Summary Background Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour ...activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. Methods BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov , number NCT01327053. Findings Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1–17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28–59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2–45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28–48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5–39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 32% of 79 patients vs 90 60% of 150) or treatment discontinuation (17 22% vs 54 36%) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3–4 adverse events were raised creatine kinase (five 6% in the 200 mg group vs 19 13% in the 800 mg group) and lipase concentration (four 5% vs eight 5%). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. Interpretation The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. Funding Novartis Pharmaceuticals Corporation.
Background The hedgehog pathway inhibitor sonidegib demonstrated meaningful tumor shrinkage in more than 90% of patients with locally advanced basal cell carcinoma (BCC) or metastatic BCC in the BCC ...Outcomes with LDE225 Treatment study. Objective This report provides long-term follow-up data collected up to 12 months after the last patient was randomized. Methods In this multicenter, randomized, double-blind phase II study, patients were randomized 1:2 to sonidegib 200 or 800 mg. The primary end point was objective response rate assessed by central review. Results Objective response rates in the 200- and 800-mg arms were 57.6% and 43.8% in locally advanced BCC and 7.7% and 17.4% in metastatic BCC, respectively. Among the 94 patients with locally advanced BCC who responded, only 18 progressed or died and more than 50% had responses lasting longer than 6 months. In addition, 4 of 5 responders with metastatic BCC maintained an objective response. Grade 3/4 adverse events and those leading to discontinuation were less frequent with sonidegib 200 versus 800 mg (38.0% vs 59.3%; 27.8% vs 37.3%, respectively). Limitations No placebo or comparator arms were used because sonidegib demonstrated efficacy in advanced BCC in a phase I study, and the hedgehog pathway inhibitor vismodegib was not yet approved. Conclusion With longer follow-up, sonidegib demonstrated sustained tumor responses in patients with advanced BCC.
Abstract Background : Although 2 doses of influenza vaccine are recommended for children aged <9 years who have not been previously vaccinated, children may receive only 1 dose because of suboptimal ...adherence to national influenza vaccination recommendations. Objective : This study evaluated the efficacy and tolerability of a single dose of the live attenuated influenza vaccine (LAIV) in previously unvaccinated children aged ≥2 years, the population for which LAIV is approved. Methods : This study was a post hoc subgroup analysis of previously published studies. Three randomized, double-blind, placebo-controlled clinical trials have evaluated the efficacy of a single dose of LAIV in previously unvaccinated young children. Single-dose efficacy, as a prespecified outcome, was evaluated in the subgroup of children aged 2 to 6 years. Reactogenicity and adverse events through 10 days after vaccination were reported after 1 and 2 doses. Results : Across all studies combined, the mean (SD) ages of the children within the subgroups analyzed were 35.8 (12.1) months for LAIV recipients and 34.5 (11.3) months for placebo recipients. The groups were balanced by sex, with 51% and 50% boys in the LAIV and placebo groups, respectively. The LAIV and placebo groups were also balanced with regard to the countries of origin, as follows: United States (35% LAIV, 31% placebo), Southeast Asia (35% LAIV, 44% placebo), South America (19% LAIV, 15% placebo), and South Africa (11% LAIV, 11% placebo). In a post hoc subgroup analysis of children aged 2 to 6 years from these 3 studies, the efficacy of a single dose of LAIV compared with placebo was 71.5% (95% CI, 52.9% to 83.4%), 87.3% (95% CI, 59.2% to 96.1%), and 59.9% (95% CI, 31.1% to 77.4%). Two of the studies compared the efficacy of 1 and 2 doses of vaccine in the same season. The 1-dose efficacy of LAIV was 87% to 92% of the 2-dose efficacy. Upon revaccination in year 2 with a single dose, year-2 efficacy was not significantly different for children who received either 1 or 2 doses in year 1 (1 dose in year 1, efficacy 64.1% 95% CI, 13.1% to 85.7%; 2 doses in year 1, efficacy 55.4% 95% CI, −23.6% to 85.9%; P = NS). All reactogenicity events associated with the first dose of LAIV were decreased after the second dose, with the exception of cough. Conclusions : A single dose of LAIV provided significant but not optimal protection against influenza in previously unvaccinated children. This finding may be of particular importance for children who are at risk of being partially immunized.
Background:
Lung cancer is the leading cause of cancer-related deaths and pulmonary carcinoids (PCs) account for almost 2% of all pulmonary malignancies. However, few published articles have reported ...prognosis and related factors of pulmonary carcinoid patients.
Material and Method:
The Surveillance, Epidemiology, and End Results (SEER) database was used to collect data of patients diagnosed with metastatic PCs from 2010 to 2016. The prognosis and survival of these patients were compared by employing Cox proportional hazards and the Kaplan-Meier survival analysis.
