired by age; index day; and propensity score for selected comorbidities, Herceptin and tamoxifen. The incidence of cumulative congestive heart failure (CHF) was compared between cohorts. Fine and Gray regression hazard model was used to evaluate the risk of CHF. RESULTS: After adjusting for age, Herceptin, tamoxifen, diabetic drug, cardiovascular drug, statin and comorbidities, the stratified Fine and Gray model revealed that the TCM cohort had an adjusted subdistribution hazard ratio (sHR) of 0.68 (95% confidence interval (CI) = 0.62-0.76, p < 0.0001) for the development of CHF. In addition, the sub-cohort analysis revealed that the Baihuasheshecao cohort compared to the non-TCM cohort had an adjusted sHR of 0.29 (95% CI = 0.15-0.56, p = 0.0002) for the development of CHF. CONCLUSION: Using TCM significantly decreased the incidence of CHF in patients with breast cancer who received conventional chemotherapy with or without radiotherapy.

Trend analysis of end-of-life care between hospice and nonhospice groups of cancer patients in Taiwan for 2002-11.

The aim of the study is to examine the effect of hospice care on quality of end-of-life (EOL) care for patients with advanced cancer in Taiwan between 2002 and 2011.It is a population-based longitudinal study following National Health Insurance medical care claims of hospice and nonhospice patients with advanced cancer in their last month of life.Utilization of hospice service doubled from 10.5% to 21.5% over the study period. Of 12,682 patients identified as having advanced cancer, 7975 (62.88%) were found to have 1 or more quality indicators (QIs) of poor EOL cancer care. After adjustments, those receiving hospice cares had a significant reduction in incidence of chemotherapy in the last 14 days of life as well as intensive care unit (ICU) admission and cardiopulmonary resuscitation (CPR) in the last month of life. The hospice care group also had significant increases in having more than 1 hospitalization and dying under hospital care, but no change in having more than 1 emergency room (ER) visit. The hospice group curve of estimated incidence rates of each QI was consistently below that of the nonhospice group in chemotherapy-with the difference between the 2 curves increasing over time-ICU admission, and CPR, and above that of the nonhospice group for dying in a hospital and having more than 1 hospitalization over the study period. The 2 groups overlapped on ER visits. Overall, hospice care was associated with less chance to have 1 or more QIs of EOL care for advanced cancer patients (RR = 0.56, 95% CI: 0.52-0.60, P < .001).The utilization of hospice services doubled over the 10-year study period. Hospice care was associated with better EOL care in patients with advanced cancer.

Epidermal Growth Factor Receptor Mutation and Anaplastic Lymphoma Kinase Gene Fusion: Detection in Malignant Pleural Effusion by RNA or PNA Analysis.

Analyzing EGFR mutations and detecting ALK gene fusion are indispensable when planning to treat pulmonary adenocarcinoma. Malignant pleural effusion (MPE) is a devastating complication of lung cancer and sometimes the only source for mutation analysis. The percentage of tumor cells in the pleural effusion may be low; therefore, mutant enrichment is required for a successful analysis. The EGFR mutation status in MPE was determined using three methods: (1) PCR sequencing of genomic DNA (direct sequencing), (2) mutant-enriched PCR sequencing of genomic DNA using peptide nucleic acid (PNA-sequencing), and (3) PCR sequencing of cDNA after reverse transcription for cellular RNA (RNA-sequencing). RT-PCR was also used to test cases for ALK gene fusion. PNA-sequencing and RNA-sequencing had similar analytical sensitivities (< 1%), which indicates similar enrichment capabilities. The clinical sensitivity in 133 cases when detecting the common EGFR exon 19 and exon 21 mutations was 56.4% (75/133) for direct sequencing, 63.2% (84/133) for PNA-sequencing, and 65.4% (87/133) for RNA-sequencing. RT-PCR and sequencing showed 5 cases (3.8%) with ALK gene fusion. All had wild-type EGFR. For EGFR analysis of MPE, RNA-sequencing is at least as sensitive as PNA-sequencing but not limited to specific mutations. Detecting ALK fusion can be incorporated in the same RNA workflow. Therefore, RNA is a better source for comprehensive molecular diagnoses in MPE.

A postmarketing surveillance study on erbitux (cetuximab) in patients with metastatic colorectal cancer refractory to irinotecan-containing treatment.

OBJECTIVE: This postmarketing surveillance study evaluated the safety and efficacy of cetuximab therapy in patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) in Taiwan. METHODS: Patients with EGFR-expressing mCRC who had failed prior irinotecan-based chemotherapy and were receiving cetuximab therapy were monitored for treatment efficacy and safety from the time of first infusion until 28 days after the last infusion regardless of the reasons fordiscontinuation. The study followed 269 patients for approximately 2 years. RESULTS: No unexpected adverse events associated with cetuximab therapy were reported, and most events were grade 1 or 2. The most common drug-related adverse events of any grade were rash (21.6%) and dermatitis acneiform (4.8%). Reported grade 3/4 events were rash (4.5%), dermatitis acneiform (0.4%), and diarrhea (0.4%). Cetuximab treatment for patients receiving second-/third-line (177 patients) or above therapy (92 patients) was associated with a median progression-free survival time of 3.37 and 3.90 months, respectively, and a median overall survival time of 17.6 and 21.1 months, respectively. The response rates for the second-/third-line treatment and fourth-line or above cetuximab treatment groups were similar (21.5% vs 17.4%; P = 0.428). CONCLUSION: Cetuximab showed no unexpected safety findings and was efficacious in treating patients with EGFR-expressing mCRC in community practice in Taiwan.

FDG uptake in sacroiliac joint due to osteitis condensans ilii shown on PET/CT in a patient with breast cancer: the value of coregistered CT in avoiding misinterpretation.

A 56-year-old woman with breast cancer underwent FDG PET/CT at follow-up. The PET images showed increased FDG uptake along right sacroiliac joint. The coregistered CT images showed diffuse sclerosis around the sacroiliac joints, but no bony destruction, periarticular erosion, or joint space narrowing. She had been complaining of intermittent lower back pain since her last pregnancy. The radiologic pictures and history of postpartum back pain were considered as typical characteristics for osteitis condensans ilii. This case reminds us that careful inspection of the coregistered CT images is important to avoid potential misinterpretation because of osteitis condensans ilii.