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The SWI/SNF complex is a chromatin remodeling complex comprised by several proteins such as SMARCA4 or SMARCB1. Mutations in its components can lead to the development of aggressive rhabdoid tumors such as epithelioid sarcoma, malignant rhabdoid tumor or small cell carcinoma of the ovary hypercalcemic type, among others. These malignancies tend to affect young patients and their prognosis is poor given the lack of effective treatments. Characteristically, these tumors are highly infiltrated by TILs, suggesting that some lymphocytes are recognizing tumor antigens. The use of those TILs as a therapeutic strategy is a promising approach worth exploring. Here, we report the clinical protocol of the TILTS study, a Phase II clinical trial assessing personalized adoptive cell therapy with TILs in patients affected by these tumor types. Clinical Trial Registration: 2023-504632-17-00 (www.clinicaltrialsregister.eu) (ClinicalTrials.gov). Article highlights Background & rationale There is a group of tumors associated with alterations in the SWI/SNF complex, such as epithelioid sarcoma, malignant rhabdoid tumor or small cell carcinoma of the ovary hypercalcemic type, among others. These tumors usually have rhabdoid features and tend to affect young patients. Patients affected by these malignancies have poor prognosis since there are no effective standard treatments. Tumors associated with alterations in the SWI/SNF complex are generally infiltrated by a high number of TILs that have been able to recognize a tumor antigen. The use of those TILs as a therapeutic strategy is a promising immunotherapy approach. The TILTS study The TILTS study is a clinical trial designed to assess the activity of adoptive cell therapy with TILs in these tumor types. The TILTS study is a prospective, single-arm, multicenter Phase II study that uses personalized TILs treatment in advanced tumors associated with alterations in the SWI/SNF complex. The primary end point is ORR per RECIST v1.1 as assessed by investigator. Secondary end points include toxicity evaluation, PFS and OS, among others. In addition, an associated translational study will be conducted in order to better understand the biology of these malignancies and their relationship with the immune system. [ABSTRACT FROM AUTHOR]

CREB gene family (ATF1, CREB1, CREM) fusions with either EWSR1 or FUS gene partners drive the pathogenesis of a wide range of neoplasms, including various soft tissue tumors, intracranial myxoid mesenchymal tumors (IMMTs), hyalinizing clear cell carcinoma (HCCC), and rare mesotheliomas. Recently, a SMARCA2::CREM fusion was reported in one case each of IMMT and HCCC. In this study, we expand the clinicopathologic and molecular spectrum of these neoplasms by describing three additional cases with SMARCA2::CREM and one with a novel SMARCA4::CREM fusion, highlighting the recurrent potential of additional CREB gene fusion partners beyond FET family members. To evaluate if these fusions define a new pathologic entity, we performed a comprehensive genomic and methylation analysis and compared the results to other related tumors. Tumors occurred in children and young adults (median age 20 years) and spanned a broad anatomic distribution, including soft tissue, intracranial, head and neck, and prostatic urethra. Microscopically, the tumors shared an undifferentiated round to epithelioid cell phenotype and a hyalinized fibrous stroma. Immunohistochemically, a polyphenotypic profile was observed, with variable expression of SOX10, desmin, and/or epithelial markers. No targetable genomic alterations were found using panel‐based DNA sequencing. By DNA methylation and transcriptomic analyses, tumors grouped closely to FET::CREB entities, but not with SMARCA4/SMARCB1‐deficient tumors. High expression of CREM by immunohistochemistry was also documented in these tumors. Patients experienced local recurrence (n = 2), locoregional lymph node metastases (n = 2), and an isolated visceral metastasis (n = 1). Overall, our study suggests that SMARCA2/4::CREM fusions define a distinct group of neoplasms with round cell to epithelioid histology, a variable immunoprofile, and a definite risk of malignancy. Larger studies are needed to further explore the pathogenetic relationship with the FET::CREB family of tumors. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Chronic neutrophil leukemia (CNL) is a rare and life-threatening disease. Cases of CNL combined with lymphoma are rare. Here, we report a case of CNL with T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in a 28-year-old male. After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression. [ABSTRACT FROM AUTHOR]

SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are a newly described entity and are typically seen in the thoracic cavity. However, these tumors have been described in other body sites, including the esophagus. These tumors are rare, aggressive neoplasms, characterized by the loss of protein product of SMARCA4 (Brahma-related gene-1) and the preservation of INI1 (SMARCB1) expression. Here, we present two tumors of SMARCA4-UT of the esophagus with its microscopic appearance and immunohistochemical profile. We also include a literature review of SMARCA4-deficient tumors of the tubular gastrointestinal tract with their immunohistochemical and mismatch repair profiles for each specimen. Due to its non-specific histologic appearance and variable staining in expanded immunohistochemical panels, this tumor frequently overlaps with other tumor types, making the diagnosis of SMARCA4-UT challenging. These tumors are often associated with intestinal metaplasia of the esophagus and are thought to represent a high-grade undifferentiated transformation of a conventional esophageal adenocarcinoma. These tumors are typically associated with poor clinical outcomes and have poor response to conventional therapies. Currently, there are no standard guidelines for treatment of these tumors; however, palliative radiotherapy and systemic chemotherapy may provide benefit. More recently, immunotherapy and novel therapeutic targets have shown some promise for these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The rare ovarian cancer subtypes ovarian clear cell carcinoma (OCCC) and Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), can have mutations in members of a complex known as SWI/SNF that regulates the accessibility of chromatin to factors involved in DNA repair and gene expression. Some mutations in a particular complex member also occur in endometrioid ovarian cancer (EnOC) and endometriosis. Patients with endometriosis have a greater risk of developing OCCC and EnOC, with endometriosis frequently present at the time of diagnosis of these malignancies. The OCCC and SCCOHT ovarian cancer subtypes are notoriously difficult to treat with chemotherapies based on platinum-drugs that are standard-of-care for most cases of ovarian cancer. Mutations in members of this chromatin-remodelling complex offer new opportunities for molecular therapeutics using drugs that inhibit different aspects of cellular processes, including DNA repair, epigenetic regulation, kinase activity, and immune checkpoints. SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

