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Introducción. El esplenúnculo se ha descrito con una incidencia global del 10 al 30 %. Puede ser una entidad de origen congénito o adquirida, frecuentemente está asociada a trauma abdominal o antecedente de esplenectomía por diversas causas. Caso clínico. Mujer en edad media, con antecedente de trauma abdominal y esplenectomía por ruptura traumática, quien 30 años después presenta un cuadro de dolor abdominal. Los estudios imagenológicos identificaron una masa sólida intrapancreática. Resultados. Fue llevada a pancreatectomía distal. Los hallazgos histológicos e inmunohistoquímicos confirmaron que la masa pancreática correspondía a un esplenúnculo intrapancreático adquirido, asociado al evento traumático previo. Conclusión. Los esplenúnculos suelen constituir un "incidentaloma". Los estudios imagenológicos se encuentran limitados, pues la tomografía computarizada, la resonancia nuclear magnética y la ultrasonografía presentan características imagenológicas similares con los tumores pancreáticos hipervascularizados, por lo que se debe practicar el estudio histopatológico durante su valoración. Esta entidad se debe incluir dentro de los diagnósticos diferenciales, con mayor énfasis en aquellos pacientes con historia de trauma abdominal y esplenectomía asociada, un escenario en el que esta lesión puede simular una neoplasia sólida del páncreas, con características malignas.
Introduction. Splenunculus has been described with an overall incidence of 10 to 30%. It can be an entity of congenital or acquired origin, it is frequently associated with abdominal trauma or a history of splenectomy for various reasons. Clinical case. Middle-aged woman, with a history of abdominal trauma and splenectomy due to traumatic rupture, who 30 years later presents with abdominal pain. Imaging studies identified a solid intrapancreatic mass. Results. She was taken to OR for distal pancreatectomy. The histological and immunohistochemical findings confirmed that the pancreatic mass corresponded to an acquired intrapancreatic splenunculus, associated with the previous traumatic event. Conclusion. Splenuncles usually constitute an "incidentaloma". Imaging studies are limited, since computed tomography, magnetic resonance imaging, and ultrasonography present similar imaging characteristics with hypervascularized pancreatic tumors, so histopathological study must be included during their evaluation. This entity should be included in the differential diagnoses, with greater emphasis on those patients with a history of abdominal trauma and associated splenectomy, a scenario in which this lesion can simulate a solid neoplasm of the pancreas, with malignant characteristics.
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Humanos , Pâncreas , Neoplasias Pancreáticas , Esplenectomia , Pancreatectomia , Baço , Esplenose , Diagnóstico DiferencialRESUMO
BACKGROUND: KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. METHODS: Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. RESULTS: Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. CONCLUSIONS: We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mutação , Omeprazol , Proteínas Proto-Oncogênicas c-met , Proteínas Proto-Oncogênicas p21(ras) , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Linhagem Celular Tumoral , Animais , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Omeprazol/farmacologia , Omeprazol/uso terapêutico , Camundongos , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Feminino , Triazinas/farmacologia , Triazinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Piperazinas , Piperidinas , Piridazinas , PiridonasRESUMO
Background: The COVID-19 pandemic in Latin America generated the need to develop low-cost, fast-manufacturing mechanical ventilators. The Universidad de La Sabana and the Fundacion Neumologica Colombiana designed and manufactured the Unisabana-HERONS (USH) ventilator. Here, we present the preclinical and clinical study results to evaluate its effectiveness and safety characteristics in an animal model (Yorkshire Sow) and five patients with acute respiratory failure receiving mechanical ventilatory support for 24 h. Methods: The effectiveness and safety outcomes included maintaining arterial blood gases and pulse oximetry saturation (SpO2), respiratory pressures and volumes (during continuous monitoring) in the range of ARDS and lung-protective strategy goals, and the occurrence of barotrauma. A significance level of 0.05 was used for statistical tests. This clinical trial was registered on Clinicaltrials.gov (NCT04497623) and approved by the ethics committee. Results: Among patients treated with the Unisabana-HERONS, the most frequent causes of acute respiratory failure were pneumonia in 3/5 (60 %) and ARDS in 2/5 (40 %). During the treatment, the ventilatory parameters related to lung protection protocols were kept within the safety range, and vital signs and blood gas were stable. The percentage of time that the respiratory pressures or volumes were out of safety range were plateau pressure >30 cm H2O: 0.00 %; driving pressure >15 cm H2O: 0.06 %; mechanical power >15 J/min: 0.00 %; and Tidal volume >8 mL/kg: 0.00 %. There were no adverse events related to the ventilator. The usability questionnaire retrieved a median score for all items between 9 and 10 (best score: 10), indicating great ease of use. Conclusion: The Unisabana-HERONS ventilator effectively provided adequate gas exchange and maintained the ventilatory parameters in the range of lung protection strategies in humans and an animal model. Furthermore, it is straightforward to use and is a low-cost medical device.
