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BACKGROUND: Radiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ (DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS. METHODS/DESIGN: This is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring < 2.5 cm with margins ≥ 3 mm, and estrogen receptor-positive status) of DCIS who underwent BCS will be randomized at a 1:1 ratio to either receive tamoxifen (5 mg/day) for 5 years or undergo RT with conventional fractions (50 Gy in 25 fractions) or hypofractionations (40.05 Gy in 15 fractions). Randomization will be stratified by the Taiwan Breast Cancer Consortium. As approximately 5% of patients cannot tolerate the side effects of low-dose tamoxifen and will receive RT, we estimate that 405 patients will be randomized to a low-dose tamoxifen arm and 405 patients to the RT arm, according to a non-inferiority margin within 5% of IBTR difference and 90% ß-power noticing non-inferiority. The primary endpoints are breast tumor recurrence, including ipsilateral, regional, contralateral, and distant recurrence of breast DCIS or invasive cancer. The secondary endpoints are overall survival and adverse effects of RT and tamoxifen. Translational studies will also be conducted for this trial. DISCUSSION: This is the first non-inferiority trial on breast DCIS. This study will provide an important recommendation for clinical physicians on whether to use low-dose adjuvant tamoxifen for patients with low-risk breast DCIS who do not want to receive adjuvant RT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT04046159, Registered on April 30, 2019.
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Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Feminino , Adulto , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/cirurgia , Receptores de Estrogênio , Mastectomia Segmentar , Tamoxifeno/uso terapêutico , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgiaRESUMO
AIMS: Paclitaxel is a widely used anti-neoplastic agent but has low oral bioavailability due to gut extrusion by P-glycoprotein (P-gp). Oral paclitaxel could be more convenient, less resource intensive, and more tolerable than intravenous administration. Encequidar (HM30181A) is a novel, minimally absorbed gut-specific P-gp inhibitor. We tested whether administration of oral paclitaxel with encequidar (oPac+E) achieved comparable AUC to intravenous paclitaxel (IVP) 80 mg/m2 . METHODS: We conducted a multi-centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615 mg/m2 divided over 3 days and encequidar 15 mg orally 1 hour prior, followed by IVP 80 mg/m2 , or the reverse sequence. PK blood samples were taken up to Day 9 for oPac+E and Day 5 for IVP. RESULTS: Forty-two patients were enrolled; 35 completed both treatment periods. AUC0-∞ was 5033.5 ± 1401.1 ng.h/mL for oPac+E and 5595.9 ± 1264.1 ng.h/mL with IVP. The geometric mean ratio (GMR) for AUC was 89.50% (90% CI 83.89-95.50). Mean absolute bioavailability of oPac+E was 12% (CV% = 23%). PK parameters did not change meaningfully after 4 weeks administration of oPac+E in an extension study. G3 treatment-emergent adverse events occurred in seven (18%) pts with oPac+E and two (5%) with IVP. Seventy-five per cent of patients preferred oPac+E over IVP. CONCLUSIONS: GMR for AUC was within the predefined acceptable range of 80-125% for demonstrating equivalence. oPac+E is tolerable and there is no evidence of P-gp induction with repeat administration. With further study, oPac+E could be an alternative to IVP.