Undifferentiated gastric carcinoma, characterized by anaplastic cells lacking distinct features of cytological or architectural differentiation, poses diagnostic and therapeutic challenges. Recent studies have suggested an association between this carcinoma and deficiencies in the SWI/SNF complex, particularly mutations in subunits such as SMARCA4. We herein report six cases of SMARCA4-deficient undifferentiated gastric carcinoma with molecular findings, highlighting the rarity and diagnostic pitfalls of this malignancy. Predominantly occurring in males over 50 years, these cases presented with nonspecific symptoms and were often diagnosed at an advanced stage. Histologically, the tumors exhibited a sheet-like growth pattern, reduced or absent epithelial markers, and loss of BRG-1 expression, with molecular analysis confirming SMARCA4 gene mutations. The response to conventional chemotherapy was poor, underscoring the importance of complete surgical resection and the development of alternative treatment modalities. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is one of the most prevalent and deadliest cancers worldwide. While the use of targeted therapies and immunotherapies in precision medicine has improved outcomes for some patients, a significant portion of individuals still fail to benefit, emphasizing the need to investigate the underlying mechanisms of resistance. Survival analyses have shown that NSCLC patients with SMARCA4 mutations often have poor prognoses. SMARCA4, the core ATPase subunit of the SWI/SNF chromatin remodeling complex, plays a critical role in regulating gene transcription by modifying chromatin accessibility. This influences essential cellular processes such as differentiation and cell cycle regulation, and SMARCA4 is widely regarded as a tumor suppressor. This review will explore the role of SMARCA4 mutations in tumor progression, its clinicopathological features in NSCLC, its impact on treatment outcomes, and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Sinonasal carcinomas are aggressive neoplasms that present a high morbidity and mortality rate with an unfavorable prognosis. This group of tumors exhibits morphological and genetic diversity. Genetic and epigenetic alterations in these neoplasms are the current targets for diagnosis and treatment. The most common type of cancer originating in the sinonasal tract is sinonasal squamous cell carcinomas (SNSCCs), which present different histological patterns and variable histological aggressiveness. A significant number of alterations have been reported in sinonasal tumors, including deficiencies in the Switch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. In the sinonasal tract, deficiencies of the subunits SMARCB1/INI1, SMARCA4/BRG1, and SMARCA2 have been noted in carcinomas, adenocarcinomas, and soft tissue tumors with a distinctive high-grade morphology and a fatal prognosis. Objective: The objective of this study is to identify the status of the SWI/SNF complex using immunohistochemistry in sinonasal squamous cell carcinomas and their association with morphology and survival. Methods: A total of 103 sinonasal carcinomas with different grades of squamous differentiation were analyzed; the selection was based on those cases with high-grade morphology. The carcinomas were then evaluated immunohistochemically for SMARCB1 and SMARCA4 proteins. Their expression was compared with the biological behavior and survival of the patients. Results: Among the SNSCCs, 47% corresponded to the non-keratinizing squamous cell carcinoma (NKSCC) type with high-grade characteristics, 40% were keratinizing squamous cell carcinomas (KSCCs), 9% were SMARCB1-deficient carcinomas, and 4% were SMARCA4-deficient carcinomas. Mosaic expression for SMARCB1 (NKSCC—33%; KSCC—21.9%) and SMARCA4 (NKSCC—14.6%; KSCC—12.2%) was identified, showing an impact on tumor size and progression. Conclusions: We identified that that the partial loss (mosaic expression) of SMARCB1 in SNSCCs is associated with high-grade malignant characteristics and a negative effect on patient survival; meanwhile, SMARCA4-mosaic expression in SNSCCs is associated with high-grade malignant characteristics and an increase in tumor size concerning the intact SMARCA4.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is one of the rare and aggressive cancers occurring mainly in adolescents and young women. It accounts for less than 0.01% of all ovarian malignancies, with around 500 cases reported to date in the medical literature. It has been postulated that these cases could be due to genetic alterations, and in 2014, studies discovered that SCCOHT is characterized by both germline and somatic deleterious mutations in SMARCA4. In this case series, we report two cases diagnosed with carcinoma ovary and found to be having mutations in SMARCA4. The patients in this case series were relatively young and both had germline SMARCA4 mutation. The first patient had FIGO stage IV disease and the second patient had FIGO stage III disease. The first patient started with paclitaxel plus carboplatin and the second patient started with gemcitabine plus docetaxel. One patient succumbed to disease within 1 year and another patient is alive at present with progression of disease. SCCOHT is very aggressive and needs diagnosis and treatment at an early stage. Early diagnosis and proper treatment may prolong survival. There is a need for evaluation of the possible role of targeted systemic therapeutic options as the conventional regimens are rarely sufficient. [ABSTRACT FROM AUTHOR]

Introduction: SMARCA4/SMARCA2 deficiencies have been linked to a variety of neoplasms and have been mainly described in cases of thoracic non-small cell lung cancers. Case Presentation: Here we present a case of SMARCA4/SMARCA2-deficient undifferentiated metastatic malignant tumor with carcinoma of unknown primary. The staining on pathology as well as the unremarkable size of the lung masses raises the possibility of dedifferentiated tumor of unknown primary. Conclusion: This case highlights the need for more routine testing of SMARCA4/SMARCA2 deficiencies as well as the development of more targeted therapies as these mutations are often associated with an aggressive course and poor outcomes.

Abstract Background SMARCA4, as one of the subunits of the SWI/SNF chromatin remodeling complex, drives SMARCA4-deficient tumors. Gastric SMARCA4-deficient tumors may include gastric SMARCA4-deficient carcinoma and gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Gastric SMARCA4-UT is rare and challenging to diagnose in clinical practice. The present report aims to provide insight into the clinicopathological characteristics and genetic alterations of gastric SMARCA4-UTs. Results We retrospectively reported four rare cases of gastric SMARCA4-UTs. All four cases were male, aged between 61 and 82 years. These tumors presented as ulcerated and transmural masses with infiltration, staged as TNM IV in cases 1, 2 and 4, and TNM IIIA in case 3. Pathologically, four cases presented solid architecture with undifferentiated morphology. Cases 2 and 3 showed focal necrosis and focal rhabdoid morphology. Immunohistochemical staining showed negative expression of epithelial markers and deficient expression of SMARCA4. Furthermore, positivity for Syn (cases 1, 2 and 3) and SALL4 (cases 1 and 2) were observed. Mutant p53 expression occurred in four cases, resulting in strong and diffuse staining of p53 expression in cases 1, 2 and 4, and complete loss in case 3. The Ki67 proliferative index exceeded 80%. 25% (1/4, case 4) of cases had mismatch repair deficiency (dMMR). Two available cases (cases 1 and 3) were detected with SMRACA4 gene alterations. The response to neoadjuvant therapy was ineffective in case 1. Conclusions Gastric SMARCA4-UT is a rare entity of gastric cancer with a poor prognosis, predominantly occurs in male patients. The tumors are typically diagnosed at advanced stages and shows a solid architecture with undifferentiated morphology. Negative expression of epithelial markers and complete loss of SMARCA4 immunoexpression are emerging as a useful diagnostic tool for rare gastric SMARCA4-UTs.

