RESUMO
We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).
Assuntos
Linfoma de Burkitt , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Translocação Genética , Humanos , Linfoma de Burkitt/genética , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patologia , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/terapia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adolescente , Masculino , Criança , Feminino , Diagnóstico Diferencial , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cromossomos Humanos Par 14/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/genética , Cromossomos Humanos Par 8/genéticaRESUMO
The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time "liquid biopsy" for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.
Assuntos
Neoplasias Encefálicas , DNA Tumoral Circulante , Humanos , Criança , DNA Tumoral Circulante/genética , Estudos de Viabilidade , Biomarcadores Tumorais , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Encefálicas/genética , MutaçãoRESUMO
BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (â¼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.
Assuntos
Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Criança , Aberrações Cromossômicas , Hepatoblastoma/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Mutação , Adulto JovemRESUMO
Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHL) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHL: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) de novo LBCL, n=22 and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder [PTLD-DLBCL], n=11. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted next-generation sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCL (11/22), 72.7% of PTLD-DLBCL (8/11), and no BL overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV positivity (P=0.033) in LBCL and lower EFS in de novo LBCL (P=0.017). NGS of select LBCL revealed distinct somatic mutations and an ultra-hypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHL are warranted.
Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Linfoma Anaplásico de Células Grandes , Apoptose , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Criança , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4 , Humanos , Ligantes , Linfoma Difuso de Grandes Células B/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores Proteína Tirosina QuinasesRESUMO
Pancreatic angiosarcoma is an exceedingly rare malignancy accounting for <1% of pancreatic neoplasms. A very limited number of pancreatic angiosarcomas have been reported in the literature without any cases described in children. We present the case of a 17-year-old female diagnosed with angiosarcoma of the pancreas following pancreaticoduodenectomy for a pancreatic mass, initially presumed to be a solid pseudopapillary neoplasm of the pancreas. The angiosarcoma was found to have a novel activating internal tandem duplication in the KDR gene (KDR-internal tandem duplication). We discuss the current literature on this disease process. This is the first reported case of pancreatic angiosarcoma in a pediatric patient and the first with an activating KDR-internal tandem duplication.
Assuntos
Hemangiossarcoma , Neoplasias Pancreáticas , Adolescente , Feminino , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Hemangiossarcoma/cirurgia , Humanos , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Receptor 2 de Fatores de Crescimento do Endotélio VascularRESUMO
Clear cell sarcoma of the kidney (CCSK) is the second most common malignant pediatric renal tumor. Two of the recurrent somatic alterations reported in CCSK are BCL-6 corepressor (BCOR) internal tandem duplication (ITD) and YWHAE-NUTM2B/E gene fusion. A minority of patients with CCSKs have other rare somatic alterations. We report two patients with CCSK showing BCOR-CCNB3 (where CCNB3 is cyclin B3) fusion, who had similar clinical presentation of a large renal mass with tumor thrombus extending through the inferior vena cava into the right atrium and a favorable response to chemotherapy. We recommend BCOR-CCNB3 fusion testing for all patients with CCSK who lack BCOR-ITD or YWHAE-NUTM2B/E gene fusions.
Assuntos
Ciclina B/genética , Neoplasias Renais/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma de Células Claras/patologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Terapia Combinada , Humanos , Neoplasias Renais/genética , Neoplasias Renais/terapia , Masculino , Nefrectomia , Prognóstico , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/terapiaRESUMO
Young males have a unique but rare predilection to develop mediastinal nonseminomatous germ cell tumors (NSGCTs) and concomitant acute megakaryoblastic leukemia (AMKL). Common cytogenetic and molecular abnormalities such as isochromosome 12p and somatic Tumor Protein P53(TP53) and Phosphatase And Tensin Homolog (PTEN) mutations have been reported in the presumed mutual neoplastic clones of origin. We report the case of a 17-year-old male who presented with a mediastinal NSGCT with high-grade sarcomatous transformation and a diagnosis of AMKL approximately 4 months later. Next-generation sequencing revealed identical KRAS Proto-Oncogene, GTPase (KRAS) p.Ala146Thr, TP53 p.Leu257Pro, and PTEN p.Leu181Pro missense mutations at similar variant allele frequencies in both the NSGCT and AMKL samples. Cytogenetic and microarray analyses detected shared copy gains in all chromosomes except chromosomes 9, 13, and Y. Multiple additional clonal chromosomal alterations were detected in the AMKL sample when compared with the NSGCT. This case emphasizes the shared clonal origins of these malignancies and identifies KRAS and other copy number alterations as potential molecular drivers in a subset of these combined diseases.
