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Introduction: Whole Exome Sequencing (WES) has emerged as an efficient tool in clinical cancer diagnostics to broaden the scope from panel-based diagnostics to screening of all genes and enabling robust determination of complex biomarkers in a single analysis., Methods: To assess concordance, six formalin-fixed paraffin-embedded (FFPE) tissue specimens and four commercial reference standards were analyzed by WES as matched tumor-normal DNA at 21 NGS centers in Germany, each employing local wet-lab and bioinformatics. Somatic and germline variants, copy-number alterations (CNAs), and complex biomarkers were investigated. Somatic variant calling was performed in 494 diagnostically relevant cancer genes. The raw data were collected and re-analyzed with a central bioinformatic pipeline to separate wet- and dry-lab variability., Results: The mean positive percentage agreement (PPA) of somatic variant calling was 76 % while the positive predictive value (PPV) was 89 % in relation to a consensus list of variants found by at least five centers. Variant filtering was identified as the main cause for divergent variant calls. Adjusting filter criteria and re-analysis increased the PPA to 88 % for all and 97 % for the clinically relevant variants. CNA calls were concordant for 82 % of genomic regions. Homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI) status were concordant for 94 %, 93 %, and 93 % of calls, respectively. Variability of CNAs and complex biomarkers did not decrease considerably after harmonization of the bioinformatic processing and was hence attributed mainly to wet-lab differences., Conclusion: Continuous optimization of bioinformatic workflows and participating in round robin tests are recommended., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MMT reports speaker and travel Expenses from Twist. JS reports speaker honoraria from DLS, Molecular Health, AstraZeneca and Biocartis, outside the submitted work. UL reports speaker fees from AstraZeneca, GSK, Novartis, Menarini, advisory board from AstraZeneca and Novartis. DH reports speaker honorary AstraZeneca, adboard BMS, WD speaker honoraries BMS & Novartis. SMB reports speaker honoraria, advisory board fees and research grants from AstraZeneca, Daiichi, Menarini, Novartis, Roche, BMS, Pfizer, Bayer, MSD, Merck, Amgen, Molecular Health, Targos, DLS, Janssen, GSK, QuIP, outside the submitted work. SL reports research grant from BMS, advisory board/speaker invitation from AstraZeneca, Eli Lilly, Roche and Takeda outside of this work. NTG reports research support from Janssen-Cilag and Advisory Boards from Janssen-Cilag, AstraZeneca, Daiichi-Sankyo and BMS outside the submitted work. WW reports research grants from Roche, MSD, BMS and AstraZeneca. Advisory board, lectures and speaker bureau fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Bayer, Janssen, Amgen, Astellas, Illumina, Eisai, Siemens, Agilent, ADC, GSK und Molecular Health. SO received reimbursement for travel expenses and payment for conference presentations from Illumina Inc. and Oxford Nanopore Technologies. CS reports research funding from BMS Stiftung Immunonkologie and institutional grants from Illumina outside the submitted work. CPS reports an investigator-initiated grant from Illumnia outside of the submitted work. PS reports grants from Inctye, BMS, Gilead, Falk, speakers bureau/advisory board from MSD, BMS, AstraZeneca, Incyte, Astellas, Janssen, Eisai, Amgen, Boehringer Ingelheim. DK reports personal fees for speaker honoraria from AstraZeneca, and Pfizer, personal fees for Advisory Board from Bristol-Myers Squibb, outside the submitted work. NP reports speaker fees from Novartis, Bayer, Roche, AstraZeneca, Illumina, BMS, MSD, PGDX/Labcorp, advisory board from Novartis, Lilly, Roche, Janssen, travel expenses from Novartis, AstraZeneca, Illumina, BMS, MSD, PGDX/Labcorp, Research grants from Illumina. JB reports grants from German Cancer Aid and consulting from MSD, outside the submitted work. AS reports participation in Advisory Board/Speaker’s Bureau for Astra Zeneca, AGCT, Bayer, Bristol-Myers Squibb, Eli Lilly, Illumina, Janssen, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, and Thermo Fisher, grants from Bayer, Bristol-Myers Squibb, and Chugai, outside the submitted work. All other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Genomic tumour profiling has a crucial role in the management of patients with solid cancers, as it helps selecting and prioritising therapeutic interventions based on prognostic and predictive biomarkers, as well as identifying markers of hereditary cancers. Harmonised approaches to interpret the results of genomic testing are needed to support physicians in their decision making, prevent inequalities in precision medicine and maximise patient benefit from available cancer management options., Methods: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group assembled a group of international experts to propose recommendations for preparing clinical genomic reports for solid cancers. These recommendations aim to foster best practices in integrating genomic testing within clinical settings. After review of available evidence, several rounds of surveys and focused discussions were conducted to reach consensus on the recommendation statements. Only consensus recommendations were reported. Recommendation statements were graded in two tiers based on their clinical importance: level A (required to maintain common standards in reporting) and level B (optional but necessary to achieve ideal practice)., Results: Genomics reports should present key information in a front page(s) followed by supplementary information in one or more appendices. Reports should be structured into sections: (i) patient and sample details; (ii) assay and data analysis characteristics; (iii) sample-specific assay performance and quality control; (iv) genomic alterations and their functional annotation; (v) clinical actionability assessment and matching to potential therapy indications; and (vi) summary of the main findings. Specific recommendations to prepare each of these sections are made., Conclusions: We present a set of recommendations aimed at structuring genomics reports to enhance physician comprehension of genomic profiling results for solid cancers. Communication between ordering physicians and professionals reporting genomic data is key to minimise uncertainties and to optimise the impact of genomic tests in patient care., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive., Methods: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised., Results: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development., Conclusion: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum set of variant alleles (tier 1) and an extended list of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. The goal of this Working Group is to promote standardization of PGx testing across clinical laboratories. This document will focus on clinical DPYD PGx testing that may be applied to all dihydropyrimidine dehydrogenase-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide., Competing Interests: Disclosure Statement The University of North Carolina Medical Genetics Laboratory, RPRD Diagnostics, AccessDx Laboratory, and the Stanford Medicine Clinical Genomics Laboratory are fee-for-service clinical laboratories that offer clinical pharmacogenomic testing. V.M.P. is the director of Scientific Affairs for Agena Bioscience, is a member of the Pharmacogene Variation Consortium (PharmVar) Steering Committee and PharmVar CYP2C and CYP3A Gene Expert Panels, and is the Association for Molecular Pathology liaison to the National Academy of Medicine Roundtable on Genomics and Precision Health. L.H.C. is supported by NIH/National Human Genome Research Institute (NHGRI) grant U01 HG007269 and NIH/National Center for Advancing Translational Sciences grant UL1 TR001427 and serves on the Clinical Pharmacogenetics Implementation Consortium (CPIC) steering committee. A.G. is the director of PharmVar, a member of CPIC, and a member of the CPIC and Pharmacogenomics Clinical Annotation Tool Scientific Advisory Boards. H.H. is an employee of AccessDx Holdings and serves on the CPIC Scientific Advisory Board and on the PharmVar CYP2D6 Gene Expert Panel. Y.J. serves as the Vice Chair of the American College of Medical Genetics and Genomics (ACMG) Membership Committee. R.C.L. is a member of the PharmVar CYP2D6 Gene Expert Panel. A.M.M. is a member of the College of American Pathologists (CAP)/ACMG Biochemical and Molecular Genetics Committee and Pharmacogenetics Workgroup, the PharmVar CYP2D6 Gene Expert Panel, the ClinGen Pharmacogenomics (PGx) Working Group, and the ClinPGx Scientific Advisory Board. S.A.S. serves on the steering committees of CPIC and PharmVar and is a member of the PharmVar CYP2C Gene Expert Panel. A.J.T.'s efforts are supported in part by RPRD Diagnostics, an independent clinical laboratory offering pharmacogenetic testing services; she also serves on the PharmVar CYP1A2, CYP2D6, DPYD, and NUDT15 Gene Expert Panels. R.H.N.v.S. is a member of the Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, is a board member and past president of the European Society for Pharmacogenomics and Personalized Therapy, serves on the PharmVar CYP3A Gene Expert Panel, and is a member of the CPIC Scientific Advisory Board. M.W.-C. is supported by NIH/NHGRI/National Institute of Child Health and Human Development/National Institute on Drug Abuse grant U24 HG010615 and NIH/NHGRI grant U24 HG013077, is a co-investigator of CPIC, is co–principal investigator and director of the Pharmacogenomics Knowledgebase, and serves on the steering committee and multiple Gene Expert Panels for PharmVar. K.E.W. serves as the CAP liaison to the National Academy of Medicine Roundtable on Genomics and Precision Health. The remaining authors have declared no related conflicts of interest., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US., Summary: Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization., Conclusion: A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose of Review: This review explores the intricacies of ethical anesthesia, exploring the necessity for precision anesthesia and its impact on patient-reported outcomes. The primary objective is to advocate for a defined aim, promoting the implementation of rules and feedback systems. The ultimate goal is to enhance precision anesthesia care, ensuring patient safety through the implementation of a teamwork and the integration of feedback mechanisms., Recent Findings: Recent strategies in the field of anesthesia have evolved from intraoperative monitorization to a wider perioperative patient-centered precision care. Nonetheless, implementing this approach encounters significant obstacles. The article explores the evidence supporting the need for a defined aim and applicable rules for precision anesthesia's effectiveness. The implementation of the safety culture is underlined. The review delves into the teamwork description with structured feedback systems., Summary: Anesthesia is a multifaceted discipline that involves various stakeholders. The primary focus is delivering personalized precision care. This review underscores the importance of establishing clear aims, defined rules, and fostering effective and well tolerated teamwork with accurate feedback for improving patient-reported outcomes. The Safe Brain Initiative approach, emphasizing algorithmic monitoring and systematic follow-up, is crucial in implementing a fundamental and standardized reporting approach within patient-centered anesthesia care practice., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Involving librarians as team members can lead to better quality in reviews. To improve their search results, an international diabetes project involved two medical librarians in a large-scale project planning of a series of systematic reviews for clinical guidelines in diabetes precision medicine., Case Presentation: The precision diabetes project was divided into teams. Four diabetes mellitus types (type 1, type 2, gestational, and monogenic) were divided into teams focusing on diagnostics, prevention, treatment, or prognostics. A search consultation plan was set up for the project to help organize the work. We performed searches in Embase and PubMed for 14 teams, building complex searches that involved non-traditional search strategies. Our search strategies generated very large amounts of records that created challenges in balancing sensitivity with precision. We also performed overlap searches for type 1 and type 2 diabetes search strategies; and assisted in setting up reviews in the Covidence tool for screening., Conclusions: This project gave us opportunities to test methods we had not used before, such as overlap comparisons between whole search strategies. It also gave us insights into the complexity of performing a search balancing sensitivity and specificity and highlights the need for a clearly defined communication plan for extensive evidence synthesis projects., (Copyright © 2024 Maria Björklund, Krister Aronsson.)

