The role of pediatric oncologist in prenatal diagnosis: A 10-year retrospective study at Assistance Publique Hôpitaux de Marseille (AP-HM).

Solid tumors or predisposition syndromes are increasingly suspected before birth. However optimal management and outcomes remain unclear. We have performed a ten-year retrospective study of oncologic indications of prenatal diagnosis in public hospitals in Marseille. Data were obtained from prenatal diagnosis center and hospital imaging databases and pediatric oncology department files. Fifty-one cases were identified, 40 with mass: adrenal 17, sacrococcygeal 9, cardiac 7, abdominal 4, ovarian 1, cervical 2; 8 with developmental abnormalities (omphalocele 4, macroglossia 4), 3 WITH familial predisposition syndromes (familial rhabdoid 2, Li-Fraumeni 1). Median detection time was 30 week. Termination of pregnancy was decided for 9 fetuses (4 cardiac lesions and suspected tuberous sclerosis, 2 sacrococcygeal tumors, 1 Beckwith-Wiedemann Syndrome, 2 SMARCB1 mutations. Preterm birth occurred in 8 cases. Eleven newborns (26,1%) required intensive care (8 for mechanical complications). Of of 17 adrenal mass ES, 4 disappeared before birth and 5 before one year. Seventeen newborns underwent surgery: 13 masses (teratoma 7, myelomeningocele 2, cystic nephroma 1, neuroblastoma 2), 4 omphaloceles, one biopsy. Surgery performed after one year for incomplete regression identified 1 neuroblastoma, 2 bronchogenic cysts and 2 nonmalignant masses. Three newborns received chemotherapy. Except one patient with BWS who died of obstructive apnea, all children are alive disease free with a median follow-up of 60 months [9-131 months]. Twelve have sequelae. Various solid tumors and cancer predisposition syndromes can be detected before birth. A multidisciplinary collaboration is strongly recommended for optimal management before and after birth.

How do young people with a hereditary cancer predisposition syndrome understand and experience cancer survivorship? "With Li-Fraumeni syndrome, it's just an intermission".

OBJECTIVES: Adolescents and young adult (AYA) cancer survivors face unique medical and psychosocial sequalae, including chronic health conditions, late effects of treatment and fear of recurrence. The meaning of cancer survivorship may be further complicated for AYAs with hereditary cancer predisposition syndromes. This study used a patient-centered framework to investigate how AYAs with Li-Fraumeni syndrome (LFS) consider cancer survivorship. METHODS: An interprofessional team conducted 30 semi-structured interviews with AYAs (aged 18-41, mean 31 years) enrolled in the National Cancer Institute's LFS Study (NCT01443468). Twenty had experienced at least one cancer diagnosis. Interview data were thematically analyzed by an inter-professional team using interpretive description and grounded theory methods. FINDINGS: Participants viewed "survivorship" as a period marked by no evidence of formerly diagnosed disease. By contrast, participants felt the label "survivor" was tenuous since LFS is characterized by multiple primary malignancies and uncertainty about intervals between one diagnosis and the next. Many AYAs viewed survivorship as requiring a high degree of suffering. Though many personally rejected "survivor" identities, almost all articulated its various functions including positive, negative, and more complicated connotations. Instead, they chose language to represent a range of beliefs about survival, longevity, prognosis, and activism. CONCLUSIONS: AYAs with LFS struggle with the term "survivor" due to their multi-organ cancer risk, short intervals between malignancies, and evolving identities. Loved ones' cancer-related suffering informed perspectives on survivorship. Survivorship care for AYAs with cancer risk syndromes requires interprofessional interventions that address their unique biomedical and psychosocial needs.

Improving protocols for whole-body magnetic resonance imaging: oncological and inflammatory applications.

Whole-body MRI is increasingly used in the evaluation of a range of oncological and non-oncological diseases in infants, children and adolescents. Technical innovation in MRI scanners, coils and sequences have enabled whole-body MRI to be performed more rapidly, offering large field-of-view imaging suitable for multifocal and multisystem disease processes in a clinically useful timeframe. Together with a lack of ionizing radiation, this makes whole-body MRI especially attractive in the pediatric population. Indications include lesion detection in cancer predisposition syndrome surveillance and in the workup of children with known malignancies, and diagnosis and monitoring of a host of infectious and non-infectious inflammatory conditions. Choosing which patients are most likely to benefit from this technology is crucial, but so is adjusting protocols to the patient and disease to optimize lesion detection. The focus of this review is on protocols and the elements impacting image acquisition in pediatric whole-body MRI. We consider the practical aspects, from scanner and coil selection to patient positioning, single-center generic and indication-specific protocols with technical parameters, motion reduction strategies and post-processing. When optimized, collectively these lead to better standardization of whole-body MRI, and when married to systematic analysis and interpretation, they can improve diagnostic accuracy.

