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Gastrointestinal stromal tumors (GISTs) are sarcomas affecting the stomach and small intestine, with a rare subtype characterized by succinate dehydrogenase B (SDHB)-loss posing significant diagnostic and therapeutic challenges. A 62-year-old man with weight loss and abdominal pain was diagnosed with a gastric GIST showing SDHB-loss. Initial treatment with Imatinib reduced the tumor size, but surgery revealed no residual tumor. Despite adjuvant Imatinib, recurrence occurred, necessitating further surgical intervention. While GISTs typically benefit from surgery and tyrosine kinase inhibitors (TKIs), those with SDHB-loss are resistant to TKIs, requiring a different management approach. This case emphasizes the importance of surgical intervention for SDHB-deficient GISTs and the need for ongoing research into effective treatments for this subtype.

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Background Gastrointestinal stromal tumors (GISTs) arise from Cajal's interstitial cell precursors and display a variety of genetic mutations, primarily in the KIT and PDGFRA genes. These mutations are linked to tumor location, prognosis, and response to treatment. This study delves into the mutational patterns of GISTs in a Mexican population and their impact on overall survival (OS) and disease-free survival (DFS). Methodology This retrospective study examined 42 GIST cases diagnosed at the Oncology Hospital of the National Medical Center XXI Century between January 2018 and December 2020. Clinical, histological, and immunohistochemical data were gathered, and mutational analysis of KIT and PDGFRA genes was conducted using second-generation sequencing. Results The study group consisted of 52.4% females and 47.6% males, with an average age of 62.6 years. The most common tumor site was the stomach (59.5%), followed by the small intestine (26.2%). KIT mutations were detected in 71.4% of cases, predominantly involving exon 11. PDGFRA mutations were observed in 7.1% of cases. Recurrence was noted in 9.5% of patients, all with high-risk tumors. No significant link was identified between specific mutations and OS or DFS. Conclusions This investigation sheds light on the genetic landscape of GISTs in the Mexican population. While no significant association was established between particular mutations and survival outcomes, the study emphasizes the importance of molecular profiling in treatment decision-making. Further studies with larger sample sizes and longer follow-up periods are necessary to validate these results and explore their clinical relevance.

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Abstract Dysregulated circular RNA (circRNA) expression profiles and their carcinogenic contributions have been noted in nearly all human cancers. This study aimed to unearth the role of circRNA Amyloid Precursor Protein (circAPP), an abnormally highly expressed circRNA in Gastrointestinal Stromal Tumors (GIST). As the results found, circAPP was upregulated in GIST tissues and cells. FISH experiment, dual-luciferase reporter experiment, and RIP experiment confirmed that circAPP promoted CDV3 expression by absorption of miR-6838-5p in GIST. Cell experiments confirmed that silencing circAPP inhibited GIST cell proliferation, migration, invasion, glucose consumption, lactate production, ATP level, expression of HK2 and PKM2, decreased ATP/ADP, and increased NAD+/NADH, but promoted apoptosis, whereas overexpression of circAPP did the exact opposite. Furthermore, miR-6838-5p depletion and CDV3 overexpression abolished the influences of downregulating circAPP and overexpressing circAPP on GIST cells, respectively. Animal experiments displayed that circAPP knockdown inhibited GIST tumor growth and liver metastasis. All in all, circAPP promotes GIST cell proliferation and the Warburg effect by miR-6838-5p/ CDV3 axis and circAPP may be a potential future therapeutic target for GIST.

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INTRODUCTION: The critical role of microRNA-128 (miR-128) in gastrointestinal-related diseases has been documented. In the current study, we tried to clarify the specific role miR-128 in gastrointestinal stromal tumor (GIST) and the underlying mechanism. METHODS: Differentially expressed genes in GIST were identified following bioinformatics analysis. Then, expression patterns of miR-128 and B-lymphoma Mo-MLV insertion region 1 (BMI-1) in clinical tissue samples and cell lines were characterized, followed by validation of their correlation. GIST-T1 cells were selected and transfected with different mimic, inhibitor, or siRNA plasmids, after which the biological functions were assayed. RESULTS: We identified low miR-128 and high BMI-1 expression in GIST tissues of 78 patients and 4 GIST cell lines. Ectopic expression of miR-128 or silencing of BMI-1 suppressed the malignant potentials of GIST-T1 cells. As a target of miR-128, BMI-1 re-expression could partly counteract the suppressive effect of miR-128 on the malignancy of GIST-T1 cells. CONCLUSION: Our study provided evidence that miR-128-mediated silencing of BMI-1 could prevent malignant progression of GIST, highlighting a promising anti-tumor target for combating GIST.