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Neoplasias , Paclitaxel , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Estudos Cross-Over , Humanos , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagemRESUMO
Objective: Although influenza vaccination reduces the risk of atrial fibrillation (AF), its protective effect in patients with gout remains unclear. The present study aimed to evaluate the protective effect of influenza vaccination in patients with gout. Methods: A total of 26,243 patients with gout, aged 55 and older, were enrolled from the National Health Insurance Research Database (NHIRD) between 1 January 2001, and 31 December 2012. The patients were divided into vaccinated (n = 13,201) and unvaccinated groups (n = 13,042). After adjusting comorbidities, medications, sociodemographic characteristics, the risk of AF during follow-up period was analyzed. Results: In influenza, non-influenza seasons and all seasons, the risk of AF was significantly lower in vaccinated than in unvaccinated patients (Adjust hazard ratio [aHR]: 0.59, 95% confidence interval [CI]: 0.50-0.68; aHR: 0.50, 95% CI: 0.42-0.63; aHR: 0.55, 95% CI: 0.49-0.62, respectively). In addition, the risk of AF significantly decreased with increased influenza vaccination (aHR: 0.85, 95% CI: 0.69-1.04; aHR: 0.72, 95% CI: 0.60-0.87; aHR: 0.40, 95% CI: 0.33-0.49, after first, 2-3 times, and ≥4 times of vaccination, respectively). Furthermore, sensitivity analysis indicated that the risk of AF significantly decreased after influenza vaccination for patients with different sexes, medication histories, and comorbidities. Conclusions: Influenza vaccination is associated with a lower risk of AF in patients with gout. This potentially protective effect seems to depend on the dose administered.
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The risk of stroke in patients with gout is high. The effect of vaccines in lowering the stroke risk in patients with gout remains unclear. We retrospectively analyzed 23,949 patients with gout (age ≥ 55 years) from the National Health Insurance Research Database over a 12-year period. The patients were divided into vaccinated (n = 11,649) and unvaccinated groups (n = 12,300). Overall, the vaccinated group had significantly lower risks of all stroke, hemorrhagic stroke, and ischemic stroke than the unvaccinated group (adjusted hazard ratio [aHR], 0.59 and 95% confidence interval [CI], 0.55-0.63; aHR, 0.60 and 95% CI, 0.49-0.73; and aHR, 0.60 and 95% CI, 0.55-0.65, respectively). The association appeared to be dose-dependent for both hemorrhagic and ischemic stroke (hemorrhagic stroke: aHR, 0.81 and 95% CI, 0.61-1.08; aHR, 0.80 and 95% CI, 0.62-1.02; and aHR, 0.37 and 95% CI, 0.28-0.48; ischemic stroke: aHR, 0.83 and 95% CI, 0.74-0.94; aHR, 0.73 and 95% CI, 0.65-0.81; and aHR, 0.42 and 95% CI, 0.38-0.47 for patients vaccinated 1, 2 or 3, and ≥4 times, respectively, during the follow-up period). Patients with a history of atrial fibrillation did not have a lower risk of hemorrhagic stroke even after receiving four vaccinations (aHR, 0.59; 95% CI, 0.25-1.38). Influenza vaccination was associated with a lower risk of all stroke in people with gout, and the association appeared to be dose-dependent.
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Chronic kidney disease (CKD) is significantly associated with lung cancer incidence. The aim of this study was to elucidate whether influenza vaccination reduces the incidence of lung cancer in patients with CKD. This cohort study enrolled patients with a record of CKD diagnosis from 2000 to 2012 in Taiwan's National Health Insurance Research Database. Included patients were divided into vaccinated and unvaccinated groups. In total 12,985 patients with CKD were enrolled. Among these patients, 5495 were vaccinated and 7490 were unvaccinated. The risk of lung cancer was significantly lower in the influenza vaccination group after adjusting for age, sex, dialysis status, lung diseases, comorbidities, level of urbanization, and monthly income (adjusted hazard ratio (HR): 0.50, 95% confidence interval (CI; 0.38−0.65), p < 0.05). Lower risk of lung cancer was observed in both sexes, all age groups, dialysis status and co-existed lung diseases. The association between the risk of lung cancer and vaccination appeared to be dose-dependent (adjusted HRs: 0.91 (0.66−1.25), 0.49 (0.34−0.71), and 0.25 (0.17−0.38) for patients who received 1, 2 or 3, and ≥4 vaccinations during the follow-up period, respectively). In conclusion, Influenza vaccination decreased the risk of lung cancer in patients diagnosed with CKD. This potentially protective effect against lung cancer appeared to be dose dependent.
