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* Context.--Rapid advancements in the understanding and manipulation of tumor-immune interactions have led to the approval of immune therapies for patients with non-small cell lung cancer. Certain immune checkpoint inhibitor therapies require the use of companion diagnostics, but methodologic variability has led to uncertainty around test selection and implementation in practice. Objective.--To develop evidence-based guideline recommendations for the testing of immunotherapy/immunomodulatory biomarkers, including programmed death ligand-1 (PD-L1) and tumor mutation burden (TMB), in patients with lung cancer. Design.--The College of American Pathologists convened a panel of experts in non-small cell lung cancer and biomarker testing to develop evidence-based recommendations in accordance with the standards for trustworthy clinical practice guidelines established by the National Academy of Medicine. A systematic literature review was conducted to address 8 key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were created from the available evidence, certainty of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework. Results.--Six recommendation statements were developed. Conclusions.--This guideline summarizes the current understanding and hurdles associated with the use of PD-L1 expression and TMB testing for immune checkpoint inhibitor therapy selection in patients with advanced non-small cell lung cancer and presents evidence-based recommendations for PD-L1 and tMb testing in the clinical setting. doi: 10.5858/arpa.2023-0536-CP), The advent of immune modulatory therapy has led to a radical shift in the treatment paradigm for patients with a wide range of cancers. The clinical impact of these therapies, [...]

Immune checkpoint therapies have been shown in numerous clinical trials to have significant clinical benefits for lung cancer patients, and there are increasing numbers of indications and therapies available. (1-13) [...]

Background Establishing a molecular genetic diagnosis of focal segmental glomerulosclerosis (FSGS)/steroid-resistant nephrotic syndrome (SRNS) can be useful for predicting post-transplant recurrence. Monogenic causes are reportedly present in approximately 20-30% of patients with FSGS/SRNS. However, the characteristics of patients who are likely to have a monogenic cause remain to be determined. Methods Pediatric recipients with SRNS and/or biopsy-proven FSGS who underwent their first kidney transplantation at our center between 1999 and 2019 were analyzed. Patients with secondary FSGS/SRNS were excluded. The recipients were divided into three groups: familial/syndromic, presumed primary, and undetermined FSGS/SRNS. Patients who met all of the following criteria were categorized as having presumed primary FSGS/SRNS: (i) nephrotic syndrome, (ii) complete or partial remission with initial steroid therapy and/or additional immunosuppressive therapies, and (iii) diffuse foot process effacement on electron microscopy in the native kidney biopsy. All patients underwent genetic testing using next-generation sequencing. Results Twenty-four patients from 23 families were analyzed in this study. Pathogenic or likely pathogenic variants in FSGS/SRNS-related genes were identified in four of four families, zero of eight families, and 10 of 11 families with familial/syndromic, presumed primary, and undetermined FSGS/SRNS, respectively. Post-transplant recurrence only occurred in patients with presumed primary FSGS/SRNS. Conclusions Our systematic approach based on precise clinicopathological findings including nephrotic syndrome, treatment responses, and diffuse foot process effacement might be useful to differentiate pediatric kidney transplant recipients with FSGS/SRNS who are likely to have a monogenic cause from patients who are not, and to predict post-transplant recurrence. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information., Author(s): Kenichiro Miura [sup.1] , Naoto Kaneko [sup.1] , Taeko Hashimoto [sup.1] [sup.2] , Kiyonobu Ishizuka [sup.1] , Yoko Shirai [sup.1] , Masataka Hisano [sup.3] , Hiroko Chikamoto [sup.1] , [...]

Author(s): Benjamin Steinman [sup.1] , Marcela Del Rio [sup.1] , Anna Zolotnitskaya [sup.1] , Nicole Hayde [sup.1] Author Affiliations: (1) grid.414114.5, 0000 0004 0566 7955, Division of Pediatric Nephrology, Children's [...]

Our institution developed and continuously improved a Neurodevelopmental Reflex (NDR) algorithm to help physicians with genetic test ordering for neurodevelopmental disorders (NDDs). To assess its performance, we performed a retrospective study of 511 patients tested through NDR from 2018 to 2019. SNP Microarray identified pathogenic/likely pathogenic copy number variations in 27/511 cases (5.28%). Among the 484 patients tested for Fragile X FMR1 CGG repeats, a diagnosis (0.20%) was established for one male mosaic for a full mutation, a premutation, and a one-CGG allele. Within the 101 normocephalic female patients tested for MECP2, two patients were found to carry pathogenic variants (1.98%). This retrospective study suggested the NDR algorithm effectively established diagnoses for patients with NDDs with a yield of 5.87%., Author(s): Xiaoli Du [sup.1] , Jennifer Elaine Glass [sup.1] , Stephanie Balow [sup.1] [sup.2] , Lisa M. Dyer [sup.1] [sup.2] , Pamela A. Rathbun [sup.1] [sup.3] , Qiaoning Guan [sup.1] [...]

