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The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for health care professionals. The 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection and intervention and reduce morbidity associated with such neoplasms. In this article, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline whole-body MRI and routine monitoring of potential malignant transformation of bony lesions. Hereditary multiple osteochondromas carry a lower risk of chondrosarcoma (<6%) but still require lifelong surveillance and baseline imaging. Related syndromes of benign bone lesions are also described. Hereditary leiomyomatosis and renal cell carcinoma syndrome, associated with fumarate hydratase pathogenic variants, is discussed in detail. Surveillance for renal cell carcinoma in pediatric age is recommended, as well as prompt intervention when a lesion is detected. Schinzel-Giedion syndrome and Rubinstein-Taybi syndrome are described for their associated malignancies and other complications, as well as expert consensus on the need for childhood cancer surveillance. Clinical recommendations, including imaging modalities and frequency of screenings, are proposed and are tailored to each syndrome's age-specific tumor risk profile. In all syndromes, patients and their families should be educated about the potential malignancy risk and advised to seek medical care for rapid growth of a mass, persistent pain, or other unexplained symptoms., (©2024 American Association for Cancer Research.)

Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions., (©2024 American Association for Cancer Research.)

Gastrointestinal (GI) polyposis and cancer in pediatric patients is frequently due to an underlying hereditary cancer risk syndrome requiring ongoing cancer screening. Identification of at-risk patients through family history, clinical features of a syndrome, or symptom onset ensures appropriate cancer risk assessment and management in childhood and beyond. In this 2024 perspective, we outline updates to the hereditary GI cancer screening guidelines first published by the American Association of Cancer Research Pediatric Cancer Predisposition Workshop in 2017. These guidelines consider existing recommendations by pediatric and adult gastroenterology consortia to ensure alignment with gastroenterology practices in managing polyposis conditions. We specifically address the recommendations for pediatric screening in familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Further, we emphasize the importance of multidisciplinary care and partnership with gastroenterology, as it is crucial in management of children and families with these conditions., (©2024 American Association for Cancer Research.)

In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop, at which international experts in pediatric cancer predisposition met to update the previously published 2017 consensus statements on pediatric cancer predisposition syndromes. Since 2017, advances in tumor and germline genetic testing and increased understanding of cancer predisposition in patients with pediatric cancer have led to significant changes in clinical care. Here, we provide an updated genetic counseling framework for pediatric oncology professionals. The framework includes referral indications and timing, somatic and germline genetic testing options, testing for adult-onset cancer predisposition syndromes in children with and without cancer, evolving genetic counseling models to meet the increased demand for genetic testing, barriers to cancer genetic testing and surveillance in children, and psychosocial and equity considerations regarding cancer genetic testing and surveillance in children. Adaptable genetic counseling services are needed to provide support to pediatric oncology provider teams and diverse patients with pediatric cancer, cancer predisposition, and their families., (©2024 American Association for Cancer Research.)

Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2, or MLH1 genes, and/or in the polymerase-proofreading genes POLE and POLD1. RRD predisposition syndromes (constitutional MMR deficiency, Lynch, and polymerase proofreading-associated polyposis) share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with constitutional MMR deficiency, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations and helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and polymerase proofreading-associated polyposis syndromes harboring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations about genetic counseling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance; develop prevention strategies; and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally., (©2024 American Association for Cancer Research.)