(1) Background: SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) is a rare and aggressive cancer that urgently requires novel therapeutic strategies. Despite the proven efficacy of immunotherapy in various cancer types, its application in SDUS remains largely unexplored. This study aims to investigate the immune microenvironment of SDUS to evaluate the feasibility of utilizing immunotherapy. (2) Methods: Multiplex immunofluorescence (mIF) was employed to examine the immune microenvironment in two cases of SDUS in comparison to other subtypes of endometrial stromal sarcomas (ESSs). This research involved a comprehensive evaluation of immune cell infiltration, cellular interactions, and spatial organization within the tumor immune microenvironment (TiME). Statistical analysis was performed to assess differences in immune cell densities and interactions between SDUS and other ESSs. (3) Results: SDUS exhibited a significantly higher density of cytotoxic T lymphocytes (CTLs), T helper (Th) cells, B cells, and macrophages compared to other ESSs. Notable cellular interactions included Th–CTL and Th–B cell interactions, which were more prominent in SDUS. The spatial analysis revealed distinct immune niches characterized by lymphocyte aggregation and a vascular-rich environment, suggesting an active and engaged immune microenvironment in SDUS. (4) Conclusions: The results suggest that SDUS exhibits a highly immunogenic TiME, characterized by substantial lymphocyte infiltration and dynamic cellular interactions. These findings highlight the potential of immunotherapy as an effective treatment approach for SDUS. However, given the small number of samples evaluated, these conclusions should be drawn with caution. This study underscores the importance of additional investigation into immune-targeted therapies for this challenging cancer subtype, with a larger sample size to validate and expand upon these preliminary findings. [ABSTRACT FROM AUTHOR]

The innate immune system serves as the first line of defense against β-coronaviruses (β-CoVs), a family of viruses that includes SARS-CoV-2. Viral sensing via pattern recognition receptors triggers inflammation and cell death, which are essential components of the innate immune response that facilitate viral clearance. However, excessive activation of the innate immune system and inflammatory cell death can result in uncontrolled release of proinflammatory cytokines, resulting in cytokine storm and pathology. PANoptosis, innate immune, inflammatory cell death initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes, has been implicated in the pathology of viral infections. Therefore, understanding the molecular mechanisms regulating PANoptosis in response to β-CoV infection is critical for identifying new therapeutic targets that can mitigate disease severity. In the current study, we analyzed findings from a cell death-based CRISPR screen with archetypal β-CoV mouse hepatitis virus (MHV) as the trigger to characterize host molecules required for inflammatory cell death. As a result, we identified SMARCA4, a chromatin regulator, as a putative host factor required for PANoptosis in response to MHV. Furthermore, we observed that gRNA-mediated deletion of Smarca4 inhibited MHV-induced PANoptotic cell death in macrophages. These findings have potential translational and clinical implications for the advancement of treatment strategies for β-CoVs and other infections. [ABSTRACT FROM AUTHOR]

Background. Undifferentiated gallbladder carcinoma is a rare type of cancer with poor prognosis, due to the absence of specific clinical manifestations, and the final diagnosis depends on pathological and immunohistochemical examinations. However, only a few reports of SMARCA4-deficient undifferentiated gallbladder tumor have been published to date. Therefore, we report the diagnosis and treatment of an undifferentiated gallbladder carcinoma with SMARCA4 deficiency. Case Presentation. A 65-year-old woman with undifferentiated gallbladder carcinoma was treated using traditional Chinese medicine and underwent palliative surgery in our hospital. The postoperative pathology showed SMARCA4-deficient undifferentiated gallbladder carcinoma with metastasis to the abdominal lymph nodes. Conclusions. This case report contributes to the limited literature regarding undifferentiated carcinoma without SMARCA4 in the gallbladder. [ABSTRACT FROM AUTHOR]

Context: Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently described aggressive neoplasm of young smokers defined by SMARCA4 inactivating mutations and characterized by cells with rhabdoid morphology, high mitotic activity, and abundant necrosis. Objective: Describe and compare 3 unusual presentations of SMARCA4-UT in older adults, including one presenting as a metastatic lesion mimicking a primary bone sarcoma. Discuss the molecular characteristics of SMARCA4-UT and their relationship to nonsmall-cell lung carcinomas with SMARCA4. Design: Three patients with SMARCA4-UTs were identified utilizing a natural language search in CoPath. hematoxylin and eosin sections from all patients as well as Papanicolaou-stained slides and Diff-Quik-stained slides for the first patient were examined. A broad range of immunostains, including BRG1/SMARCA4, were evaluated. Molecular testing was performed via next-generation sequencing. Results: The 3 patients were aged 58, 70, and 70 years. All had a significant smoking history. The first patient presented with an iliac bone mass and mediastinal lymphadenopathy, the second with mediastinal adenopathy, and the third with a paratracheal mass. All 3 tumors showed a diffuse proliferation of pleomorphic, rhabdoid cells with high mitotic activity and tumor necrosis. SMARCA4 was lost in all 3 tumors by immunohistochemistry. Molecular testing revealed SMARCA4 alterations in the first 2. Conclusions: Thoracic SMARCA4-UT should be considered in the differential diagnosis of pleomorphic rhabdoid tumors in older adults with a smoking history. Although most present as lung and/or mediastinal masses, they may occasionally present as a metastasis and mimic an undifferentiated sarcoma, representing a potential diagnostic pitfall. [ABSTRACT FROM AUTHOR]

This critical review investigates the impact of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations on survival outcomes in non-small cell lung cancer (NSCLC) through an analysis of 21 peer-reviewed articles. Survival analyses across this review demonstrated consistently worse outcomes for SMARCA4-mutated vs. SMARCA4 wild-type NSCLC patients, specifically emphasizing class 1 truncating mutations as an independent factor for poor overall survival. In addition, this review explores the clinicopathologic characteristics of SMARCA4 mutations and their impact on various treatment modalities, including immune checkpoint inhibitors (ICIs) both with and without Kirsten rat sarcoma viral oncogene homolog (KRAS) co-mutations. The potential ineffectiveness of ICI treatment in NSCLC is explored through the impact of SMARCA4/KRAS co-mutations on the tumor microenvironment. Moreover, this NSCLC review consistently reported statistically worse overall survival outcomes for SMARCA4/KRAS co-mutations than SMARCA4 wild-type/KRAS-mutated cohorts, extending across ICIs, chemo-immunotherapy (CIT), and KRAS G12C inhibitors. Designing prospective clinical SMARCA4-mutated or SMARCA4/KRAS co-mutated NSCLC trials to evaluate targeted therapies and immunotherapy may lead to a better understanding of how to improve cancer patients' outcomes and survival rates. [ABSTRACT FROM AUTHOR]

