Malignant Rhabdoid Tumor Of Kidney Research Articles

Doxycycline hydrochloride inhibits the progress of malignant rhabdoid tumor of kidney by targeting MMP17 and MMP1 through PI3K-Akt signaling pathway

ObjectiveTo identify therapeutic targets for malignant rhabdoid tumors of kidney (MRTK) and to investigate the effects and underlying mechanism of doxycycline hydrochloride on these tumors. MethodsGene expression and clinical data of MRTK were retrieved from the TARGET database. Differentially expressed genes (DEGs) and prognostic-related genes (PRGs) were selected through a combination of statistical analyses. The functional roles of MMP17 and MMP1 were elucidated through RNA overexpression and intervention experiments. Furthermore, in vitro and in vivo studies provided evidence for the inhibitory effect of doxycycline hydrochloride on MRTK. Additionally, transcriptome sequencing was employed to investigate the underlying molecular mechanisms. Results3507 DEGs and 690 PRGs in MRTK were identified. Among these, we focused on 41 highly expressed genes associated with poor prognosis and revealed their involvement in extracellular matrix regulatory pathways. Notably, MMP17 and MMP1 stood out as particularly influential genes. When these genes were knocked out, a significant inhibition of proliferation, invasion and migration was observed in G401 cells. Furthermore, our study explored the impact of the matrix metalloproteinase inhibitor, doxycycline hydrochloride, on the malignant progression of G401 both in vitro and in vivo. Combined with sequencing data, the results indicated that doxycycline hydrochloride effectively inhibited MRTK progression, due to its ability to suppress the expression of MMP17 and MMP1 through the PI3K-Akt signaling pathway. ConclusionDoxycycline hydrochloride inhibits the expression of MMP17 and MMP1 through the PI3K-Akt signaling pathway, thereby inhibiting the malignant progression of MRTK in vivo and in vitro.

Co-Existent Rhabdoid Tumor of the Brain and the Kidney in Newborn Girl: A Case Report

Malignant rhabdoid tumor of kidney (MRTK) is highly aggressive tumor of infancy and childhood. MRTK is unique in its significant association with primary brain tumours or brain metastases. We describe a case of malignant rhabdoid tumor of kidney, who first presented as posterior fossa brain tumor. Renal tumor was discovered incidentally during cerebral medullary MRI.

Global Chromatin Changes Resulting from Single-Gene Inactivation-The Role of SMARCB1 in Malignant Rhabdoid Tumor.

Simple SummaryMalignant rhabdoid tumors (MRT), one of the most lethal, treatment-resistant human cancers, arises in young children within brain, kidney, liver and/or soft tissues. Generally, cancer arises in older adults, and results from multiple significant changes (mutations) accumulating in the genetic blueprint (DNA) of a person’s tissues. This blueprint is composed of a 4-letter alphabet. Together, the multiple significant changes in the blueprint then allow a cell to go “out of control”, becoming a cancer cell. The striking thing about MRT is that it has only a single spelling change, so that mutation must be very powerful to lead to such a lethal cancer. Using a model system that we developed, we show herein how this single mutation alters how the whole of the DNA is arranged, thereby having its profound and lethal effects. We present insights into how this mutation arrests maturation of the cells, keeping them in a cancer “state”.Human cancer typically results from the stochastic accumulation of multiple oncogene-activating and tumor-suppressor gene-inactivating mutations. However, this process takes time and especially in the context of certain pediatric cancer, fewer but more ‘impactful’ mutations may in short order produce the full-blown cancer phenotype. This is well exemplified by the highly aggressive malignant rhabdoid tumor (MRT), where the only gene classically showing recurrent inactivation is SMARCB1, a subunit member of the BAF chromatin-remodeling complex. This is true of all three presentations of MRT including MRT of kidney (MRTK), MRT of the central nervous system (atypical teratoid rhabdoid tumor—ATRT) and extracranial, extrarenal rhabdoid tumor (EERT). Our reverse modeling of rhabdoid tumors with isogenic cell lines, either induced or not induced, to express SMARCB1 showed widespread differential chromatin remodeling indicative of altered BAF complex activity with ensuant histone modifications when tested by chromatin immunoprecipitation followed by sequencing (ChIP-seq). The changes due to reintroduction of SMARCB1 were preponderantly at typical enhancers with tandem BAF complex occupancy at these sites and related gene activation, as substantiated also by transcriptomic data. Indeed, for both MRTK and ATRT cells, there is evidence of an overlap between SMARCB1-dependent enhancer activation and tissue-specific lineage-determining genes. These genes are inactive in the tumor state, conceivably arresting the cells in a primitive/undifferentiated state. This epigenetic dysregulation from inactivation of a chromatin-remodeling complex subunit contributes to an improved understanding of the complex pathophysiological basis of MRT, one of the most lethal and aggressive human cancers.