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Latin American populations, characterized by intricate admixture patterns resulting from the intermingling of ancestries from European, Native American (NA) Asian, and African ancestries which result in a vast and complex genetic landscape, harboring unique combinations of novel variants. This genetic diversity not only poses challenges in traditional population genetics methods but also opens avenues for a deeper understanding of its implications in health. In cancer, the interplay between genetic ancestry, lifestyle factors, and healthcare disparities adds a layer of complexity to the varying incidence and mortality rates observed across different Latin American subpopulations. This complex interdependence has been unveiled through numerous studies, whether conducted on Latin American patients residing on the continent or abroad, revealing discernible differences in germline composition that influence divergent disease phenotypes such as higher incidence of Luminal B and Her2 breast tumors, EGFR and KRAS mutated lung adenocarcinomas in addition to an enrichment in BRCA1/2 pathogenic variants and a higher than expected prevalence of variants in colorectal cancer associated genes such as APC and MLH1. In prostate cancer novel risk variants have also been solely identified in Latin American populations. Due to the complexity of genetic divergence, inputs from each individual ancestry seem to carry independent contributions that interplay in the development of these complex disease phenotypes. By understanding these unique population characteristics, genomic ancestries hold a promising avenue for tailoring prognostic assessments and optimizing responses to oncological interventions.
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Neoplasias , Humanos , América Latina/epidemiologia , Neoplasias/genética , Neoplasias/epidemiologia , Masculino , Feminino , Genômica , Neoplasias da Mama/genética , Neoplasias da Mama/epidemiologiaRESUMO
Introducción: El cáncer de pulmón (CP) es una enfermedad con gran impacto a nivel mundial en el número de muertes y en costos en salud. La alta incidencia y mortalidad de esta enfermedad asociada al diagnóstico tardío, y la mejoría del pronóstico ante una detección temprana, determinan que sea una patología pasible de beneficiarse mediante detección temprana. La tomografía de baja dosis de radiación (TCBD) demostró ser un método que se pue- de realizar periódicamente a un grupo de personas con alto riesgo de desarrollar CP y así reducir la mortalidad por esta enfermedad. Sin embargo, este beneficio es tal cuan- do se encuentra desarrollado bajo un programa organizado y con participación multi- disciplinaria especializada en cáncer de pulmón. Métodos: Se plantea determinar lineamientos básicos para el desarrollo de la detección temprana de cáncer de pulmón en América Latina para que pueda ser realizada en forma uniforme, con el menor riesgo y el máximo beneficio esperado. Se analizaron las principales publicaciones referidas a este tema, contemplando la diversidad de atención y acceso de América Latina. Resultado: Se desarrollan requerimientos mínimos para la implementación de un pro- grama. Discusión: El número de programas en la región es escaso y depende más de esfuerzos individuales que de políticas generales de salud. Consideramos que estos lineamien- tos pueden servir de apoyo para el desarrollo de más programas en la región y de for- ma más homogénea.
