ABSTRACT
Background: Congenital mesoblastic nephroma (CMN) is a rare renal tumor with good prognosis in children; however, cellular CMN is a special subtype with poor prognosis. The ETV6 fusion gene has been found in some cellular CMNs, whereas CMNs with TPM3::NTRK1 fusion gene have not been reported. This study aims to share the progression and treatment of a case of CMNs with TPM3::NTRK1 fusion gene, in order to provide experience for the diagnosis and treatment of such specific diseases. Case Description: We report a case of CMN with TPM3::NTRK1 fusion gene and a 3-year course of disease that originated during the fetal period. The child experienced rapid tumor progression 22 months after birth, followed by tumor recurrence 3 months after complete resection of CMN. Although traditional chemotherapy could not prevent the tumor progression. The tropomyosin receptor kinase (TRK) inhibitor larotrectinib resulted in significant inhibitory effects on metastatic lesions in the lungs, liver, and peritoneum. However, the patient ultimately died as the tumor became resistant to larotrectinib. Conclusions: CMN, is a rare pediatric renal tumor that warrant prompt surgical management. A watchful waiting approach may allow for aggressive growth of metastatic disease, as seen in this case of cellular CMN with TPM3::NTRK1 fusion gene, TRK inhibitors can play significant roles in the treatment of CMN with TPM3::NTRK1 fusion gene, but we still need to pay attention to the phenomenon of drug resistance to larotrectinib caused by site mutations of TRKA.
ABSTRACT
A previously healthy 11-year-old male was found to have a mass in the pancreatic head after several months of abdominal pain and jaundice. Pathology was consistent with a World Health Organization grade 2 pancreatic neuroendocrine tumor. He developed refractory hypertension and was found to have Cushing syndrome from ectopic ACTH secretion, with oligometastatic liver disease. He underwent surgical resection of the pancreatic tumor and metastases. Postoperatively, his Cushing syndrome resolved, but it reemerged 1 year later in the setting of disease recurrence. He was not a candidate for bilateral adrenalectomy. Ketoconazole therapy was inadequate and he was started on metyrapone, lanreotide, cabergoline, and spironolactone. Although this regimen was well-tolerated, his Cushing syndrome recurred 4 months later as his metastatic disease burden increased. Osilodrostat was begun and the dose was gradually increased in response to his uncontrolled Cushing syndrome. Osilodrostat resulted in rapid improvement and eventual normalization of his urinary free cortisol at a dose of 18â mg twice daily. He had no adverse effects. This rare case highlights the successful off-label use of osilodrostat, a medication intended for refractory Cushing disease in adult patients, in a pediatric patient with Cushing syndrome caused by ectopic ACTH secretion.
ABSTRACT
Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.
Subject(s)
Leukemia, Myelomonocytic, Juvenile , Adult , Child , Humans , Leukemia, Myelomonocytic, Juvenile/genetics , Mutation , Prospective Studies , Proto-Oncogene Proteins c-cbl/geneticsABSTRACT
Adjuvant chemotherapy for osteosarcoma and Ewing sarcoma consists of conventional cytotoxic regimens that have changed little over the past decades. There is an urgent need for agents that are more effective and have less long-term toxicity. Receptor tyrosine kinases regulate cell growth and proliferation of these tumors, and small-molecule inhibitors for many of these kinases are now available. In this article, we review published phase II trials for patients with recurrent disease and highlight the pathways targeted by available agents, as well as the toxicity and efficacy results seen to date. We also discuss the difficulties in identifying biomarkers to facilitate rational patient selection, as well as published and proposed strategies for how these inhibitors can be combined with conventional chemotherapy or other targeted agents. It is hoped future trials can capitalize on this growing experience to optimize the use of this exciting class of agents.