Characterizing Pediatric Familial Adenomatous Polyposis in Patients Undergoing Colectomy in the United States.

OBJECTIVE: To characterize a multi-institutional cohort of pediatric patients who underwent colectomy for familial adenomatous polyposis (FAP). STUDY DESIGN: In this retrospective cohort study, diagnosis and procedure codes were used to identify patients who underwent colectomy for FAP within the Pediatric Health Information System (PHIS). The inclusion criteria were validated at 3 children's hospitals and applied to PHIS to generate a cohort of patients with FAP between 2 and 21 years who had undergone colectomy between 2009 and 2019. Demographics, clinical and surgical characteristics, and endoscopic procedure trends as identified through PHIS are described. Descriptive and comparative statistics were used to analyze data. RESULTS: Within the PHIS, 428 pediatric patients with FAP who underwent colectomy were identified. Median age at colectomy was 14 years (range 2-21 years); 264 patients (62%) received an ileal pouch anal anastomosis and 13 (3%) underwent ileorectal anastomosis. Specific anastomotic surgical procedure codes were not reported for 151 patients (35%). Endoscopic assessment at the surgical institution occurred in 40% of the cohort before colectomy and in 22% of the cohort following colectomy. CONCLUSIONS: In this cohort, colectomy took place at an earlier age than suggested in published guidelines. Ileal pouch anal anastomosis is the predominant procedure for pediatric patients with FAP who underwent colectomy in US pediatric centers. Endoscopic assessment trends before and after surgery suggest that the surgical institution plays a limited role in the care of this population.

How Genetics and Genomics Advances Are Rewriting Pediatric Cancer Research and Clinical Care.

In the last two decades, thanks to the data that have been obtained from the Human Genome Project and the development of next-generation sequencing (NGS) technologies, research in oncology has produced extremely important results in understanding the genomic landscape of pediatric cancers, which are the main cause of death during childhood. NGS has provided significant advances in medicine by detecting germline and somatic driver variants that determine the development and progression of many types of cancers, allowing a distinction between hereditary and non-hereditary cancers, characterizing resistance mechanisms that are also related to alterations of the epigenetic apparatus, and quantifying the mutational burden of tumor cells. A combined approach of next-generation technologies allows us to investigate the numerous molecular features of the cancer cell and the effects of the environment on it, discovering and following the path of personalized therapy to defeat an "ancient" disease that has had victories and defeats. In this paper, we provide an overview of the results that have been obtained in the last decade from genomic studies that were carried out on pediatric cancer and their contribution to the more accurate and faster diagnosis in the stratification of patients and the development of new precision therapies.

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Gynecological lesions in hereditary cancer predisposition syndromes.

Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.

Whole-body magnetic resonance imaging in pediatric oncology - recommendations by the Oncology Task Force of the ESPR.

The purpose of this recommendation of the Oncology Task Force of the European Society of Paediatric Radiology (ESPR) is to indicate reasonable applications of whole-body MRI in children with cancer and to address useful protocols to optimize workflow and diagnostic performance. Whole-body MRI as a radiation-free modality has been increasingly performed over the last two decades, and newer applications, as in screening of children with germ-line mutation cancer-related gene defects, are now widely accepted. We aim to provide a comprehensive outline of the diagnostic value for use in daily practice. Based on the results of our task force session in 2018 and the revision in 2019 during the ESPR meeting, we summarized our group's experiences in whole-body MRI. The lack of large evidence by clinical studies is challenging when focusing on a balanced view regarding the impact of whole-body MRI in pediatric oncology. Therefore, the final version of this recommendation was supported by the members of Oncology Task Force.

Breast cancer risk (un)awareness among women suffering from neurofibromatosis type 1 in Poland.