Introduction: Lung cancer (LC) is a disease with a great impact worldwide in the number of deaths and health costs. The high incidence and mortality of this disease associated with late diagnosis and the improved prognosis with early detection determine that it is a pathology that can benefit from early detection. Low radiation dose tomography (LDCT) demonstrated a method that can be performed periodically to a group of people at high risk of developing CP and thus reduce mortality from this disease. However, this benefit is such when it is developed under an organized program with multidisciplinary participation specialized in lung cancer. Methods: It is proposed to determine basic guidelines for the development of early de- tection of lung cancer in Latin America so that it can be carried out uniformly, with the lowest risk and the maximum expected benefit. The main publications referring to this topic were analyzed, considering the diversity of care and access in Latin America. Result: Minimum requirements are developed for the implementation of a program. Discussion: The number of programs in the region is small and depends more on individual efforts than on general health policies. We consider that these guidelines can serve as support for the development of more programs in the region and in a more ho- mogeneous way.
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Humanos , Planos e Programas de Saúde , Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico , Equipe de Assistência ao Paciente/organização & administração , Serviços Preventivos de Saúde/organização & administração , Tomografia/métodos , Incidência , Mortalidade , Educação Profissionalizante , Política de Saúde , América LatinaRESUMO
Aim: To describe the clinical picture and diagnosis of an episode of severe hypocalcemia in a patient with systemic lupus erythematosus (SLE) in remission, with chronic diarrhea that led to the diagnosis of celiac disease (CD). Case presentation: 22-year-old patient, diagnosed with SLE at age 10, in remission. He consulted for a two-month history of paresthesias, muscle spasms, myalgias, and episodes of tetany in the previous week, associated with malabsorptive postprandial diarrhea. His laboratory tests showed severe hypocalcemia, vitamin D deficiency, severe hypomagnesemia, and mild hypokalemia. In the study for CD, serology reported normal anti-tissue transglutaminase IgA, antigliadin IgA, and IgG and low total IgA levels. Enteroscopy revealed erosive bulbo-duodenitis, with villous atrophy and increased intraepithelial lymphocytes in the pathology, which, together with the immunohistochemical study, allowed the diagnosis of CD, Marsh 3a type. Management was initiated with a gluten-free diet, with a positive clinical response. Conclusion: CD should be suspected in patients with SLE who present with diarrhea, abdominal pain, nausea/vomiting, recurrent oral aphthosis, and anemia. In rare seronegative CD cases, other causes of villous atrophy, mainly infectious, toxic, and immunological, must be ruled out. There is an association between CD and SLE, so diagnosis must be early and timely with the best testing scheme available to achieve effective treatment before complications occur.
Objetivo: Describir la presentación clínica y diagnóstico de un episodio de hipocalcemia grave en un paciente con lupus eritematoso sistémico (LES) en remisión, con diarrea crónica que condujo al diagnóstico de enfermedad celíaca (EC). Presentación del caso: Paciente de 22 años, con diagnóstico de LES a los 10 años, en remisión. Consultó por 2 meses de evolución de parestesias, espasmos musculares, mialgias y episodios de tetania en la semana previa, asociado a diarrea posprandial malabsortiva. Sus laboratorios mostraron hipocalcemia grave, déficit de vitamina D, hipomagnesemia grave e hipopotasemia leve. En el estudio para EC la serología reportó antitransglutaminasa tisular IgA, antigliadina IgA e IgG normales y niveles de IgA total bajos. La enteroscopia evidenció bulboduodenitis erosiva, con atrofia de las vellosidades y aumento de linfocitos intraepiteliales en la patología, que junto al estudio inmunohistoquímico permitieron concluir el diagnóstico de EC, tipo Marsh 3a. Se inició el manejo con una dieta libre de gluten, con una respuesta clínica positiva. Conclusión: La EC debe sospecharse en pacientes con LES que inicien con diarrea, dolor abdominal, náuseas/vómitos, aftosis oral recurrente y anemia. En los casos de EC seronegativa, los cuales son poco comunes, se deben descartar otras causas de atrofia de las vellosidades principalmente infecciosas, tóxicas e inmunitarias. Existe una asociación entre EC y LES, por lo cual el diagnóstico debe ser precoz y oportuno con el mejor esquema de pruebas disponible para lograr realizar un tratamiento efectivo antes de que se presenten las complicaciones.