Background: The curricula of Ayurveda programmes emphasise various theoretical constructs such as Tridosha (three factors determining the state of health), Agnibala (digestive strength), Samprapti (patho-physiology), among others. It is often argued that practitioners follow an individualised approach based on these principles while treating patients. Yet, dependable data on their real-world influence is lacking. The aim of this study was to record the extent to which these constructs drive decision-making among Ayurveda practitioners and to examine whether these constructs determine individualisation of the interventions., Methods: We employed an emailed survey to record physicians' perceptions. Convenience sampling was chosen as the sampling method. Registered Ayurveda practitioners located across India with a minimum of five years of clinical experience were invited to participate. Five case-based scenarios depicting different clinical conditions were presented to the physicians. Questions that accompanied each case scenario asked the physicians to record clinical diagnoses, treatment plans, and the Ayurveda principles that determined their treatment., Results: A total of 141 physicians responded, from whom we received 152 responses as seven physicians responded to more than one scenario. The results suggest a significant lack of consensus among physicians regarding clinical diagnoses, interventions, and their understanding of pathophysiology in the given clinical scenarios. Many conflicting opinions were also noted., Conclusion: Theoretical constructs do not appear to determine either prescriptions or individualisation uniformly. Two ethical questions arise: "Is this situation due to an inherently weak theoretical framework of Ayurveda?" and "How can one justify spending hundreds of hours teaching these theories?"

