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Simple Summary: Mutation of the SMARCB1 gene can cause one of the most aggressive and lethal cancers of early childhood and infancy, malignant rhabdoid tumor (MRT). Despite the standard multimodal therapy (resection, conventional chemotherapy, and radiotherapy), the outlook for young children with MRT is poor. For infants, the disease can also preclude the use of radiotherapy. Numerous experimental treatments explore epigenetic mechanisms, but the DNA damage response has not yet been extensively evaluated as a therapeutic approach for MRT. We report a new therapeutic strategy for SMARCB1-deficient MRTs, combining PARP1 inhibition and DNA damage induction. The observed synergy between the PEGylated PARP1 inhibitor talazoparib (PEG~TLZ) and the DNA alkylating agent temozolomide (TMZ) may lead to improved therapeutic strategies for patients with this challenging cancer. We identified a new potential biomarker of response to PEG~TLZ+TMZ, O6-methylguanine methyltransferase (MGMT), and uncovered dysregulated signaling pathways involved in the response. Additionally, we elucidated the pro-survival role of SMARCB1 loss in MRT cells. Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4)—a pivotal component of the SWI/SNF chromatin remodeling complex—is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss of SMARCB1 was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response. [ABSTRACT FROM AUTHOR]

Background: Although positron emission tomography combined with computed tomography (PET-CT) plays an important role in detecting various types of childhood malignancy, it has low positive predictive value, owing to the nonspecific uptake of 18F-fluorodeoxyglucose (FDG) by normal tissue in various benign conditions. Case summary: A 5-year-old male patient with a malignant rhabdoid tumor originating in the left neck underwent primary tumor resection concurrently with ipsilateral lymph node dissection after receiving neoadjuvant chemotherapy consisting of cyclophosphamide, carboplatin, etoposide, vincristine, and doxorubicin. He later received the same adjuvant chemotherapy as well as proton therapy for the primary tumor. Sixteen months after completing the initial therapy, follow-up PET-CT revealed a novel area of glucose hypermetabolism in the right side of the tongue, which was suspected of being a recurrence. However, a physical examination and magnetic resonance imaging (MRI) demonstrated no evidence of tumor recurrence. The patient had a significant leftward deviation of the tongue, suggesting left hypoglossal nerve paralysis. Denervation of the ipsilateral intrinsic tongue muscles secondary to the treatment had caused atrophy in the ipsilateral muscles and compensatory hypertrophy in the contralateral muscles, which increased FDG uptake. Physicians should carefully confirm any diagnosis of a locally recurrent tumor because PET-CT often produces ambiguous findings. [ABSTRACT FROM AUTHOR]

This paper aims to explore the epidemiology, clinical characteristics, and prognosis of extracranial malignant rhabdoid tumors (eMRTs) in children. A systematic review and meta-analysis of studies published in PUBMED, MEDLINE, Web of Science, Embase, Cochrane, and China National Knowledge Infrastructure (CNKI) was conducted. The search was limited to studies published between Jan 1, 1990 to Dec 31, 2022, with the last search done on Jan 31, 2023. We identified 496 papers through the literature search, and 12 retrospective cohort studies with 398 patients were included. The pooled age at diagnosis for malignant rhabdoid tumor of the kidney (MRTK) was 10.009 months (95%CI (7.542–12.476)), while extracranial malignant rhabdoid tumor (EERT) was 25.917 months (95%CI (17.304–34.530)). Among the 398 patients with eMRTs, chemotherapy treatment rate (86.8% (95%CI (74.4–96.0%))) was more frequently than radiotherapy treatment (45.4% (95%CI (38.1–52.6%))). The rate of metastasis in all patients was 41.4% (95%CI (33.9–48.9%)), in which the lung metastasis was occupied 70.4% (95%CI (58.0–81.6%)). SMARCB1/INI1 mutation was up to 93.2% (95%CI (81.3–99.8%)). The rate of total surgical resection was 50.4% (95%CI (35.2–65.6%)), while pooled proportion of death in all patients was 68.7% (95%CI (56.9–79.5%)). Conclusion: EMRTs are highly malignant tumors associated with high mortality rates. The loss of SMARCB1/INI1 gene and the protein expression is observed in the vast majority of eMRTs patients. Patients that suffered MRTK are younger than patients with extrarenal EERT and are more prone to lung metastasis, but there is no significant difference in overall survival, possibly due to the higher rate of R0 resection of primary tumors in MRTK. Trial registration: The study was registered on PROSPERO with registration number CRD42023400985. What is Known: • Malignant rhabdoid tumor (MRT) is a rare and highly malignant tumor that may originate from embryonic stem cells. The incidence of MRT is exceptionally low, estimated at 0.00006%. • Malignant rhabdoid tumor of the kidney (MRTK) and extrarenal extra-cranial malignant rhabdoid tumor (EERT) tend to manifest between 11 to 18 months of age, with a 5-year survival rate of approximately 17%-36%. What is New: • There is no comprehensive meta-analysis or large-scale case series that reported to systematically introduce the eMRTs clinic outcome and prog-nosis based on largely pooled data. • This study performed a meta-analysis through an extensive literature search and clinical data analysis in order to mainly explore the clinical characteris-tics and prognosis of eMRTs, improving the understanding of eMRTs in children.. [ABSTRACT FROM AUTHOR]

