Explore the vast range of titles available.

FoundationOne ® CDx (F1CDx) is a United States (US) Food and Drug Administration (FDA)-approved companion diagnostic test to identify patients who may benefit from treatment in accordance with the approved therapeutic product labeling for 28 drug therapies. F1CDx utilizes next-generation sequencing (NGS)-based comprehensive genomic profiling (CGP) technology to examine 324 cancer genes in solid tumors. F1CDx reports known and likely pathogenic short variants (SVs), copy number alterations (CNAs), and select rearrangements, as well as complex biomarkers including tumor mutational burden (TMB) and microsatellite instability (MSI), in addition to genomic loss of heterozygosity (gLOH) in ovarian cancer. CGP services can reduce the complexity of biomarker testing, enabling precision medicine to improve treatment decision-making and outcomes for cancer patients, but only if test results are reliable, accurate, and validated clinically and analytically to the highest standard available. The analyses presented herein demonstrate the extensive analytical and clinical validation supporting the F1CDx initial and subsequent FDA approvals to ensure high sensitivity, specificity, and reliability of the data reported. The analytical validation included several in-depth evaluations of F1CDx assay performance including limit of detection (LoD), limit of blank (LoB), precision, and orthogonal concordance for SVs (including base substitutions [SUBs] and insertions/deletions [INDELs]), CNAs (including amplifications and homozygous deletions), genomic rearrangements, and select complex biomarkers. The assay validation of >30,000 test results comprises a considerable and increasing body of evidence that supports the clinical utility of F1CDx to match patients with solid tumors to targeted therapies or immunotherapies based on their tumor’s genomic alterations and biomarkers. F1CDx meets the clinical needs of providers and patients to receive guideline-based biomarker testing, helping them keep pace with a rapidly evolving field of medicine.

Let G be a group that is either virtually soluble or virtually free, and let ω be a weight on G. We prove that if G is infinite, then there is some maximal left ideal of finite codimension in the Beurling algebra $\\ell^1(G, \\omega)$, which fails to be (algebraically) finitely generated. This implies that a conjecture of Dales and Żelazko holds for these Banach algebras. We then go on to give examples of weighted groups for which this property fails in a strong way. For instance, we describe a Beurling algebra on an infinite group in which every closed left ideal of finite codimension is finitely generated and which has many such ideals in the sense of being residually finite dimensional. These examples seem to be hard cases for proving Dales and Żelazko’s conjecture.

Clinical tests that rely on next-generation sequencing to evaluate large numbers of cancer genes can be validated using pooled cell lines with known mutations. As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95–99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests.

Background High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. Methods In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. Results We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2 , which occur in 10% of skin cancers and are highly associated with increased TMB. Conclusions These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2 , which may be another example of regulatory mutations contributing to tumorigenesis.

Using high-coverage targeted next-generation sequencing, this report provides a catalog of genetic alterations in colorectal and lung cancers, identifying previously unknown alterations, such as JAK2 mutations and KIF5B-RET fusions, that may represent druggable targets. Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non–small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8–3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.

One of the hallmarks of the Gram-negative bacterium Pseudomonas aeruginosa is its ability to thrive in diverse environments that includes humans with a variety of debilitating diseases or immune deficiencies. Here we report the complete sequence and comparative analysis of the genomes of two representative P. aeruginosa strains isolated from cystic fibrosis (CF) patients whose genetic disorder predisposes them to infections by this pathogen. The comparison of the genomes of the two CF strains with those of other P. aeruginosa presents a picture of a mosaic genome, consisting of a conserved core component, interrupted in each strain by combinations of specific blocks of genes. These strain-specific segments of the genome are found in limited chromosomal locations, referred to as regions of genomic plasticity. The ability of P. aeruginosa to shape its genomic composition to favor survival in the widest range of environmental reservoirs, with corresponding enhancement of its metabolic capacity is supported by the identification of a genomic island in one of the sequenced CF isolates, encoding enzymes capable of degrading terpenoids produced by trees. This work suggests that niche adaptation is a major evolutionary force influencing the composition of bacterial genomes. Unlike genome reduction seen in host-adapted bacterial pathogens, the genetic capacity of P. aeruginosa is determined by the ability of individual strains to acquire or discard genomic segments, giving rise to strains with customized genomic repertoires. Consequently, this organism can survive in a wide range of environmental reservoirs that can serve as sources of the infecting organisms.