Background: Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice., Methods: The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility., Results: As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available., Conclusion: Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer., Competing Interests: Disclosure MFM reports receipt of a fee to institution as an invited speaker from Novartis; part-time employment in PEGASCY. CBW reports receipt of a fee for participation in Advisory Board from BMS, Celgene, Rafael, RedHill, Roche, Shire/Baxalta; receipt of a fee as an invited speaker from Amgen, AstraZeneca, Bayer, BMS, Celgene, Chugai, Falk, GSK, Janssen, Merck, MSD, Roche, Servier, Sirtex, Taiho; receipt of a fee for an expert testimony from Janssen; receipt of travel support from Bayer, Celgene, RedHill, Roche, Servier, Taiho; non-financial interest for receipt of research grant both personal and to institution from Roche; non-financial interest for serving as an officer in AIO—Arbeitsgemeinschaft Internistische Onkologie (Germany); non-financial interest for advisory role in EU Commission—DG RTD as a member of the EU Commission Mission Board for Cancer. ASt reports receipt of a fee for participation in Advisory Board from Aignostics, Amgen, AstraZeneca, Bayer, Eli Lilly, Illumina, Janssen, MSD, Pfizer, Seattle Genetics, Thermo Fisher; receipt of a fee to institution for participation in Advisory Board from BMS, Novartis, Takeda; receipt of a fee as an invited speaker from Incyte, Roche; receipt of research grant to institution from Bayer, BMS, Chugai, Incyte. FB reports receipt of a fee to institution for participation in Advisory Board from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Ignyta, Merck, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi Aventis, Seattle Genetics, Takeda; non-financial interest as a principal investigator from AstraZeneca, BMS, F. Hoffmann-La Roche Ltd., Innate Pharma, Merck, Mirati, Piere Fabre. AB reports receipt of a fee for participation in Advisory Board from Sanofi; receipt of a fee as an invited speaker from Roche. IB reports receipt of a fee as an invited speaker from AstraZeneca. JB reports receipt of a fee for participation in Advisory Board from BMS, Janssen, MSD; receipt of funding for study to institution from BMS. EC reports receipt of a fee for participation in Advisory Board from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Janssen, Eli Lilly, Medscape, MSD, Novartis, Pfizer; receipt of a fee as an invited speaker from Astellas, AstraZeneca, Clovis, Janssen, Medscape, Pfizer; receipt of funding to institution from AstraZeneca; receipt of research grants to institution from Bayer, Janssen, Pfizer; receipt of a fee to institution as a local principal investigator from Janssen, MSD, Pfizer. RD reports receipt of a fee for participation in Advisory Board from Foundation Medicine, Roche; receipt of a fee as an invited speaker from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Ipsen, Janssen, Libbs, Eli Lilly, Merck Sharp & Dohme, Roche, Sanofi, Servier, Takeda; part-time employment in Oncoclinicas; owning stocks/shares in Trialing; receipt of a research grant from Merck; receipt of research grants to institution from AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Novartis. AK reports receipt of a fee to institution for participation in Advisory Board from Roche; receipt of a fee as an invited speaker from Roche; funding to institution from Bristol Myers Squibb (BMS); non-financial interest as a principal investigator from Roche. AC reports receipt of a fee as an invited speaker from BMS, MSD, Novartis, Pierre Fabre. FMB reports receipt of a fee for participation in Advisory Board from Biovica, Eisai, Karyopharm, Protai, Seagen, Theratechnologies, Zentalis Pharmaceuticals; receipt of a fee for consultancy from AbbVie, AstraZeneca, Black Diamond Therapeutics, EcoR1, F. Hoffmann-La Roche Ltd., GT Aperion Therapeutics, Infinity Pharmaceuticals, Lengo Therapeutics, Loxo Oncology, Menarini Group, OnCusp Therapeutics, Seagen, Tallac Therapeutics, Zymeworks; non-financial interest as a coordinating principal investigator from AstraZeneca; non-financial interest as a local principal investigator from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, Calithera Biosciences, Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., KLUS Pharma, Novartis, Taiho Pharmaceuticals Co.; receipt of research grants to institution from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Puma Biotechnology, Repare Therapeutics, Taiho Pharmaceuticals Co., Takeda Pharmaceuticals Co.; non-financial interest for serving as a Steering Committee Member from Genentech Inc.; receipt of travel support from Cholangiocarcinoma Foundation, European Organisation for Research and Treatment (EORTC), European Society for Medical Oncology (ESMO). SM reports receipt of a fee for participation in Advisory Board, Study Scientific Committee member from Roche, receipt of a fee as DSMB member from Biophytis, IQVIA, Kedrion Biopharma, Servier, Yuhan Corporation. RM reports receipt of a fee for participation in Advisory Board from GSK, AstraZeneca, Merck; receipt of a fee as an invited speaker from GSK, AstraZeneca, Clovis Oncology; receipt of a fee for expert testimony from Shionogi and Ellipses. NN reports receipt of a fee for participation in Advisory Board from Amgen, AstraZeneca, Bayer, Biocartis, Incyte, Novartis, Roche; receipt of a fee as an invited speaker from Eli Lilly, Illumina, Merck, MSD, Thermo Fisher, Roche, Novartis, Sophia Genetics, GSK, Servier; receipt of research grants to institution from AstraZeneca, Biocartis, Illumina, Incyte, Merck, QIAGEN, Roche, Thermo Fisher. JRF reports receipt of a fee for participation in Advisory Board from AstraZeneca, Bain Capital, Daiichi Sankyo, Merck, MultiplexDX, Inc., Paige.AI, Personalis, Repare Therapeutics, Roche Tissue Diagnostics; receipt of a fee for consulting from Eli Lilly, Goldman Sachs, Paige.AI, Repare Therapeutics, Saga Diagnostics; financial interest as a member of Board of Directors from Grupo Oncoclinicas, Odyssey Bio; owning stock options in Paige.AI, Repare Therapeutics; non-financial interest from a leadership role as a President of International Quality Network for Pathology (IQN Path) and a Past President of Italian Cancer Society (SIC). JR reports receipt of grants/research support from MSD, AstraZeneca; receipt of a fee to institution for participation in Advisory Board from AstraZeneca, EDIMARK; for conducting sponsored research to institution from Merck; receipt of a fee to institution as an invited speaker from AstraZeneca, Sanofi, Takeda, Janssen, Roche; non-financial interest for a leadership role as a Secretary of EORTC Lung Cancer Group. MR reports receipt of a fee for participation in Advisory Board from myMedEd; receipt of a fee as an invited speaker from Clinical Care Options, MJH Holdings, myMedEd, Physician’s Education Resource; receipt of a fee for review guideline pathways from Change Healthcare; receipt of a fee to institution as a local principal investigator from AstraZeneca, Merck, or co-principal investigator from Merck and local co-principal investigator from Pfizer; non-financial interest for serving as a Steering Committee Member from AstraZeneca, Merck; non-financial interest for advisory role in Tempus Labs, Zenith Pharmaceuticals; non-financial interest for providing editorial services for medical writing from AstraZeneca, Pfizer; non-financial interest as a member of ASCO. ER reports receipt of a fee to institution for participation in Advisory Board from Amgen, AstraZeneca, GSK, Roche; receipt of a fee to institution as an invited speaker from BMS, Clovis; receipt of funding for data base to institution from AstraZeneca. ASc reports receipt of a fee for participation in Advisory Board from Incyte; receipt of a fee as an invited speaker from Amgen, Aristea—MSD, Tesaro-GSK. CS reports receipt of a fee for participation in Advisory Board from Blueprint Medicines, Cogent Biosciences, Deciphera Pharmaceuticals, IDRx, Immunicum, New Bay; receipt of a fee as an invited speaker from Roche, PharmaMar; receipt of a fee as Steering Committee Member, both personal and to institution, from Deciphera, NewBay; receipt of research grants to institution from IDRx; receipt of travel grant from Bayer AG, Gilead, Pfizer, PharmaMar; non-financial interest as ESMO Faculty member and serving as a member of Board of Directors in the Spanish Group for Sarcoma Research (GEIS) and Spanish Society of Medical Oncology (SEOM). JM reports receipt of a fee for participation in Advisory Board from Amgen, Amunix Pharmaceuticals, AstraZeneca, Janssen, Pfizer, Roche; receipt of a fee to institution for participation in Advisory Board from Nuage Therapeutics; receipt of a fee as an invited speaker from AstraZeneca, GuardantHealth, MSD; receipt of research grants to institution from Amgen, AstraZeneca, Pfizer Oncology; non-financial interest from receiving product samples for access to drugs in early development for preclinical testing from AstraZeneca. FA reports receipt of a fee to institution for participation in Advisory Board from AstraZeneca, Boston Pharmaceutics, Daiichi Sankyo, Gilead, Guardant Health, Eli Lilly, N-Power Medicine, Novartis, Owkin, Pfizer, Roche, Servier; receipt of a personal fee for participation in Advisory Board from Lilly France; receipt of research grants to institution from AstraZeneca, Daiichi Sankyo, Guardant Health, Ely Lilly, Novartis, Owkin, Pfizer, Roche., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Currently, genetic tests that predict cancer risk or risk of recurrence in patients who have had their cancer treated with curative intent must have proven "clinical utility" to be recommended by the organizations responsible for publishing the standard-of-care guidelines for cancer care.Based on the current definition of clinical utility, most patients are denied testing for cancer-predisposing genes or pathogenic germline variants even though germline testing has been proven as highly accurate in identifying pathogenic germline variant carriers, there are measures recommended to prevent and diagnose early cancers associated with particular PGVs, and disparities in patient access to genetic tests are well described.Similarly, despite dozens of studies demonstrating that detected circulating tumor DNA (ctDNA) after curative intention therapy of different cancer types is a highly accurate biomarker that predicts recurrence, the major organizations that publish guidelines for cancer monitoring after curative intention therapy recommend against using ctDNA assays to detect minimal residual disease and thereby predict recurrence for all solid tumor malignancies.Here, the primary reasons that these genetic tests are considered to lack proven clinical utility and the primary evidence suggesting that a broader definition of clinical utility should be considered are discussed. By expanding the definition of clinical utility, many patients will benefit from the information gained from having these genetic tests.