Malignant rhabdoid tumors (MRTs) are rare tumors with high mortality rates and poor prognoses. MRTs occur mainly in the central nervous system, kidneys, and soft tissues, but rarely in the omentum. MRTs occur more commonly in infants and children and less frequently in adults. Here, we report the first observed case of MRT in an adult omentum. A 35-year-old man with abdominal distension and pain was admitted to the emergency department. Previously, several hospitals considered patients with cirrhosis who had not received active treatment. Computed tomography and magnetic resonance imaging revealed diffuse omental thickening and massive ascites. The surgery was performed at our hospital, and the pathological diagnosis was MRT with a SMARCB1(INI-1) deletion. Postoperatively, his symptoms improved, and he underwent five cycles of chemotherapy. However, 6 months after surgery, the tumor developed liver metastases, and the patient subsequently died. Primary MRT of the greater omentum is rare, and its pathological diagnosis usually requires extensive clinicopathological evaluation of various differential diagnoses and an appropriate work-up to exclude other malignancies associated with SMARCB1 deletion. At the same time, the lack of specific signs of omental MRT and its rapid progression should alert clinicians. [ABSTRACT FROM AUTHOR]

Background: Although positron emission tomography combined with computed tomography (PET-CT) plays an important role in detecting various types of childhood malignancy, it has low positive predictive value, owing to the nonspecific uptake of 18F-fluorodeoxyglucose (FDG) by normal tissue in various benign conditions. Case summary: A 5-year-old male patient with a malignant rhabdoid tumor originating in the left neck underwent primary tumor resection concurrently with ipsilateral lymph node dissection after receiving neoadjuvant chemotherapy consisting of cyclophosphamide, carboplatin, etoposide, vincristine, and doxorubicin. He later received the same adjuvant chemotherapy as well as proton therapy for the primary tumor. Sixteen months after completing the initial therapy, follow-up PET-CT revealed a novel area of glucose hypermetabolism in the right side of the tongue, which was suspected of being a recurrence. However, a physical examination and magnetic resonance imaging (MRI) demonstrated no evidence of tumor recurrence. The patient had a significant leftward deviation of the tongue, suggesting left hypoglossal nerve paralysis. Denervation of the ipsilateral intrinsic tongue muscles secondary to the treatment had caused atrophy in the ipsilateral muscles and compensatory hypertrophy in the contralateral muscles, which increased FDG uptake. Physicians should carefully confirm any diagnosis of a locally recurrent tumor because PET-CT often produces ambiguous findings.