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Backgrounds: The risk of stroke is higher among patients with chronic obstructive pulmonary disease (COPD) than among the healthy population. Moreover, women generally have worse long-term stroke outcomes than men. Methods: The data of 6681 women with COPD (aged ≥ 65 years) registered in Taiwan's National Health Insurance Research Database were retrospectively analyzed from January 1, 2001 to December 31, 2011. After 1:1 propensity score matching, the patients were divided into vaccinated and unvaccinated groups. Results: In total, 5102 women were enrolled. The vaccinated group had a significantly lower risk of total, hemorrhagic, and ischemic stroke than the unvaccinated group (adjusted hazard ratio [aHR]: 0.60, 95% confidence interval [CI]: 0.54-0.67; aHR: 0.59, 95% CI: 0.43-0.83; and aHR: 0.59, 95% CI: 0.52-0.68, respectively). A lower risk of stroke was observed among the women aged 65-74 and ≥75 years, and the association was dose-dependent in all types of stroke (aHR: 1.08, 95% CI: 0.92-1.26; aHR: 0.70, 95% CI: 0.60-0.82; and aHR: 0.32, 95% CI: 0.26-0.38 for those vaccinated 1, 2 to 3, and ≥4 times, respectively, during the follow-up period). Women with a CHA2DS2-VASc score (conditions and characteristics included congestive heart failure, hypertension, diabetes, stroke, vascular disease, age, and sex) of 2-3 and ≥4 had a significantly lower risk of ischemic stroke while receiving more vaccinations. A smaller significant lower risk of hemorrhagic stroke after more than 4 times of vaccination was noted in the women with a CHA2DS2-VASc score of ≥4. Both interrupted and non-interrupted vaccination was associated with lower risk of stroke occurrence. Conclusion: Influenza vaccination is associated with a lower risk of total, hemorrhagic, and ischemic stroke among women with COPD, and the association is dose-dependent. However, the findings may be limited by unmeasurable confounders. Further investigations on this subject are warranted.
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Previous studies have indicated that influenza vaccination reduces the development of lung cancer. However, the protective effects of influenza vaccination on primary liver cancer in patients with chronic kidney disease (CKD) are unclear. This cohort study identified 12,985 patients aged at least 55 years who had received a diagnosis of CKD between 1 January 2001 and 31 December 2012 from the National Health Insurance Research Database of Taiwan. The patients were classified according to vaccination status. Propensity score matching was used to reduce selection bias. Cox proportional hazards regression analysis was used to evaluate the correlation between influenza vaccination and primary liver cancer in patients with CKD. The prevalence of primary liver cancer was lower in patients with CKD who had received an influenza vaccine (adjusted hazard ratio: 0.45, 95% confidence interval [CI]: 0.35−0.58, p < 0.001). The protective effects were observed regardless of sex, age, and comorbidities. Moreover, dose-dependent protective effects were observed. In the subgroup analysis, where the patients were classified by the number of vaccinations received, the adjusted hazard ratios for 1, 2−3, and ≥4 vaccinations were 0.86 (95% CI: 0.63−1.17), 0.45 (95% CI: 0.31−0.63), and 0.21 (95% CI: 0.14−0.33), respectively. In conclusion, influenza vaccination was associated with a lower incidence of liver cancer in patients with CKD.
