Resistance to RET targeted therapy in Thyroid Cancer: Molecular basis and overcoming strategies.

Thyroid cancer is the most frequently diagnosed endocrine malignancy, with an increasing incidence over the last decades. The recent advances in understanding the molecular mechanisms underlying the carcinogenesis of thyroid cancer have led to a better therapeutic approach of these tumors. This has allowed the development and approval of several drugs during the past decade. The rearranged during transfection [RET] protooncogene encodes a transmembrane receptor tyrosine kinase, which is activated by chromosomal rearrangements or point mutations in multiple malignancies, including thyroid cancer. Selective RET inhibitors have proved their value in the treatment algorithm in molecularly selected patients with significantly high response rates and duration of response. Notwithstanding, there are patients who experiment rapid progression or tumor recurrence after an early response to those targeted therapies, which suggest the existence of primary and acquired mechanisms of resistance that have been largely unknown to date. In the present review, we attempt to provide a comprehensive analysis of the most relevant mechanisms of resistance to RET inhibitors which could help in the development of next generation MKI and RET inhibitors, along with combination strategies with different targeted therapies that could potentially overcome these resistances.

Phrenic nerve schwannoma as an incidental intraoperative finding. Case report.

INTRODUCTION AND IMPORTANCE: Peripheral neuronal sheath tumors are rare lesions that can arise from the lining of the neuronal axons of any nerve in the body. Schwannomas are usually solitary and encapsulated, slow growing, predominantly benign, with a malignant transformation rate of less than 2% and very low recurrence. The phrenic nerve schwannoma is rare in the neck and usually is asymptomatic. CASE PRESENTATION: We present a case of a phrenic nerve schwannoma as an incidental intraoperative finding in the study of a patient with a cervical mass of progressive growth on the right side of the neck in contact with the anterior scalene muscle and pain intermittent. Resection of the mass was done with preservation of the endoneurium. Intraoperative stimulation after resection had a proper functionality of the phrenic nerve. In the follow-up, the patient had not any damage of the function of the phrenic nerve. CLINICAL DISCUSSION: This tumor is generated by a deficiency of merlin with the consequent cell proliferation. The diagnostic imaging (CT or MRI) are the studies of choice. The differential diagnosis of these lesions has an impact on the presence or absence of oncological disease or progression of a previously treated one. The ideal management is surgical and the anatomical and/or functional preservation of the nerve depend of the tumor infiltration. CONCLUSION: The phrenic nerve schwannoma is rare in the neck. The ideal management is surgical, and this pathology must be considered in patients with masses in the Station IV and supraclavicular fossa of the neck.

Squamous cell carcinoma of the conjunctiva. Case report.

INTRODUCTION: The prevalence of squamous cell carcinoma of the eyeball is low, and this is a rare condition. There are multiple therapeutic strategies for the treatment and depend on the degree of local involvement and extension of the tumor which, in turn, will have an impact on the patient's prognosis. PRESENTATION OF CASE: We present a case of a patient with a mass of progressive growth on the left eyeball whit vision damage. The biopsy showed a squamous cell carcinoma of the conjunctiva, and imaging studies showed orbital invasion cT4bN0cM0, so surgery was indicated. The surgery was done with macroscopic margins of 5 mm. After resection, a radial free flap reconstruction was performed. Adjuvant treatment with radiotherapy was performed without complications. After six months, the patient manifested an improvement in his quality of life, and there is no evidence of relapse. DISCUSSION: The prevalence of squamous cell carcinoma of the conjunctiva is low. The most important risk factor is exposure to UV rays. Most are derived from conjunctival intraepithelial neoplasms. There are topical management protocols with chemotherapeutic agents and in patients with ocular or orbital invasion, enucleation and exanteration are the treatments of choice. CONCLUSION: The squamous cell carcinoma of the conjunctive is rare. The management in the locally advanced tumors is surgical. The use of a radial free flap reconstruction is one of the reconstructive strategies to take into account, and the knowledge of additional strategies required to control the disease is important to ensure an optimal treatment.

Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

Outcomes of systemic targeted therapy in recurrent renal cell carcinoma treated with adjuvant sunitinib.