SMARCB1 or SMARCA4-deficient sinonasal carcinoma or thoracic undifferentiated tumor has aggressive nature with a poor prognosis. Patients with this disease were diagnosed by immunohistochemistry or next-generation sequencing. Those who were able to receive a surgery tended to be cured, while the others treated with chemotherapy, radiation therapy, or immune checkpoint inhibitor were often insensitive to these therapies. However, one having CD274 (PD-L1) amplification showed the response to immune checkpoint inhibitor and a good prognosis. We believed that this report could provide promising information for determining the optimal treatment option. [ABSTRACT FROM AUTHOR]

Background: SMARCA4, as one of the subunits of the SWI/SNF chromatin remodeling complex, drives SMARCA4-deficient tumors. Gastric SMARCA4-deficient tumors may include gastric SMARCA4-deficient carcinoma and gastric SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Gastric SMARCA4-UT is rare and challenging to diagnose in clinical practice. The present report aims to provide insight into the clinicopathological characteristics and genetic alterations of gastric SMARCA4-UTs. Results: We retrospectively reported four rare cases of gastric SMARCA4-UTs. All four cases were male, aged between 61 and 82 years. These tumors presented as ulcerated and transmural masses with infiltration, staged as TNM IV in cases 1, 2 and 4, and TNM IIIA in case 3. Pathologically, four cases presented solid architecture with undifferentiated morphology. Cases 2 and 3 showed focal necrosis and focal rhabdoid morphology. Immunohistochemical staining showed negative expression of epithelial markers and deficient expression of SMARCA4. Furthermore, positivity for Syn (cases 1, 2 and 3) and SALL4 (cases 1 and 2) were observed. Mutant p53 expression occurred in four cases, resulting in strong and diffuse staining of p53 expression in cases 1, 2 and 4, and complete loss in case 3. The Ki67 proliferative index exceeded 80%. 25% (1/4, case 4) of cases had mismatch repair deficiency (dMMR). Two available cases (cases 1 and 3) were detected with SMRACA4 gene alterations. The response to neoadjuvant therapy was ineffective in case 1. Conclusions: Gastric SMARCA4-UT is a rare entity of gastric cancer with a poor prognosis, predominantly occurs in male patients. The tumors are typically diagnosed at advanced stages and shows a solid architecture with undifferentiated morphology. Negative expression of epithelial markers and complete loss of SMARCA4 immunoexpression are emerging as a useful diagnostic tool for rare gastric SMARCA4-UTs. [ABSTRACT FROM AUTHOR]

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive tumors of the central nervous system (CNS), accounting for 1–3% of all pediatric CNS tumors. In general, AT/RTs are associated with biallelic inactivation of SMARCB1, resulting in the loss of expression of the integrase interactor 1 (INI1) protein. In this report, we describe the clinical course of an infant patient who presented with fatigue, postprandial vomiting, and disability of left side movement. Histological examination revealed classical features indicative of rhabdoid tumors, yet an atypical immunohistochemical profile with preserved INI1 expression was observed. Molecular diagnostics further elucidated the presence of a heterozygous frameshift variant, SMARCA4 c.2693del, p.(Asn898Thrfs*12), underscoring the distinctive genetic foundations of the case. Surgical resection of the tumor was administered with subsequent chemotherapy to the patient, but the condition worsened dynamically, and a decision was made to give the patient palliative therapy. We report on a patient with AT/RT caused by a rare mutation of the SMARCA4 gene and an aggressive course of disease to provide more information and characteristics of these tumors. [ABSTRACT FROM AUTHOR]

The reactivated adult epicardium produces epicardium-derived cells (EPDCs) via epithelial-mesenchymal transition (EMT) to benefit the recovery of the heart after myocardial infarction (MI). SMARCA4 is the core catalytic subunit of the chromatin re-modeling complex, which has the potential to target some reactivated epicardial genes in MI. However, the effects of epicardial SMARCA4 on MI remain uncertain. This study found that SMARCA4 was activated over time in epicardial cells following MI, and some of activated cells belonged to downstream differentiation types of EPDCs. This study used tamoxifen to induce lineage tracing and SMARCA4 deletion from epicardial cells in Wt1-CreER;Smarca4 fl/fl ;Rosa26-RFP adult mice. Epicardial SMARCA4 deletion reduces the number of epicardial cells in adult mice, which was related to changes in the activation, proliferation, and apoptosis of epicardial cells. Epicardial SMARCA4 deletion reduced collagen deposition and angiogenesis in the infarcted area, exacerbated cardiac injury in MI. The exacerbation of cardiac injury was related to the inhibition of generation and differentiation of EPDCs. The alterations in EPDCs were associated with inhibited transition between E -CAD and N-CAD during the epicardial EMT, coupled with the down-regulation of WT1, SNAIL1, and PDGF signaling. In conclusion, this study suggests that Epicardial SMARCA4 plays a critical role in cardiac injury caused by MI, and its regulatory mechanism is related to epicardial EMT. Epicardial SMARCA4 holds potential as a novel molecular target for treating MI. [Display omitted] • Lineage tracing and SMARCA4 deletion in epicardial cells were achieved using Wt1-CreER;Smarca4fl/fl;Rosa26-RFP mice. • Epicardial SMARCA4 deletion exacerbated cardiac injury in myocardial infarction. • Epicardial SMARCA4 deletion inhibited the generation and differentiation of EPDCs in myocardial infarction. • The effects of Epicardial SMARCA4 deletion on EPDCs were related to the obstruction of epicardial EMT. [ABSTRACT FROM AUTHOR]

Introduction : Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly aggressive malignant neoplasm characterized by high-grade undifferentiated morphologic features and recurrent inactivating mutations of SMARCA4. These tumors consistently exhibit loss of SMARCA4 (BRG1) while displaying variable expression of other nonspecific markers. Recently, we encountered a SMARCA4-UT demonstrating immunoreactivity for GATA3, and we sought to characterize this phenomenon in a larger series. Methods : A total of nine SMARCA4-UTs were examined from 3 large academic institutions. The clinicopathologic and molecular characteristics were studied and GATA3 immunohistochemistry was performed. Results : The cohort included 5 male and 4 female patients, with a median age of 54 years and a median smoking history of 37 pack-years. At initial diagnosis, mediastinal lymph node involvement was observed in 5 patients (56%) while distant metastases were present in 7 patients (78%). The median survival was 6 months. Histologically, the tumors were characterized by sheets of undifferentiated epithelioid and/or rhabdoid cells, accompanied by frequent mitotic figures and necrosis. Immunohistochemically, all tumors displayed a complete loss of BRG1 expression. Notably, 4 of 9 tumors (44%) were positive for GATA3 expression, including one tumor that exhibited strong and diffuse immunoreactivity. Conclusions : GATA3 expression in SMARCA4-UT may pose diagnostic challenges, requiring differentiation from other GATA3-positive tumors. This distinction is crucial for accurate prognostication and treatment decisions. [ABSTRACT FROM AUTHOR]