Subject(s)
Antineoplastic Agents , Bone Neoplasms , Osteosarcoma , Protein Kinase Inhibitors , Sarcoma, Ewing , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Clinical Trials, Phase II as Topic , Humans , Osteosarcoma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Sarcoma, Ewing/drug therapyABSTRACT
BACKGROUND: Disruption of cell-cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein. METHODS: Palbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28-day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (stratum I) and heavily pretreated (stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities. RESULTS: A total of 21 patients were enrolled on stratum I and 14 patients on stratum II. The MTD for both strata was 75 mg/m2 . Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. No patients had an objective response to palbociclib therapy. CONCLUSIONS: Palbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Adolescent , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Brain Neoplasms/pathology , Child , Child, Preschool , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Disease Progression , Female , Humans , Male , Piperazines/adverse effects , Piperazines/pharmacokinetics , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/adverse effects , Pyridines/pharmacokinetics , Young AdultSubject(s)
Leukemia, Myeloid, Acute/complications , Sweet Syndrome/diagnosis , Child , Female , Humans , Prognosis , Sweet Syndrome/etiologyABSTRACT
Several hereditary cancer predisposition syndromes are associated with genitourinary (GU) manifestations in children. The GU manifestation may be the first symptom of a more global syndrome to arise, which places the pediatric urologist in a unique position to impact the health of the child. Some GU manifestations are pathognomonic for a particular hereditary cancer predisposition syndrome, which can prompt genetic testing and enhanced surveillance for other features of the condition. In other cases, knowledge of an underlying hereditary cancer predisposition syndrome alters treatment decisions. This review focuses on hereditary cancer predisposition syndromes that impact the GU tract and are likely to be seen by a pediatric urologist.
ABSTRACT
Cancer development is influenced by hereditary mutations, somatic mutations due to random errors in DNA replication, or external factors. It remains unclear how distinct cell-intrinsic and -extrinsic factors impact oncogenesis within the same tissue type. We investigated murine soft tissue sarcomas generated by oncogenic alterations (KrasG12D activation and p53 deletion), carcinogens (3-methylcholanthrene [MCA] or ionizing radiation), and in a novel model combining both factors (MCA plus p53 deletion). Whole-exome sequencing demonstrated distinct mutational signatures in individual sarcoma cohorts. MCA-induced sarcomas exhibited high mutational burden and predominantly G-to-T transversions, while radiation-induced sarcomas exhibited low mutational burden and a distinct genetic signature characterized by C-to-T transitions. The indel to substitution ratio and amount of gene copy number variations were high for radiation-induced sarcomas. MCA-induced tumors generated on a p53-deficient background showed the highest genomic instability. MCA-induced sarcomas harbored mutations in putative cancer-driver genes that regulate MAPK signaling (Kras and Nf1) and the Hippo pathway (Fat1 and Fat4). In contrast, radiation-induced sarcomas and KrasG12Dp53-/- sarcomas did not harbor recurrent oncogenic mutations, rather they exhibited amplifications of specific oncogenes: Kras and Myc in KrasG12Dp53-/- sarcomas, and Met and Yap1 for radiation-induced sarcomas. These results reveal that different initiating events drive oncogenesis through distinct mechanisms.
Subject(s)
Carcinogenesis/genetics , Neoplasms, Experimental/genetics , Neoplasms, Radiation-Induced/genetics , Oncogenes/genetics , Sarcoma/genetics , Animals , Carcinogenesis/radiation effects , Carcinogens/toxicity , DNA Mutational Analysis , Genomic Instability/radiation effects , Humans , Methylcholanthrene/toxicity , Mice , Neoplasms, Experimental/chemically induced , Oncogenes/radiation effects , Proto-Oncogene Proteins p21(ras)/genetics , Sarcoma/chemically induced , Tumor Suppressor Protein p53/genetics , Exome SequencingABSTRACT
Although many patients with newly diagnosed Ewing sarcoma can become long-term survivors, relapse remains an important clinical problem for which there is no standard approach. Several prognostic factors have been identified, and these may help guide patient counseling and therapy decisions. A variety of chemotherapy regimens have produced responses in patients with recurrent Ewing sarcoma, but no comparative studies have been completed to show superiority of any one particular approach. In addition, the optimum length of therapy for salvage regimens and use of local control measures remains unknown. The likelihood of cure remains low and the gaps in our knowledge are great, and so enrollment on clinical trials should be strongly encouraged for these patients when feasible. Because Ewing sarcoma is relatively rare, some pediatric and adult oncologists may be less familiar with the management of relapsed patients. In this review, we address common questions facing the clinician and patient, and provide an update on new strategies for therapy.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Bone Neoplasms/drug therapy , Histiocytic Sarcoma/drug therapy , Nivolumab/therapeutic use , Adolescent , Bone Neoplasms/immunology , Bone Neoplasms/secondary , Female , Histiocytic Sarcoma/immunology , Histiocytic Sarcoma/pathology , Humans , Prognosis , Remission InductionABSTRACT
Anaplastic astrocytomas are aggressive glial cancers that present poor prognosis and high recurrence. Heterozygous IDH1 R132H mutations are common in adolescent and young adult anaplastic astrocytomas. In a majority of cases, the IDH1 R132H mutation is unique to the tumor, although rare cases of anaplastic astrocytoma have been described in patients with mosaic IDH1 mutations (Ollier disease or Maffucci syndrome). Here, we present two siblings with IDH1 R132H mutant high grade astrocytomas diagnosed at 14 and 26 years of age. Analysis of IDHR132H mutations in the siblings' tumors and non-neoplastic tissues, including healthy regions of the brain, cheek cells, and primary teeth indicate mosaicism of IDHR132H. Whole exome sequencing of the tumor tissue did not reveal any other common mutations between the two siblings. This study demonstrates the first example of IDH1 R132H mosaicism, acquired during early development, that provides an alternative mechanism of cancer predisposition.