The main goal of this study was to draw the attention of physicians to commonly undisclosed risk of breast cancer (BrCa) in women suffering from neurofibromatosis type 1 (NF-1), which is 5-fold higher than in the general population. NF-1 related BrCa arises earlier (< 50 years) and is more advanced, with an increased mortality. NF-1 is one of the most frequent monogenic diseases worldwide and a tumor predisposition syndrome. The Nf1 gene is an important negative regulator of the Ras oncogene and belongs to the family of the 12 the most important BrCa predisposition genes. Planning introduction of BrCa screening guidelines for NF-1 women in Poland we started with assessment of BrCa risk awareness and current preventive practices in this population by a survey published in an open access internet profile dedicated exclusively to patients with NF-1 in Poland, with 1928 participants. As a result, we revealed that the awareness of this specific risk was declared by only 30% out of 138 responders, and only 21% of them received this information from medical professionals. In all 4 (2.89%) women suffering from BrCa the cancer was diagnosed before the 50th year of age. It exceeds significantly the expected prevalence of BrCa in the general population of Polish women. We conclude that the limited awareness of NF-1 related BrCa risk in Polish patients warrants the educational effort directed both to the NF-1 patients by professional counseling and to the medical community, in order to increase the efficacy of preventive measures and decrease BrCa mortality.

Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition.

Cancer predisposition syndromes (CPS) result from germline pathogenic variants, and they are increasingly recognized in the etiology of many pediatric cancers. Herein, we report the genetic/genomic analysis of 40 pediatric patients enrolled from 2016 to 2018. Our diagnostic workflow was successful in 50% of screened cases. Overall, the proportion of CPS in our case series is 10.9% (20/184) of enrolled patients. Interestingly, 12.5% of patients achieved a conclusive diagnosis through the analysis of chromosomal imbalance. Indeed, we observed germline microdeletions/duplications of regions encompassing cancer-related genes in 50% of patients undergoing array-CGH: EIF3H duplication in a patient with infantile desmoplastic astrocytoma and low-grade Glioma; SLFN11 deletion, SOX4 duplication, and PARK2 partial deletion in three neuroblastoma patients; a PTPRD partial deletion in a child diagnosed with glioblastoma multiforme. Finally, we identified two cases due to DICER1 germline mutations.

Whole-body magnetic resonance imaging of pediatric cancer predisposition syndromes: special considerations, challenges and perspective.

Cancer predisposition syndromes increase the incidence of tumors during childhood and are associated with significant morbidity and mortality. Imaging is paramount for ensuring early detection of neoplasms, impacting therapeutic interventions and potentially improving outcome. While conventional imaging techniques involve considerable exposure to ionizing radiation, whole-body MRI is a radiation-free modality that allows continuous imaging of the entire body and has increasingly gained relevance in the surveillance, diagnosis, staging and monitoring of pediatric patients with cancer predisposition syndromes. Nevertheless, widespread implementation of whole-body MRI faces several challenges as a screening tool. Some of these challenges include developing clinical indications, variability in protocol specifications, image interpretation as well as coding and billing practices. These factors impact disease management, patient and family experience and research collaborations. In this discussion we review the aforementioned special considerations and the potential direction that might help overcome these challenges and promote more widespread use of whole-body MRI in children with cancer predisposition syndromes.

Effective Immunotherapy of Glioblastoma in an Adolescent with Constitutional Mismatch Repair-Deficiency Syndrome.

BACKGROUND: Individuals with constitutional mismatch repair-deficiency syndrome (CMMR-D) are characterised by early occurrence of colon cancer, haematological malignancies, and brain tumors (malignant gliomas, high-grade gliomas) in childhood, adolescence, and early adulthood. High mutational tumor burden is typical of glioblastoma in CMMR-D patients and could be a reason why this type of glioblastoma responds well to immunotherapies, including those that employ checkpoint inhibitors. OBSERVATION: We describe a case of an adolescent with CMMR-D that had been genetically proven by whole exome sequencing (c.2T>A/p.M1K and c.2521delT/p.W841fs PMS2 gene mutation). The patient presented successively with colon cancer and glioblastoma with a high mutational burden. The individualized glioblastoma therapy was based on the biological tumor profile and included immunotherapy with a combination of vaccination with autologous dendritic cells producing IL-12 and nivolumab, in addition to radiotherapy with metronomic temozolomide. The patient is still alive 21 months after the initial glioblastoma diagnosis and shows a complete therapeutic response documented by repeated magnetic resonance examinations. CONCLUSION: Individuals with CMMR-D should be regularly examined using established algorithms. Whole body magnetic resonance imaging can play a key role, because it enables the early diagnosis of malignancy during the asymptomatic period. Malignancies in CMMR-D patients usually exhibit a hypermutated genotype and respond to immunotherapy. Conventional glioblastoma therapy is only palliative. Patients can benefit from an individualized therapeutic plan based on the tumor biological profile. Extensive molecular analysis of the tumor tissue is necessary. Key words hereditary cancer predisposition syndromes - glioblastoma - whole exome sequencing - immunotherapy - vaccines - checkpoint inhibitors This study was supported by the research project of the Czech Ministry of Health AZV 16-33209A (Next generation sequencing and express profiling as diagnostic tools for personalized therapeutic plans in children with solid tumors). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 26. 9. 2018 Accepted: 18. 11. 2018.