We sought to evaluate the unique benefits and challenges the virtual recruitment and interviewing platform had on general surgery residency applicants. Applicants who interviewed for a categorical position at our institution during the 2021 and 2022 Match season were contacted to participate in the anonymous online survey focused on applicant behavior related to the virtual interview format. Data were analyzed using chi-square and paired t-tests. A response rate of 56.7 ​% (n ​= ​135) was achieved. Applicants accepted a median of 17 (IQR 13–20) interviews in 2021 and 15 (IQR 11–19) interviews in 2022. More than half (54 ​%) of applicants indicated they applied to more programs, and 53 ​% accepted more interviews, because of the virtual format. The greatest advantages of the virtual interviews as cited by applicants were saving money (96.3 ​%), saving time (49.6 ​%), and avoiding travel risks (43.7 ​%). The top limitations of virtual interviews were less exposure to current residents and faculty (61.5 ​%), to the city or location of the program (58.5 ​%), and difficultly comparing programs (57.8 ​%). The 2022 Match cycle included use of the supplemental application; however, 85 ​% of applicants did not feel that the supplemental improved their overall application. Some applicants (20 ​%) who “signaled” programs did not receive an interview offer from any of the programs they signaled. The transition to virtual interviews saved applicants time and money but limited their exposure. Future efforts to maintain virtual interviews will need to be balanced against the intangible benefit of human interaction and observing a program's culture. •Applicants applied to more programs and accepted more interviews due to the virtual format.•ERAS supplemental application was perceived by 85 ​% of applicants to not improve their overall application.•The Signaling feature was of uncertain utility, as 20 ​% of applicants did not receive an interview offer from any program they signaled.•Virtual interviews saved applicants time and money but limited their exposure.

Hepatocellular carcinoma (HCC) in proximity to major hepatic vasculature poses a risk for invasion, which would contraindicate liver transplantation, yet, is difficult to treat with thermal ablation. This study was undertaken to evaluate the feasibility of irreversible electroporation (IRE) as a bridge to transplantation for high-risk tumors. All patients with HCC in proximity to major hepatic vasculature treated with laparoscopic IRE as bridge to transplantation were studied. Patient and tumor characteristics, length of stay, and treatment-related complications were recorded. Tumor response was assessed with CT and explant pathology. Five patients with a median Model for End Stage Liver Disease (MELD) of 13 (7–21) underwent IRE. The median tumor size was 2.7 cm (1.5–3.7 cm). Adjacent structures included the right portal vein, hepatic veins/inferior vena cava (IVC) and left portal vein. Length of stay was one day for all patients. One patient suffered portal vein thrombosis. The transplant occurred at a median of 142 days (47–264) after IRE. Pathologic necrosis ranged from 30 to 100 per cent, without any vascular invasion. Four patients remain alive with no evidence of disease with median follow-up of 403 (227–623) days. The remaining patients died because of transplant-related complications onpost IRE day 297. IRE shows promise as a bridge to liver transplant for high risk HCC in a preliminary series, justifying further prospective evaluation.

We construct a unital pre-C*-algebra A0A_0 which is stably finite, in the sense that every left invertible square matrix over A0A_0 is right invertible, while the C*-completion of A0A_0 contains a nonunitary isometry, and so it is infinite.

Even Spivak recognizes that Bhubaneswari Bhaduri, her example of a woman who, so restricted by the confines of her community, commits suicide and \"turn[s] her body into a text of woman/writing, [. . .] was not a 'true' subaltern [since] she was a woman of the middle class\" (64). Rather than draw attention to a minor character in the king's journey (i.e., La Cava), the chronicler opts to construct its narrative around the subject of power.