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Carney-Stratakis syndrome (CSS) is an autosomal dominant rare syndrome, with incomplete penetrance, characterized by the association of paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GISTs). CSS is caused by germline heterozygous loss-of-function pathogenic variants (PVs) in the succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD), with SDHB and SDHD being the most frequent. To date, only 2 germline SDHC PVs (c.43 C > T; c.405 + 1G > A) have been described in 3 patients with CSS. Three patients with CSS and very distinct clinical presentations are reported here: 1 caused by a germline SDHC large deletion and the others with metastatic GIST and negative genetic investigation for SDHx defects. Two cases (1 and 2) presented with pheochromocytoma (case 1 also with abdominal paraganglioma) and metastatic GIST. Although these 2 cases fulfilled the diagnostic criteria for CSS, the genetic investigation for SDHx PVs by next-generation sequencing and multiplex ligation-dependent probe amplification was negative. Case 3 had a large abdominal paraganglioma and a small low-grade GIST not associated with recurrence or metastasis. This case harbored a germline SDHC exon 3 deletion, not previously reported. In conclusion, CSS is a rare and morbid disease with distinct clinical presentations and genetic heterogeneity, which can contribute to underdiagnosis.

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Abstract Succinate dehydrogenase inhibitors (SDHIs), fungicides currently most used in agriculture in Brazil, act by blocking the enzyme succinate dehydrogenase (SDH) from plant pathogens. However, studies show that SDHIs can not only inhibit SDH activity in target fungi, but also block that activity in human cells. Considering the medical and agricultural implications of SDH, the purpose of this narrative review is to describe the relationship between exposure to fungicides SDHIs and epigenetic regulation of SDH associated with the development of gastrointestinal stromal tumor, pheochromocytoma/paraganglioma, and cancer. The results obtained with the research showed that the human SDH enzyme exhibited sensitivity to some tested SDHIs, which may cause microcephaly and defects in neurological development. Deficiency of SDH activity causes accumulation of succinate which can act as an oncometabolite inhibit-ing iron-dependent dioxygenases and alpha-ketoglutarate, eleven translocation -TET and histone demethylases, inducing epigenetic changes that lead to multiple cancers and other diseases. Therefore, further in vitro and in vivo analyzes should be performed to assess susceptibility to diseases influenced by the toxic effect of SDHIs.

Resumo Os inibidores da succinato desidrogenase (SDHIs), fungicidas atualmente mais utilizados na agricultura no Brasil, atuam bloqueando a enzima succinato desidrogenase (SDH) de fitopatógenos. No entanto, estudos mostram que SDHIs podem nao apenas inibir a atividade de SDH em fungos alvo, mas também bloquear essa atividade em células humanas. Considerando as implicares médicas e agrícolas do SDH, o objetivo desta revisao narrativa é descrever a relaqao entre a exposiqao a fungicidas SDHIs e a regulaqao epigenética do SDH associada ao desenvolvimento de tumor estromal gastrointestinal, feocromocitoma/paraganglioma e cáncer. Os resultados obtidos com a pesquisa mostraram que a enzima SDH humana apresentou sensibilidade a alguns SDHIs testados, que podem causar microcefalia e defeitos no desenvolvimento neurológico. A deficiencia da atividade da SDH causa acumulo de succinato que pode atuar como um oncometabólito inibindo as dioxigenases dependentes de ferro e alfa-cetoglutarato, onze translocaqóes -TET e histonas desmetilases, induzindo alteraqóes epigenéticas que levam a múltiplos canceres e outras doenqas. Portanto, análises adicionais in vitro e in vivo devem ser realizadas para avaliar a suscetibilidade a doenqas influenciadas pelo efeito tóxico dos SDHIs.

Resumen Los inhibidores de la succinato deshidrogenasa (SDHI), los fungicidas actualmente más utilizados en la agricultura en Brasil, actúan bloqueando la enzima succinato deshidrogenasa (SDH) de los patógenos de las plantas. Sin embargo, los estudios muestran que los SDHI no solo pueden inhibir la actividad de SDH en los hongos objetivo, sino que también bloquean esa actividad en las células humanas. Teniendo en cuenta las implicaciones médicas y agrícolas de SDH, el propósito de esta revisión narrativa es describir la relación entre la exposición a fungicidas SDHI y la regulación epigenética de SDH asociada con el desarrollo de tumores del estro-ma gastrointestinal, feocromocitoma/paraganglioma y cáncer. Los resultados obtenidos con la investigación mostraron que la enzima SDH humana mostró sensibilidad a algunos SDHI probados, lo que puede causar microcefalia y defectos en el desarrollo neurológico. La deficiencia de la actividad de SDH provoca la acumulación de succinato que puede actuar como un oncometabolito que inhibe las dioxigenasas dependientes de hierro y el alfa-cetoglutarato, once translocaciones -TET e histona desmetilasas, induciendo cambios epigenéticos que conducen a múltiples cánceres y otras enfermedades. Por lo tanto, se deben realizar más análisis in vitro e in vivo para evaluar la susceptibilidad a enfermedades influenciadas por el efecto tóxico de los SDHI.