Implementing precision medicine hinges on the integration of omics data, such as proteomics, into the clinical decision-making process, but the quantity and diversity of biomedical data, and the spread of clinically relevant knowledge across multiple biomedical databases and publications, pose a challenge to data integration. Here we present the Clinical Knowledge Graph (CKG), an open-source platform currently comprising close to 20 million nodes and 220 million relationships that represent relevant experimental data, public databases and literature. The graph structure provides a flexible data model that is easily extendable to new nodes and relationships as new databases become available. The CKG incorporates statistical and machine learning algorithms that accelerate the analysis and interpretation of typical proteomics workflows. Using a set of proof-of-concept biomarker studies, we show how the CKG might augment and enrich proteomics data and help inform clinical decision-making., (© 2022. The Author(s).)

Innovations in health care are growing exponentially, resulting in improved quality of and access to care, as well as rising societal costs of care and variable reimbursement. In recent years, digital health technologies and artificial intelligence have become of increasing interest in cardiovascular medicine owing to their unique ability to empower patients and to use increasing quantities of data for moving toward personalised and precision medicine. Health technology assessment agencies evaluate the money spent on a health care intervention or technology to attain a given clinical impact and make recommendations for reimbursement considerations. However, there is a scarcity of economic evaluations of cardiovascular digital health technologies and artificial intelligence. The current health technology assessment framework is not equipped to address the unique, dynamic, and unpredictable value considerations of these technologies and highlight the need to better approach the digital health technologies and artificial intelligence health technology assessment process. In this review, we compare digital health technologies and artificial intelligence with traditional health care technologies, review existing health technology assessment frameworks, and discuss challenges and opportunities related to cardiovascular digital health technologies and artificial intelligence health technology assessment. Specifically, we argue that health technology assessments for digital health technologies and artificial intelligence applications must allow for a much shorter device life cycle, given the rapid and even potentially continuously iterative nature of this technology, and thus an evidence base that maybe less mature, compared with traditional health technologies and interventions., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose: K-MASTER project is a Korean national precision medicine platform that screened actionable mutations by analyzing next-generation sequencing (NGS) of solid tumor patients. We compared gene analyses between NGS panel from the K-MASTER project and orthogonal methods., Materials and Methods: Colorectal, breast, non-small cell lung, and gastric cancer patients were included. We compared NGS results from K-MASTER projects with those of non-NGS orthogonal methods (KRAS, NRAS, and BRAF mutations in colorectal cancer [CRC]; epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] fusion, and reactive oxygen species 1 [ROS1] fusion in non-small cell lung cancer [NSCLC], and Erb-B2 receptor tyrosine kinase 2 (ERBB2) positivity in breast and gastric cancers)., Results: In the CRC cohort (n=225), the sensitivity and specificity of NGS were 87.4% and 79.3% (KRAS); 88.9% and 98.9% (NRAS); and 77.8% and 100.0% (BRAF), respectively. In the NSCLC cohort (n=109), the sensitivity and specificity of NGS for EGFR were 86.2% and 97.5%, respectively. The concordance rate for ALK fusion was 100%, but ROS1 fusion was positive in only one of three cases that were positive in orthogonal tests. In the breast cancer cohort (n=260), ERBB2 amplification was detected in 45 by NGS. Compared with orthogonal methods that integrated immunohistochemistry and in situ hybridization, sensitivity and specificity were 53.7% and 99.4%, respectively. In the gastric cancer cohort (n=64), ERBB2 amplification was detected in six by NGS. Compared with orthogonal methods, sensitivity and specificity were 62.5% and 98.2%, respectively., Conclusion: The results of the K-MASTER NGS panel and orthogonal methods showed a different degree of agreement for each genetic alteration, but generally showed a high agreement rate.