Mitochondrial dysfunction in DDR-related cancer predisposition syndromes.

Given the key role of mitochondria in various cellular events, it is not surprising that mitochondrial dysfunction (MDF) is seen in many pathological conditions, in particular cancer. The mechanisms defining MDF are not clearly understood and may involve genetic defects, misbalance of reactive oxygen species (ROS), impaired autophagy (mitophagy), acquired mutations in mitochondrial or nuclear DNA and inability of cells to cope with the consequences. The importance of MDF arises from its detection in the syndromes with defective DNA damage response (DDR) and cancer predisposition. Here, we will focus on the dual role of these syndromes in cancer predisposition and MDF with specific emphasis on impaired autophagy.

Using family history forms in pediatric oncology to identify patients for genetic assessment.

OBJECTIVE: We set out to identify and offer genetic testing to the 5%-10% of pediatric cancer patients who have been estimated to carry germline mutations in inherited cancer predisposition syndromes. Clinical genetic testing has become widely available, and thus in busy oncology clinics, tools are needed to identify patients who could benefit from a referral to genetics. METHODS: We studied the clinical utility of administering a family history form in the pediatric oncology long-term follow-up clinic to identify patients who might have an inherited cancer predisposition syndrome. Genetic testing involved primarily Sanger sequencing in clia (Clinical Laboratory Improvement Amendments)-certified laboratories. RESULTS: Of 57 patients who completed forms, 19 (33.3%) met criteria for referral to genetics. A significant family history of cancer was present for 4 patients, and 12 patients underwent genetic testing. Of 18 genetic tests ordered, none identified a pathogenic mutation, likely because of a small sample size and a candidate-gene approach to testing. Three families were also identified for further assessment based on a family history of breast cancer, with two of families having members eligible for BRCA1 and BRCA2 testing. CONCLUSIONS: Genetic testing in pediatric oncology patients is important to guide the management of patients who have an inherited cancer predisposition syndrome and to identify other family members at risk when mutations are identified. When no mutations are identified, that information is often reassuring to families who are worried about siblings. However, in the absence of an identified genetic cause in a patient, some uncertainty remains.

Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach.

As next-generation sequencing (NGS) has become more widely used, germline and rare genetic variations responsible for inherited illnesses, including cancer predisposition syndromes (CPSs) that account for up to 10% of childhood malignancies, have been found. The CPSs are a group of germline genetic disorders that have been identified as risk factors for pediatric cancer development. Excluding a few "classic" CPSs, there is no agreement regarding when and how to conduct germline genetic diagnostic studies in children with cancer due to the constant evolution of knowledge in NGS technologies. Various clinical screening tools have been suggested to aid in the identification of individuals who are at greater risk, using diverse strategies and with varied outcomes. We present here an overview of the primary clinical and molecular characteristics of various CPSs and summarize the existing clinical genomics data on the prevalence of CPSs in pediatric cancer patients. Additionally, we discuss several ethical issues, challenges, limitations, cost-effectiveness, and integration of genomic newborn screening for CPSs into a healthcare system. Furthermore, we assess the effectiveness of commonly utilized decision-support tools in identifying patients who may benefit from genetic counseling and/or direct genetic testing. This investigation highlights a tailored and systematic approach utilizing medical newborn screening tools such as the genome sequencing of high-risk newborns for CPSs, which could be a practical and cost-effective strategy in pediatric cancer care.

Case report: Turcot syndrome type 2 in a developing country within the Caribbean.