OBJECTIVE: To assess the efficacy and tolerability of rechallenge with sunitinib and other targeted therapies (TTs) in patitents with relapsed recurrent renal cell carcinoma (RCC) in the advanced setting. METHODS: In this multi-institutional retrospective study, patients with relapsed RCC were rechallenged with sunitinib or other systemic TTs as a first-line therapeutic approach after failed adjuvant sunitinib treatment. Patient characteristics, treatments and clinical outcomes were recorded. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR) and overall survival (OS). RESULTS: A total of 34 patients with relapses were recorded, and 25 of these (73.5%) were men. Twenty-five patients were treated with systemic TT: 65% of patients received TT against the vascular endothelial growth factor pathway (including sunitinib), 21.7% received mammalian target of rapamycin inhibitors and 13% received immunotherapy. The median (interquartile range) time to relapse was 20.3 (5.2-20.4) months from diagnosis, and 7.5 months (1.0-8.5) from the end of adjuvant suntinib treatment. At a median follow-up of 23.5 months, 24 of the 25 patients had progressed on first-line systemic therapy. The median PFS was 12.0 months (95% confidence interval [CI] 5.78-18.2). There were no statistical differences in PFS between different treatments or sunitinib rechallenge. PFS was not statistically different in patients relapsing on or after adjuvant suntinib treatment (≤ 6 or >6 months after adjuvant suntinib ending). The ORR was 20.5%. The median OS was 29.1 months (95% CI 16.4-41.8). CONCLUSIONS: Rechallenge with sunitinib or other systemic therapies is still a feasible therapeutic option that provides patients with advanced or metastastic RCC with additional clinical benefits with regard to PFS and OS after failed response to adjuvant sunitinib.

Trastornos posoperatorios del metabolismo del calcio postiroidectomía / Postoperative calcium metabolism disorders after thyroidectomy

Introducción: revisión narrativa que explica el panorama actual de la hipocalcemia y el hipoparatiroidismo como complicaciones de la tiroidectomía, su diagnóstico y tratamiento; con una descripción de las nuevas estrategias de prevención y tratamiento. Métodos: los motores de búsqueda utilizados fueron PubMed, Clinical Key, Embase, Cochrane y Lilacs, se incluyeron referencias en español e inglés, publicadas entre 2016 y 2020. Los artículos seleccionados se revisaron utilizando CONSORT, STROBE o PRISMA, según el caso. Resultados: fueron seleccionados 35 artículos que tenían relación directa con el tema, entre ellos: metanálisis, revisiones sistemáticas, estudios prospectivos y observacionales, revisiones narrativas y consensos de expertos, procedentes de los cinco continentes. La hipocalcemia y el hipotiroidismo en sus dos formas se relacionan con la afectación de la vascularización de las glándulas paratiroides o su exérecis accidental, existiendo factores predisponentes propios del paciente, derivados de la técnica quirúrgica o la característica patológica de la lesión en el tiroides. Como estrategias de prevención disponemos de herramientas ópticas para definir en el perioperatorio la disposición de las paratiroides; además existe la posibilidad de autotrasplantarlas al identificarlas en la pieza anatómica. El mejor marcador del estado metabólico del calcio es la PTHi. Conclusiones: la preservación de las paratiroides y de su irrigación es la mejor estrategia para prevenir los trastornos posoperatorios del calcio

Introduction: narrative review explaining the current picture of hypocalcemia and hypoparathyroidism as complications of thyroidectomy, describing new strategies employed for their diagnosis and treatment. Methods: searches in the PubMed, Clinical Key, Embase, Cochrane and Lilacs databases; references in Spanish and English, published between 2016 and 2020 were included. The selected articles were reviewed using CONSORT, STROBE or PRISMA, as appropriate. Results: 35 articles directly related with the topic were selected, including meta-analyses, systematic reviews, prospective and observational studies, narrative reviews and expert consensus, on all five continents. The two forms of hypocalcemia and hypoparathyroidism can result from devascularization or accidental removal of the parathyroid glands, patient-specific factors, or from the surgical technique or the pathological characteristics of the thyroid lesion. Preventive strategies include the use of optical tools for preoperative determination of parathyroid glands location; as well as the possibility of autotransplantation after confirming parathyroid tissue in the biopsy specimen. The best marker of calcium metabolism is iPTH. Conclusions: preservation of the parathyroid glands and their irrigation is the best strategy to prevent postoperative calcium disorders.