Background/aim: The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options. The aim of this study was to present data that demonstrate the different levels of actionability for multi-gene panels used in genetic testing of breast cancer patients and their family members., Materials and Methods: We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing. We reviewed positive results in respect of risk estimation and management, cascade family testing, secondary findings and information for treatment decision-making., Results: A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high, moderate, low and with insufficient evidence for breast cancer risk genes, respectively. Six point seven percent of individuals were double heterozygotes., Conclusion: Germline findings in 92% of individuals are linked to evidence-based treatment information and risk estimates for predisposition to breast and/or other cancer types. The use of germline findings for treatment decision making expands the indication of genetic testing to include individuals that could benefit from targeted treatments., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks., Materials and Methods: Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation., Results: One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events., Conclusion: A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition., Competing Interests: Alanna J. Church Honoraria: The Jackson Laboratory Consulting or Advisory Role: AlphaSights, The Jackson Laboratory, Bayer Travel, Accommodations, Expenses: Bayer Laura B. Corson Employment: Sema4 Stock and Other Ownership Interests: Alnylam, Inovio Pharmaceuticals, Agios Consulting or Advisory Role: Biomatics Patents, Royalties, Other Intellectual Property: Patent from work done at H3 Biomedicine before 2016 Brennan Decker Employment: Foundation Medicine Stock and Other Ownership Interests: Avidea Technologies, Roche Consulting or Advisory Role: Foundation Medicine, Avidea Technologies Catherine M. Clinton Employment: Helix OpCo LLC Mark A. Applebaum Consulting or Advisory Role: Fennec Pharma Rochelle Bagatell Uncompensated Relationships: Ymabs Therapeutics Inc Steven G. DuBois Consulting or Advisory Role: Bayer, Amgen Research Funding: Merck (Inst), Roche/Genentech (Inst), Lilly (Inst), Curis (Inst), Loxo (Inst), BMS (Inst), Eisai (Inst), Pfizer (Inst), Turning Point Therapeutics (Inst), Bayer (Inst), Salarius Pharmaceuticals (Inst) Travel, Accommodations, Expenses: Roche/Genentech, Salarius Pharmaceuticals Uncompensated Relationships: Ymabs Therapeutics Inc Julia L. Glade-Bender Research Funding: Eisai (Inst), Lilly (Inst), Loxo (Inst), Roche/Genentech (Inst), Bayer (Inst) Patents, Royalties, Other Intellectual Property: Patent on a T lympboblastic lymphoma cell line, CUTLL1 Travel, Accommodations, Expenses: Amgen (Inst) Uncompensated Relationships: SpringWorks Therapeutics, Bristol Myers Squibb, Merck, Eisai Open Payments Link: https://openpaymentsdata.cms.gov/physician/708514 AeRang Kim Research Funding: Esai (Inst); AstraZeneca (Inst); Oncternal (Inst); Ascentage (Inst); BioAlta (Inst). Theodore W. Laetsch Consulting or Advisory Role: Novartis, Bayer, Cellectis, Aptitude Health, Clinical Education Alliance, Deciphera, Jumo Health, Massive Bio, Med Learning Group, Medscape, Physicans' Education Resource, Y-mAbs Therapeutics Research Funding: Pfizer (Inst), Novartis (Inst), Bayer (Inst), AbbVie (Inst), Amgen (Inst), Atara Biotherapeutics (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Epizyme (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Jubilant Pharmaceuticals (Inst), Novella Clinical (Inst), Servier (Inst), Foundation Medicine (Inst), Merck Sharp & Dohme (Inst) Margaret E. Macy Stock and Other Ownership Interests: Johnson & Johnson, GE Healthcare, Varian Medical Systems Consulting or Advisory Role: Ymabs Therapeutics Inc Research Funding: Bayer (Inst), Ignyta (Inst), Roche (Inst), Lilly (Inst), Merck (Inst), Oncternal Therapeutics Inc (Inst), AbbVie (Inst), Jubilant DraxImage (Inst), Actuate Therapeutics (Inst) Patents, Royalties, Other Intellectual Property: Patent for non-invasive methods of leukemia cell detection with MRI/MRS—Patent No. 8894975 Luke Maese Honoraria: Jazz Pharmaceuticals Consulting or Advisory Role: Jazz Pharmaceuticals Amit J. Sabnis Consulting or Advisory Role: Cardinal Health Joshua D. Schiffman Employment: PEEL Therapeutics Leadership: PEEL Therapeutics Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics Honoraria: Affymetrix Consulting or Advisory Role: N-of-One, Fabric Genomics Samuel L. Volchenboum Stock and Other Ownership Interests: Litmus Health Consulting or Advisory Role: Accordant Travel, Accommodations, Expenses: Sanford Health Daniel A. Weiser Consulting or Advisory Role: Illumina Radiopharmaceuticals Jonathan A. Nowak Research Funding: NanoString Technologies, Illumina Katherine A. Janeway Honoraria: Foundation Medicine, Takeda Consulting or Advisory Role: Bayer, Ipsen Travel, Accommodations, Expenses: Bayer Brian D. Crompton Employment: Acceleron Pharma (I) Stock and Other Ownership Interests: Acceleron Pharma (I) Research Funding: Gradalis Junne Kamihara Stock and Other Ownership Interests: PanTher Therapeutics (I), ROME Therapeutics (I), TellBio (I) Honoraria: Pfizer (I), NanoString Technologies (I), Foundation Medicine (I), Ikena Oncology (I) Consulting or Advisory Role: ROME Therapeutics (I), Third Rock Ventures (I), Tekla Capital Management (I) Research Funding: PureTech (I), Ribon Therapeutics (I), ACD Biotechne (I) Patents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics (I), Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics (I), Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc (I) No other potential conflicts of interest were reported. Alanna J. Church Honoraria: The Jackson Laboratory Consulting or Advisory Role: AlphaSights, The Jackson Laboratory, Bayer Travel, Accommodations, Expenses: Bayer Laura B. Corson Employment: Sema4 Stock and Other Ownership Interests: Alnylam, Inovio Pharmaceuticals, Agios Consulting or Advisory Role: Biomatics Patents, Royalties, Other Intellectual Property: Patent from work done at H3 Biomedicine before 2016 Brennan Decker Employment: Foundation Medicine Stock and Other Ownership Interests: Avidea Technologies, Roche Consulting or Advisory Role: Foundation Medicine, Avidea Technologies Catherine M. Clinton Employment: Helix OpCo LLC Mark A. Applebaum Consulting or Advisory Role: Fennec Pharma Rochelle Bagatell Uncompensated Relationships: Ymabs Therapeutics Inc Steven G. DuBois Consulting or Advisory Role: Bayer, Amgen Research Funding: Merck (Inst), Roche/Genentech (Inst), Lilly (Inst), Curis (Inst), Loxo (Inst), BMS (Inst), Eisai (Inst), Pfizer (Inst), Turning Point Therapeutics (Inst), Bayer (Inst), Salarius Pharmaceuticals (Inst) Travel, Accommodations, Expenses: Roche/Genentech, Salarius Pharmaceuticals Uncompensated Relationships: Ymabs Therapeutics Inc Julia L. Glade-Bender Research Funding: Eisai (Inst), Lilly (Inst), Loxo (Inst), Roche/Genentech (Inst), Bayer (Inst) Patents, Royalties, Other Intellectual Property: Patent on a T lympboblastic lymphoma cell line, CUTLL1 Travel, Accommodations, Expenses: Amgen (Inst) Uncompensated Relationships: SpringWorks Therapeutics, Bristol Myers Squibb, Merck, Eisai Open Payments Link: https://openpaymentsdata.cms.gov/physician/708514 AeRang Kim Research Funding: Esai (Inst); AstraZeneca (Inst); Oncternal (Inst); Ascentage (Inst); BioAlta (Inst). Theodore W. Laetsch Consulting or Advisory Role: Novartis, Bayer, Cellectis, Aptitude Health, Clinical Education Alliance, Deciphera, Jumo Health, Massive Bio, Med Learning Group, Medscape, Physicans' Education Resource, Y-mAbs Therapeutics Research Funding: Pfizer (Inst), Novartis (Inst), Bayer (Inst), AbbVie (Inst), Amgen (Inst), Atara Biotherapeutics (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Epizyme (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Jubilant Pharmaceuticals (Inst), Novella Clinical (Inst), Servier (Inst), Foundation Medicine (Inst), Merck Sharp & Dohme (Inst) Margaret E. Macy Stock and Other Ownership Interests: Johnson & Johnson, GE Healthcare, Varian Medical Systems Consulting or Advisory Role: Ymabs Therapeutics Inc Research Funding: Bayer (Inst), Ignyta (Inst), Roche (Inst), Lilly (Inst), Merck (Inst), Oncternal Therapeutics Inc (Inst), AbbVie (Inst), Jubilant DraxImage (Inst), Actuate Therapeutics (Inst) Patents, Royalties, Other Intellectual Property: Patent for non-invasive methods of leukemia cell detection with MRI/MRS—Patent No. 8894975 Luke Maese Honoraria: Jazz Pharmaceuticals Consulting or Advisory Role: Jazz Pharmaceuticals Amit J. Sabnis Consulting or Advisory Role: Cardinal Health Joshua D. Schiffman Employment: PEEL Therapeutics Leadership: PEEL Therapeutics Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics Honoraria: Affymetrix Consulting or Advisory Role: N-of-One, Fabric Genomics Samuel L. Volchenboum Stock and Other Ownership Interests: Litmus Health Consulting or Advisory Role: Accordant Travel, Accommodations, Expenses: Sanford Health Daniel A. Weiser Consulting or Advisory Role: Illumina Radiopharmaceuticals Jonathan A. Nowak Research Funding: NanoString Technologies, Illumina Katherine A. Janeway Honoraria: Foundation Medicine, Takeda Consulting or Advisory Role: Bayer, Ipsen Travel, Accommodations, Expenses: Bayer Brian D. Crompton Employment: Acceleron Pharma (I) Stock and Other Ownership Interests: Acceleron Pharma (I) Research Funding: Gradalis Junne Kamihara Stock and Other Ownership Interests: PanTher Therapeutics (I), ROME Therapeutics (I), TellBio (I) Honoraria: Pfizer (I), NanoString Technologies (I), Foundation Medicine (I), Ikena Oncology (I) Consulting or Advisory Role: ROME Therapeutics (I), Third Rock Ventures (I), Tekla Capital Management (I) Research Funding: PureTech (I), Ribon Therapeutics (I), ACD Biotechne (I) Patents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics (I), Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics (I), Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc (I) No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumor types, being the sixth leading cause of mortality worldwide and the fourth in Europe. Globally, it has a mortality/incidence ratio of 98%, and the 5‑year survival rate in Europe is only 3%. Although risk factors, such as obesity, diabetes mellitus, smoking, alcohol consumption and genetic factors, have been identified, the causes of PDAC remain elusive. Additionally, the only curative treatment for PDAC is surgery with negative margins. However, upon diagnosis, ~30% of the patients already present with locally advanced disease. In these cases, a multidisciplinary approach is required to improve disease‑related symptoms and prolong patient survival. In the present article, a comprehensive review of PDAC epidemiology, physiology and treatment is provided. Moreover, guidelines on patient treatment are suggested. Among the different available therapeutic options for the treatment of advanced PDAC, results are modest, most likely due to the complexity of the disease, and so the prognostic remains poor. Molecular approaches based on multi‑omics research are promising and will contribute to groundbreaking personalized medicine. Thus, economic investment that promotes research of pancreatic cancer will be critical to the development of more efficient diagnostic and treatment strategies.