ABSTRACT
Cancer results from the accumulation of genetic mutations in a susceptible cell of origin. We and others have also shown that injury promotes sarcoma development, but how injury cooperates with genetic mutations at the earliest stages of tumor formation is not known. Here, we utilized dual recombinase technology to dissect the complex interplay of the timing of KrasG12D activation, p53 deletion, and muscle injury in sarcomagenesis using a primary mouse model of soft tissue sarcoma. When mutations in oncogenic Kras and p53 are separated by 3 weeks, few sarcomas develop without injury. However, the transformation potential of these tumor-initiating cells can be unmasked by muscle injury. In the absence of Kras mutations, injury of the muscle with global deletion of p53 results in sarcomas with amplification of chromosomal regions encompassing the Met or Yap1 gene. These findings demonstrate a complex interplay between the timing of genetic mutations and perturbations in the tumor microenvironment, which provides insight into the earliest stages of sarcoma development.
Subject(s)
Cell Transformation, Neoplastic/genetics , Muscle Neoplasms/etiology , Muscle, Skeletal/injuries , Sarcoma, Experimental/etiology , Wounds and Injuries/complications , Animals , Cell Line, Tumor , DNA Nucleotidyltransferases/genetics , Disease Models, Animal , Integrases/genetics , Mice , Mice, Transgenic , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Time Factors , Tumor Microenvironment/genetics , Tumor Suppressor Protein p53/geneticsSubject(s)
Neurofibromatosis 2/diagnosis , Skull/pathology , Biopsy , Child , Combined Modality Therapy , Genetic Testing , Humans , Magnetic Resonance Imaging , Male , Neurofibromatosis 2/drug therapy , Neurofibromatosis 2/genetics , Neurofibromatosis 2/surgery , Phenotype , Symptom Assessment , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Genetically engineered mouse models that employ site-specific recombinase technology are important tools for cancer research but can be costly and time-consuming. The CRISPR-Cas9 system has been adapted to generate autochthonous tumours in mice, but how these tumours compare to tumours generated by conventional recombinase technology remains to be fully explored. Here we use CRISPR-Cas9 to generate multiple subtypes of primary sarcomas efficiently in wild type and genetically engineered mice. These data demonstrate that CRISPR-Cas9 can be used to generate multiple subtypes of soft tissue sarcomas in mice. Primary sarcomas generated with CRISPR-Cas9 and Cre recombinase technology had similar histology, growth kinetics, copy number variation and mutational load as assessed by whole exome sequencing. These results show that sarcomas generated with CRISPR-Cas9 technology are similar to sarcomas generated with conventional modelling techniques and suggest that CRISPR-Cas9 can be used to more rapidly generate genotypically and phenotypically similar cancers.
Subject(s)
CRISPR-Cas Systems , Integrases , Sarcoma, Experimental/genetics , Animals , Electroporation , Gene Editing/methods , Male , Mice , Mice, Nude , Mutation , NIH 3T3 Cells , Neurilemmoma/genetics , Neurilemmoma/pathology , Sarcoma, Experimental/pathologyABSTRACT
Patients with common variable immunodeficiency (CVID) have a higher incidence of autoimmune disease, which may mark the disease onset; however, anemia secondary to pure red cell aplasia is an uncommon presenting feature. Here, we describe a case of CVID-like humoral immune deficiency in a child who initially presented with red cell aplasia and ultimately developed progressive bone marrow failure. Although bone marrow transplantation (BMT) has been associated with high mortality in CVID, our patient was successfully treated with a matched sibling BMT and engrafted with >98% donor chimerism and the development of normal antibody titers to diphtheria and tetanus toxoids.