Introduction: Multiple endocrine neoplasia (MEN) syndromes are a group of hereditary cancer syndromes that can predispose children to endocrine neoplasms developing within the head and neck., Objective: To examine the neoplastic manifestations of MEN type 1 (MEN1) and MEN type 2 (MEN2) in the pediatric head and neck., Methods: Single-institution, retrospective review of pediatric MEN between 2005 and 2022., Results: Fifty-three children were genetically confirmed with MEN (15 MEN1, 34 MEN2A, and 4 MEN2B), while three patients received clinical diagnoses of MEN1. The male to female ratio was essentially equal (1.15:1), and a documented family history of cancer was present in 89% (50/56). After multidisciplinary evaluation, a familial MEN diagnosis was confirmed in 91% (51/56). The mean ages of initial presentation and surgical intervention were 8.9 years (SD 5) and 9.8 years (SD 4.8), respectively. Although patients with MEN2 received surgery earlier than patients with MEN1 (8.7 vs 12.7 years), surgical patients with MEN2 in this cohort were older relative to current American Thyroid Association (ATA) guidelines primarily due to late presentation. Thyroid malignancies were identified in 36% (9/25) of thyroidectomy specimens (21 MEN2A, 4 MEN2B), with medullary thyroid carcinoma (MTC) present in five MEN2A patients and three MEN2B patients (89%), and papillary thyroid carcinoma (PTC) present in one MEN2A patient (11%). Nearly 90% (8/9) of thyroid malignancies were occult, with some occurring earlier than predicted by current guidelines (ATA-MOD and ATA-H). Central neck dissections were performed in 24% (2 MEN1, 2 MEN2A, and 4 MEN2B), with two MEN2B (50%) demonstrating cervical lymph node (LN) metastases. Additional histopathologic findings included C-cell hyperplasia in 57% (12/21) of MEN2A thyroidectomy patients. Of the eight MEN1 parathyroidectomy patients, four demonstrated parathyroid hyperplasia and four presented with parathyroid adenoma., Conclusion: Nearly 60% required head and neck procedures. While MEN1 guidelines were appropriate for our cohort, we identified patients with MEN2 that developed MTC earlier than expected based on current ATA guidelines, including children in categories considered lower risk. In conjunction with a multidisciplinary approach, pediatric head and neck surgeons should be aware of the potential need for earlier surgical intervention in the pediatric MEN2 population., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Approximately 7.5% of pediatric cancer deaths occur in the first 30 days post diagnosis, termed early death (ED). Previous database-level analyses identified increased ED in Black/Hispanic patients, infants, late adolescents, those in poverty, and with specific diagnoses. Socioeconomic and clinical risk factors have never been assessed at the medical record level and are poorly understood., Methods: We completed a retrospective case-control study of oncology patients diagnosed from 1995 to 2016 at Children's Hospital Colorado. The ED group (n = 45) was compared to a non-early death (NED) group surviving >31 days, randomly selected from the same cohort (n = 44). Medical records and death certificates were manually reviewed for sociodemographic and clinical information to identify risk factors for ED., Results: We identified increased ED risk in central nervous system (CNS) tumors and, specifically, high-grade glioma and atypical teratoid/rhabdoid tumor. There was prolonged time from symptom onset to seeking care in the ED group (29.4 vs. 9.8 days) with similar time courses to diagnosis thereafter. Cause of death was most commonly from tumor progression in brain/CNS tumors and infection in hematologic malignancies., Conclusions: In this first medical record-level analysis of ED, we identified socioeconomic and clinical risk factors. ED was associated with longer time from first symptoms to presentation, suggesting that delayed presentation may be an addressable risk factor. Many individual patient-level risk factors, including socioeconomic measures and barriers to care, were unable to be assessed through record review, highlighting the need for a prospective study to understand and address childhood cancer ED., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD., Patients and Methods: We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation., Results: Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10 -12 ), immunohistochemistry (86%, P = 4.6 × 10 -3 ), or tumor mutational burden (80%, P = 9.1 × 10 -4 ). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10 -5 )., Conclusion: LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

The timely identification of germline genetic causes of pediatric bone marrow failure (BMF) impacts medical screening practices, family counseling, therapeutic decision-making, and risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). At diagnosis, treatment decisions need to be made quickly to mitigate risks associated with profound cytopenias. As genetic testing options are rapidly evolving, an efficient multi-disciplinary approach and algorithm, including early involvement of a genetics team, is needed to expedite diagnosis and therapeutic decision-making. This process aids in the identification of appropriate candidates for molecular genetic testing. We present our single center experience reviewing the implementation of genetic counseling and a diagnostic and therapeutic algorithm used to guide genetic evaluation of pediatric BMF. Disease-specific next-generation sequencing (NGS) panels were most often pursued in patients who presented with a clinical phenotype consistent with a known inherited BMF syndrome and when trying to reduce incidental or uninformative results. Broader BMF NGS panels were most often utilized when unable to narrow the suspected etiology to a single disorder. Whole exome sequencing helped with optimizing treatment decision-making in higher risk children with BMF who required expedited hematopoietic stem cell transplantation. The experience has led to improvements to our process for evaluating patients with BMF., (© 2021 National Society of Genetic Counselors.)