Rationale: No evidence-based tools exist to enhance precision in the selection of patient-specific optimal treatment durations to study in tuberculosis clinical trials. Objectives: To develop risk stratification tools that assign patients with tuberculosis into risk groups of unfavorable outcome and inform selection of optimal treatment duration for each patient strata to study in clinical trials. Methods: Publicly available data from four phase 3 trials, each evaluating treatment duration shortening from 6 to 4 months, were used to develop parametric time-to-event models that describe unfavorable outcomes. Regimen, baseline, and on-treatment characteristics were evaluated as predictors of outcomes. Exact regression coefficients of predictors were used to assign risk groups and predict optimal treatment durations. Measurements and Main Results: The parametric model had an area under the receiver operating characteristic curve of 0.72. A six-item risk score (HIV status, smear grade, sex, cavitary disease status, body mass index, and Month 2 culture status) successfully grouped participants into low (1,060/3,791; 28%), moderate (1,740/3,791; 46%), and high (991/3,791; 26%) risk, requiring treatment durations of 4, 6, and greater than 6 months, respectively, to reach a target cure rate of 93% when receiving standard-dose rifamycin-containing regimens. With current one-duration-fits-all approaches, high-risk groups have a 3.7-fold (95% confidence interval, 2.7-5.1) and 2.4-fold (1.9-2.9) higher hazard risk of unfavorable outcomes compared with low- and moderate-risk groups, respectively. Four-month regimens were noninferior to the standard 6-month regimen in the low-risk group. Conclusions: Our model discrimination was modest but consistent with current models of unfavorable outcomes. Our results showed that stratified medicine approaches are feasible and may achieve high cure rates in all patients with tuberculosis. An interactive risk stratification tool is provided to facilitate decision-making in the regimen development pathway.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare EP was supported by a career development grant K08AG055670 from the National Institute on Aging and is investigator of an investigator initiated grant to the Brigham and Women’s Hospital from Boehringer Ingelheim, not related to the topic of the submitted work.

Background: The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC)., Research Question: How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC?, Methods: We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution., Results: A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples., Interpretation: Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing, and to determine a minimal set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations on a minimal panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories in designing assays for PGx testing. When developing these recommendations, the Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations with regard to PGx testing. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document is focused on clinical CYP2D6 PGx testing that may be applied to all cytochrome P450 2D6-metabolized medications. These recommendations are not meant to be interpreted as prescriptive but to provide a reference guide for clinical laboratories that may be either implementing PGx testing or reviewing and updating their existing platform., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Clinical annotations are one of the most popular resources available on the Pharmacogenomics Knowledgebase (PharmGKB). Each clinical annotation summarizes the association between variant-drug pairs, shows relevant findings from the curated literature, and is assigned a level of evidence (LOE) to indicate the strength of support for that association. Evidence from the pharmacogenomic literature is curated into PharmGKB as variant annotations, which can be used to create new clinical annotations or added to existing clinical annotations. This means that the same clinical annotation can be worked on by multiple curators over time. As more evidence is curated into PharmGKB, the task of maintaining consistency when assessing all the available evidence and assigning an LOE becomes increasingly difficult. To remedy this, a scoring system has been developed to automate LOE assignment to clinical annotations. Variant annotations are scored according to certain attributes, including study size, reported P value, and whether the variant annotation supports or fails to find an association. Clinical guidelines or US Food and Drug Administration (FDA)-approved drug labels which give variant-specific prescribing guidance are also scored. The scores of all annotations attached to a clinical annotation are summed together to give a total score for the clinical annotation, which is used to calculate an LOE. Overall, the system increases transparency, consistency, and reproducibility in LOE assignment to clinical annotations. In combination with increased standardization of how clinical annotations are written, use of this scoring system helps to ensure that PharmGKB clinical annotations continue to be a robust source of pharmacogenomic information., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The term "biobanking" is often misapplied to any collection of human biological materials (biospecimens) regardless of requirements related to ethical and legal issues or the standardization of different processes involved in tissue collection. A proper definition of biobanks is large collections of biospecimens linked to relevant personal and health information (health records, family history, lifestyle, genetic information) that are held predominantly for use in health and medical research. In addition, the International Organization for Standardization, in illustrating the requirements for biobanking (ISO 20387:2018), stresses the concept of biobanks being legal entities driving the process of acquisition and storage together with some or all of the activities related to collection, preparation, preservation, testing, analysing and distributing defined biological material as well as related information and data. In this review article, we aim to discuss the basic principles of biobanking, spanning from definitions to classification systems, standardization processes and documents, sustainability and ethical and legal requirements. We also deal with emerging specimens that are currently being generated and shaping the so-called next-generation biobanking, and we provide pragmatic examples of cancer-associated biobanking by discussing the process behind the construction of a biobank and the infrastructures supporting the implementation of biobanking in scientific research., (© 2021. The Author(s).)

Background: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples., Methods: Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed., Results: Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients., Conclusions: This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine., (© 2021. The Author(s).)

Given the expansion of genetics in medicine, there is a growing need to develop approaches to engage patients in understanding how genetics affects their health. Various qualitative methods have been applied to gain a deeper understanding of patient perspectives in topics related to genetics. Community dialogues (CD) are a bi-directional research method that invites community members to discuss a pertinent, challenging topic over the course of a multi-week period and the community members openly discuss their positions on the topic. Authors discuss the first application of the CD method to the topic of pharmacogenetics testing. Additional CD are needed to engage diverse participant populations on this topic to improve genetics literacy, enhance physician engagement and drive policy change.

Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

The primary goal of precision medicine is to maximize the benefit-risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene-drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA-PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug-metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Precision dosing is progressing beyond the conceptual and proof-of-concept stages toward implementation. As the availability of dosing algorithms, tools, and platforms increases, so do the investment in technology services and actual implementation of clinical services offering these solutions to patients. Nowhere is this needed more than in pediatric populations, which are still reliant on adult drug development and bridging strategies to support dosing, often in the absence of actual dose-finding studies in the target pediatric population. Still, there is more work to be done to ensure that proper governance of these services is maintained, and that sustainability of these early implementations is guided by new science as it evolves and meaningful outcome data to confirm that such services deliver on both clinical and economic return on investment. In addition, the field should ensure that all approaches beyond a therapeutic drug monitoring-driven, pharmacokinetic-centric approach should be considered as the tools and services evolve, especially when pediatric-specific pharmacokinetic/pharmacodyamic and pharmacogenetic data are available and shown to be useful to guide dosing. This review evaluates current pediatric precision dosing efforts, highlighting their utility, longevity, and sustainability and assesses the current process for implementing such approaches examining current barriers that stand in the way of broader implementation and the stakeholders that must engage to ensure its ultimate success., (© 2021, The American College of Clinical Pharmacology.)