Subject(s)
Bone Marrow Transplantation , Common Variable Immunodeficiency/therapy , Red-Cell Aplasia, Pure/complications , Child , Common Variable Immunodeficiency/immunology , Humans , Immunity, Humoral , Male , Red-Cell Aplasia, Pure/immunologyABSTRACT
We discuss the generation of primary soft tissue sarcomas in mice using the Cre-loxP system to activate conditional mutations in oncogenic Kras and the tumor suppressor p53 (LSL-Kras(G12D/+); p53(flox/flox)). Sarcomas can be generated either by adenoviral delivery of Cre recombinase, activation of transgenic Cre recombinase with tamoxifen, or through transplantation of isolated satellite cells with Cre activation in vitro. Various applications of these models are discussed, including anticancer therapies, metastasis, in vivo imaging, and genetic requirements for tumorigenesis.
Subject(s)
Genetic Engineering/methods , Sarcoma/genetics , Adenoviridae/genetics , Animals , Cell Separation , Cell Transformation, Neoplastic , Disease Models, Animal , Integrases/metabolism , Mice , Mice, Transgenic , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Sarcoma/pathology , Tamoxifen/pharmacology , Tumor Suppressor Protein p53/geneticsABSTRACT
Some patients with soft-tissue sarcoma (STS) report a history of injury at the site of their tumor. Although this phenomenon is widely reported, there are relatively few experimental systems that have directly assessed the role of injury in sarcoma formation. We recently described a mouse model of STS whereby p53 is deleted and oncogenic Kras is activated in muscle satellite cells via a Pax7(CreER) driver following intraperitoneal injection with tamoxifen. Here, we report that after systemic injection of tamoxifen, the vast majority of Pax7-expressing cells remain quiescent despite mutation of p53 and Kras. The fate of these muscle progenitors is dramatically altered by tissue injury, which leads to faster kinetics of sarcoma formation. In adult muscle, quiescent satellite cells will transition into an active state in response to hepatocyte growth factor (HGF). We show that modulating satellite cell quiescence via intramuscular injection of HGF increases the penetrance of sarcoma formation at the site of injection, which is dependent on its cognate receptor c-MET. Unexpectedly, the tumor-promoting effect of tissue injury also requires c-Met. These results reveal a mechanism by which HGF/c-MET signaling promotes tumor formation after tissue injury in a mouse model of primary STS, and they may explain why some patients develop a STS at the site of injury.
Subject(s)
Hepatocyte Growth Factor/metabolism , Muscle, Skeletal/cytology , Proto-Oncogene Proteins c-met/metabolism , Sarcoma/metabolism , Soft Tissue Neoplasms/metabolism , Alleles , Animals , Cardiotoxins/metabolism , Female , Mice , Mice, Inbred C57BL , PAX7 Transcription Factor/metabolism , Signal Transduction , Tumor Suppressor Protein p53/metabolism , ras Proteins/metabolismABSTRACT
Metastasis causes most cancer deaths, but is incompletely understood. MicroRNAs can regulate metastasis, but it is not known whether a single miRNA can regulate metastasis in primary cancer models in vivo. We compared the expression of miRNAs in metastatic and nonmetastatic primary mouse sarcomas and found that microRNA-182 (miR-182) was markedly overexpressed in some tumors that metastasized to the lungs. By utilizing genetically engineered mice with either deletion of or overexpression of miR-182 in primary sarcomas, we discovered that deletion of miR-182 substantially decreased, while overexpression of miR-182 considerably increased, the rate of lung metastasis after amputation of the tumor-bearing limb. Additionally, deletion of miR-182 decreased circulating tumor cells (CTCs), while overexpression of miR-182 increased CTCs, suggesting that miR-182 regulates intravasation of cancer cells into the circulation. We identified 4 miR-182 targets that inhibit either the migration of tumor cells or the degradation of the extracellular matrix. Notably, restoration of any of these targets in isolation did not alter the metastatic potential of sarcoma cells injected orthotopically, but the simultaneous restoration of all 4 targets together substantially decreased the number of metastases. These results demonstrate that a single miRNA can regulate metastasis of primary tumors in vivo by coordinated regulation of multiple genes.