Introduction: Cancer predisposition syndromes are germline pathogenic variants in genes that greatly raise the risk of developing neoplastic diseases. One of the most well-known is Li-Fraumeni syndrome (LFS), which is due to pathogenic variants in the TP53 gene. Children with LFS have higher risks for multiple malignancies before adulthood, often with rare and aggressive subtypes., Objective: To examine head and neck manifestations of LFS in children treated at a tertiary children's hospital over a 20-year period., Methods: A retrospective review of LFS children with neoplastic disease presenting in traditional Otolaryngologic head and neck subsites from 2000 to 2019, with patient charts reviewed for relevant clinical, imaging, and operative data., Results: Of the 40 LFS patients initially identified, 27 neoplastic tumors were identified in 20 children within this cohort (20 primary, 7 second primary). Head and neck subsites aside from the brain or orbit were involved in 22% (6/27) of these tumors, representing 20% (4/20) of primary tumors and 29% (2/7) of second primary tumors. Both second primaries within the head and neck were within the radiation fields of the first primary tumor. The mean ages at primary and second primary diagnosis were 4.6 years (SD 3.5) and 12 years (SD 1.4), respectively. The male/female ratio was 1:6 among all patients with head and neck tumors. All 6 head and neck tumors were sarcomas. Rhabdomyosarcoma ( N  = 3, 50%) was the most common pathology, and the other 3 demonstrated rare tumor pathological subtypes (synovial cell sarcoma, pleomorphic myxoid liposarcoma, mandibular osteosarcoma). The neck was the most common subsite (75%) within this group for primary tumor presentation., Conclusion: This study identifies a high potential for head and neck involvement in children with LFS, which has not been previously described in the literature. Otolaryngological care should be included in a multidisciplinary care team surveilling these patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals., Patients and Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation., Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years., Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD., Competing Interests: Hagit N. BarisConsulting or Advisory Role: Sanofi, Igentify LtdSpeakers' Bureau: Sanofi, Takeda, Pfizer Donald BaselHonoraria: BioMarinConsulting or Advisory Role: iQvia Deborah T. BlumenthalConsulting or Advisory Role: AstraZeneca, Novocure, Takeda Miriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmune Sara RhodeHonoraria: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics Roula FarahHonoraria: Novo NordiskConsulting or Advisory Role: Novo Nordisk William D. FoulkesResearch Funding: AstraZeneca David GassEmployment: X4 PharmaceuticalsHonoraria: X4 PharmaceuticalsSpeakers' Bureau: Precisionscientia Heather HampelStock and Other Ownership Interests: Genome MedicalConsulting or Advisory Role: InVitae, Genome Medical, Promega, 23andMe Jordan R. HansfordConsulting or Advisory Role: Bayer Craig HarlosTravel, Accommodations, Expenses: GlaxoSmithKline Nobuko HijiyaHonoraria: NovartisConsulting or Advisory Role: Novartis, IncyteResearch Funding: Pfizer Junne KamiharaStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioHonoraria: Pfizer, NanoString Technologies, Third Rock Ventures, Foundation MedicineConsulting or Advisory Role: ROME Therapeutics, Third Rock VenturesResearch Funding: PureTech, Ribon Therapeutics, ACD BiotechnePatents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics, Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics, Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc Jeffrey KnipsteinEmployment: PRA Health SciencesConsulting or Advisory Role: Atheneum Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche, ServierTravel, Accommodations, Expenses: Shire, Gilead Sciences Simon C. LingHonoraria: AbbvieResearch Funding: Abbvie, Gilead Sciences Michael P. LinkConsulting or Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology Rebecca Loret de MolaEmployment: Huron Consulting Maura MassiminoConsulting or Advisory Role: Oncoscience, Novartis Gary MasonEmployment: Janssen Research & Development, MerckStock and Other Ownership Interests: Johnson & Johnson, MerckTravel, Accommodations, Expenses: Janssen Research & Development Kim E. NicholsStock and Other Ownership Interests: IncyteResearch Funding: Incyte/Novartis, Alpine Immune Sciences Enrico OpocherConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Michael OsbornTravel, Accommodations, Expenses: Amgen, Pfizer Benjamin OshrineHonoraria: Mesoblast Alyssa ReddyConsulting or Advisory Role: Novartis, AstraZeneca Lara ReichmanResearch Funding: Illumina Marc RemkeStock and Other Ownership Interests: Bayer, BB Biotech Ventures, BioNTech AG, InVitae, IDEXX Laboratories Kami Wolfe SchneiderOther Relationship: Journal of Genetic Counseling Duncan StearnsConsulting or Advisory Role: AstraZenecaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/792397 Patrick TombocHonoraria: Unicare Health PlanConsulting or Advisory Role: UniCare Health Plan An Van DammeConsulting or Advisory Role: Octapharm, Pfizer, BayerResearch Funding: Johnson & JohnsonTravel, Accommodations, Expenses: Pfizer, Sobi, Shire, Roche Ira WinerResearch Funding: Oncoceutics David S. ZieglerConsulting or Advisory Role: Bayer, AmgenTravel, Accommodations, Expenses: Bayer Cynthia HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel David MalkinConsulting or Advisory Role: Bayer Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, Bristol Myers SquibbNo other potential conflicts of interest were reported.