Alport syndrome spectrum can be considered as a group of genetic diseases affecting the major basement membrane collagen type IV network in various organs including the ear, eye, and kidney. The living donor candidate evaluation is an ever-changing landscape. Recently, next-generation sequence (NGS) panels have become readily available and provide opportunities to genetically screen recipient and donor candidates for collagen network gene variants. In this review, our aim is to provide a comprehensive update on the role of genetic testing for the evaluation of potential living kidney donors to kidney candidates with Alport syndrome spectrum. We examine the utility of genetic testing in the evaluation of potential donors for recipients with Alport syndrome spectrum, and discuss risks and unresolved challenges. Suggested algorithms in the context of related and unrelated donation are offered. In contemporary practice, an approach to the evaluation of living donor candidates for transplant candidates with Alport syndrome spectrum can incorporate genetic testing in algorithms tailored for donor-recipient relationship status. Ongoing research is needed to inform optimal practice., Author(s): Yasar Caliskan [sup.1] , Krista L. Lentine [sup.1] Author Affiliations: (1) grid.262962.b, 0000 0004 1936 9342, Saint Louis University Center for Abdominal Transplantation, , 1201 S. Grand Blvd, 63110, [...]

Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E is caused by mutations in [beta]-sarcoglycan (SGCB). Together, [beta]-, [alpha]-, [gamma]-, and [delta]-sarcoglycan form a 4-protein transmembrane complex (SGC) that localizes to the sarcolemma. Biallelic loss-of-function mutations in any subunit can lead to LGMD. To provide functional evidence for the pathogenicity of missense variants, we performed deep mutational scanning of SGCB and assessed SGC cell surface localization for all 6,340 possible amino acid changes. Variant functional scores were bimodally distributed and perfectly predicted pathogenicity of known variants. Variants with less severe functional scores more often appeared in patients with slower disease progression, implying a relationship between variant function and disease severity. Amino acid positions intolerant to variation mapped to points of predicted SGC interactions, validated in silico structural models, and enabled accurate prediction of pathogenic variants in other SGC genes. These results will be useful for clinical interpretation of SGCB variants and improving diagnosis of LGMD; we hope they enable wider use of potentially life-saving gene therapy., Introduction Recessive mutations in [beta]-sarcoglycan (SGCB) cause limb-girdle muscular dystrophy type R4/2E (LGMDR4/2E), resulting in muscle wasting, progressive weakness, degeneration of skeletal muscle, and often premature death (1, 2). [beta]-Sarcoglycan [...]

Byline: Harsh. Sheth, Dhairya. Pancholi, Riddhi. Bhavsar, Ashraf. Mannan, Aparna. Ganapathy, Mayank. Chowdhury, Sudhir. Shah, Dhawal. Solanki, Frenny. Sheth, Jayesh. Sheth Background: Neurological diseases are phenotypically and genotypically heterogeneous. Clinical [...]

Background This nationwide study assessed the impact of nationally agreed cancer genetics guidelines on use of BRCA1/2 germline testing, risk management advice given by health professionals to women with pathogenic BRCA1/2 variants and uptake of such advice by patients. Methods Clinic files of 883 women who had initial proband screens for BRCA1/2 pathogenic variants at 12 familial cancer clinics between July 2008-July 2009 (i.e. before guideline release), July 2010-July 2011 and July 2012-July 2013 (both after guideline release) were audited to determine reason given for genetic testing. Separately, the clinic files of 599 female carriers without a personal history of breast/ovarian cancer who underwent BRCA1/2 predictive genetic testing and received their results pre- and post-guideline were audited to ascertain the risk management advice given by health professionals. Carriers included in this audit were invited to participate in a telephone interview to assess uptake of advice, and 329 agreed to participate. Results There were no significant changes in the percentages of tested patients meeting at least one published indication for genetic testing - 79, 77 and 78% of files met criteria before guideline, and two-, and four-years post-guideline, respectively ([chl] = 0.25, p = 0.88). Rates of documentation of post-test risk management advice as per guidelines increased significantly from pre- to post-guideline for 6/9 risk management strategies. The strategies with the highest compliance amongst carriers or awareness post-release of guidelines were annual magnetic resonance imaging plus mammography in women 30-50 years (97%) and annual mammography in women > 50 years (92%). Of women aged over 40 years, 41% had a risk-reducing bilateral mastectomy. Amongst women aged > 40 years, 75% had a risk-reducing salpingo-oophorectomy. Amongst women who had not had a risk-reducing bilateral mastectomy, only 6% took risk-reducing medication. Fear of side-effects was cited as the main reasons for not taking these medicines by 73% of women. Conclusions Guidelines did not change the percentages of tested patients meeting genetic testing criteria but improved documentation of risk management advice by health professionals. Effective approaches to enhance compliance with guidelines are needed to improve risk management and quality of care. Keywords: Guidelines, Compliance, Genetic testing, Cancer risk, BRCA1 and BRCA2, Author(s): Bettina Meiser[sup.1], Rajneesh Kaur[sup.1], April Morrow[sup.1], Michelle Peate[sup.1,2], W. K. Tim Wong[sup.1,3], Emily McPike[sup.1], Elisa Cops[sup.4], Cassandra Nichols[sup.5], Rachel Austin[sup.6], Miriam Fine[sup.7], Letitia Thrupp[sup.4], Robyn Ward[sup.8,9], Finlay Macrae[sup.10,11], Janet [...]

Byline: Dhanya. Narayanan, Moni. Tuteja, Adam. McIntyre, Robert. Hegele, Nadege. Calmels, Cathy. Obringer, Vincent. Laugel, Kausik. Mandal, Shubha. Phadke Background: Cockayne syndrome is an autosomal recessive disorder caused by biallelic [...]