Assuntos
Biomarcadores Tumorais/genética , Leucemia Megacarioblástica Aguda/patologia , Neoplasias do Mediastino/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Testiculares/patologia , Adolescente , Análise Citogenética , Humanos , Leucemia Megacarioblástica Aguda/complicações , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Megacarioblástica Aguda/genética , Masculino , Neoplasias do Mediastino/complicações , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/genética , Mutação , Neoplasias Embrionárias de Células Germinativas/complicações , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/genética , Proto-Oncogene Mas , Neoplasias Testiculares/complicações , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/genéticaRESUMO
Myeloid sarcoma (MS) is a neoplastic condition composed of immature myeloid cells involving an extramedullary site. We investigated underlying chromosomal and molecular alterations to assess potential molecular markers of prognosis and outcome in this rare pediatric disease. We conducted a retrospective review of clinicopathologic and cytogenetic data from 33 pediatric patients with MS (ages 1 month-18 years) at our institution over a 32 year period (1984-2016). Tissue-based cancer microarray and targeted next-generation sequencing analysis were performed on six cases. The median age at diagnosis was 2.8 years with a male-to-female ratio of 2.6:1. MS is commonly presented with concomitant marrow involvement (n = 12, 36.4%) or as a recurrence of acute myeloid leukemia (AML; n = 14, 42.4%). The skin (n = 18, 54.5%) and soft tissue (n = 9, 27.3%) were the most common sites of involvement. Twenty-one of 25 samples (84.0%) harbored chromosomal aberrations; KMT2A alterations (n = 10, 40.0%) or complex cytogenetics (n = 7, 28.0%) were most frequent. Mutations in RAS, tyrosine kinase, cell signaling, and chromatin remodeling genes were detected. When compared to pediatric patients with AML without extramedullary involvement (EMI), inferior overall survival (OS) was observed (18.8 months vs. 89.3 months, p = .008). Pediatric patients with MS with non-favorable cytogenetics [abnormalities other than t(8;21), inv(16)/t(16;16), or t(15;17)] had a significantly lower OS compared to patients with AML with non-favorable cytogenetics and no extramedullary involvement (8.0 months vs. 28.1 months, p < .001). Pediatric MS is a rare disease with diverse clinical presentations. Non-favorable cytogenetics may be a poor prognostic marker for pediatric patients with MS and molecular diagnostics can assist with risk stratification and identify potentially actionable targets.
Assuntos
Sarcoma Mieloide , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B-lymphoblast population which declined with similar kinetics as his JMML-associated abnormalities, suggesting that a B-lymphoblast population in JMML does not always progress to acute leukemia.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Células Precursoras de Linfócitos B/patologia , Deleção Cromossômica , Cromossomos Humanos Par 7 , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/patologia , Masculino , Indução de RemissãoRESUMO
BRAF p.V600E mutations are detected in greater than 50% of pediatric Langerhans cell histiocytosis (LCH) lesions. However, the use of mutation-specific BRAF V600E immunohistochemistry (IHC) as a surrogate for molecular testing in pediatric LCH is unknown. We tested the mutation-specific BRAF V600E monoclonal antibody (clone VE1) in formalin-fixed, paraffin-embedded LCH samples from 26 pediatric patients (14 males and 12 females, ages 7 mo-17 y) using allele-specific real-time polymerase chain reaction (PCR) with a limit of detection of 0.5% as the comparative gold standard. BRAF VE1 staining was scored for both intensity (0-3+) and percentage of immunoreactive tumor cells (0%-100%). BRAF VE1 immunoreactivity was determined using both lenient (≥1+, ≥1%) and stringent (≥2+, ≥10%) scoring criteria. Using lenient-scoring criteria, we found that the sensitivity and specificity of IHC compared with allele-specific real-time PCR were 100.0% and 18.2%, respectively. The poor specificity of lenient IHC analysis was attributable to weak, 1+ staining in both BRAF-mutated and wild-type LCH. Using stringent-scoring criteria, we found that specificity improved to 100.0% at the expense of sensitivity that decreased to 80.0%. Stringent scoring generated 3 false-negative results, but in all cases, neoplastic tissue comprised less than 5% of the stained section and/or the specimen was decalcified. In conclusion, highly sensitive molecular assays remain the gold standard for BRAF mutation analysis in LCH paraffin-embedded lesions. To avoid false-positive results, unequivocal VE1 staining of 2+ intensity in greater than or equal to 10% neoplastic histiocytes is required. However, negative VE1 results require additional studies to exclude false-negatives, and stringent-scoring criteria may not be optimal for scant or decalcified specimens.