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but highly aggressive ovarian malignant neoplasm lacking a unified clinical management process. Most patients are diagnosed at an advanced stage and have an extremely poor prognosis with an overall probability of survival less than 10 %. Here, we describe the case of a patient with advanced SCCOHT achieved a survival of over 5 years after receiving multiple cycles of immunotherapy combined with anti-angiogenic therapy or CDK4/6 inhibitors. At the same time, we also summarized the case reports and clinical trials of immunotherapy in SCCOHT. [ABSTRACT FROM AUTHOR]

Abstract SMARCA4‐deficient undifferentiated thoracic tumors are a rare phenomenon. A 40‐year‐old male was newly diagnosed with SMARCA4‐deficient undifferentiated non‐small cell lung cancer. He had a history of heavy smoking and job‐related exposure to metal dust and melted nickel. CT imaging showed numerous right‐sided pleural masses and soft tissue plaques, but no metastases. CT‐guided biopsy of a pleural mass confirmed the diagnosis. He was prescribed six cycles of carboplatin paclitaxel, and follow‐up imaging showed largely stable disease. Treatment was changed to nivolumab due to shortness of breath, and he received one cycle of nivolumab without considerable side effects. Unfortunately, during the second cycle of his nivolumab, the patient presented with new weakness. Imaging showed spinal cord metastasis and he underwent a laminectomy; he was subsequently followed up as an outpatient. The objective of this publication was to explore SMARCA4‐deficient undifferentiated thoracic tumors, other related SMARCA4‐deficient tumors, and their overall pattern of presentation. The genetic aberrations of this case are compared to recent publications that also discuss genetic aberrations commonly occurring with this disease process, with an ultimate goal of hastening detection and adding to the library of treatment results.

Almost all medulloblastomas (MB) of the Wingless/Int-1 (WNT) type are characterized by hotspotmutations in CTNNB1, and mouse models have convincingly demonstrated the tumor-initiating role of these mutations. Additional alterations in SMARCA4 are detected in ~20% of WNT MB, but their functional role is mostly unknown. We, therefore, amended previously described brain lipid binding protein (Blbp)-cre::Ctnnb1(ex3)fl/wt mice by the introduction of floxed Smarca4 alleles. Unexpectedly, mutated and thereby stabilized ß-catenin on its own induced severe developmental phenotypes in male and female Blbp-cre::Ctnnb1(ex3)fl/wt mice in our hands, including a thinned cerebral cortex, hydrocephalus, missing cerebellar layering, and cell accumulations in the brainstem and cerebellum. An additional loss of SMARCA4 even resulted in prenatal death for most mice. Respective Blbp-cre:: Ctnnb1(ex3)fl/wt::Smarca4fl/rec mutants (male and female) developed large proliferative lesions in the cerebellum evolving from E13.5 to E16.5. Histological and molecular analysis of these lesions by DNA methylation profiling and single-cell RNA sequencing suggested an origin in early undifferentiated SOX2-positive cerebellar progenitors. Furthermore, upregulated WNT signaling, altered actin/cytoskeleton organization, and reduced neuronal differentiation were evident in mutant cells. In vitro, cells harboring alterations in both Ctnnb1 and Smarca4 were negatively selected and did not show tumorigenic potential after transplantation in adult female recipient mice. However, in cerebellar explant cultures, mutant cells displayed significantly increased proliferation, suggesting an important role of the embryonic microenvironment in the development of lesions. Altogether, these results represent an important first step toward the unraveling of tumorigenic mechanisms induced by aberrant WNT signaling and SMARCA4 deficiency. [ABSTRACT FROM AUTHOR]

Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise. [ABSTRACT FROM AUTHOR]

Primary cutaneous SMARCA4‐deficient undifferentiated malignant neoplasm (SD‐UMN) is a rare and recently described entity characterized by the loss of expression of the SMARCA4 (BRG1) protein, which is involved in chromatin remodeling. SD‐UMN presents a diagnostic challenge due to its rarity and unique histopathological and immunohistochemical features. In this report, we present a case of primary cutaneous SD‐UMN in a 67‐year‐old man who presented with a rapidly growing, ulcerated, and bleeding nodule on his right cheek. Histopathological examination revealed a highly cellular dermal tumor consisting of pleomorphic epithelioid cells with prominent mitotic figures and necrosis, lacking any morphological evidence of differentiation. Immunohistochemical analysis showed a complete loss of SMARCA4 and SMARCA2 expression, while INI‐1 expression remained intact. p53 was diffusely expressed, and p16 was completely absent. In addition, a range of markers, including high‐molecular‐weight cytokeratin, p63, SOX10, INSM1, MCPyV, NKX2.2, CD99, CDX2, CD56, ERG, NUT, desmin, androgen receptor, chromogranin, CD34, and CD43 were all negative. To date, only two cases of primary cutaneous SMARCA4‐deficient undifferentiated tumors have been reported in the literature. Therefore, this case report adds to the limited body of knowledge on the clinical and histopathological features of this novel entity. The report highlights the importance of considering SD‐UMN in the differential diagnosis of undifferentiated cutaneous tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. We aimed to examine the association of SMARCA4ms with clinicopathological factors, patient survival, and co-occurrence with other gene mutations identified through an NGS panel in GEA patients. SMARCA4ms were identified in 19 out of 256 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046), but not with other clinicopathological variables, including survival (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA. Background: The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. Methods: A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. Results: SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. Conclusions: These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA. [ABSTRACT FROM AUTHOR]

SMARCA4-deficient undifferentiated thoracic tumors are a rare phenomenon. A 40-year-old male was newly diagnosed with SMARCA4-deficient undifferentiated non-small cell lung cancer. He had a history of heavy smoking and job-related exposure to metal dust and melted nickel. CT imaging showed numerous right-sided pleural masses and soft tissue plaques, but no metastases. CT-guided biopsy of a pleural mass confirmed the diagnosis. He was prescribed six cycles of carboplatin paclitaxel, and follow-up imaging showed largely stable disease. Treatment was changed to nivolumab due to shortness of breath, and he received one cycle of nivolumab without considerable side effects. Unfortunately, during the second cycle of his nivolumab, the patient presented with new weakness. Imaging showed spinal cord metastasis and he underwent a laminectomy; he was subsequently followed up as an outpatient. The objective of this publication was to explore SMARCA4-deficient undifferentiated thoracic tumors, other related SMARCA4-deficient tumors, and their overall pattern of presentation. The genetic aberrations of this case are compared to recent publications that also discuss genetic aberrations commonly occurring with this disease process, with an ultimate goal of hastening detection and adding to the library of treatment results. [ABSTRACT FROM AUTHOR]