DICER1 syndrome is a rare hereditary cancer predisposition syndrome that has relevance to pediatric urology providers due to its association with many various pediatric genitourinary malignancies. We describe the case of a pediatric patient who was eventually diagnosed with a pathogenic DICER1 germline variant after undergoing resection of a cystic nephroma and pleuropulmonary blastoma., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Previous surveys of adults with cancer have revealed increased levels of genetic knowledge, varying levels of worry, and high satisfaction with cancer genetic counseling. We sought to determine the impact of cancer genetic counseling on parental levels of genetic knowledge, worry about cancer, and satisfaction in the context of suspected cancer predisposition in a child. We hypothesized that parents would be satisfied with cancer genetic counseling and that cancer genetic counseling would improve baseline parental genetic knowledge and decrease levels of worry. Parents were recruited from a pediatric cancer predisposition clinic in the United States. A survey was administered to two cohorts: One cohort had received cancer genetic counseling in the past and only completed one survey (post-only, n = 26), and another cohort completed the survey before and after cancer genetic counseling (pre/post, n = 23). The survey included questions on demographics, knowledge of genetics, worry levels, and satisfaction with the cancer genetic counseling service. The post-genetic counseling survey also contained a free-text section for parents to indicate what they took away from the sessions. Parental levels of genetics knowledge increased by an average of 1.9 points (p = .01), with 65.2% of parents demonstrating an increase in genetics knowledge score. Average worry levels did not change significantly (p = .37), with 52.2% of parents indicating decreased worry, and 34.8% indicating increased worry. Overall, 91.8% of parents reported high levels of satisfaction. Our results show that cancer genetic counseling in a pediatric cancer predisposition clinic improves parental levels of genetics knowledge. Satisfaction rates suggest that parents find this service beneficial. These results demonstrate the positive impacts of cancer genetic counseling on parents of children in which a hereditary cancer syndrome is known or suspected., (© 2020 National Society of Genetic Counselors.)

CBL is a mammalian gene encoding the protein CBL, which is an E3 ubiquitin-protein ligase involved in cell signaling and protein ubiquitination. Pathogenic variants in this gene have been implicated in a number of human cancers, particularly acute myeloid leukemia (AML). Here, we present a 5-year-old male patient with a history of AML, diffuse midline glioma, and left brain lesion with histiocytic features. A variant of uncertain significance (VUS): p.L493F was detected in his CBL gene via clinical evaluation. Protein modeling predicts this variant to be pathogenic. Details of the clinical evaluation and modeling assay are discussed., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