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In Colombia, coccidioidomycosis is a rare entity, and the intestinal manifestation is infrequent, with around a dozen cases reported in the world literature. This article reports the case of a 29-year-old male Venezuelan immigrant with a 4-month history of abdominal pain, jaundice, nausea, and vomiting. The tomography and the endoscopic study revealed a circumferential exophytic mass in the second portion of the duodenum. The biopsy revealed multiple spherules filled with round fungal endospores with a final diagnosis of disseminated coccidioidomycosis. The patient was discharged before the final pathology report with fluconazole doses of 200 mg every other day and an order for outpatient magnetic resonance cholangiography for outpatient follow-up, which he has not attended.
La coccidioidomicosis en Colombia es una entidad infrecuente y la presentación intestinal es extremadamente rara, con alrededor de una docena de casos reportados en la literatura mundial. En el presente artículo se reporta el caso de un paciente inmigrante venezolano masculino de 29 años con historia de dolor abdominal, ictericia, náuseas y vómito de 4 meses de evolución. La tomografía y el estudio endoscópico evidenciaron una masa exofítica circunferencial en la segunda porción del duodeno. La biopsia reveló múltiples esférulas llenas de endosporas fúngicas redondas con diagnóstico final de coccidioidomicosis diseminada. El paciente fue dado de alta antes del reporte final anatomopatológico con dosis de fluconazol de 200 mg interdiario y orden de colangiorresonancia ambulatoria para control ambulatorio, mismo al cual no ha asistido.
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The current landscape of targeted therapies directed against oncogenic driver alterations in non-small cell lung cancer (NSCLC) is expanding. Patients with EGFR-mutant NSCLC can derive significant benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including the third-generation EGFR TKI osimertinib. However, invariably, all patients will experience disease progression with this therapy mainly due to the adaptation of cancer cells through primary or secondary molecular mechanisms of resistance. The comprehension and access to tissue and cell-free DNA next-generation sequencing have fueled the development of innovative therapeutic strategies to prevent and overcome resistance to osimertinib in the clinical setting. Herein, we review the biological and clinical implications of molecular mechanisms of osimertinib resistance and the ongoing development of therapeutic strategies to overcome or prevent resistance.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Mutação , Resistencia a Medicamentos Antineoplásicos/genética , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) is a recently described genetic disorder that gathers autoinflammatory symptoms and myeloid dysplasia. The first description was reported in 2020, and subsequently, a growing number of cases have been described worldwide. Herein, we describe a case of a 72-year-old male patient with VEXAS syndrome with p.Met41Val mutation of the UBA1 gene, prominent supraglottic larynx involvement, and costochondritis. To our knowledge, this is the first report of VEXAS syndrome in Colombia and South America. This disease could present features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. Supraglottic larynx chondritis and costochondritis are atypical manifestations. These features were proposed previously to differentiate relapsing polychondritis from VEXAS syndrome but are not entirely reliable like in the case described. A diagnosis of VEXAS should be considered in male patients with incomplete or complete features of the previously described conditions, refractory to treatment, requiring high-dose glucocorticoids, and associated progressive hematologic abnormalities. Key Points ⢠VEXAS syndrome is a recently described genetic (somatic mutations in UBA1 gene) disorder that gathers autoinflammatory and hematologic manifestations. ⢠VEXAS syndrome should be considered in male patients with incomplete or complete features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, refractory to treatment, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. ⢠Glucocorticoids ameliorate symptoms effectively. However, other treatment options are limited due to a lack of evidence. Traditional immunosuppressants and biological therapy have been used empirically with limited efficacy and a transient effect. Bone marrow transplant offers a curative approach, but it has high morbidity and mortality.