Abstract Background A fetal-onset cervical mass may cause postnatal airway obstruction, and ex utero intrapartum treatment (EXIT) to secure the airway while maintaining fetal-placental circulation may be life-saving. Malignant rhabdoid tumors (MRT) are highly aggressive tumors, and when they develop in utero, the prognosis is even worse, with almost no reports of survival beyond the neonatal period. Herein, we report a case of a primary cervical MRT and describe our treatment using EXIT for securing the airway, wherein the infant’s life was saved. Case presentation A 40-year-old Japanese woman with no relevant medical or surgical history was diagnosed with a fetal left cervical mass and polyhydramnios during the third trimester. Fetal magnetic resonance imaging indicated the possibility of postnatal airway obstruction, and delivery using EXIT was planned. The infant was delivered by a planned cesarean section at 39 weeks and 5 days gestation, and tracheostomy was performed using EXIT. Postnatal contrast-enhanced computed tomography revealed suspected metastatic lesions in the subcutaneous tissue, lungs, and thymus, in addition to the mass in the left cervical region. MRT was diagnosed by biopsy of a subcutaneous mass in the left thigh, and chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide was initiated. The tumors regressed, and the infant was successfully weaned from artificial ventilation. After discharge from the hospital, she had a recurrent cervical mass and intracranial metastasis, and radiotherapy was initiated. Conclusions In our case, fetal diagnosis enabled advance planning of delivery using EXIT, thus saving the infant’s life. The use of chemotherapy for MRT, which has a poor prognosis, allowed tumor regression and enabled the infant to survive beyond the neonatal period.

Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 (RUNX1) and RUNX1-Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1- binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo. We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5'-TGTGGT-3'), inhibited survivin expression in vivo. Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Extrarenal malignant rhabdoid tumor (EMRT) is a rare and high-mortality malignant tumor, which is more common in infants and rarely seen in adults. We firstly report a case of liver malignant rhabdoid tumor (MRT) with a loss of SMARCB1 gene (alias INI1, SNF5, BAF47) expression in a middle-aged woman, and preliminarily summarize the clinical characteristics and discuss its potential treatment of liver MRT by reviewing 55 cases reported in the past. Case presentation We report a 40-year-old woman who was admitted to our hospital for right epigastric pain. Previously, the patient was treated with liver hematoma in another hospital until she came to our hospital for abdominal pain again. In our hospital, we performed surgical treatment on her and the pathology diagnosed EMRT with negative expression of SMARCB1. After surgery, the patient underwent genetic testing, but failed to screen for sensitive targeted or conventional chemotherapy drugs, and she did not receive further treatment. Due to lack of timely diagnosis and effective chemotherapy drugs, tumor recurrence and metastasis occurred one year after surgery. Then the patient chose traditional Chinese medicine for treatment. And the metastatic tumors had still progressed after one year of treatment, but the patient didn’t have obvious discomfort symptoms. Conclusions Liver MRT is a highly aggressive tumor with high metastatic potential and poor prognosis. It lacks specific symptoms and signs and is easy to be ignored and misdiagnosed. The mortality rate is extremely high as there is no effective treatment. But most tumors are accompanied by SMARCB1 deficiency, which may offer new research directions for cancer therapeutics. For the present, early detection, early diagnosis and early resection remain the key to improve the prognosis of patients.

Background: A fetal-onset cervical mass may cause postnatal airway obstruction, and ex utero intrapartum treatment (EXIT) to secure the airway while maintaining fetal-placental circulation may be life-saving. Malignant rhabdoid tumors (MRT) are highly aggressive tumors, and when they develop in utero, the prognosis is even worse, with almost no reports of survival beyond the neonatal period. Herein, we report a case of a primary cervical MRT and describe our treatment using EXIT for securing the airway, wherein the infant's life was saved.Case Presentation: A 40-year-old Japanese woman with no relevant medical or surgical history was diagnosed with a fetal left cervical mass and polyhydramnios during the third trimester. Fetal magnetic resonance imaging indicated the possibility of postnatal airway obstruction, and delivery using EXIT was planned. The infant was delivered by a planned cesarean section at 39 weeks and 5 days gestation, and tracheostomy was performed using EXIT. Postnatal contrast-enhanced computed tomography revealed suspected metastatic lesions in the subcutaneous tissue, lungs, and thymus, in addition to the mass in the left cervical region. MRT was diagnosed by biopsy of a subcutaneous mass in the left thigh, and chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide was initiated. The tumors regressed, and the infant was successfully weaned from artificial ventilation. After discharge from the hospital, she had a recurrent cervical mass and intracranial metastasis, and radiotherapy was initiated.Conclusions: In our case, fetal diagnosis enabled advance planning of delivery using EXIT, thus saving the infant's life. The use of chemotherapy for MRT, which has a poor prognosis, allowed tumor regression and enabled the infant to survive beyond the neonatal period. [ABSTRACT FROM AUTHOR]

Malignant rhabdoid tumors (MRT) are uncommon, highly aggressive tumors arising usually from the central nervous system and kidneys. Nonrenal and noncentral nervous systems MRT are rare in neonates. To the best of our knowledge, only five cases of congenital MRT of neck have been described till date. We present a rare case of congenital MRT of the neck in a neonate along with review of literature.