With limited access to trained clinical geneticists and/or genetic counselors in the majority of healthcare systems globally, and the expanding use of genetic testing in all specialties of medicine, many healthcare providers do not receive the relevant support to order the most appropriate genetic test for their patients. Therefore, it is essential to educate all healthcare providers about the basic concepts of genetic testing and how to properly utilize this testing for each patient. Here, we review the various genetic testing strategies and their utilization based on different clinical scenarios, and test characteristics, such as the types of genetic variation identified by each test, turnaround time, and diagnostic yield for different clinical indications. Additional considerations such as test cost, insurance reimbursement, and interpretation of variants of uncertain significance are also discussed. The goal of this review is to aid healthcare providers in utilizing the most appropriate, fastest, and most cost-effective genetic test for their patients, thereby increasing the likelihood of a timely diagnosis and reducing the financial burden on the healthcare system by eliminating unnecessary and redundant testing.

Genetic maps have been fundamental to building our understanding of disease genetics and evolutionary processes. The gametes of an individual contain all of the information required to perform a de novo chromosome-scale assembly of an individual's genome, which historically has been performed with populations and pedigrees. Here, we discuss how single-cell gamete sequencing offers the potential to merge the advantages of short-read sequencing with the ability to build personalized genetic maps and open up an entirely new space in personalized genetics.

Adoptive cell therapy (ACT) with tumor-infiltrating T cells (TILs) has emerged as a promising therapy for the treatment of unresectable or metastatic solid tumors. One challenge to finding a universal anticancer treatment is the heterogeneity present between different tumors as a result of genetic instability associated with tumorigenesis. As the epitome of personalized medicine, TIL-ACT bypasses the issue of intertumoral heterogeneity by utilizing the patient's existing antitumor immune response. Despite being one of the few therapies capable of inducing durable, complete tumor regression, many patients fail to respond. Recent research has focused on increasing therapeutic efficacy by refining various aspects of the TIL protocol, which includes the isolation, ex vivo expansion, and subsequent infusion of tumor specific lymphocytes. This review will explore how the therapy has evolved with time by highlighting various resistance mechanisms to TIL therapy and the novel strategies to overcome them.

OBJECTIVE. The purpose of this article is to familiarize radiologists with the evidence-based imaging guidelines of major oncologic societies and organizations and to discuss approaches to effective implementation of the most recent guidelines in daily radiology practice. CONCLUSION. In an era of precision oncology, radiologists in practice and radiologists in training are key stakeholders in multidisciplinary care, and their awareness and understanding of society guidelines is critically important.

Precision or personalized medicine is currently gaining a lot of attention. Clinical evidence for its effectiveness has been established based on randomized clinical trials accounting for classical risk factors, such as hypertension, diabetes, and serum lipids. However, besides such classical risk factors, the genetic background should be considered, at least for heritable traits, including atherosclerotic cardiovascular disease (ASCVD). Such classical risk factors are almost always incidents that have already occurred in which it may be too late to start treatment, instead of indicators of presymptomatic state. Human genome information is associated with most traits, including ASCVD. Two methods of implementing precision medicine for ASCVD using human genome information are currently being investigated: the use of rare genetic variations that have large effect sizes and polygenic risk scores that are composed of multiple common genetic variations. This review article emphasizes the importance of clinical as well as genetic diagnoses when implementing precision medicine. Precision medicine should be considered based on comprehensive genetic analyses, encompassing rare to common genetic variations.

The POSEIDON ( P atient- O riented S trategies E ncompassing I ndividualize D O ocyte N umber) criteria were developed to help clinicians identify and classify low-prognosis patients undergoing assisted reproductive technology (ART) and provide guidance for possible therapeutic strategies to overcome infertility. Since its introduction, the number of published studies using the POSEIDON criteria has increased steadily. However, a critical analysis of existing evidence indicates inconsistent and incomplete reporting of critical outcomes. Therefore, we developed guidelines to help researchers improve the quality of reporting in studies applying the POSEIDON criteria. We also discuss the advantages of using the POSEIDON criteria in ART clinical studies and elaborate on possible study designs and critical endpoints. Our ultimate goal is to advance the knowledge concerning the clinical use of the POSEIDON criteria to patients, clinicians, and the infertility community., Competing Interests: SE and CA declare receipt of unrestricted research grants from Merck and lecture fees from Merck. SS declares the receipt of honorarium for lectures from Merck, MSD, and Ferring. PH has received unrestricted research grants from MSD, Merck, and Ferring as well as honoraria for lectures from MSD, Merck, Gedeon–Richter, Theramex, and IBSA. CYA has received unrestricted grants from Gedeon-Richter and honoraria for lectures from IBSA, Ferring, and Merck. FU and AV have received honoraria for lectures from MSD and Merck. The funders listed above had no involvement with the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Esteves, Conforti, Sunkara, Carbone, Picarelli, Vaiarelli, Cimadomo, Rienzi, Ubaldi, Zullo, Andersen, Orvieto, Humaidan and Alviggi.)

Decades of research have produced extensive evidence of the contribution of genetic factors to the efficacy and toxicity of antipsychotics. Numerous genetic variants in genes controlling drug availability or involved in antipsychotic processes have been linked to treatment variability. The complex mechanism of action and multitarget profile of most antipsychotic drugs hinder the identification of pharmacogenetic markers of clinical value. Nevertheless, the validity of associations between variants in CYP1A2, CYP2D6, CYP2C19, ABCB1, DRD2, DRD3, HTR2A, HTR2C, BDNF, COMT, MC4R genes and antipsychotic response has been confirmed in independent candidate gene studies. Genome wide pharmacogenomic studies have proven the role of the glutamatergic pathway in mediating antipsychotic activity and have reported novel associations with antipsychotic response. However, only a limited number of the findings, mainly functional variants of CYP metabolic enzymes, have been shown to be of clinical utility and translated into useful pharmacogenetic markers. Based on the currently available information, actionable pharmacogenetics should be reduced to antipsychotics' dose adjustment according to the genetically predicted metabolic status (CYPs' profile) of the patient. Growing evidence suggests that such interventions will reduce antipsychotics' side-effects and increase treatment safety. Despite this evidence, the use of pharmacogenetics in psychiatric wards is minimal. Hopefully, further evidence on the clinical and economic benefits, the development of clinical protocols based on pharmacogenetic information, and improved and cheaper genetic testing will increase the implementation of pharmacogenetic guided prescription in clinical settings., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Despite numerous clinical series, consistent karyotype-phenotype correlations for Turner syndrome have not been established, although a lower level of 45,X is generally thought to be associated with a milder phenotype. This limits personalized counseling for women with 45,X/46,XX mosaicism. To better understand the phenotypic spectrum associated with various levels of 45,X/46,XX mosaicism, we compared patients evaluated in the Massachusetts General Hospital Turner Syndrome Clinic to determine if cardiac, renal, and thyroid abnormalities correlated with the percentage of 45,X cells present in a peripheral blood karyotype. of the 118 patients included in the study, 78 (66%) patients had non-mosaic 45,X and 40 (34%) patients had varying levels of 45,X/46,XX mosaicism. Patients with ≤70% 45,X compared with those with >70% 45,X had a significantly lower frequency of cardiac and renal anomalies. The presence of hypothyroidism was somewhat lower for the ≤70% 45,X group, but was not statistically significant. Supplemental tissue testing on another tissue type, typically buccal mucosa, was often useful in counseling patients with 45,X mosaicism. Given the modest sample size of patients with varying levels of mosaicism and the variability of Turner syndrome abnormalities, we hope this preliminary study will inspire a multicenter collaboration, which may lead to modification of clinical guidelines. Because several patients with ≤70% 45,X were ascertained from perinatal care referrals, we still advise women with 45,X mosaicism pursuing pregnancy to receive standard Turner syndrome cardiac surveillance. There is an opportunity to personalize counseling and surveillance for patients based on percentage of 45,X cells on chromosome analysis., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Rising trends in the incidence and mortality of early-onset colorectal cancer (CRC) in those who are younger than 50 years have been well established. These trends have spurred intense investigation focused on elucidating the epidemiology and characteristics of early-onset CRC, as well as on identifying strategies for early detection and prevention. In this review, we provide a contemporary update on early-onset CRC with a particular focus on epidemiology, molecular characterization, red flag signs and symptoms, and screening for early-onset CRC., (Copyright © 2021 AGA Institute. All rights reserved.)