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Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising from the intestinal pacemaker cells of Cajal. They compose a heterogenous group of tumors due to a variety of molecular alterations. The most common gain-of-function mutations in GISTs are either in the KIT (60-70%) or platelet-derived growth factor receptor alpha (PDGFRA) genes (10-15%), which are mutually exclusive. However, a smaller subset, lacking KIT and PDGFRA mutations, is considered wild-type GISTs and presents distinct molecular findings with the activation of different proliferative pathways, structural chromosomal and epigenetic changes, such as inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also NTRK fusions. Currently, a molecular evaluation of GISTs is imperative in many scenarios, aiding in treatment decisions from the (neo)adjuvant to the metastatic setting. Here, we review the most recent data on the molecular profile of GISTs and highlight therapeutic implications according to distinct GIST molecular subtypes.

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Resumen Objetivos: Presentar caso clínico y revisión de la literatura sobre asociación de tumores poco frecuentes compatibles con diagnóstico de tríada de Carney. Paciente y Métodos: Revisión de ficha clínica de paciente de sexo femenino de 39 años de edad con antecedentes de asma, quien acude a servicio de urgencias por síntomas respiratorios. En estudio con imágenes se evidencia masa pulmonar en lóbulo superior derecho probablemente hamartoma y masa en la bifurcación carotídea izquierda compatible con posible paraganglioma. Se completó el estudio con endoscopia digestiva alta sin evidencia de tumor gástrico y PET-CT (tomografía de emisión de positrones-tomografía computarizada) que descartó otras lesiones. Resultados: La paciente fue sometida a resección quirúrgica de ambos tumores (pulmonar y carotídeo). En estudio histopatológico diferido, se plantean los diagnósticos de paraganglioma carotideo y hamartoma pulmonar, el cual, luego de una segunda revisión histopatológica, es corregido a condroma pulmonar. Discusión: La tríada de Carney se compone por la asociación de al menos 2 de 3 tumores: tumor estromal gastrointestinal (GIST), paraganglioma extra-adrenal y condroma pulmonar. Su expresión es variable, coexistiendo en forma completa en solo el 22% de los casos. Conclusión: Los pacientes con sospecha de tríada de Carney deben recibir evaluación multidisciplinaria, estudio completo en búsqueda de tumores asociados y seguimiento a largo plazo por posibles recurrencias o metástasis.

Objective: To present a clinical case and review of the literature on the infrequent association of pulmonary and extra thoracic tumors compatible with Carney's triad. Patient and Methods: Review of clinical records of a 39 years-old female patient with history of asthma who presented in the emergency department with respiratory symptoms. An imaging study showed a pulmonary mass in the right upper lobe with the aspect of hamartoma and a mass in the left carotid artery bifurcation compatible with a possible paraganglioma. Upper gastrointestinal endoscopy showed no evidence of gastric tumor and a PET-CT (Positron Emission Tomography - Computed Tomography) excluded other lesions. Results: Patient underwent surgical resection of both tumors (pulmonary and carotid). Diagnosis of carotid paraganglioma and pulmonary hamartoma were stated by histopathology. However, lung tumor after a second pathological analysis was confirmed to be a pulmonary chondroma. Discussion: Carney's triad is defined by the association of at least 2 of 3 tumors: Gastrointestinal Stromal Tumor (GIST), extraadrenal paraganglioma and pulmonary chondroma. Its expression is variable, coexisting completely in only 22% of cases. Conclusion: Patients with suspected Carney's triad should receive a multidisciplinary assessment, a complete study searching associated tumors and long-term follow-up for recurrences or metastases.