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Arterite de Células Gigantes , Laringe , Síndromes Mielodisplásicas , Poliarterite Nodosa , Policondrite Recidivante , Síndrome de Sweet , Idoso , Arterite de Células Gigantes/complicações , Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/genética , Humanos , Imunossupressores/uso terapêutico , Masculino , Síndromes Mielodisplásicas/complicações , Policondrite Recidivante/complicações , Policondrite Recidivante/diagnóstico , Policondrite Recidivante/genética , Síndrome de Sweet/complicações , VacúolosRESUMO
Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups.
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Neoplasias Meníngeas , Meningioma , Everolimo/uso terapêutico , Humanos , Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Estudos Prospectivos , Receptores de Somatostatina/uso terapêutico , Somatostatina/uso terapêuticoRESUMO
EGFR exon 20 insertions represent a subgroup of NSCLC patients posed with a therapy dilemma. In this issue of Cancer Cell, Elamin and colleagues demonstrate that only insertions localized in the near loop respond to poziotinib. Pharmacological inhibition of spindle assembly checkpoint components inhibits tumor growth in poziotinib-resistant exon 20 insertions.
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Receptores ErbB , Neoplasias Pulmonares , Receptores ErbB/genética , Éxons/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: The exomphalos minor or small omphalocele is a defect of the abdominal wall smaller than 5 cm, located in the umbilical cord. It presents a sac containing intra-abdominal organs, mainly the small intestine. The main surgical objective is to repair the defected wall, preserving the intra-abdominal structures inside the sac. A floating gallbladder is unusual in this pathology; however, it must be removed when that occurs due to the risk of torsion, inflammation, and volvulus. PRESENTATION OF CASE: We present the case of a 7-day-old patient who comes to the emergency room with an abdominal mass. The physical examination shows minor exomphalos with local signs of inflammation. Genetic, chromosomal, and imaging studies are solicited. The abdominal ultrasonography report shows the absence of the gallbladder in the liver. The patient requires surgical correction of abdominal wall defect. The gallbladder is found inside the sac of defect that does not have a hepatic fixation; a cholecystectomy is performed. The patient presents a satisfactory postoperative evolution and is discharged. CONCLUSIONS: The exomphalos minor is a malformation of the abdominal wall. It needs surgical treatment; this must be done carefully, preserving the intra-abdominal organs inside the sac as much as possible. The gallbladder without hepatic fixation, elongated meso, or suspended by its pedicle is unusual in pediatric age, and they present a higher risk of torsion, inflammation, and necrosis. For this reason, cholecystectomy is indicated. A minor exomphalos has a better prognosis when the defect is small. It is not associated with malformations or associated structural alterations.
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Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.
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Neoplasias Pulmonares/terapia , Receptores ErbB/metabolismo , Humanos , MutaçãoRESUMO
Small cell lung cancer (SCLC) is a highly proliferative lung cancer that is not amenable to surgery in most cases due to the high metastatic potential. Precision medicine has not yet improved patients' survival due to the lack of actionable mutations. Intra- and intertumoral heterogeneity allow the neoplasms to adapt to various microenvironments and treatments. Further studying this heterogeneous cancer might yield the discovery of actionable mutations. First-line SCLC treatment has added immunotherapy to its armamentarium. There has been renewed interest in SCLC, and numerous clinical trials are underway with novel therapeutic approaches. Understanding the molecular and genetic landscape of this heterogeneous and lethal disease will pave the way for novel drug development.
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KRAS mutations are one of the most prevalent oncogenic alterations in cancer. Until recently, drug development targeting KRAS did not convey clinical benefits to patients. Specific KRASG12C inhibitors, such as sotorasib and adagrasib, have been designed to bind to the protein's mutant structure and block KRASG12C in its GDP-bound inactive state. Phase 1/2 trials have shown promising anti-tumor activity, especially in pretreated non-small cell lung cancer patients. As expected, both primary and secondary resistance to KRASG12C inhibitors invariably occurs, and molecular mechanisms have been characterized in pre-clinical models and patients. Several mechanisms such as tyrosine kinase receptors (RTKs) mediated feedback reactivation of ERK-dependent signaling can result in intrinsic resistance to KRAS target therapy. Acquired resistance to KRASG12C inhibitors include novel KRAS mutations such as Y96D/C and other RAS-MAPK effector protein mutations. This review focuses on the intrinsic and acquired mechanisms of resistance to KRASG12C inhibitors in KRASG12C mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it.