Malignant rhabdoid tumors (MRT) represent a very rare group of tumors in infants that have an aggressive clinical behavior, are refractory to therapy, and have a high mortality rate. We present two cases that demonstrate the importance of early diagnosis for further treatment. The first case was a 4 and a half month old boy that presented with an enlarged liver and was treated as hepatoblastoma with metastatic changes in the lung parenchyma after the diagnosis. The second case was a female neonate presenting with hardening on the right side of the abdomen which was treated as MRT of the liver after radiological and clinical evaluation. In both cases, the initial histopathologic diagnosis was hepatoblastoma, but later analyses confirmed the diagnosis of MRT. From our experience, imaging findings can be a valuable tool in directing further evaluation since even histopathologic differentiation from the small cell undifferentiated hepatoblastoma is a real challenge.

Malignant rhabdoid tumor (MRT) is a rare, SWItch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1)-deficient, aggressive tumor, occurring predominantly in children below 3 years of age. Primary adrenal MRT is extremely rare, with only 3 cases reported in the literature. A previously healthy 14-year-old female presented with left upper quadrant/epigastric abdominal pain. Imaging studies revealed an 8.0 × 8.0 × 6.5 cm, heterogeneous, partially enhancing mass along the superior margin of the left kidney encasing the adrenal gland. Surgical resection of the tumor revealed a hypercellular heterogeneous neoplasm arising from the adrenal gland. It was composed predominantly of primitive small round blue cells with focal true rosettes and areas of vague glandular epithelial differentiation and chondroid differentiation. Classic rhabdoid-type cytoplasmic inclusions were focally present. Mitoses, tumor necrosis, and hemorrhage were readily seen. Tumor cells showed complete loss of SMARCB1 (INI1) nuclear staining, demonstrated strong, and diffuse positivity for glypican 3, patchy positivity for CD99, cytokeratin, Sal-like protein 4, Lin-28 homolog A, epithelial membrane antigen, and S100. Molecular studies revealed biallelic frameshift mutations in the SMARCB1 gene (c.673delG and c.683dupT) without pathogenic copy number aberrations. The histologic, immunohistochemical, and molecular findings support a diagnosis of MRT. The unusual age, location, and mutations of this case expand the clinicopathologic and molecular spectrum of MRT. [ABSTRACT FROM AUTHOR]

Background: Extrarenal malignant rhabdoid tumor (EMRT) is a rare and high-mortality malignant tumor, which is more common in infants and rarely seen in adults. We firstly report a case of liver malignant rhabdoid tumor (MRT) with a loss of SMARCB1 gene (alias INI1, SNF5, BAF47) expression in a middle-aged woman, and preliminarily summarize the clinical characteristics and discuss its potential treatment of liver MRT by reviewing 55 cases reported in the past.Case Presentation: We report a 40-year-old woman who was admitted to our hospital for right epigastric pain. Previously, the patient was treated with liver hematoma in another hospital until she came to our hospital for abdominal pain again. In our hospital, we performed surgical treatment on her and the pathology diagnosed EMRT with negative expression of SMARCB1. After surgery, the patient underwent genetic testing, but failed to screen for sensitive targeted or conventional chemotherapy drugs, and she did not receive further treatment. Due to lack of timely diagnosis and effective chemotherapy drugs, tumor recurrence and metastasis occurred one year after surgery. Then the patient chose traditional Chinese medicine for treatment. And the metastatic tumors had still progressed after one year of treatment, but the patient didn't have obvious discomfort symptoms.Conclusions: Liver MRT is a highly aggressive tumor with high metastatic potential and poor prognosis. It lacks specific symptoms and signs and is easy to be ignored and misdiagnosed. The mortality rate is extremely high as there is no effective treatment. But most tumors are accompanied by SMARCB1 deficiency, which may offer new research directions for cancer therapeutics. For the present, early detection, early diagnosis and early resection remain the key to improve the prognosis of patients. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of competing interest None.