While most individuals with a clinical diagnosis of Neurofibromatosis type 1 (NF1) have a detectable pathogenic variant in the NF1 gene, other conditions have phenotypic features overlapping with NF1. Without molecular confirmation, individuals may be misdiagnosed and have a different underlying condition. Namely, if a child has constitutional mismatch repair deficiency (CMMRD), early detection and prevention strategies for cancer risk would include surveillance recommendations not typically recommended for children with NF1. This study aimed to explore phenotypes of individuals with a clinical diagnosis of NF1 to identify subpopulations who may benefit from further genetic counseling or testing for an alternate diagnosis. Retrospective review of 240 medical records of children who attended a neurocutaneous clinic identified 135 children with a molecularly confirmed pathogenic variant in NF1 or autosomal dominant pattern of clinical NF1 ("controls") and 102 children deemed "at-risk" for another condition like CMMRD. Clinical presentation, family history of NF1, personal history of cancer, and family history of cancer were compared. When comparing clinical presentation, family history, and cancer history, minimal statistical differences were found, indicating that the at-risk population appears clinically indistinguishable from those with a clear diagnosis of NF1. Given the lack of distinguishable features between the at-risk and control population, this study suggests that tiered genetic testing for all individuals being evaluated for NF1 may be beneficial for identifying patients who may be misdiagnosed with NF1 and subsequently mismanaged. This study suggests that at-risk population with a suspected NF1 diagnosis may benefit from further evaluation. Correct diagnosis of constitutional mismatch repair deficiency is crucial to diagnose cancer at an early stage or prevent cancer from occurring. PREVENTION RELEVANCE: This study suggests that at-risk population with a suspected NF1 diagnosis may benefit from further evaluation. Correct diagnosis of constitutional mismatch repair deficiency is crucial to diagnose cancer at an early stage or prevent cancer from occurring., (©2021 American Association for Cancer Research.)

Introduction: Wilms tumor (WT) is the most common renal malignancy of children and can be seen in WAGR syndrome (WT, aniridia, genitourinary anomalies, and intellectual disability). WAGR results from a contiguous gene deletion within the 11p13 region, encompassing the WT1 gene, often responsible for WT development, and the PAX6 gene, responsible for aniridia. Aniridia, a pan-ocular disease resulting from iris hypoplasia, is thought to increase the risk for WT development if their genetic alteration spans both the WT1 and the PAX6 genes on 11p13. Case Description: We describe a unique case of a patient with aniridia secondary to a heterozygous PAX6 nonsense mutation who developed WT despite no additional identifiable germline genetic drivers for this disease. Discussion: Isolated mutations in PAX6 previously have not been associated with increased risk of WT development case raises the question of if surveillance for WT should be continued in patients with aniridia with an isolated PAX6 mutation identified.

Multiple genetic conditions predispose to the development of rhabdomyosarcoma. Much of the literature on rhabdomyosarcoma in genetic syndromes does not sub-divide the location or the pathology of the sarcomas. Therefore, there are limited data on genitourinary specific associations with certain genetic syndromes. We summarize, here, the primary differential considerations for rhabdomyosarcoma of the genitourinary system. Primary considerations include DICER1 pathogenic variation, Li-Fraumeni syndrome, constitutional mismatch repair deficiency, mosaic variegated aneuploidy, neurofibromatosis type 1, Noonan syndrome, other RASopathies, Costello syndrome, and Beckwith-Wiedemann syndrome. Some conditions may present with specific pathological, clinical and/or family history features, but for others, the genitourinary tumor may be the only presenting sign at the time of diagnosis. Genetic evaluation with counseling and/or testing may help identify an underlying tumor predisposition. This manuscript serves as an introduction to germline considerations for children with genitourinary rhabdomyosarcoma., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-20-76). The series “Pediatric Urologic Malignancies” was commissioned by the editorial office without any funding or sponsorship. NGC served as the unpaid Guest Editor of the series. Dr. Schultz reports grants from Pine Tree Apple Classic Fund, Children's Minnesota and Rein in Sarcoma, during the conduct of the study. The authors have no other conflicts of interest to declare., (2020 Translational Andrology and Urology. All rights reserved.)

Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma, and brain tumors including pineoblastoma and pituitary blastoma. In May 2016, the International PPB Registry convened the inaugural International DICER1 Symposium to develop consensus testing and surveillance and treatment recommendations. Attendees from North America, Europe, and Russia provided expert representation from the disciplines of pediatric oncology, endocrinology, genetics, genetic counseling, radiology, pediatric surgery, pathology, and clinical research. Recommendations are provided for genetic testing; prenatal management; and surveillance for DICER1 -associated pulmonary, renal, gynecologic, thyroid, ophthalmologic, otolaryngologic, and central nervous system tumors and gastrointestinal polyps. Risk for most DICER1 -associated neoplasms is highest in early childhood and decreases in adulthood. Individual and caregiver education and judicious imaging-based surveillance are the primary recommended approaches. These testing and surveillance recommendations reflect a consensus of expert opinion and current literature. As DICER1 research expands, guidelines for screening and treatment will continue to be updated. Clin Cancer Res; 24(10); 2251-61. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The Code of Ethics (COE) of the National Society of Genetic Counselors (NSGC) was adopted in 1992 and was later revised and adopted in 2006. In 2016, the NSGC Code of Ethics Review Task Force (COERTF) was convened to review the COE. The COERTF reviewed ethical codes written by other professional organizations and suggested changes that would better reflect the current and evolving nature of the genetic counseling profession. The COERTF received input from the society's legal counsel, Board of Directors, and members-at-large. A revised COE was proposed to the membership and approved and adopted in April 2017. The revisions and rationale for each are presented.

In an effort to increase the diversity of the membership of the National Society of Genetic Counselors (NSGC), the Membership Committee provided two $500 scholarships to genetic counseling students planning to attend the NSGC AEC meeting in Dallas, Texas in October 2010. Requirements for applicants of both scholarships included enrollment in the fall of 2010, good standing at an accredited genetic counseling training program, and NSGC membership or plans to join in 2011. Students who are from communities underrepresented in the NSGC, including, but not limited to, those of minority cultural/ethnic backgrounds and those with disabilities were eligible to apply for the "Diversity" scholarship. Students from all backgrounds who have an interest in diversity issues were eligible to apply for the "General" scholarship. Applicants wrote essays 1000 words or less answering the following questions: How has your identity as a member of a group underrepresented in the genetic counseling profession affected your pursuit of this career? What do you feel is lacking in genetic counseling to address the issues of underrepresented groups? What strategies do you recommend for addressing these issues and/or increasing diversity? Why do you think diversity is an important issue for the field of genetic counseling? What strategies do you recommend to attract and retain students, especially those from underrepresented populations, into the field of genetic counseling? How do you envision contributing to these strategies? The essays by the award recipients elucidated interesting perspectives and ideas for increasing diversity in the genetic counseling profession.

African Americans account for about 12.7% of the United States population, but only 1% of the National Society of Genetic Counselors' membership identifies as African American. Since individuals often seek health care from providers sharing similar backgrounds, training genetic counselors from diverse backgrounds is critical. Psychology and biology students (N=552) at four universities completed a self-administered online survey assessing the influence of genetic counseling awareness, demographics, and career decisions on students' interest in pursuing genetic counseling as a career. More African Americans (83%) than Caucasians (62%) reported having chosen a career (p< or = .001). Of the 65% of students who indicated interest in the career description of genetic counseling, fewer African Americans (50%) than Caucasians (74%) had heard of genetic counseling (p< or = .001). Specific strategies to overcome recruiting barriers such as early career selection and lack of awareness of the genetic counseling career among African Americans are suggested.

In an open study 30 hypertensive outpatients have been treated with Indapamide in a dosage of 2,5 mg daily in the morning for eight weeks. In the course of this treatment a highly significant decrease of blood pressure could be observed. The antihypertensive effect came up gently in the beginning. Indapamide has been well tolerated by all patients. The rate of adverse reactions was low. Syncopal episodes did not occur. The biochemical data monitored (fasting glucose level, creatinine, urea, potassium, sodium, calcium, chloride) did not show any significant deviation. According to the present data Indapamide may be used as basic medication in the treatment of genuine hypertension. The gentle effect in the beginning prevents syncopal episodes, however a sufficient period of treatment, at least eight weeks, is needed to assess the success of the therapy.

In a 50-year-old female patient who had suffered from coronary heart disease for about 3 years, a cerebral embolus resulted in left-sided hemiparesis. Four days later she became anuric. Acute thromboembolis occlusion of the renal arteries was assumed and renal angiography was performed. The angiography showed complete obstruction of the left renal artery and partial obstruction of the right renal artery. Due to the poor general condition of the patient it was not possible to carry out renovascular surgery or streptokinasetherapy. An attempt was therefore made to remove the emboli from the renal arteries by a new technique (transfemoral embolus aspiration). The subsequent angiography showed normal circulation in the right kidney and improved circulation in the left kidney. Ten days of dialysis treatment were required until urine production started again. Death then occurred from other causes. The autopsy confirmed free permeable renal vessels and absence of permanent sequelae in the parenchyma.