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MET inhibitors have shown activity in non-small-cell lung cancer patients (NSCLC) with MET amplification and exon 14 skipping (METΔex14). However, patient stratification is imperfect, and thus, response rates have varied widely. Here, we studied MET alterations in 474 advanced NSCLC patients by nCounter, an RNA-based technique, together with next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR), exploring correlation with clinical benefit. Of the 474 samples analyzed, 422 (89%) yielded valid results by nCounter, which identified 13 patients (3%) with METΔex14 and 15 patients (3.5%) with very-high MET mRNA expression. These two subgroups were mutually exclusive, displayed distinct phenotypes and did not generally coexist with other drivers. For METΔex14, 3/8 (37.5%) samples positive by nCounter tested negative by NGS. Regarding patients with very-high MET mRNA, 92% had MET amplification by FISH and/or NGS. However, FISH failed to identify three patients (30%) with very-high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit. Our results indicate that quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-met , RNA Mensageiro , RNA Neoplásico , Análise de Sequência de RNA , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-met/biossíntese , Proteínas Proto-Oncogênicas c-met/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genéticaRESUMO
Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.
RESUMO
OBJECTIVES: The objectives of this study are to evaluate the relationship between authorship networking, socioeconomic factors, and scientific productivity across Latin America. METHODS: In a bibliometric analysis of cancer-related Latin-American publications, the relationship between authorship network indicators, sociodemographic factors, and number of peer-reviewed indexed publications per country was explored. A systematic review of the literature for cancer publications between 2000 and 2018 using the Scopus database limited to Latin-American authors was used for the construction of coauthorship and publication networks and their respective metrics. Sociodemographic variables including percentage of invested gross domestic product in research, population, and cancer incidence were also estimated. Multiple linear regression models were constructed to determine the relationship between productivity and the aforementioned variables. RESULTS: A total of 8,528 articles across nine countries were included. Brazil was the most productive nation with 41.8% of identified references followed by Mexico (16.6%) and Argentina (12.9%). Latin America experienced a 9% growth in number of publications across the studied time frame. After analyzing networking and sociodemographic variables, number of authors in a collaboration network and percentage of invested gross domestic product were associated with high productivity yielding a multiple regression model with an R2 value of 0.983. CONCLUSIONS: This study indicates that extensive authorship networking and a high investment in research strongly predict cancer-related productivity.
Assuntos
Indexação e Redação de Resumos/estatística & dados numéricos , Autoria/normas , Revisão da Pesquisa por Pares/métodos , Publicações/estatística & dados numéricos , Bibliometria , Gerenciamento de Dados , Eficiência , Humanos , Incidência , América Latina/epidemiologia , Neoplasias/epidemiologia , Publicações/tendências , Fatores SocioeconômicosRESUMO
Introduction: The therapy of patients with lung adenocarcinoma has significantly changed after the discovery of epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 10-15% of Caucasian lung cancer patients and are associated with favorable outcome to orally administered EGFR tyrosine kinase inhibitors (TKIs), like erlotinib. However, as soon as the tumor cells are under the pressure of the specific inhibitor, compensatory signaling pathways are activated and resistance emerges. Areas covered: In this review we will focus on the mechanisms of resistance to the first-generation EGFR TKI, erlotinib, and will mainly summarize the findings throughout the last 10 years in the field of EGFR-mutant lung cancer. Expert opinion: Widespread research has been performed and several mechanisms of resistance to EGFR TKIs, especially first- and second-generation, have been identified. Still, no adequate combinatory therapies have received regulatory approval for the treatment of EGFR-mutant patients at the time of resistance. The third-generation EGFR TKI, osimertinib has been approved for patients whose tumor has become resistant through the secondary T790M resistant EGFR mutation. The identification of the mechanisms of resistance and the application of the adequate therapy to each patient is still an unmet need.