PIK3CB Inhibitor GSK2636771 in Cancers With Mutation/Deletion or Loss of PTEN Protein Expression: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols N and P.

Purpose: PTEN loss contributes to aberrant signaling of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin pathway and may confer sensitivity to therapies targeting the PI3K pathway. The PIK3CB inhibitor GSK2636771 demonstrated efficacy in tumors with mutations and may similarly show efficacy in patients with PTEN loss.

Methods: Two nonrandomized, open-label phase II subprotocols within the context of the NCI-MATCH trial targeted PTEN tumor alterations in patients with advanced relapsed/refractory solid tumors, lymphoma, or myeloma: mutation/deletion (arm N) or loss of PTEN protein expression (arm P).

Complications From Transcatheter Pulmonary Valve Replacement With Self-Expanding Prestent.

Self-expanding valve platforms are providing new and versatile options for transcatheter pulmonary valve replacement in patients with a large native or patched right ventricular outflow tract. We describe 4 cases of acute reintervention required after successful implantation of an Alterra Adaptive Prestent followed by SAPIEN S3.

Phase II Study of Copanlisib in Patients With PTEN Loss: Results From NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols Z1G and Z1H.

Purpose: Copanlisib, a pan-class phosphatidylinositol 3-kinase (PI3K) inhibitor with activity predominantly against the PI3K-delta and PI3K-alpha isoforms, has shown promising results in preclinical cancer models with PTEN loss. Herein, we report the activity and safety data from the Z1G and Z1H subprotocols, which included patients with PTEN loss, of the National Cancer Institute Molecular Analysis for Therapy Choice trial.

Methods: Patients with complete loss of cytoplasmic and nuclear PTEN as determined by immunohistochemistry regardless of mutation or deletion status were included in subprotocol Z1G, and patients with a deleterious mutation in the gene and retained expression of PTEN were included in subprotocol Z1H.

Phase II Study of Defactinib (VS6063) in Patients With Tumors With Loss: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol U.

Purpose: The NCI-MATCH trial assigned patients with solid tumors, lymphomas, or multiple myeloma to targeted therapies on the basis of identified genetic alterations from tumor biopsies. In preclinical models, ()-inactivated tumors display sensitivity to focal adhesion kinase (FAK) inhibition. The EAY131-U subprotocol evaluated the efficacy of defactinib, a FAK inhibitor, in patients with -altered tumors.

Phase II Study of Sunitinib in Tumors With Mutations: Results From the NCI MATCH ECOG-ACRIN Trial (EAY131) Subprotocol V.

Purpose: The NCI-MATCH study is a tumor-agnostic platform trial enrolling patients to targeted therapies on the basis of genomic alterations. Subprotocol V investigated sunitinib in patients with tumors harboring - mutations.

Methods: EAY131-V, is an open-label, single-arm, phase II study.

Phase II Study of Palbociclib in Patients with Tumors with CDK4 or CDK6 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1C.

Purpose: Amplification of cyclin-dependent kinase 4 (CDK4) and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests that inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-Molecular Analysis for Therapy Choice trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors.

Patients And Methods: Patients had a solid malignancy or lymphoma with progression on at least one systemic therapy for advanced disease or with no standard-of-care therapy available.

The minimal computational substrate of fluid intelligence.

The quantification of cognitive powers rests on identifying a behavioural task that depends on them. Such dependence cannot be assured, for the powers a task invokes cannot be experimentally controlled or constrained a priori, resulting in unknown vulnerability to failure of specificity and generalisability. Evaluating a compact version of Raven's Advanced Progressive Matrices (RAPM), a widely used clinical test of fluid intelligence, we show that LaMa, a self-supervised artificial neural network trained solely on the completion of partially masked images of natural environmental scenes, achieves representative human-level test scores a prima vista, without any task-specific inductive bias or training.

Realistic morphology-preserving generative modelling of the brain.

Medical imaging research is often limited by data scarcity and availability. Governance, privacy concerns and the cost of acquisition all restrict access to medical imaging data, which, compounded by the data-hungry nature of deep learning algorithms, limits progress in the field of healthcare AI. Generative models have recently been used to synthesize photorealistic natural images, presenting a potential solution to the data scarcity problem.

Compressed representation of brain genetic transcription.

The architecture of the brain is too complex to be intuitively surveyable without the use of compressed representations that project its variation into a compact, navigable space. The task is especially challenging with high-dimensional data, such as gene expression, where the joint complexity of anatomical and transcriptional patterns demands maximum compression. The established practice is to use standard principal component analysis (PCA), whose computational felicity is offset by limited expressivity, especially at great compression ratios.

