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A 15-year-old patient with metastatic synovial sarcoma conveyed to his palliative care physician that his dying wish was to start gender-affirming hormone therapy. His medical team was able to identify resources to support both him and his family as they navigated the immense difficulty of a cancer diagnosis and began to understand their child's gender identity. Literature on the care of gender diverse pediatric patients with terminal illness is minimal, but applications from adult literature, and research on supporting gender diverse adolescents more broadly, provided guidance for palliative care, oncology, and gender-affirming care teams. We believe that honoring and supporting the gender identity of adolescents with terminal illness is an essential aspect of end-of-life care. This case report outlines challenges faced by multidisciplinary pediatric team members who provided gender-affirming care for a minor under hospice care and amplifies the need for future research and guidelines pertinent to this patient population.
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Cuidados Paliativos , Personas Transgénero , Humanos , Adolescente , Cuidados Paliativos/ética , Personas Transgénero/psicología , Masculino , Femenino , Cuidados Paliativos al Final de la VidaRESUMEN
Metastatic neuroblastoma to the bone and septic joint shares the same incidence in age and clinical symptomology. Here we discuss a three-year-old male who presented with anemia, persistent hip pain, and a refusal to bear weight. A thorough evaluation based on a broad differential diagnosis allowed for an expedient diagnosis of metastatic neuroblastoma. The timely diagnosis allowed for rapid enrolment in a children's oncology group (COG) clinical trial for advanced neuroblastoma. The patient tolerated the therapy without adverse events and remains in remission.
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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.
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Neoplasias Encefálicas , Neoplasias Colorrectales , Síndromes Neoplásicos Hereditarios , Humanos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN/genética , Genómica , Células Germinativas/patología , Inestabilidad de Microsatélites , Repeticiones de Microsatélite , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genéticaRESUMEN
Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.
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Antígeno B7-H1/antagonistas & inhibidores , Reparación del ADN/genética , Replicación del ADN/genética , Mutación de Línea Germinal , Adolescente , Adulto , Biomarcadores de Tumor , Niño , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Neoplasias/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , Análisis de Supervivencia , Microambiente Tumoral , Adulto JovenRESUMEN
Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.
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Transformación Celular Neoplásica , Reparación de la Incompatibilidad de ADN , ADN Polimerasa Dirigida por ADN , Regulación Neoplásica de la Expresión Génica , Inestabilidad de Microsatélites , Neoplasias/genética , Humanos , Secuenciación del ExomaRESUMEN
Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.
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Neoplasias Encefálicas/genética , Metilación de ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/genética , Reparación del ADN/genética , Glioma/genética , Adolescente , Adulto , Niño , Preescolar , Trastornos por Deficiencias en la Reparación del ADN/complicaciones , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Adulto JovenRESUMEN
Recurrent Respiratory Papillomatosis (RRP) is a benign disease of the airway that can result in symptoms ranging from mild dysphonia to respiratory distress to respiratory failure related to colonization of the lung parenchyma. It is a disease that typically begins in childhood and can require treatment indefinitely, though may remit in adolescence. Although treatment includes surgical management, certain cases require adjuvant therapy. Many therapies have been tried over the years with varying levels of success. Our patient presented as a 7 month old male in respiratory distress, who was subsequently diagnosed with RRP. He has required a tracheostomy, ventilation, and frequent surgical debridement for the last 20 months. Due to the aggressiveness of his disease, he was started on systemic bevacizumab (Avastin) in an effort to stabilize his lesions. Though early effect seemed apparent based on Derkay scores, systemic bevacizumab has failed to elicit clinical improvement in our patient. He remains with a tracheostomy receiving bevacizumab 10 mg/kg as an intermittent infusion approximately every 4 weeks along with surgical debridement with little to no clinical improvement thus far. In light of the recent successes with bevacizumab therapy, this case highlights the difficulty in finding new treatment for this disease.
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Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Infecciones por Papillomavirus/tratamiento farmacológico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Quimioterapia Adyuvante , Desbridamiento , Humanos , Lactante , Masculino , Infecciones por Papillomavirus/cirugía , Infecciones del Sistema Respiratorio/cirugía , TraqueostomíaRESUMEN
PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN , Enzimas Reparadoras del ADN/genética , Pruebas Genéticas , Mutación , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Estudios de Casos y Controles , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Síndromes Neoplásicos Hereditarios/metabolismo , Fenotipo , Valor Predictivo de las PruebasRESUMEN
Constitutional mismatch repair deficiency syndrome is a cancer predisposition syndrome caused by autosomal recessive biallelic (homozygous) germline mutations in the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The clinical spectrum includes neoplastic and non-neoplastic manifestations. We present the case of a 7-year-old boy who presented with T-lymphoblastic lymphoma and glioblastoma, together with non-neoplastic manifestations including corpus callosum agenesis, arachnoid cyst, developmental venous anomaly, and hydrocephalus. Gene mutation analysis revealed pathogenic biallelic mutations of PMS2 and heterozygous DICER1 variant predicted to be pathogenic. This report is the first to allude to a possible interaction of the mismatch repair system with DICER1 to cause corpus callosum agenesis.
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Agenesia del Cuerpo Calloso/etiología , ARN Helicasas DEAD-box/genética , Reparación de la Incompatibilidad de ADN/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Mutación , Ribonucleasa III/genética , Niño , Glioblastoma , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T PrecursorasRESUMEN
Glioblastoma (GBM) is the most common primary tumor of the CNS and carries a dismal prognosis. The aggressive invasion of GBM cells into the surrounding normal brain makes complete resection impossible, significantly increases resistance to the standard therapy regimen, and virtually assures tumor recurrence. Median survival for newly diagnosed GBM is 14.6 months and declines to 8 months for patients with recurrent GBM. New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome. We have demonstrated that TROY (TNFRSF19), a member of the TNFR super-family, plays an important role in GBM invasion and resistance. Knockdown of TROY expression inhibits GBM cell invasion, increases sensitivity to temozolomide, and prolongs survival in an intracranial xenograft model. Propentofylline (PPF), an atypical synthetic methylxanthine compound, has been extensively studied in Phase II and Phase III clinical trials for Alzheimer's disease and vascular dementia where it has demonstrated blood-brain permeability and minimal adverse side effects. Here we showed that PPF decreased GBM cell expression of TROY, inhibited glioma cell invasion, and sensitized GBM cells to TMZ. Mechanistically, PPF decreased glioma cell invasion by modulating TROY expression and downstream signaling, including AKT, NF-κB, and Rac1 activation. Thus, PPF may provide a pharmacologic approach to target TROY, inhibit cell invasion, and reduce therapeutic resistance in GBM.