Results:
A total of 1763 patients were analyzed. The liver (668, 25.6%) was shown to be the most common metastatic site in the isolated organ metastasis cohort, followed by the lung (636, 24.4%), bone (562, 21.6%), and brain (460, 17.6%). Among the patients, the tumor metastasized to a single distant site included the liver, bone, lung, and brain. Cancer-specific survival (CSS) in metastatic PCs is determined by the site of metastasis and the total number of such sites. Pulmonary carcinoid patients with isolated liver metastasis manifested more favorable survival rates in comparison to patients having isolated metastasis in the lung, brain, or bone. The median CSS was 45, 7, 6, 5 months (P = 0.011). The number of distant metastatic sites and the location of distant metastasis were found to be independent risk factors for CSS. For patients with distant isolated metastasis, liver metastasis (P < 0.0001) had better CSS in comparison to those with bone metastasis. When compared to patients whose carcinoids had metastasized to the bones, patients with a brain (P = 0.273) or lung (P = 0.483) metastasis had the same CSS.
Conclusion:
Cancer-specific survival in metastatic PCs depends on the site of metastasis and the total number of such locations. PC patients with isolated liver metastasis manifested more favorable survival in comparison to patients with isolated metastasis in the lung, brain, or bone.
Both vitamin K antagonists (VKAs) and novel oral anticoagulants (NOACs) are effective for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients. This study evaluated the utilization of ...VKA and NOACs in NVAF patients before and after catheter ablation in China. Prescription data were retrospectively collected between January 1, 2016, and December 31, 2016, including indication of use, dose, renal function, and risk assessment (CHA2DS2-VASc score and HAS-BLED score) in Zhongshan Hospital of Fudan University. Trends and factors associated with anticoagulants use before and after ablation were evaluated. A total of 475 patients with NVAF who received ablation were included in the analysis. Of all, 53.26% of them received antithrombotic therapy preablation. Warfarin was prescribed in 35.26%, with NOACs in 11.37%. Four hundred seventy-three patients received antithrombotic therapy (99.58%) postablation, 236 patients with NOACs (49.68%). CHA2DS2-VASc score, HAS-BLED score, hypertension, diabetes mellitus, and alcohol were independently associated with anticoagulant utilization before catheter ablation. The higher CHA2DS2-VASc score was associated with less frequent prescription of NOACs postablation. The preablation anticoagulation use was still inadequate in China, and CHA2DS2-VASc score was a significant factor influencing the preablation anticoagulant utilization. The utilization rate of NOACs increased significantly postablation, especially for dabigatran, which implied that more physicians prefer to prescribe NOACs for NVAF patients after ablation in our country and may be attributed to the aspects such as ease of NOAC use but also possibly the greater safety and efficacy. Furthermore, the physicians may reluctant to use NOACs for high stroke risk atrial fibrillation patients after catheter ablation.
Summary T-lymphoma invasion and metastasis 1 has been implicated in tumor invasion and metastasis. However, the regulatory mechanisms underlying aberrant T-lymphoma invasion and metastasis 1 ...expression in human colorectal cancer have not been well defined. To investigate the relationship between methylation status and expression levels of T-lymphoma invasion and metastasis 1 gene, methylation-specific polymerase chain reaction, and immunohistochemistry staining were performed in 232 matched samples of human colorectal cancer tissue and normal colorectal mucosa. Results showed that T-lymphoma invasion and metastasis 1 protein was overexpressed in colorectal cancer, especially in metastatic cases ( P < .001). The degree of T-lymphoma invasion and metastasis 1 promoter methylation was a little lower in cancer tissues than in matched normal mucosa ( P < .05), and the expression level of T-lymphoma invasion and metastasis 1 was inversely related to the methylation status in cancer tissues ( P < .001). Colon cancer cell lines HT29 and LS174T were treated with demethylating agent 5-aza-2′-deoxycytidine, resulting in promoter hypomethylation accompanied by reexpression of T-lymphoma invasion and metastasis 1 mRNA and protein. In contrast, colon cancer cell lines SW620 and LoVo were treated with hypermethylation agent S -adenosylmethionine, resulting in T-lymphoma invasion and metastasis 1 promoter hypermethylation, accompanied by suppression of T-lymphoma invasion and metastasis 1 expression and inhibition of cell growth, plate colony formation, and migration. The present study demonstrates that overexpression of T-lymphoma invasion and metastasis 1 is associated with hypomethylation status of T-lymphoma invasion and metastasis 1 promoter region in colorectal cancer tissues. It suggests that promotor hypomethylation of T-lymphoma invasion and metastasis 1 may play a role in the progression and metastasis of colorectal cancer. Pharmacologic reversal of T-lymphoma invasion and metastasis 1 promoter hypomethylation may inhibit cell proliferation and migration.
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