Rhabdoid tumor predisposition syndrome (RTPS) is a rare disorder associated with malignant rhabdoid tumor of the kidney (RTK), atypical teratoid rhabdoid tumor (ATRT), and/or other extracranial, extrarenal rhabdoid tumors (EERT), and these pediatric malignancies are difficult to treat. Presently, most of the information regarding clinical manifestations, treatment, and outcomes of rhabdoid tumors comes from large data registries and case series. Our current understanding of treatments for patients with rhabdoid tumors may inform how we approach patients with RTPS. In this manuscript, we review the genetic and clinical features of RTPS and, using known registry data and clinical reports, review associated tumor types ATRT, RTK, and EERT, closing with potential new approaches to treatment. We propose collaborative international efforts to study the use of SMARC (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin)-targeting agents, high-dose consolidative therapy, and age-based irradiation of disease sites in RTPS., (© 2024 Wiley Periodicals LLC.)

Malignant rhabdoid tumors (MRT) are uncommon, highly aggressive tumors arising usually from the central nervous system and kidneys. Nonrenal and noncentral nervous systems MRT are rare in neonates. To the best of our knowledge, only five cases of congenital MRT of neck have been described till date. We present a rare case of congenital MRT of the neck in a neonate along with review of literature. [ABSTRACT FROM AUTHOR]

Extrarenal malignant rhabdoid tumors (MRT) are highly aggressive tumors of childhood with a poor overall prognosis. While most commonly found within the kidney and central nervous system, MRT can also occur in other locations and present highly specific challenges for pediatric surgical providers in an effort to achieve a meaningful resection. Cervical rhabdoid tumors are extremely rare. We report the multidisciplinary management of a patient with a complex cervicothoracic malignant rhabdoid tumor who underwent successful surgical resection with a greater than one year survival.

Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E−10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E−7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated β-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations. [ABSTRACT FROM AUTHOR]

Purpose: Malignant rhabdoid tumor (MRT) is a rare, highly aggressive sarcoma with an uncertain cell of origin. Despite the existing standard of intensive multimodal therapy, the prognosis of patients with MRT is very poor. Novel antitumor agents are needed for MRT patients. Forkhead box transcription factor 1 (FOXM1) is overexpressed and is correlated with the pathogenesis in several human malignancies. In this study, we identified the clinicopathological and prognostic values of the expression of FOXM1 and its roles in the progression of MRT. Methods: We investigated the FOXM1 expression levels and their clinical significance in 23 MRT specimens using immunohistochemistry and performed clinicopathologic and prognostic analyses. We also demonstrated correlations between the downregulation of FOXM1 and oncological characteristics using small interfering RNA (siRNA) and FOXM1 inhibitor in MRT cell lines. Results: Histopathological analyses revealed that primary renal MRTs showed significantly low FOXM1 protein expression levels (p = 0.032); however, there were no significant differences in other clinicopathological characteristics or the survival rate. FOXM1 siRNA and FOXM1 inhibitor (thiostrepton) successfully downregulated the mRNA and protein expression of FOXM1 in vitro and the downregulation of FOXM1 inhibited cell proliferation, drug resistance to chemotherapeutic agents, migration, invasion, and caused the cell cycle arrest and apoptosis of MRT cell lines. A cDNA microarray analysis showed that FOXM1 regulated FANCD2 and NBS1, which are key genes for DNA damage repair. Conclusion: This study demonstrates that FOXM1 may serve as a promising therapeutic target for MRT. [ABSTRACT FROM AUTHOR]

Purpose of Review: Pediatric renal tumors account for 7% of new cancer diagnoses in children. Here, we will review results from recently completed clinical trials informing the current standard of care and discuss targeted and immune therapies being explored for the treatment of high risk or relapsed/refractory pediatric renal malignancies. Recent Findings: Cooperative group trials have continued to make improvements in the care of children with pediatric tumors. In particular, trials that standardize treatment of rare cancers (e.g., bilateral Wilms tumor) have improved outcomes significantly. Summary: We have seen improvements in event free and overall survival in recently completed clinical trials for many pediatric renal tumors. Still, there are subsets of rarer cancers where outcomes remain poor and new therapeutic strategies are needed. Future trials aim to balance treatment toxicity with treatment efficacy for those with excellent outcomes while identifying novel therapeutics for those with poor outcomes. [ABSTRACT FROM AUTHOR]