Summary: SMARCA4 is a gene traditionally considered a tumor suppressor. Recent research has however found that SMARCA4 likely promotes cancer growth and is a good target for cancer treatment. The drug carbamazepine, an autophagy inducer, was used on colorectal cancer cell lines, HCT1116 and Hke3 (KRAS mutant and wildtype). Our study finds that Carbamazepine affects SMARCA4 levels and that this effect is different depending on the KRAS mutation status. This study analyzes the effect of carbamazepine on early-stage autophagy via ULK1 as well as simulates the docking of carbamazepine on KRAS, depending on the mutation status. Our study highlights the therapeutic uses of carbamazepine on cancer, and we propose that carbamazepine in conjunction with other chemotherapies may prove useful in targeting KRAS-mutated colorectal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Rhabdoid tumors are a group of rare and aggressive pediatric cancers that are associated with dismal survival rates. These tumors are classified within the ~20% of all cancers showing mutations in the subunits of the SWI/SNF chromatin remodeling complex. Chromatin remodelers are large protein complexes that control gene expression at least in part through regulating DNA accessibility. In rhabdoid tumor cell lines, which harbor inactivating mutations in the SMARCB1 gene, the SWI/SNF subunit BRG1—a synthetic lethal target in these cells—retains functionality in chromatin remodeling and regulation of the rhabdoid genome. The aim of this study was to assess the contribution of BRG1 to rhabdoid gene regulation across multiple rhabdoid cell lines. These data provide valuable insights in understanding how gene regulation following SMARCB1 loss is achieved, which may be broadly applicable to other cancers marked by SWI/SNF subunit mutation. Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1—which becomes essential in the absence of SMARCB1—but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression in SMARCB1-deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines. We find that although BRG1-regulated open chromatin sites are distinct at the locus level, the biological characteristics of the loci are very similar, converging on a set of thematically related genes and pointing to the involvement of the AP-1 transcription factor. The open chromatin sites regulated by BRG1 colocalize with histone-marked enhancers and intriguingly include almost all super-enhancers, revealing that BRG1 plays a critical role in maintaining super-enhancer function in this setting. These studies can explain the essentiality of BRG1 to rhabdoid tumor cell identity and survival and implicate the involvement of AP-1 as a critical downstream effector of rhabdoid tumor cell transcriptional programs. [ABSTRACT FROM AUTHOR]

With the advent of molecular immunohistochemistry and next generation sequencing, Switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex altered tumors have gained recognition recently. SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily B member 1 (SMARCB1) and SMARCA4 are the primary SWI/SNF components altered in several recently described undifferentiated malignancies in head and neck region with predilection for paranasal sinuses in SMARCB1-deficient tumors and nasal cavity in SMARCA4-deficient tumors. However, to the best of our knowledge, SMARCA4-deficient tumors of the oropharynx have not been described. We present an unusual case of SMARCA4-deficient carcinoma of the oropharynx (palatine tonsil) which is the first case in the literature, expanding the topographic distribution of SMARCA4-deficient tumors in the head and neck region and emphasizing the importance of BRG1 as an essential immunohistochemical marker for the diagnosis of this distinct entity. [ABSTRACT FROM AUTHOR]

ABSTRACT Background SMARCA4 is a component gene of the SWI/SNF (SWItch/Sucrose NonFermentable) chromatin remodeling complex; undifferentiated tumors associated with its functional deletion have been described in several organs. However, no established treatment for these tumors currently exists. Case In this study, we report a case of a SMARCA4‐deficient undifferentiated urothelial carcinoma with high PD‐L1 expression that was effectively treated with nivolumab after early relapse following treatment for non‐invasive bladder cancer. The histological morphology of the rhabdoid‐like undifferentiated tumor of unknown primary led us to suspect a SWI/SNF‐deficient tumor, and subsequent immunostaining led to the diagnosis of a SMARCA4‐deficient undifferentiated tumor. This effort also led to the identification of the developmental origin of this SMARCA4‐deficient undifferentiated tumor as a non‐invasive bladder cancer. We also carried out a detailed immune phenotypic assay on peripheral T cells. In brief, a phenotypic change of CD8+T cells from naive to terminally differentiated effector memory cells was observed. Conclusion Regardless of the organ of cancer origin or cancer type, SWI/SNF‐deficient tumors should be suspected in undifferentiated and dedifferentiated tumors, and immune checkpoint inhibitors may be considered as a promising treatment option for this type of tumor. The pathogenesis of SMARCA4‐deficient anaplastic tumors awaits further elucidation for therapeutic development.

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.

SMARCA4-deficient gastric carcinoma has been reported sporadically since 2016. Only 29 patients have been reported; nevertheless, it is aggressive and highly malignant with poor outcomes. It has an immunohistochemical phenotype showing loss of SMARCA4 expression and can be accompanied by codeletion of other switch/sucrose non-fermentable chromatin-remodeling complex subunits. Microscopically, it displays high-grade undifferentiated histological morphology with rhabdoid cell differentiation. Rarely does the tumor contain a purely or partly adenocarcinoma component. Here, we report two cases to demonstrate these unusual morphologies analyzed using morphological and immunohistochemical techniques. In addition, there is a lack of research on the classification of these morphologies. Therefore, our report will aid the diagnosis and classification of SMARCA4-deficient gastric carcinoma. [ABSTRACT FROM AUTHOR]

Background: Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4- UT) is a distinct clinicopathological entity with an aggressive clinical course. Additionally, SMARCA4/BRG1 deficiency can be observed in a few patients with non-small cell lung cancer (NSCLC). We aimed to compare the clinicopathological, immunohistochemical and prognostic features of SMARCA4-deficient NSCLC (SMARCA4-dNSCLC) with those of thoracic SMARCA4-UT. Methods: Patients with BRG1-deficient tumors in the lung or thorax were enrolled in the study from the Department of Pathology of West China Hospital, Sichuan University, from January 2014 to June 2022. We retrospectively collected the clinicopathological and immunohistochemical features and outcomes of these patients. Results: Seventy-two patients had tumors in the lung or thorax with BRG1-deficient expression, including 52 patients with SMARCA4-dNSCLC and 20 patients with thoracic SMARCA4-UT. Among the patients with SMARCA4-dNSCLC, 98.1% were male, 85.7% were smokers, and 79.5% (35/44) had tumor-node-metastasis (TNM) III-IV tumors. Among the patients with thoracic SMARCA4-UT, all were males who smoked, and 93.75% (15/16) had TNM III-IV tumors. Pure solid architecture and necrosis were the predominant pathological features. Rhabdoid morphology was observed in some SMARCA4-dNSCLCs (10/52, 19.2%) and thoracic SMARCA4-UTs (11/20, 55%). In most patients with thoracic SMARCA4-UT, the tumors exhibited scattered weak expression or negative expression of epithelial markers, and positive expression of CD34 and Syn. Overall survival (OS) and progression-free survival (PFS) were not significantly different between patients with SMARCA4-dNSCLC and patients with thoracic SMARCA4-UT (p = 0.63 and p = 0.20, respectively). Conclusions: Thoracic SMARCA4-DTs include SMARCA4-dNSCLC and thoracic SMARCA4-UT. Both have overlapping clinicopathological features and poor prognosis. We hypothesize that thoracic SMARCA4-UT may be the undifferentiated or dedifferentiated form of SMARCA4-dNSCLC. However, further studies with larger cohorts and longer follow-up periods are needed. [ABSTRACT FROM AUTHOR]