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Patients with type 2 diabetes mellitus (T2DM) have a higher risk of chronic kidney disease (CKD) due to vascular complications and chronic inflammation. T2DM contributes to a higher risk of mortality and morbidity related to influenza. In Taiwan, influenza vaccination is recommended for patients with T2DM. A previous meta-analysis reported the efficacy of influenza vaccination in reducing hospitalization and mortality in patients with diabetes; however, the renal protective effect of the vaccine remains unclear. This study evaluated whether influenza vaccination could reduce the incidence of CKD and dialysis in patients with T2DM. The study cohort included all patients aged ≥55 years who were diagnosed as having T2DM between 1 January 2000 and 31 December 2012, by using data from Taiwan's National Health Insurance Research Database. Each patient was followed up with to assess factors associated with CKD. A time-dependent Cox proportional hazard regression model after adjustment for potential confounders was used to calculate the hazard ratio (HR) of CKD in the vaccinated and unvaccinated patients. The study population comprised 48,017 eligible patients with DM; 23,839 (49.7%) received influenza vaccination and the remaining 24,178 (50.3%) did not. The adjusted HRs (aHRs) for CKD/dialysis decreased in the vaccinated patients compared with the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs: 0.47/0.47, 0.48/0.49, and 0.48/0.48, respectively, all p < 0.0001). We observed similar protective effects against CKD during the influenza and noninfluenza seasons. Regardless of comorbidities or drug use, influenza vaccination was an independent protective factor. Furthermore, aHRs for CKD/dialysis were 0.71 (0.65−0.77)/0.77 (0.68−0.87), 0.57 (0.52−0.61)/0.69 (0.56−0.70), and 0.30 (0.28−0.33)/0.28 (0.24−0.31) in the patients who received 1, 2−3, and ≥4 vaccinations during the follow-up period, respectively. This population-based cohort study demonstrated that influenza vaccination exerts a dose-dependent and synergistic protective effect against CKD in the patients with T2DM with associated risk factors.
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Oraxol consists of an oral dosage form of the chemotherapeutic agent paclitaxel administered with a novel P-glycoprotein inhibitor encequidar methanesulfonate monohydrate (formerly named HM30181A), which allows oral treatment of cancers that would otherwise be treated with intravenous paclitaxel. Here we describe the population pharmacokinetics (popPK) analyses for oral paclitaxel in patients with advanced/metastatic solid tumors to characterize pharmacokinetic (PK) profiles and quantify sources of PK variability. The best fit popPK model for oral paclitaxel, based on data from seven clinical studies (197 patients with advanced/metastatic solid tumors), involves a linear two-compartment structural model containing first-order absorption with a short lag time and first-order elimination as well as a log additive error. In this popPK model, lower population estimates of central volume for Asian patients versus Caucasian patients did not translate into clinical meaningful differences in oral paclitaxel exposure. Age, sex, body weight or surface area, mild hepatic impairment, and mild to moderate renal impairment had no clinically meaningful effects on the systemic exposure of oral paclitaxel. Simulations were performed on clinical therapeutic dose (oral paclitaxel 205 mg/m2 once daily ×3 days per week) to predict exposure of oral paclitaxel and to support treatment benefits observed in a pivotal phase III trial.
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Antineoplásicos , Neoplasias , Administração Intravenosa , Administração Oral , Antineoplásicos/farmacocinética , Humanos , Neoplasias/tratamento farmacológico , PaclitaxelRESUMO
The evolutionary trajectories that drive clinical and therapeutic consequences in localized breast cancers (BCs) with ipsilateral breast tumor relapse (IBTR) remain largely unknown. Analyses of longitudinal paired whole-exome sequencing data from 10 localized BC patients with IBTR reveal that, compared to primary breast tumors, homologous recombination (HR) deficiency, inactivation of the HR pathway, chromosomal instability, and somatic driver mutations are more frequent. Furthermore, three major models of evolution in IBTR are summarized, through which relative contributions of mutational signatures shift, and the subclonal diversity expansions are shown. Optimal treatment regimens are suggested by the clinically relevant molecular features, such as HR deficiency (20%) or specific alterations (30%) with sensitivity to available FDA-approved drugs. Finally, a rationale for the development of the therapeutic management framework is provided. This study sheds light on the complicated evolution patterns in IBTR and has significant clinical implications for future improvement of treatment decisions.
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Whole-genome doubling (WGD) is an early macro-evolutionary event in tumorigenesis, involving the doubling of an entire chromosome complement. However, its impact on breast cancer subtypes remains unclear. Here, we performed a comprehensive and quantitative analysis of WGD and its influence on breast cancer subtypes in patients from Taiwan and consequently highlight the genomic association between WGD and homologous recombination deficiency (HRD). A higher manifestation of WGD was reported in triple-negative breast cancer, conferring high chromosomal instability (CIN), while HER2 + tumors exhibited early WGD events, with widely varied CIN levels, compared to luminal-type tumors. An association of higher activity of de novo indel signature 2 with WGD and HRD in Taiwanese breast cancer patients was reported. A control test between WGD and pseudo non-WGD samples was further employed to support this finding. The study provides a better comprehension of tumorigenesis in breast cancer subtypes, thus assisting in personalized treatment.
