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In this international, nonrandomized study, vismodegib, an oral inhibitor of the ligand that activates the hedgehog pathway, showed responses in patients with locally advanced or metastatic basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate. Basal-cell carcinoma is the most common cancer. It is estimated that more than 2.1 million new patients were treated for nonmelanoma skin cancer in 2006 in the United States 1 ; approximately 80% of nonmelanoma skin cancers are basal-cell carcinomas. Although most basal-cell carcinomas are readily treated by means of various surgical methods, these lesions occasionally progress to an advanced state that is no longer amenable to surgery or radiation therapy (locally advanced basal-cell carcinoma) or, more rarely, the lesions spread to distant sites (metastatic basal-cell carcinoma). When this study was designed, there was no approved therapy for advanced basal-cell carcinoma. . . .

Background In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration–approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC. Methods One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity. The primary end point was IRF-assessed ORR. Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety. Results At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up). Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response). ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC). Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC). Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort. Adverse events remained consistent with clinical experience. Thirty-three deaths (31.7%) were reported; none were related to vismodegib. Conclusions This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC. Trial registration This study was registered prospectively with Clinicaltrials.gov , number NCT00833417 on January 30, 2009.

The robust detection of disease-associated splice events from RNAseq data is challenging due to the potential confounding effect of gene expression levels and the often limited number of patients with relevant RNAseq data. Here we present a novel statistical approach to splicing outlier detection and differential splicing analysis. Our approach tests for differences in the percentages of sequence reads representing local splice events. We describe a software package called Bisbee which can predict the protein-level effect of splice alterations, a key feature lacking in many other splicing analysis resources. We leverage Bisbee’s prediction of protein level effects as a benchmark of its capabilities using matched sets of RNAseq and mass spectrometry data from normal tissues. Bisbee exhibits improved sensitivity and specificity over existing approaches and can be used to identify tissue-specific splice variants whose protein-level expression can be confirmed by mass spectrometry. We also applied Bisbee to assess evidence for a pathogenic splicing variant contributing to a rare disease and to identify tumor-specific splice isoforms associated with an oncogenic mutation. Bisbee was able to rediscover previously validated results in both of these cases and also identify common tumor-associated splice isoforms replicated in two independent melanoma datasets.

High resolution gridded mean daily temperature datasets are valuable for research and applications in agronomy, meteorology, hydrology, ecology, and many other disciplines depending on weather or climate. The gridded datasets and the models used for their estimation are being constantly improved as there is always a need for more accurate datasets as well as for datasets with a higher spatial and temporal resolution. We developed a spatio-temporal regression kriging model for Croatia at 1 km spatial resolution by adapting the spatio-temporal regression kriging model developed for global land areas. A geometrical temperature trend, digital elevation model, and topographic wetness index were used as covariates together with measurements from the Croatian national meteorological network for the year 2008. This model performed better than the global model and previously developed models for Croatia, based on MODIS land surface temperature images. The R2 was 97.8% and RMSE was 1.2 °C for leave-one-out and 5-fold cross-validation. The proposed national model still has a high level of uncertainty at higher altitudes leaving it suitable for agricultural areas that are dominant in lower and medium altitudes.

Pre-analytical factors can significantly affect circulating cell-free DNA (cfDNA) analysis. However, there are few robust methods to rapidly assess sample quality and the impact of pre-analytical processing. To address this gap and to evaluate effects of DNA extraction methods and blood collection tubes on cfDNA yield and fragment size, we developed a multiplexed droplet digital PCR (ddPCR) assay with 5 short and 4 long amplicons targeting single copy genomic loci. Using this assay, we compared 7 cfDNA extraction kits and found cfDNA yield and fragment size vary significantly. We also compared 3 blood collection protocols using plasma samples from 23 healthy volunteers (EDTA tubes processed within 1 hour and Cell-free DNA Blood Collection Tubes processed within 24 and 72 hours) and found no significant differences in cfDNA yield, fragment size and background noise between these protocols. In 219 clinical samples, cfDNA fragments were shorter in plasma samples processed immediately after venipuncture compared to archived samples, suggesting contribution of background DNA by lysed peripheral blood cells. In summary, we have described a multiplexed ddPCR assay to assess quality of cfDNA samples prior to downstream molecular analyses and we have evaluated potential sources of pre-analytical variation in cfDNA studies.

Limited information is available regarding real-world treatment patterns and their effectiveness and safety in patients with locally advanced basal cell carcinoma, including patients not typically represented in clinical trials. The purpose of the current study was to describe how clinicians diagnose and treat locally advanced basal cell carcinoma in the United States. This prospective, multicenter, observational registry study included patients with newly diagnosed, Hedgehog pathway inhibitor-naive locally advanced basal cell carcinoma without basal cell carcinoma nevus syndrome (n = 433) treated at 75 US academic and community practices, including dermatology, Mohs surgery, and medical oncology sites. The main outcomes of this study were treatment patterns and associated effectiveness and safety for patients with locally advanced basal cell carcinoma in real-world settings. Determination of locally advanced basal cell carcinoma was mainly based on lesion size (79.6% of patients), histopathology (54.3%), extent of involvement (49.0%), and location (46.2%). Within 90 days of determination of locally advanced disease, 115 patients (26.6%) received vismodegib, 251 (58.0%) received surgery/other (non-vismodegib) treatment, and 67 (15.5%) had not yet received treatment (observation). Vismodegib-treated patients had a higher prevalence of high-risk clinical features predictive for locoregional recurrence than those with non-vismodegib treatment or observation. Clinical response rate was 85.1% with vismodegib and 94.9% with non-vismodegib treatment (primarily surgery). The most common adverse events with vismodegib were ageusia/dysgeusia, muscle spasms, alopecia, and weight loss. Rates of cutaneous squamous cell cancers were comparable between vismodegib and non-vismodegib treatment. This prospective observational study offers insight on real-world practice, treatment selection, and outcomes for a nationally representative sample of US patients with locally advanced basal cell carcinoma. For patients with lesions that were not amenable to surgery, vismodegib treatment was associated with effectiveness and safety that was consistent with that observed in clinical trials.