Aggressive uncommon pediatric renal tumor: Rhabdoid tumor of kidney

Rhabdoid tumor of kidney is one of the uncommon pediatric renal neoplasms with highly aggressive clinical course. We are presenting a case of 1 year child with abdominal distension and hematuria. On Contrast enhanced computed tomography (CECT) a heterogenous mass in lower pole of kidney was detected. Histopathological and immunohistochemical study after radical nephrectomy revealed Malignant rhabdoid tumor of kidney. It has a tendency to metastasize early and it is associated with synchronous presence of other malignancies. No definite effective treatment for this tumor is available till now. This further necessitates the early diagnosis and prompt management which can be life saving for the patient. We are presenting this case to emphasize on its rarity and aggressive clinical behaviour. Keywords: Rhabdoid tumor, Kidney neoplasm.

A phase I study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

10541 Background: HMG-CoA reductase inhibitors (statins) can inhibit IL-6-mediated STAT3 activation, a critical pathway in pediatric CNS and solid tumors. Statins also inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We therefore conducted a phase 1 trial of simvastatin in combination with topotecan and cyclophosphamide in children with relapsed/refractory (r/r) solid and CNS tumors. Methods: Eligible patients were 1-29 years of age with a r/r solid or CNS tumor. Simvastatin was administered orally twice daily on days 1-21, with topotecan 0.75 mg/m2/dose IV and cyclophosphamide 250 mg/m2/dose IV on days 1-5. Four dose levels (DLs) were planned: 140, 180, 225, 290 mg/m2/dose. A 3+3 design was used to determine the maximum tolerated dose (MTD). Pharmacokinetic and pharmacodynamic analyses were performed. Results: The median (range) age of 14 eligible patients was 11.5 years (1 - 23). Diagnoses included neuroblastoma (N = 4), sarcoma (N = 7), and one each of malignant rhabdoid tumor of kidney, medulloblastoma, and Wilms tumor. Eleven DLT-evaluable patients received a median of 4 cycles (range: 1-6). There were 3 cycle 1 DLTs, grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) increased at DL 1, and grade 4 CPK increased at DL 0 (100 mg/m2/dose). Grade 3/4 treatment-related cycle 1 adverse events occurring in ≥ 10% patients were neutropenia (100%), leukopenia (100%), thrombocytopenia (91%), lymphopenia (91%), anemia (55%), febrile neutropenia (55%) and CPK increased (18%). Best overall response was partial response in 1 patient and stable disease in four. Simvastatin and simvastatin acid Cmax (geomean 82.5 and 12.6 ng/mL) and AUC0-6 (geomean 82.5 and 12.6 ng•h/mL) were comparable with reported pediatric literature values (Cmax 3.5 and 0.4-2.1 ng/mL; AUC0-8 10.7 and 3.8 ng•h/mL) after correction for the higher doses (3.77 vs 0.16 mg/kg) used in our study. Patient peripheral blood mononuclear cells showed maximum phospho-(p)STAT3 inhibition on Day 5, with recurrence by Day 21 despite continued simvastatin dosing. Plasma IL6 levels showed sustained IL6 inhibition with decrease to normal values by Day 21 in all patients, indicating potential on target effects. Conclusions: For this first-in-pediatrics trial of statins as anti-cancer therapy, the MTD of simvastatin with chemotherapy was 100 mg/m2/dose. This combination was well-tolerated with predominantly hematologic toxicity and predictable DLTs related to simvastatin. Clinical trial information: NCT02390843.