NUT carcinoma and thoracic SMARCA4‐deficient undifferentiated tumour are unique entities in the 5th edition of the World Health Organisation (WHO) Classification of Thoracic Tumours, whose definitions include molecular genetic abnormalities. These aggressive tumours require rapid work‐ups on biopsies, but a broad list of differential diagnoses poses challenges for practising pathologists. This review provides an update on their key clinicopathological and molecular characteristics, as well as controversies regarding tumour classification and diagnostic strategy. Phenotypical assessment plays a substantial role in diagnosis because recurrent and predictable clinicopathological findings exist, including robust immunohistochemical phenotypes. Accurate diagnosis is crucial for appropriate management and a clearer understanding of the disease. [ABSTRACT FROM AUTHOR]

Purpose: SMARCA4-deficient thoracic tumors, characterized by distinct clinicopathological, morphological, immunohistochemical, and genetic features, differ significantly from conventional non-small-cell lung carcinomas (NSCLCs). This group encompasses both SMARCA4-deficient NSCLCs (SMARCA4-NSCLCs) and SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs). The efficacy of PD-1 inhibitors in treating SMARCA4-deficient thoracic tumors remains uncertain. Methods: Medical records of 36 patients diagnosed with stage IIIB, IIIC, or IV SMARCA4-deficient thoracic tumors were analyzed. We assessed the clinical, pathological, and genetic features of these patients through immunohistochemistry (IHC) and a 68-gene panel next-generation sequencing (NGS). We compared the differences between SMARCA4-NSCLCs and SMARCA4-UTs, and evaluated the impact of chemotherapy and immunotherapy on patient outcomes. Results: The majority of patients with SMARCA4-deficient thoracic tumors were heavy-smoking males, averaging 64.6 years in age. IHC predominantly showed weak or negative staining for markers such as TTF-1, CK5/6, p40, synaptophysin, chromogranin A, and CD56, which are often associated with adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumors. The most common genetic mutations identified via NGS included TP53, CDKN2A, KRAS, STK11, NF1, and PTEN. No significant overall survival (OS) difference was observed between SMARCA4-NSCLCs and SMARCA4-UTs (p=0.366). The median OS for patients treated with chemotherapy (n=9) was 447 days, while the median OS for patients undergoing PD-1-inhibitor-based therapy (n=16) was not reached (p=0.105). Conclusion: SMARCA4-deficient thoracic tumors exhibit distinct characteristics from conventional NSCLCs, and PD-1 inhibitors show promise in treating advanced SMARCA4-deficient thoracic tumors. [ABSTRACT FROM AUTHOR]

SMARCA4-deficient undifferentiated tumors are a rare clinical entity with an aggressive clinical course, poor prognosis, and no standard-of-care therapeutic approach. These have most frequently been documented in the lung and thoracic cavity. There is a growing body of evidence for the role of immunotherapy in SMARCA4-deficient lung cancer, a disease process that historically does very poorly with cytotoxic chemotherapy alone. We present three cases where the primary tumors were instead found within the gastrointestinal system: two originating from the small bowel and one from the esophagus. In all three cases, clinical response was seen with pembrolizumab therapy, with two of the three patients receiving long-term benefit. Our series suggests that anti-PD1 immunotherapy may have promising efficacy for undifferentiated carcinomas of the gastrointestinal tract with SMARCA4 deficiency. [ABSTRACT FROM AUTHOR]

Background and objective The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC. Methods 46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC. Results Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC. Conclusion Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.

Undifferentiated carcinoma of the esophagus is an entity that is included in WHO classification of digestive systems fifth edition (2018). The definition of this entity is a malignant esophageal epithelial tumor that lacks definite microscopic features of squamous, glandular, or neuroendocrine differentiation. It is a challenging diagnosis to make due to lack of diagnostic criteria. We report a case from a 45 years old man with a mass in the lower third of esophagus. Biopsy showed an epitheloid neoplasm with sheet like growth pattern and no glandular formation. The tumor cells had prominent nucleoli and indistinct cell borders. There were occasional rhabdoid cells. By immunostains, tumor cells were focally positive for pankeratin, keratin 7, synaptophysin, negative for CDX2 and p40, INSM1, chromogranin, and CD56. Background intestinal metaplasia (Barrett esophagus) was present. Next generation sequencing of the tumor revealed SMARCA4 deep deletion. The tumor showed loss of SMARCA4 by immunostain. This case demonstrates that undifferentiated carcinoma of the esophagus with SMARCA4 deletion can express synaptophysin. Awareness of this entity is important for the correct classification of this tumor. [ABSTRACT FROM AUTHOR]

(1) Background: SMARCA4-deficient undifferentiated uterine sarcoma (SDUS) is a rare and aggressive cancer that urgently requires novel therapeutic strategies. Despite the proven efficacy of immunotherapy in various cancer types, its application in SDUS remains largely unexplored. This study aims to investigate the immune microenvironment of SDUS to evaluate the feasibility of utilizing immunotherapy. (2) Methods: Multiplex immunofluorescence (mIF) was employed to examine the immune microenvironment in two cases of SDUS in comparison to other subtypes of endometrial stromal sarcomas (ESSs). This research involved a comprehensive evaluation of immune cell infiltration, cellular interactions, and spatial organization within the tumor immune microenvironment (TiME). Statistical analysis was performed to assess differences in immune cell densities and interactions between SDUS and other ESSs. (3) Results: SDUS exhibited a significantly higher density of cytotoxic T lymphocytes (CTLs), T helper (Th) cells, B cells, and macrophages compared to other ESSs. Notable cellular interactions included Th–CTL and Th–B cell interactions, which were more prominent in SDUS. The spatial analysis revealed distinct immune niches characterized by lymphocyte aggregation and a vascular-rich environment, suggesting an active and engaged immune microenvironment in SDUS. (4) Conclusions: The results suggest that SDUS exhibits a highly immunogenic TiME, characterized by substantial lymphocyte infiltration and dynamic cellular interactions. These findings highlight the potential of immunotherapy as an effective treatment approach for SDUS. However, given the small number of samples evaluated, these conclusions should be drawn with caution. This study underscores the importance of additional investigation into immune-targeted therapies for this challenging cancer subtype, with a larger sample size to validate and expand upon these preliminary findings.