Phase II Trial of Afatinib in Patients With -Mutated Solid Tumors Excluding Lung Cancer: Results From NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol A.

Purpose: National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) was a multicohort phase 2 trial that assigned patients with advanced pretreated cancers to molecularly targeted therapies on the basis of tumor genomic testing. NCI-MATCH Arm A evaluated afatinib, an EGFR tyrosine kinase inhibitor (TKI) approved for advanced non-small cell lung cancer, in patients with tumors other than lung cancer harboring mutations.

Methods: Patients with advanced pretreated cancers other than lung cancer found to have selected actionable mutations were offered participation in Arm A.

Phase II Study of Osimertinib in Patients With Epidermal Growth Factor Receptor Mutations: Results From the NCI-MATCH ECOG-ACRIN (EAY131) Trial Subprotocol E.

Purpose: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with mutations.

Methods: Eligible patients had mutations (T790M or rare activating) and received osimertinib 80 mg once daily.

Computational limits to the legibility of the imaged human brain.

Our knowledge of the organisation of the human brain at the population-level is yet to translate into power to predict functional differences at the individual-level, limiting clinical applications and casting doubt on the generalisability of inferred mechanisms. It remains unknown whether the difficulty arises from the absence of individuating biological patterns within the brain, or from limited power to access them with the models and compute at our disposal. Here we comprehensively investigate the resolvability of such patterns with data and compute at unprecedented scale.

Trastuzumab and Pertuzumab in Patients with Non-Breast/Gastroesophageal HER2-Amplified Tumors: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol J.

Purpose: NCI-MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors.

Patients And Methods: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories.

The New NCI Precision Medicine Trials.

Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target.

The NCI-MATCH trial: lessons for precision oncology.

The NCI-MATCH (Molecular Analysis for Therapy Choice) trial ( NCT02465060 ) was launched in 2015 as a genomically driven, signal-seeking precision medicine platform trial-largely for patients with treatment-refractory, malignant solid tumors. Having completed in 2023, it remains one of the largest tumor-agnostic, precision oncology trials undertaken to date. Nearly 6,000 patients underwent screening and molecular testing, with a total of 1,593 patients (inclusive of continued accrual from standard next-generation sequencing) being assigned to one of 38 substudies.

Trametinib in Patients With , , or -Mutant Tumors: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols S1 and S2.

Purpose: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with ([S1] or [S2]) altered tumors.

Methods: Eligible patients had tumors with deleterious inactivating or mutations by the customized Oncomine AmpliSeq panel.

Phase II Study of Palbociclib (PD-0332991) in CCND1, 2, or 3 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1B.

Purpose: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy.

National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH).

Over the past decade, multiple trials, including the precision medicine trial National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance.

Population, Clinical, and Scientific Impact of National Cancer Institute's National Clinical Trials Network Treatment Studies.

Purpose: In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all adult network group trials has never been systematically examined.

Methods: We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes.

Phase II Study of Afatinib in Patients With Tumors With Human Epidermal Growth Factor Receptor 2-Activating Mutations: Results From the National Cancer Institute-Molecular Analysis for Therapy Choice ECOG-ACRIN Trial (EAY131) Subprotocol EAY131-B.

Purpose: National Cancer Institute-Molecular Analysis for Therapy Choice is a multicohort trial that assigns patients with advanced cancers to targeted therapies on the basis of central tumor genomic testing. Arm B evaluated afatinib, an ErbB family tyrosine kinase inhibitor, in patients with -activating mutations.

Methods: Eligible patients had selected single-nucleotide variants or insertions/deletions detected by the National Cancer Institute-Molecular Analysis for Therapy Choice next-generation sequencing assay.

Deep forecasting of translational impact in medical research.

The value of biomedical research-a $1.7 trillion annual investment-is ultimately determined by its downstream, real-world impact, whose predictability from simple citation metrics remains unquantified. Here we sought to determine the comparative predictability of future real-world translation-as indexed by inclusion in patents, guidelines, or policy documents-from complex models of title/abstract-level content versus citations and metadata alone.

Phase II Study of Taselisib in -Mutated Solid Tumors Other Than Breast and Squamous Lung Cancer: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol I.

Purpose: mutations frequently contribute to oncogenesis in solid tumors. Taselisib, a potent and selective inhibitor of phosphoinositide 3-kinase, has demonstrated clinical activity in -mutant breast cancer. Whether mutations predict sensitivity to taselisib in other cancer types is unknown.

Phase II Study of Copanlisib in Patients With Tumors With Mutations: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1F.

Purpose: Activating mutations in are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an α and δ isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with mutations (with or without loss).