小児肉腫型腎腫瘍の臨床像 : I. 横紋筋肉腫様型腎腫瘍の2症例報告と文献的考察

小児肉腫型腎腫瘍の臨床像 : I. 横紋筋肉腫様型腎腫瘍の2症例報告と文献的考察

Malignant rhabdoid tumour of kidney - a rare aggressive tumour

Malignant rhabdoid tumour of kidney is a rare highly aggressive neoplasm of childhood. We present the case of a 18- months old girl presenting with decreased appetite, abdominal distention of 20 days duration and 3 episodes of haematuria. The patient underwent left radical nephrectomy and histopathological examination of the excised specimen confirmed the diagnosis of malignant rhabdoid tumour of the kidney. This case highlights the need to consider malignant rhabdoid tumour of the kidney of possibility young children in presenting with a renal mass.

Pure malignant rhabdoid tumor of the left kidney in an adult: A case report and review of the literature

Malignant rhabdoid tumors of the kidney (MRTKs) are extremely rare. Pure MRTKs in adult patients are particularly rare and have not been previously reported in China. Due to the non-specific clinical symptoms, it is difficult but also essential to be able to give a definite diagnosis. The present study reports a case of pure adult malignant rhabdoid tumor in a patient’s left kidney with characteristic clinicopathological features. Considering the fact that the characteristic findings are often not observed in clinical symptom and imaging studies, the histological features, immunohistochemical staining and cytogenetic studies may aid in confirming the diagnosis of pure MRTKs. Although pure adult MRTKs remain extremely uncommon, it is necessary to consider this possibility when such types of renal tumors are encountered.

Clinicopathologic study of renal cell carcinoma with rhabdoid features

To study the clinicopathologic features and biologic behavior of renal cell carcinoma (RCC) with rhabdoid features. Ten cases of RCC with rhabdoid features collected during the period from 1995 to 2005 were enrolled into the study. The clinical findings were analyzed and the hematoxylin and eosin-stained sections were reviewed. Immunohistochemistry and electron microscopy were also performed. The age of patients ranged from 33 to 69 years (mean age = 52 years). Nine of the patients were males and 1 female. Five patients showed evidence of perinephric invasion. Two patients presented with regional lymph node metastases and 1 patient showed distant metastasis to the lung. Histologically, the rhabdoid foci were characterized by loosely cohesive trabeculae, acini, lobules and clusters of rhabdoid cells in otherwise clear cell RCC (9 cases) or papillary RCC (1 case). The rhabdoid cells were round to polygonal in shape and contained globular eosinophilic inclusion bodies in the cytoplasm, eccentric nuclei, vesicular chromatin pattern and prominent nucleoli. Coagulative tumor necrosis was commonly seen. Immunohistochemical study showed that the rhabdoid cells were diffusely positive for CD10 (10/10), cytokeratin AE1/AE3 (10/10), epithelial membrane antigen (10/10) and vimentin (10/10). Focal staining for neuron-specific enolase and S-100 protein was also noted. They were negative for CK7, CK20 and myogenic markers (including myogenin, smooth muscle actin and muscle-specific actin). The mean Ki-67 labeling index of the rhabdoid component was higher than that of the non-rhabdoid component (P < 0.05). Follow-up information was available in 8 patients. While 6 patients are still alive without recurrence, 2 patients died of the disease 6 and 29 months respectively after the operation. RCC with rhabdoid elements are mainly observed in clear cell RCC and need to be distinguished from oncocytic renal tumors and malignant rhabdoid tumor of kidney. The higher proliferative activity in the rhabdoid areas may indicate more aggressive biologic behavior.

Novel germ-line deletion of SNF5/INI1/SMARCB1 gene in neonate presenting with congenital malignant rhabdoid tumor of kidney and brain primitive neuroectodermal tumor.

We describe a neonate who had a rare tumor combination of a malignant rhabdoid tumor of the kidney (MRTK) and a brain primitive neuroectodermal tumor (PNET). Genetic alterations of the SNF5/INI1/SMARCB1 gene were investigated by PCR-single-strand conformation polymorphism (SSCP), loss of heterozygosity (LOH), sequence, and karyotyping analyses, and the gene expression level was determined by real-time quantitative RT-PCR analysis. PCR band signals of each exon of the hSNF5/INI1 were weak or nearly undetectable in both MRTK and PNET, whereas those of the corresponding normal kidney were clearly detected. Aberrantly migrating SSCP bands led to identification of a nucleotide change in intron 8. Although this was regarded as a polymorphism, only the changed nucleotide was observed in the normal kidney of the patient. Allelic states in the parents were heterozygous for the polymorphism in the father and homozygous for the normal sequence in the mother. Thus, it was evident that a substantial genetic part of the maternal normal allele including SNF5/INI1 was deleted as a de novo germ-line mutation. In both tumors, LOH at microsatellite loci on the long arm of chromosome 22 was evident, and expression of SNF5/INI1 mRNA was drastically decreased compared to that in control tissues (0.7-3.9 vs. 123.6-153.5). Deletion of a substantial genetic part demonstrated in our patient is the novel appearance of a germ-line deletion of the SNF5/INI1 gene. Additional large somatic deletions resulted in total inactivation of the gene in both tumors. Our patient provides evidence for an important role of SNF5/INI1germ-line mutation in predisposing patients to multiple rhabdoid tumors.