Malignant rhabdoid tumor of the liver is a rare, highly aggressive primary hepatic malignancy occurring primarily in infants. Establishing a definitive diagnosis is challenging due to its rarity, non-specific clinicoradiologic findings, and overlapping morphologic features. Herein, we present the cytomorphologic and immunocytochemical characteristics of a rare case of primary hepatic Malignant rhabdoid tumor (MRT) in an infant. A 5-month-old female child presented with progressively increasing firm mass in the upper abdomen, progressive pallor, sudden onset respiratory distress, and difficulty feeding. On examination, the child had massive, firm nodular hepatomegaly. Ultrasonography of the abdomen revealed a heterogeneously hypoechoic lesion in the left lobe of the liver. Serum alpha-fetoprotein levels were within normal limits. An ultrasound-guided fine-needle aspiration cytology (FNAC) from the liver mass showed predominantly dispersed large, markedly pleomorphic tumor cells with round to oval eccentrically placed nuclei, prominent nucleoli, and moderate cytoplasm. On immunocytochemistry, tumor cells showed positivity for vimentin, cytokeratin, and EMA and demonstrated a loss of INI1, confirming the diagnosis of MRT. The index report highlights the distinctive clinicopathological features of a hepatic malignant rhabdoid tumor along with the key differential diagnoses, which may pose a diagnostic conundrum. A high index of clinical suspicion and a thorough understanding of its cytomorphological and immunochemical characteristics are crucial for an accurate diagnosis., (© 2023 Wiley Periodicals LLC.)

Malignant rhabdoid tumors (MRT) represent a distinct group of aggressive tumors usually occurring in infancy involving a variety of anatomic locations including the kidney, brain, soft tissue and liver. The molecular hallmark of these tumors is the presence of deletions and/or mutations of SMARCB1 or rarely SMARCA4 that lead to the absence of INI1 or BRG1 proteins, core components of the SWI/SNF chromatin remodeling complex. MRT of the liver are rare tumors that comprise less than 5% of malignant pediatric liver tumors. They are currently diagnosed on the basis of documenting both INI1 negative immunoreactivity and rhabdoid morphology. In the absence of molecular testing, MRT lacking classic rhabdoid morphology are currently classified as small cell undifferentiated hepatoblastoma (HB). Here we report a case of MRT initially classified as a INI1 negative small cell HB. Whole Exome Sequencing with Transcriptome subsequently showed homozygous deletion of SMARCB1 on chromosome 22q11.23 with evidence of loss of expression of the gene, establishing the diagnosis of MRT. As molecular testing of these tumors is performed on a more routine basis, this case illustrates that the INI negative small cell undifferentiated variant of HB actually represents MRT, a tumor unrelated to HB.

Malignant rhabdoid tumors and atypical teratoid/rhabdoid tumors of the central nervous system are primitive malignancies associated with a poor prognosis. These tumors have previously been characterized by inactivation of the switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex protein integrase interactor 1 (INI1), encoded by the SMARCB1 gene. In the last decade, sporadic publications have shown that a different SWI/SNF protein, brahma-related gene 1 (BRG1), encoded by the SMARCA4 gene, is associated with a similar rhabdoid phenotype and possible germline mutation termed rhabdoid tumor predisposition syndrome type 2. We sought to determine the presence of BRG1 expression in pediatric embryonal tumors. Using a local tissue microarray consisting of 28 tumors diagnosed as having an undifferentiated, polyphenotypic, or rhabdoid morphology, expression of BRG1 by immunohistochemistry was performed. Four cases showed loss of INI1, while 3 of the remaining 24 cases demonstrated loss of BRG1. Two cases were diagnosed as soft tissue sarcomas, and 1 case was diagnosed as a small cell carcinoma of the ovary, hypercalcemic type. Survival ranged from less than 6 months after diagnosis to more than 5 years at the time of last follow-up. In conclusion, we demonstrate that BRG1 immunohistochemistry is a useful second-line immunostain for the workup of undifferentiated, polyphenotypic or rhabdoid pediatric tumors that demonstrate retained expression of INI1. [ABSTRACT FROM AUTHOR]

The article presents answers to a clinical quiz about an uncommon presentation of flank pain and gross hematuria in a young patient.