Assuntos
Histiocitose de Células de Langerhans/enzimologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Lactente , MasculinoRESUMO
Uterine papillary serous carcinoma (UPSC) represents 10% of endometrial carcinomas. Significant number of patients initially present with extrauterine disease. The role of adjuvant treatment in low stage, especially polyp-confined UPSC is controversial. This multi-institutional study evaluated the significance of positive pelvic washing (PW) and adjuvant treatment on disease recurrence in a setting of endometrial polyp-confined UPSC. Surgical pathology files from 3 institutions were searched for cases of endometrial polyp-confined UPSC. Following histologic review, cases were clinically staged as Stage I, without myoinvasion or lymphovascular invasion. Clinicopathologic characteristics, results of PW, and type of adjuvant therapy were recorded. Statistical analysis using the Kaplan-Meier method for survival and Fisher exact test were performed. Thirty-three patients were included in the study. All patients were diagnosed with polyp-confined UPSC. The size of the polyp ranged from 0.3 to 4.3 cm. PW was positive for tumor cells in 8/33 (24%) patients. Twenty-two patients (66.6%) received some type of adjuvant treatment. Six patients (18%) developed recurrent disease. There was no significant difference in disease-free survival in the patients receiving adjuvant treatment versus not (P=0.375). However, there was significant association (P=0.0013) between positive PW and disease recurrence. Data are conflicting whether positive PW affects prognosis in low-stage endometrial carcinomas. Our study showed that in UPSC, malignant cells can be present in PW without lymphovascular invasion or myoinvasion and may have negative prognostic implication. Our data also reflect the controversies in the role of adjuvant treatment in endometrium-confined UPSC.
Assuntos
Cistadenocarcinoma Papilar/patologia , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Terapia Combinada , Cistadenocarcinoma Papilar/diagnóstico , Cistadenocarcinoma Papilar/terapia , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/terapia , Intervalo Livre de Doença , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/terapia , Endométrio/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Patologia Cirúrgica , Pelve/patologia , Pólipos/patologia , Pólipos/terapia , Prognóstico , Útero/patologiaRESUMO
Clear cell papillary renal cell carcinoma is a distinct variant of renal cell carcinoma that shares some overlapping histological and immunohistochemical features of clear cell renal cell carcinoma and papillary renal cell carcinoma. Although the clear cell papillary renal cell carcinoma immunohistochemical profile is well described, clear cell papillary renal cell carcinoma mRNA expression has not been well characterized. We investigated the clear cell papillary renal cell carcinoma gene expression profile using previously identified candidate genes. We selected 17 clear cell papillary renal cell carcinoma, 15 clear cell renal cell carcinoma, and 13 papillary renal cell carcinoma cases for molecular analysis following histological review. cDNA from formalin-fixed paraffin-embedded tissue was prepared. Quantitative real-time PCR targeting alpha-methylacyl coenzyme-A racemase (AMACR), BMP and activin membrane-bound inhibitor homolog (BAMBI), carbonic anhydrase IX (CA9), ceruloplasmin (CP), nicotinamide N-methyltransferase (NNMT), schwannomin-interacting protein 1 (SCHIP1), solute carrier family 34 (sodium phosphate) member 2 (SLC34A2), and vimentin (VIM) was performed. Gene expression data were normalized relative to 28S ribosomal RNA. Clear cell papillary renal cell carcinoma expressed all eight genes at variable levels. Compared with papillary renal cell carcinoma, clear cell papillary renal cell carcinoma expressed more CA9, CP, NNMT, and VIM, less AMACR, BAMBI, and SLC34A2, and similar levels of SCHIP1. Compared with clear cell renal cell carcinoma, clear cell papillary renal cell carcinoma expressed slightly less NNMT, but similar levels of the other seven genes. Although clear cell papillary renal cell carcinoma exhibits a unique molecular signature, it expresses several genes at comparable levels to clear cell renal cell carcinoma relative to papillary renal cell carcinoma. Understanding the molecular pathogenesis of clear cell papillary renal cell carcinoma will have a key role in future sub-classifications of this unique tumor.
Assuntos
Carcinoma Papilar/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Transcriptoma , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND AND OBJECTIVES: The role of HER2 in patients with early stage/resected gastric cancer is controversial. This study investigates the prevalence and prognostic value of HER2 in patients undergoing curative intent resection for gastric adenocarcinoma. METHODS: HER2 status was evaluated in 111 patients with gastric adenocarcinoma treated surgically between 1/00 and 6/11 with tissue available for analysis. Immunohistochemistry (IHC) for HER2 was graded by two blinded pathologists. IHC was scored as 0+/1+: negative, 2+: equivocal, and 3+: positive. Fluorescence in situ hybridization (FISH) for HER2 was performed on equivocal (2+) samples, and in cases of pathologist disagreement. RESULTS: HER2 expression as measured by IHC was negative in 61 (55%), equivocal in 37 (33.3%), and positive in 13 (11.7%) cases. FISH was positive in 8 of 37 samples tested, for a total of 21 HER2-positive cases (18.9%, 95% CI 11.6-26.2%). Patients with HER2-positive tumors were less likely to have signet ring cell features (23.8% vs. 53.9%, P = 0.008). HER2 status was not associated with tumor size, location, perineural or lymphovascular invasion, margin status, nodal metastasis, or stage (P > 0.05). HER2 status was not associated with OS (P = 0.385). CONCLUSIONS: HER2 amplification/over-expression is present in patients with resected gastric adenocarcinoma, but is not associated with the presence of adverse prognostic factors. Our results suggest HER2 is not prognostic for patients with resected gastric adenocarcinoma.
Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Idoso , Biomarcadores Tumorais/metabolismo , Transfusão de Sangue , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Complicações Pós-Operatórias , Prevalência , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgiaAssuntos
Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Piridazinas/uso terapêutico , Adolescente , Feminino , Humanos , Imidazóis/farmacologia , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Piridazinas/farmacologia , RecidivaRESUMO
Recognition of patients with multiple diagnoses, and the unique challenges they pose to clinicians and laboratorians, is increasing rapidly as genome-wide genetic testing grows in prevalence. We describe a unique patient with dual diagnoses of PDCD10-related cerebral cavernous malformations and ETV6-related thrombocytopenia with associated neutropenia. She presented with brain abscesses as an infant, which is highly atypical for these disorders in isolation. Confirming her diagnoses depended on thorough phenotyping both during and after her acute illness. Furthermore, the causative variant in ETV6 is a novel single-exon deletion that required multiple modalities with manual review to confirm, including unique use of polymorphic nucleotides in trio exome data. She illustrates the special challenges of patients with multiple diagnoses, and the multiple tools clinicians and laboratorians must use to treat them.
RESUMO
Risk stratification and molecular targeting have been key to increasing cure rates for pediatric cancers in high-income countries. In contrast, precise diagnosis in low-resource settings is hindered by insufficient pathology infrastructure. The Global HOPE program aims to improve outcomes for pediatric cancer in Sub-Saharan Africa (SSA) by building local clinical care and diagnostic capacity. This study aimed to assess the feasibility of implementing molecular assays to improve leukemia diagnoses in SSA. Custom NanoString nCounter gene fusion assays, previously validated in the US, were used to test samples from suspected leukemia patients. The NanoString platform was chosen due to relatively low cost, minimal technical and bioinformatics expertise required, ability to test sub-optimal RNA, and rapid turnaround time. Fusion results were analyzed blindly, then compared to morphology and flow cytometry results. Of 117 leukemia samples, 74 were fusion-positive, 30 were negative, 7 were not interpretable, and 6 failed RNA quality. Nine additional samples were negative for leukemia by flow cytometry and negative for gene fusions. All 74 gene fusions aligned with the immunophenotype determined by flow cytometry. Fourteen samples had additional information available to further confirm the accuracy of the gene fusion results. The testing provided a more precise diagnosis in >60% of cases, and 9 cases were identified that could be treated with an available tyrosine kinase inhibitor, if detected at diagnosis. As risk-stratified and targeted therapies become more available in SSA, implementing this testing in real-time will enable the treatment of pediatric cancer to move toward incorporating risk stratification for optimized therapy.
RESUMO
The survival rate of pediatric acute myeloid leukemia (pAML) is currently around 60%. While survival has slowly increased over the past few decades, the development of novel agents likely to further improve survival for this heterogeneous patient population has been limited by gaps in the pAML pre-clinical pipeline. One of the major hurdles in evaluating new agents for pAML is the lack of pAML patient-derived xenograft (PDX) models. Unlike solid tumors and other types of leukemias, AML is notoriously hard to establish in mouse models, likely due in part to the need for specific human microenvironment elements. Our laboratory at TCH/BCM addressed this gap by establishing a systematic PDX workflow, leveraging advanced immunodeficient hosts and capitalizing on our high volume of pAML patients and close coordination between labs and clinical sections. Patients treated at TCH are offered the chance to participate in specimen banking protocols that allow blood and bone marrow collection as well as the collection of relevant clinical data. All patients who consent and have samples available are trialed for PDX development. In addition, samples from the Children's Oncology Group (COG) are also trialed for PDX generation. Serially transplanting PDX models are validated using short tandem repeat (STR) and characterized using both targeted DNA/RNA next generation sequencing and RNAseq. As of March 2023, this systematic approach has resulted in 26 serially transplanting models. Models have been shared with requesting labs to facilitate external pAML pre-clinical studies. Available PDX models can be located through the BCM PDX Portal. We expect our growing PDX resource to make a significant contribution to expediting the testing of promising novel therapeutics for pAML.