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Resumen Los tumores del estroma gastrointestinal (GIST) son tumores infrecuentes del tracto digestivo. Sus localizaciones más frecuentes son el estómago, intestino delgado, colon y recto; su aparición en otros lugares fuera del trato gastrointestinal como el mesenterio, epiplón o retroperitoneo es infrecuente. La tomografía axial computarizada (TAC) y la resonancia magnética (RM) son los estudios de imágenes de primera elección. La recesión quirúrgica es el estándar de oro para los tumores localizados y en los tumores avanzados o metastásicos son tratados con imatinib. A continuación, se presenta el caso de un paciente masculino de 53 años de edad sin antecedentes de patologías previos con cuadro clínico de dolor abdominal generalizado, pérdida de peso de 20 kg aproximadamente, distención abdominal, melena, hematemesis y astenia; en el examen físico presentó abdomen distendido y en la palpación se encontró endurecimiento epigástrico y mesogástrico, y marco colónico izquierdo. En la tomografía de abdomen se observó una masa tumoral de aspecto infiltrativo de aparente origen gástrico, con crecimiento extragástrico e infiltración del bazo, páncreas, raíz mesentérica, epiplón mayor, colon transverso, asas intestinales delgadas e infiltración en el hilio hepático, y metástasis hepática. Además, el cuadro se asoció con enfermedad respiratoria por coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2; neumonía por coronavirus de 2019 [COVID-19]). Se realizó una biopsia percutánea ecodirigida en el hipocondrio izquierdo y la histología reportó un GIST. En este artículo se revisa la clínica, diagnóstico y tratamiento del GIST gigante extradigestivo.

Abstract Giant extraintestinal gastrointestinal stromal tumors (GIST) are rare tumors of the digestive tract. Its most frequent locations are the stomach, small intestine, colon, and rectum. Its appearance in other places outside the gastrointestinal tract such as the mesentery, omentum, or retroperitoneum is infrequent. Computerized axial tomography (CT) and magnetic resonance imaging (MRI) are the imaging studies of the first choice. Surgical recession is the gold standard for localized tumors and advanced or metastatic tumors are treated with imatinib. This study presents the case of a male patient of 53 years with no history of previous pathologies. The patient was admitted with a clinical condition of generalized abdominal pain, weight loss of approximately 20 kg, abdominal distention, melena, hematemesis, and asthenia. Physical examination revealed a distended abdomen and palpation revealed epigastric and mesogastric hardening and left colonic frame. The abdominal tomography revealed a tumor mass with an infiltrative appearance of apparent gastric origin, with extragastric growth and infiltration of the spleen, pancreas, mesenteric root, greater omentum, transverse colon, thin intestinal loops, and infiltration in the hepatic hilum, and liver metastases. Moreover, the condition was related to the severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2). An ultrasound-guided percutaneous biopsy was performed in the left upper quadrant and histology reported a GIST. In this article medical condition, diagnosis, and treatment of the Giant extraintestinal gastrointestinal stromal, is reviewed.

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Introducción: El tumor del estroma gastrointestinal, es el tumor mesenquimal más frecuente en el tracto digestivo, que causa sangrado y obstrucción, con una incidencia de 10 a 20 casos por millón de habitantes. La prevalencia es mayor, debido el curso clínico largo de la enfermedad. Objetivo: Presentar un caso inusual de cirugía electiva, con tumor del estroma gastrointestinal digestivo, operado en el servicio de cirugía general. Caso clínico: Paciente masculino de 57 años de edad, que consulta por dolor abdominal en mesogastrio, acompañado de vómitos postprandiales tardíos, pérdida de peso y episodios recurrentes de sangrado digestivo bicolor, se ingresa de forma electiva y se estudia. Se interviene quirúrgicamente con el diagnóstico presuntivo de tumor abdominal. Se encuentra durante la laparotomía tumor de 14 por 20 centímetros que compromete la luz del intestino delgado, se decide realizar extracción del tumor y anastomosis término terminal convencional. El paciente fue egresado a los ocho días con evolución favorable y pendiente de resultado anatomopatológico, el cual informó tumor del estroma gastrointestinal. Conclusiones: Los tumores del estroma gastrointestinal son poco frecuentes como causa de cirugía electiva en los servicios de cirugía general(AU)

Introduction: Gastrointestinal stromal tumor is the most frequent mesenchymal tumor in the digestive tract, causing bleeding and obstruction, with an incidence of 10 to 20 cases per million inhabitants. The prevalence is higher, due to the long clinical course of the disease. Objective: To present an unusual case of elective surgery, with a gastrointestinal digestive stromal tumor, operated on in the general surgery service. Clinical case: A 57-year-old male patient who consulted for abdominal pain in the mesogastrium, accompanied by late postprandial vomiting, weight loss and recurrent episodes of bicolor digestive bleeding, was admitted electively and studied. Surgery was performed with the presumptive diagnosis of abdominal tumor. During the laparotomy, a 14 by 20-centimeter tumor that compromises the lumen of the small intestine is found; it is decided to perform extraction of the tumor and a conventional end-to-end anastomosis. The patient was discharged after eight days with a favorable evolution and pending histopathological result, which reported a gastrointestinal stromal tumor. Conclusions: Gastrointestinal stromal tumors are rare as a cause of elective surgery in general surgery services(AU)

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