During the first ten month of the past year (1974) we did 310 selective coronary arteriographies by the Sones technique at the Department of Cardiology of the Medical Clinic Würzburg. The incidence of complications in this comparatively small group was 0%. In seven cases we did an emergency coronary arteriography. Six of these patients were transferred immediately after examination to the Department of cardiac Surgery of the University of Erlangen for emergency aortocoronary vein bypass. One of these patients died within the next 6 hours postoperatively. Five patients in this group are in good condition. Three patients had a double aorto-coronary vein bypass.

Within 12 months, 315 coronary arteriographies were performed by the Sones-technique. There were no deaths. 6 of these patients with impending infarction were investigated as out-patients. Six patients with impending reinfarction were hospitalized before coronary arteriography. Nine patients were transferred to the Department of Cardiovascular Surgery of the University Hospital of Erlangen within 4-24 hours after the beginning of coronary arteriography. For one patient there was a transfer delay of 48 hours and in a second case 2 months. No problems arose from the geographical separation of both departments and the ambulant catheterization in certain cases.

In a 49-year-old man with crescendo angina, elevated serum cholesterol level and an old posterior myocardial infarction, selective coronary arteriography showed multiple arteriosclerotic aneurysms of the right coronary artery associated with extensive and severe arteriosclerotic disease of the left coronary artery. The patient's mother and brother have both died of a myocardial infarction. Another brother suffers from angina and has documented arteriosclerotic coronary artery disease. Two sisters suffer from angina as well. The possibility of embolization of distal vessels from a friable clot of the aneurysms as a cause of the patient's infarction is discussed. To the best of our knowledge, this is the tenth patient with nonfistulous arteriosclerotic coronary artery aneurysm diagnosed and documented angiographically ante mortem. Including the present case and reviewing the literature, the prevalence of this condition among nonfistulous coronary aneurysms diagnosed ante mortem is 35 per cent and henceforth cannot be regarded as an incidental autopsy finding in cardiac asymptomatic patients.

Of 61 patients with mitral valve defects operated on, 9 had a heart with an external volume of more than 1700 ml. Five of these patients died, four are still alive today. Three patients from the group with an external heart volume between 1247 ml and 1700 ml died, and in the group of patients with an external heart volume of less than 1247 ml no patient has died as yet. Under certain circumstances, the preoperative size of the heart can be a measure with which the limits of surgical mitral valve replacement can be defined.

Experiments were performed on strips from the right ventricle of the rat in order to investigate the influence of temperature and Ca++-removal on the length-tension relationship. Temperature change (22-38 degrees) had no effect on the resting, non-stimulated muscle. The isometric minima curves of the electrically stimulated preparations at 18 degrees and 38 degrees (diastolic length-tension relationship), however, were shifted to the right compared to those at 28 degrees. When temperature decreased (at fixed muscle length), the diastolic tension surmounted a maximum at the optimal temperature (28 degrees) and declined with further cooling. Moreover the electrolyte exchange characteristics (Ca, K, Na), which follow upon a variation in temperature, were studied. The calcium content of the stimulated preparations showed a similar dependence on temperature as the diastolic tension, indicating that calcium might play a role with respect to the influence of temperature on the diastolic length-tension relationship. Indeed an addition of EDTA to the bath solution caused a parallel shift of the isometric minima curve to the right. These results show that an active mechanism might contribute to the increase of diastolic tension in response to stretch.

In 7 healthy-hearted probands the arterial-coronary-venous oxygen difference for glucose, K+, lactate, pO2, pCO2 and pH during a glucagon infusion was determined and compared with the values before and 10 minutes after infusion. Contradictory to the unchanged myocardial lactate extraction and the positively or negatively influenced K+-uptake recorded in the literature, in this contingent there was a statistically significant myocardial lactate production and an unchanged potassium uptake. The respiratory quotient of the heart increased. These changes are regarded as the result of a direct hormonal influence on the myocardial metabolism and have nothing to do with the change of an aerobic into an anaerobic metabolic state.