Medulloblastoma is the most common malignant pediatric brain tumor and has been linked to known cancer predisposition syndromes. We report a case of medulloblastoma of a 12-year-old Indo-Trinidadian female with a strong family history of colorectal carcinoma. In collaboration with the SickKids-Caribbean Initiative (SCI), her tumor was confirmed to be a WHO grade 4 medulloblastoma - Wnt subtype. Genetic testing further confirmed the presence of a pathogenic APC gene variant [c.3183_3187del (p.Gln1062*)] which led to a diagnosis of Turcot syndrome type 2. The index patient received multimodal therapy which included surgery, radiation and chemotherapy and is currently post end-of-treatment and in remission. This case report aims to highlight the complexity of diseases and the need for expertise in identifying them in low-and-middle income countries, the need for access to specialized testing and the benefits of collaborating between low-and-middle income and high-income countries when managing complex oncology patients.

Cancer Predisposition Syndromes and Thyroid Cancer: Keys for a Short Two-Way Street.

Cancer predisposition syndromes are entities determined especially by germinal pathogenic variants, with most of them autosomal dominantly inherited. The risk of a form of cancer is variable throughout life and affects various organs, including the thyroid. Knowing the heterogeneous clinical picture and the existing genotype-phenotype correlations in some forms of thyroid cancer associated with these syndromes is important for adequate and early management of patients and families. This review synthesizes the current knowledge on genes and proteins involved in cancer predisposition syndromes with thyroid cancer and the phenomena of heterogeneity (locus, allelic, mutational, and clinical).

Public Awareness and Acceptability of PGT-M in Cancer Predisposition Syndromes.

Cancer Predisposition Syndromes (CPSs), also known as Hereditary Cancer Syndromes (HCSs), represent a group of genetic disorders associated with an increased lifetime risk of developing cancer. In this article, we provide an overview of the reproductive options for patients diagnosed with CPS, focusing on the emerging role of Preimplantation Genetic Testing for Monogenic disorders (PGT-M). Specifically, we conducted a literature review about the awareness and acceptability of its application to CPSs. Based on the available data, the awareness of the applicability of PGT-M for CPSs appears to be limited among both patients and physicians, and a heterogeneous set of factors seems to influence the acceptability of the procedure. Our findings highlight the need for increasing education about the use of PGT-M for CPSs. In this context, guidelines developed by professional or institutional bodies would represent a useful reference tool to assist healthcare professionals in providing proper preconception counseling.

Liquid biopsy-based early tumor and minimal residual disease detection: New perspectives for cancer predisposition syndromes.

Genetic predisposition is one of the major measurable cancer risk factors. Affected patients have an enhanced risk for cancer and require life-long surveillance. However, current screening measures are mostly invasive and only available for certain tumor types. Particularly in hereditary cancer syndromes, liquid biopsy, in addition to monitoring therapy response and assessing minimal residual disease, holds great potential for surveillance at the precancerous stage and potentially even diagnostics. Exploring these options and future clinical translation could help reduce cancer risk and mortality in high-risk individuals and enhance patients' adherence to tailored surveillance protocols.

Simultaneous Occurrence of Multiple Neoplasms in Children with Cancer Predisposition Syndromes: Collaborating with Abnormal Genes.

The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that increase the risk of developing cancer at an earlier age compared to the risk for the general population. This article aims to provide a comprehensive analysis of three unique cases involving pediatric patients with CPS who were diagnosed with multiple simultaneous or metachronous cancers. The first case involves a child with embryonal rhabdomyosarcoma, nephroblastoma, glioma, and subsequent medulloblastoma. Genetic analysis identified two pathogenic variants in the BRCA2 gene. The second case involves a child with alveolar rhabdomyosarcoma, juvenile xanthogranuloma, gliomas, and subsequent JMML/MDS/MPS. A pathogenic variant in the NF1 gene was identified. The third case involves a child with pleuropulmonary blastoma and pediatric cystic nephroma/nephroblastoma, in whom a pathogenic variant in the DICER1 gene was identified. Multiple simultaneous and metachronous cancers in pediatric patients with CPSs are a rare but significant phenomenon. Comprehensive analysis and genetic testing play significant roles in understanding the underlying mechanisms and guiding treatment strategies for these unique cases. Early detection and targeted interventions are important for improving outcomes in these individuals.