A 21-year-old male masked palm civet died after 2 months of continuous abdominal distention and poor appetite. Grossly, both musk glands were markedly swelled. Microscopically, round, polygonal and spindle neoplastic cells proliferated diffusely in the right musk gland and a metastatic focus was observed in the lung. The neoplastic cells had abundant cytoplasm with faintly eosinophilic inclusions that ultrastructurally corresponded to whorl aggregates of intermediate filaments. Immunohistochemically, these cells were positive for vimentin, cytokeratins and glial fibrillary acidic protein and negative for desmin. Based on these findings, the tumor was diagnosed as malignant rhabdoid tumor. Papillary adenoma was seen in the opposite musk gland. T-cell lymphoma of the lymph nodes, small intestine and liver was considered as the cause of death. [ABSTRACT FROM AUTHOR]

Purpose: Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency.Methods: The functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using a Drosophila melanogaster model of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells.Results: Knockdown of Snr1, the fly orthologue of SMARCB1, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g. CG10348, the fly orthologue of transcriptional regulator PRDM16. Subsequently, PRDM16 was found to be over-expressed in ATRT samples and knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells reduced proliferation.Conclusions: These results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT. [ABSTRACT FROM AUTHOR]

The liver is the third most common site of abdominal tumors in children. This review article aims to summarize current evidence surrounding identification and diagnosis of primary hepatic tumors in the pediatric population based upon clinical presentation, epidemiology, and risk factors as well as classical imaging, histopathological, and molecular diagnostic findings. Readers will be able to recognize the features and distinguish between benign and malignant hepatic tumors within different age groups.

[Display omitted] Soft tissue sarcomas (STSs) are rare mesechymal malignancies characterized by distintive molecular, histological and clinical features. Many STSs are considered as predominatly epigenetic diseases due to underlying chromatin deregulation. Discovery of deregulated functional antagonism between the chromatin remodeling BRG1/BRM-associated (BAFs) and the histone modifying Polycomb repressor complexes (PRCs) has provided novel actionable targets. In epithelioid sarcoma (ES), extracranial, extrarenal malignant rhabdoid tumors (eMRTs) and synovial sarcoma (SS), the total or partial loss of the BAF core subunit SMARCB1, driven by different alterations, is associated with PRC2 deregulation and dependency on its enzymatic subunit, EZH2. In these SMARCB1-deficient STSs, aberrant EZH2 expression and/or activity emerged as a druggable vulnerability. Although preclinical investigation supported EZH2 targeting as a promising therapeutic option, clinical studies demonstrated a variable response to EZH2 inhibitors. Actually, whereas the clinical benefit recorded in ES patients prompted the FDA approval of the EZH2 inhibitor tazemetostat, the modest and sporadic responses observed in eMRT and SS patients highlighted the need to deepen mechanistic as well as pharmacological investigations to improve drug effectiveness. We summarize the current knowledge of different mechanisms driving SMARCB1 deficiency and EZH2 deregulation in ES, eMRT and SS along with preclinical and clinical studies of EZH2-targeting agents. Possible implication of the PRC2- and enzymatic-independent functions of EZH2 and of its homolog, EZH1, in the response to anti-EZH2 agents will be discussed together with combinatorial strategies under investigation to improve the efficacy of EZH2 targeting in these tumors. [ABSTRACT FROM AUTHOR]

We present a rare case of malignant rhabdoid tumor (ovarian small cell carcinoma of hypercalcemic type) in a 24-year-old female with fulminant course. Clinically, hypercalcemia was not found at the time of primary diagnosis. However, it appeared later during the course of tumor progression. Histologically, the tumor showed classical features of small cell carcinoma of hypercalcemic type. Therapy included radical surgery with adjuvant chemotherapy. Despite this intensive therapy, the disease recurred and the patient died 10 months after the diagnosis. We discuss the diagnosis and therapy of this tumor, as well as its recent classification as malignant rhabdoid tumor.