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Neoplasias da Mama/genética , Genoma Humano/genética , Recombinação Homóloga/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/classificação , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , TaiwanRESUMO
PURPOSE: We evaluated the safety and efficacy of biweekly capecitabine in combination with oxaliplatin in previously untreated patients with locally advanced or metastatic gastric cancer. METHODS: Patients received oral capecitabine 1,000 mg/m(2) twice daily on days 1-10 plus oxaliplatin 85 mg/m(2) as a 2-h intravenous infusion on day 1, every 2 weeks (XELOX). The primary endpoint was overall response rate. Secondary endpoints included progression-free survival, overall survival, and toxicity. RESULTS: From March 2007 to October 2010, 46 patients were enrolled in this phase II study. The median age was 64 years (range 32-85). A total of 391 (median 7.5, range 1-29) cycles were delivered. Among the 41 patients evaluable for tumor response, 9 showed partial response and 25 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 22 % (95 % CI 10-42 %) and 20 % (95 % CI 9-34 %), respectively. In the ITT analysis, the progression-free survival and overall survival were 5.6 months (95 % CI 4.1-6.3 months) and 8.0 months (95 % CI 6.3-10.1 months), respectively. The most common hematological toxicities were thrombocytopenia (35 %) and leucopenia (34 %), whereas the most common non-hematological toxicities were neuropathy (35 %), fatigue (33 %), diarrhea (27 %), vomiting (26 %), and hand-foot syndrome (25 %). Major grade 3-4 toxicities were anemia (11 %), diarrhea (9 %), and hand-foot syndrome (7 %). No patient died of treatment-related toxicities. CONCLUSIONS: Although the biweekly XELOX regimen failed its primary response rate endpoint, it showed modest efficacy and an acceptable safety profile in the treatment of advanced gastric cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Esquema de Medicação , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Neoplasias Gástricas/patologiaRESUMO
PURPOSE: Docetaxel, capecitabine, and cisplatin are effective chemotherapeutic agents for breast cancer with significant synergistic cytotoxicity demonstrated by in vitro studies. The purpose of this study was to assess the efficacy of a combination of docetaxel, capecitabine, and cisplatin (TXP) in patients diagnosed with locally advanced breast cancer (LABC). METHODS: Patients (n = 42) with chemotherapy-naïve LABC (stage IIIa or IIIb) were enrolled. The chemotherapeutic regimen consisted of 4-6 cycles of intravenous docetaxel (60 mg/m(2)) and cisplatin (50 mg/m(2)) on day 1, plus oral capecitabine (1,800 mg/m(2)/day) on day 1-14, repeated every 3 weeks. Upon completion of therapy, the primary tumor was resected when not contraindicated. RESULTS: Median patient age was 48.5 years (range 31-66 years). Median tumor size was 6.8 cm (range 2.7-15 cm), 29 patients were node-positive, and 12 patients were hormone receptor positive. A total of 216 cycles (median 5; range 3-6 cycles) were administered without prophylactic G-CSF. The predominant toxicities were grade 3/4 neutropenia (30%/28%) and no grade 3/4 thrombocytopenia, febrile neutropenia, or grade 4 non-hematological toxicities were observed. Grade 3 non-hematological toxicities included hand-foot syndrome (5.6%) and vomiting (0.5%). The overall clinical response rate was 97.6% (41/42). Six of the 42 patients (14.3%) achieved a complete pathological response. Of 22 patients who completed 6 cycles of combination treatment, the complete pathological response was 27.3% (6/22). CONCLUSIONS: A combination of TXP can be administered safely without prophylactic G-CSF, and appears to be an effective neoadjuvant regimen in patients with LABC.