Abstract Purpose To improve the understanding of special types of tumors, we summarized and analyzed the clinicopathological features and prognostic factors of SMARCA4‐deficient non‐small cell lung cancer (SMARCA4‐dNSCLC). Methods We selected 105 patients with SMARCA4‐dNSCLC and 221 patients with SMARCA4‐intact non‐small cell lung cancer (SMARCA4‐iNSCLC) by performing immunohistochemical analysis of 1520 NSCLC samples, and we assessed the patients' clinicopathological features and survival state. Results (1) SMARCA4‐dNSCLC was significantly associated with older age, male sex, smoking history, larger invasive tumor size, higher tumor proliferation index (Ki‐67), more adrenal metastases, more lymph node metastases, and few EGFR mutations (p

Clear cell carcinomas are rare and relatively chemo-insensitive ovarian cancers with a characteristic molecular pathogenesis. Alterations in ARID1A, a component of the multiprotein chromatin remodeling complex SWI/SNF, are likely early events in the development of ovarian clear cancers arising from atypical endometriosis. Insight into additional driver events and particularly mutations in the same chromatin remodeling complex is limited. Isolated loss of SMARCA4, encoding the ATPase of the SWI/SNF complex, characterizes other aggressive gynecologic cancers including small cell carcinomas of the ovary hypercalcemic type (SCCOHT), undifferentiated endometrial carcinomas (UDEC), and uterine sarcomas (SDUS). The ovarian clear cell carcinoma of a 48-year-old showed in the initial surgical specimen a subclonal loss of SMARCA4 in addition to an ARID1A mutation, i.e., two alterations in the SWI/SNF heterochromatin remodeling complex. We anticipated that the SMARCA4 loss would worsen the disease course in analogy to SCCOHT, UDEC, and SDUS. However, the disease did not accelerate. Instead, the recurrent disease showed restored SMARCA4 expression while retaining the ARID1A mutation. Combinatorial redundancy, diversity and sequence in the SWI/SNF complex assembly as well as DNA- and tissue-specificity may explain the observed irrelevance of SMARCA4 loss in the presented ARID1A mutated ovarian clear cell carcinoma.

Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy and clinical benefits from targeted therapies were observed only in a minority of patients with sarcomas. The rarity of these tumors, paucity of actionable mutations, and limitations in the chemical composition of current targeted therapies hindered the use of these approaches in sarcomas. Targeted protein degradation (TPD) is an innovative pharmacological modality to directly alter protein abundance with promising clinical potential in cancer, even for undruggable proteins. TPD is based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs), which trigger ubiquitin-dependent degradation of protein of interest. In this review, we will discuss major features of PROTAC and PROTAC-derived genetic systems for target validation and cancer treatment and focus on the potential of these approaches to overcome major issues connected to targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets. A deeper understanding of these strategies might provide new fuel to drive molecular and personalized medicine to sarcomas. [ABSTRACT FROM AUTHOR]

The co-occurrence of multiple disease processes can pose diagnostic challenges. We report an unusual case of a patient found to have co-occurrences of an IDH1-mutant high-grade glioma along with cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. Somatic testing was done on the tumor and identified a SMARCA4 and two TP53 variants. Within the literature, little is known about the association of high-grade gliomas with these germline variants. Such findings furthermore not only inform complex diagnoses, but have the potential to play a crucial role in the ongoing care of a patient. [ABSTRACT FROM AUTHOR]

Background: Aberrant expression of SWI/SNF complex subunits is closely associated with tumorigenesis. The clinicopathological and prognostic significance of altered SMARCA2 and SMARCA4 subunits has not been well evaluated in gastric adenocarcinoma. Methods: We collected 1271 postoperative cases of gastric adenocarcinoma and then constructed tissue microarrays (TMA), from which we obtained the immunohistochemistry expression of SMARCA2 and SMARCA4. Next, we screened the variables related to the loss of SMARCA2 and SMARCA4 by univariate correlation analysis and multivariate logistic regression analysis. Then, we identified the variables related to prognosis by univariate and multivariate Cox regression analysis. Finally, we constructed a nomogram prognostic model and evaluated it. Results: The loss of SMARCA2 and SMARCA4 occurred in 236 (18.57%) and 86 (6.77%) cases, respectively, including 26 cases of co-loss. After multivariate logistic regression, variables independently associated with SMARCA2 loss were T stage, differentiation status, WHO histological classification, and EBER. Variables independently associated with SMARCA4 loss were differentiation status, WHO histological classification, PD-L1, and MMR. Survival analysis revealed that the SMARCA2 and SMARCA4 lost groups showed worse survival than the corresponding present groups (P = 0.032 and P = 0.0048, respectively). Univariate and multivariate Cox analyses identified independent prognostic factors, including age, T stage, N stage, M stage, SMARCA2, and chemotherapy. Conclusion: The loss of SMARCA2 and SMARCA4 correlated with poor differentiation, leading to a worse prognosis. SMARCA2, as an independent prognostic factor, combined with other clinicopathological variables, established a novel nomogram prognostic model, which outperformed the AJCC TNM model. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical features and prognosis of non - small lung cancer (NSCLC) patients harboring SMARCA4 mutation, and detect the clinical significance of SMARCA4 gene via bioinformatics method. Methods: Clinical data from 35 patients with NSCLC harboring SMARCA4 mutations were retrospectively reviewed. According to the type of co - mutated gene, the patients were divided into several groups. The survival rate was calculated by Kaplan-Meier method. The expression of SMARCA4 in NSCLC tissue and normal lung tissue was investigated by TIMER database and GEPIA database. The cBioPortal database was used to analyze frequencies and types of SMARCA4 gene mutation, as well as the relationship of SMARCA4 mutation and prognosis. SMARCA4- related protein - protein interaction network was constructed by STRING database. Results: SMARCA4-mutated NSCLC patients were mainly old males, and lung adenocarcinoma was the main pathological type. The accompanying mutated genes included EGFR (14 cases), TP53 (11 cases), KRAS (4 cases), ERBB2 (4 cases), etc. Survival analysis found that the prognosis of patients with EGFR mutation was better than that of wild type, while the prognosis of patients with KRAS mutation was worse than that of wild type. Bioinformatics analysis showed that 8% of NSCLC patients carried SMARCA4 gene mutation, including missense mutations, splicing mutations and deletion mutations. In general, lung adenocarcinoma patients with SMARCA4 mutations had a poorer prognosis than wild- type patients. Conclusion: SMARCA4 mutations may affect the prognosis of NSCLC patients, and the accompanied mutations may have different effects on the prognosis, providing specific evidence for the precise treatment of lung cancer. [ABSTRACT FROM AUTHOR]