Identification of a novel zinc finger gene, zf5-3, as a potential mediator of neuroblastoma differentiation.

We established a unique parental neuroblastoma cell line, NUB-7, which mimics the bipotentiality of neuroblastoma in vivo along neuronal and Schwann cell lineages following dibutyryl cAMP and retinoic acid treatments, respectively. Differential display identified a putative novel zinc finger gene as a potential differentiation-responsive gene coincident with retinoic acid treatment of NUB-7. This cDNA clone, now designated zf5-3, was mapped to chromosome 19 using somatic cell hybrids, and a larger cDNA clone further localized this gene to band 13.1-13.2 by fluorescent in situ hybridization. zf5-3 possesses 4 characteristic zinc finger DNA-binding motifs as determined by its nucleic acid and proposed amino acid sequence. Expression of zf5-3 is restricted to fetal neuronal, hepatic and renal tissues and their tumor-derived cell lines, including 8/9 neuroblastomas and 2/2 malignant rhabdoid tumors of kidney. The restricted expression in the kidney of zf5-3 to collecting tubules and ureter epithelium is suggestive of an ectodermal histogenesis of malignant rhabdoid tumors of kidney. During development of the fetal human brain, high levels of zf5-3 mRNA are restricted to the mitotically active, undifferentiated neuroblasts. Morphological evidence of overt differentiation was generally accompanied by a marked loss in zf5-3 expression. Therefore, the neuronal tissue expression profile and the down-regulation coincident with retinoic acid-induced neuroblastoma maturation implicate zf5-3 as a potential mediator of their differentiation.

Malignant rhabdoid tumor of kidney with 11p deletion: D. McFadden, M.D.; T. Pantzar, M.D. B.C.'s Children's Hospital, Vancouver, BC

Malignant rhabdoid tumor of kidney with 11p deletion: D. McFadden, M.D.; T. Pantzar, M.D. B.C.'s Children's Hospital, Vancouver, BC

Wilms' tumor and other renal tumors of childhood: A selective review from the National Wilms' Tumor Study Pathology Center

Selected studies of Wilms' tumor and related renal neoplasms in children, which have been based on the National Wilms' Tumor Study Pathology Center collection of more than 2,600 renal tumors of childhood, are reviewed. The purpose of the review is to illustrate the value of the collaborative approach to uncommon pathologic specimens and to distinguish several tumors often confused with Wilms' tumor, including renal adenocarcinoma, renal teratoma, and renal neurogenic tumors. The unfavorable prognostic significance of anaplastic cells in Wilms' tumor is emphasized. Two recently described clinicopathologic entities--clear cell sarcoma of kidney and malignant rhabdoid tumor of kidney--and morphologic variants often confused with Wilms' tumor or congenital mesoblastic nephroma of infancy are discussed. Clear cell sarcoma of kidney and malignant rhabdoid tumor of kidney are, apparently, distinctive neoplasms, not Wilms' tumor variants.

Absence of immunoperoxidase staining for myoglobin in the malignant rhabdoid tumor of the kidney.

Malignant rhabdoid tumor of the kidney, a clinically and pathologically unique tumor of early childhood, has been recently distinguished from nephroblastoma. Skeletal muscle histogenesis has been considered because of its aggressive course and histologic resemblance to rhabdomyosarcoma. Application of an indirect immunoperoxidase technique for myoglobin, an early marker of myogenesis, failed to show the protein in four malignant rhabdoid tumors of kidney. This substantiates the lack of ultrastructural evidence of skeletal muscle differentiation in these tumors.