For many decades, kriging and deterministic interpolation techniques, such as inverse distance weighting and nearest neighbour interpolation, have been the most popular spatial interpolation techniques. Kriging with external drift and regression kriging have become basic techniques that benefit both from spatial autocorrelation and covariate information. More recently, machine learning techniques, such as random forest and gradient boosting, have become increasingly popular and are now often used for spatial interpolation. Some attempts have been made to explicitly take the spatial component into account in machine learning, but so far, none of these approaches have taken the natural route of incorporating the nearest observations and their distances to the prediction location as covariates. In this research, we explored the value of including observations at the nearest locations and their distances from the prediction location by introducing Random Forest Spatial Interpolation (RFSI). We compared RFSI with deterministic interpolation methods, ordinary kriging, regression kriging, Random Forest and Random Forest for spatial prediction (RFsp) in three case studies. The first case study made use of synthetic data, i.e., simulations from normally distributed stationary random fields with a known semivariogram, for which ordinary kriging is known to be optimal. The second and third case studies evaluated the performance of the various interpolation methods using daily precipitation data for the 2016–2018 period in Catalonia, Spain, and mean daily temperature for the year 2008 in Croatia. Results of the synthetic case study showed that RFSI outperformed most simple deterministic interpolation techniques and had similar performance as inverse distance weighting and RFsp. As expected, kriging was the most accurate technique in the synthetic case study. In the precipitation and temperature case studies, RFSI mostly outperformed regression kriging, inverse distance weighting, random forest, and RFsp. Moreover, RFSI was substantially faster than RFsp, particularly when the training dataset was large and high-resolution prediction maps were made.

Limited information is available regarding real-world treatment patterns and their effectiveness and safety in patients with locally advanced basal cell carcinoma, including patients not typically represented in clinical trials. The purpose of the current study was to describe how clinicians diagnose and treat locally advanced basal cell carcinoma in the United States. This prospective, multicenter, observational registry study included patients with newly diagnosed, Hedgehog pathway inhibitor-naive locally advanced basal cell carcinoma without basal cell carcinoma nevus syndrome (n = 433) treated at 75 US academic and community practices, including dermatology, Mohs surgery, and medical oncology sites. The main outcomes of this study were treatment patterns and associated effectiveness and safety for patients with locally advanced basal cell carcinoma in real-world settings. Determination of locally advanced basal cell carcinoma was mainly based on lesion size (79.6% of patients), histopathology (54.3%), extent of involvement (49.0%), and location (46.2%). Within 90 days of determination of locally advanced disease, 115 patients (26.6%) received vismodegib, 251 (58.0%) received surgery/other (non-vismodegib) treatment, and 67 (15.5%) had not yet received treatment (observation). Vismodegib-treated patients had a higher prevalence of high-risk clinical features predictive for locoregional recurrence than those with non-vismodegib treatment or observation. Clinical response rate was 85.1% with vismodegib and 94.9% with non-vismodegib treatment (primarily surgery). The most common adverse events with vismodegib were ageusia/dysgeusia, muscle spasms, alopecia, and weight loss. Rates of cutaneous squamous cell cancers were comparable between vismodegib and non-vismodegib treatment. This prospective observational study offers insight on real-world practice, treatment selection, and outcomes for a nationally representative sample of US patients with locally advanced basal cell carcinoma. For patients with lesions that were not amenable to surgery, vismodegib treatment was associated with effectiveness and safety that was consistent with that observed in clinical trials.

Backround/Objectives: Colorectal cancer presents a significant quality of life (QoL) challenge as a result of both the disease and its treatments. This study aimed to validate and culturally adapt the Cleveland Clinic Colorectal Cancer Quality of Life Questionnaire (CCF-CaQL) for Serbian-speaking colorectal cancer patients. Methods: The CCF-CaQL offers a detailed assessment of the physical, emotional, social, and functional impacts of the disease. This study, conducted at the University Clinical Center of Serbia, involved 150 colorectal cancer patients undergoing treatment. The translation and adaptation process followed the EORTC Quality of Life Group’s guidelines, ensuring cultural relevance and comprehensibility. Statistical analyses, including Cronbach’s alpha for internal consistency and Pearson’s correlation for concurrent validity, reliability, and known-groups validity, were performed using SPSS and R software. Results: The Serbian version of the CCF-CaQL maintains strong psychometric properties with high internal consistency (Cronbach’s alpha = 0.85) and significant correlations with the FACT-C questionnaire, confirming its validity. Known-groups validity showed distinct variations in QoL scores based on tumor location, stoma presence, and neoadjuvant therapy status, highlighting its sensitivity to different clinical conditions. Conclusions: The CCF-CaQL questionnaire has been skillfully translated, culturally adapted, and carefully validated through psychometric evaluations for Serbian patients diagnosed with colorectal cancer.

CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors. All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (QuadWT). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and QuadWT. A total of 102 patients were included in this study of which 14 had mutations of CDKN2A (CDKN2Amut), 21 had TP53 mutations (TP53mut), and 12 were QuadWT. TP53mut, CDKN2Amut and QuadWT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2Amut cohort and a trend towards worsened median TTP in the QuadWT cohort. Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used.