The treatment of depression represents a major challenge for healthcare systems and choosing among the many available drugs without objective guidance criteria is an error-prone process. Recently, pharmacogenetic biomarkers entered in prescribing guidelines, giving clinicians the possibility to use this additional tool to guide prescription and improve therapeutic outcomes. This marked an important step towards precision psychiatry, which aim is to integrate biological and environmental information to personalise treatments. Only genetic variants in cytochrome enzymes are endorsed by prescribing guidelines, but in the future polygenic predictors of treatment outcomes may be translated into the clinic. The integration of genetics with other relevant information (e.g., concomitant diseases and treatments, drug plasma levels) could be managed in a standardised way through ad hoc software. The overcoming of the current obstacles (e.g., staff training, genotyping and informatics facilities) can lead to a broad implementation of precision psychiatry and represent a revolution for psychiatric care.Key pointsPrecision psychiatry aims to integrate biological and environmental information to personalise treatments and complement clinical judgementPharmacogenetic biomarkers in cytochrome genes were included in prescribing guidelines and represented an important step towards precision psychiatryTherapeutic drug monitoring is an important and cost-effective tool which should be integrated with genetic testing and clinical evaluation in order to optimise pharmacotherapyOther individual factors relevant to pharmacotherapy response (e.g., individual's symptom profile, concomitant diseases) can be integrated with genetic information through artificial intelligence to provide treatment recommendationsThe creation of pharmacogenetic services within healthcare systems is a challenging and multi-step process, education of health professionals, promotion by institutions and regulatory bodies, economic and ethical barriers are the main issues.

Opinion Statement: Gastrointestinal stromal tumor (GIST) constitutes a paradigm for clinically effective targeted inhibition of oncogenic driver mutations. Therefore, GIST has emerged as a compelling clinical and biological model to study oncogene addiction and to validate preclinical concepts for drug response and drug resistance. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the essential drivers of GIST progression throughout all stages of the disease. Interestingly, KIT/PDGFRA genotype predicts the response to first-line imatinib and to all tyrosine kinase inhibitors (TKIs) approved or in investigation after imatinib failure. Considering that TKIs are effective only against a subset of KIT or PDGFRA resistance mutations, close monitoring of tumor dynamics with non-invasive methods such as liquid biopsy emerges as a necessary step forward in the field. Liquid biopsy, in contrast to solid tumor biopsy, aims to characterize tumors irrespective of heterogeneity. Although there are several components in the peripheral blood, most recent studies have been focused on circulating tumor (ct)DNA, due to the technological feasibility, the stability of DNA itself and DNA alterations, and the therapeutic development in precision oncology largely based on the identification of genetic driver mutations. In the present review, we systematically dissect the current wealth of data of ctDNA in GIST. To do so, a critical understanding of the promises and limitations of the current technologies will be followed by an exposition of the knowledge gathered with such studies in GIST. Collectively, our goal is to establish clear premises that can be used as the foundations to build future studies towards the clinical implementation of ctDNA evaluation in GIST patients.

Since the introduction of sensitive assays for serum thyroid-stimulating hormone (TSH) clinicians have advised hypothyroid patients to adjust the dose of levothyroxine (L-T4) in order to achieve a normal serum TSH. A minority of patients are dissatisfied with this treatment strategy and experience symptoms. Some indirect evidence suggests that a normal serum TSH may not necessarily reflect euthyroidism at the tissue level in patients treated with L-T4. Increasingly hypothyroid patients demand higher doses of L-T4 or liothyronine (L-T3) or animal thyroid extract, often purchased online, and titrate the dose against symptoms, although ample evidence suggests that combination treatment (L-T4 with L-T3) is no more effective than L-T4 alone. Community surveys show that up to 53% of treated hypothyroid patients at any time have a serum TSH outside the normal range. The recommendation by guidelines that the upper limit of the normal range for serum TSH should not be exceeded is supported by robust evidence and is generally accepted by clinicians and patients. However, until recently the lower limit of serum TSH for optimal L-T4 replacement has been controversial. New evidence obtained by two independent large population studies over the past two years has shown that mortality of hypothyroid patients treated with levothyroxine is increased when the serum TSH exceeds or is reduced outside the normal reference range. It is estimated that the implementation of a policy of normalising serum TSH in hypothyroid patients will reduce the risk of death of 28.3 million people in the USA and Europe alone.

The accessibility of pharmacogenomic (PGx) testing has grown substantially over the last decade and with it has arisen a demand for patients to be counseled on the use of these tests. While guidelines exist for the use of PGx results; objective determinants for who should receive PGx testing remain incomplete. PGx clinical services have been created to meet these screening and education needs and significant variability exists between these programs. This article describes the practices of four PGx clinics during pretest counseling sessions. A description of the major tenets of the benefits, limitations and risks of testing are compiled. Additional tools are provided to serve as a foundation for those wishing to begin or expand their own counseling service.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes) 1 . In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Background: The concept of personalized medicine has received widespread attention in the last decade. However, personalized medicine depends on correct diagnosis and monitoring of patients, for which personalized reference intervals for laboratory tests may be beneficial. In this study, we propose a simple model to generate personalized reference intervals based on historical, previously analyzed results, and data on analytical and within-subject biological variation., Methods: A model using estimates of analytical and within-subject biological variation and previous test results was developed. We modeled the effect of adding an increasing number of measurement results on the estimation of the personal reference interval. We then used laboratory test results from 784 adult patients (>18 years) considered to be in a steady-state condition to calculate personalized reference intervals for 27 commonly requested clinical chemistry and hematology measurands., Results: Increasing the number of measurements had little impact on the total variation around the true homeostatic set point and using ≥3 previous measurement results delivered robust personalized reference intervals. The personalized reference intervals of the study participants were different from one another and, as expected, located within the common reference interval. However, in general they made up only a small proportion of the population-based reference interval., Conclusions: Our study shows that, if using results from patients in steady state, only a few previous test results and reliable estimates of within-subject biological variation are required to calculate personalized reference intervals. This may be highly valuable for diagnosing patients as well as for follow-up and treatment., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)