Manejo del trauma penetrante de cuello en dos hospitales de Bogotá, Colombia / Management of penetrating neck trauma at two hospitals in Bogotá, Colombia

Introducción. El manejo del trauma penetrante de cuello en pacientes estables, según la zona de Monson lesionada, orienta la solicitud de pruebas diagnósticas para identificar lesiones vasculares, de las vías aéreas y del tubo digestivo. Materiales y métodos. Se trata de un estudio observacional, descriptivo y retrospectivo. Se incluyeron pacientes de 15 años o más con trauma penetrante de cuello, que consultaron a los dos hospitales de la Sociedad de Cirugía de Bogotá en un periodo de cinco a seis años. Se recolectó la información demográfica, clínica y de las pruebas diagnósticas practicadas, para determinar su utilidad. Las variables cualitativas se describieron con frecuencias relativas y absolutas, y las cuantitativas, con medias y desviaciones estándar. Resultados. Inicialmente, se incluyeron 148 pacientes, de los cuales 133 fueron catalogados como estables durante la valoración primaria, con un promedio de edad de 33,04 años (desviación estándar, DE=12,9); la mayoría (88,7 %) eran hombres. La mediana de la estancia hospitalaria fue de dos días (rango intercuartílico, RIQ=1-4 días). En la mayoría (117; 87,9 %) de los casos, la herida fue causada con arma cortopunzante. En casi todas las pruebas diagnósticas, se reportaron pocos hallazgos anormales, a excepción de la angiotomografía (angio-TC) que se practicó en 59 pacientes y demostró 43 resultados anormales. Se decidió tratamiento quirúrgico en siete pacientes catalogados como estables al ingreso y, en 14, por resultados anormales de las pruebas diagnósticas. Se presentaron cinco fallecimientos. Conclusión. El examen físico, la observación clínica y la angio-TC son suficientes para identificar lesiones vasculares, de la vía aérea o del tubo digestivo en los pacientes con trauma penetrante de cuello, en hospitales que no son considerados como especializados en trauma

Introduction: Management of penetrating neck trauma in stable patients according to the affected Monson zone directs the diagnostic tests to identify vascular, airway and digestive tract lesions. Materials and methods: A retrospective descriptive observational study was conducted. We included 15 year-old or older patients with penetrating neck trauma that consulted at the two hospitals of the Sociedad de Cirugía in Bogotá, Colombia, during a 5 to 6 year period. Demographic and clinical information was collected, as well as the results of the diagnostic tests applied in order to determine their utility. Qualitative variables were described with relative and absolute frequencies and quantitative variables with median and standard deviations. Results: 148 patients were enrolled initially, of which 133 were classified as stable during the primary assessment, with an average age of 33.04 years (SD: 12.9), the majority being men (88.7%). The median hospital stay was 2 days (IQR=1-4 days). The most frequent wound mechanism was a sharp bladed weapon in 117 cases (87.9%). A low proportion of abnormal findings were reported in the diagnostic tests, except for angiography CT which was performed in 59 patients with 43 with abnormal findings. Surgical management was defined for 7 patients classified as stable at admission and for 14 patients after abnormal findings found in the diagnostic tests. Five deaths were registered. Conclusion: Physical examination, clinical observation and angiography CT are sufficient to identify vascular, airway and digestive lesions in patients with penetrating neck trauma at hospitals that are not considered specialized in trauma

Cuatro lustros de la facultad de medicina / Four decades of medical school

La trayectoria educativa de la Sociedad de Cirugía de Bogotá-Hospital de San José existe desde su creación y origen, su filosofía siempre ha sido la docencia y la asistencia desde cuando diez ilustres y altruistas fundadores pensaron en replicar a sus colegas los conocimientos médicos adquiridos por ellos en países europeos y en Norteamérica; de igual forma brindar asistencia social en salud a la población menos favorecida en una época difícil donde no existía el sistema subsidiado en salud y la atención llamada de caridad era parte de la labor institucional. Por el Hospital de San José han cursado y realizado prácticas académicas diferentes estudiantes de instituciones como las universidades Nacional, Javeriana y Militar, así como la universidad del Rosario hasta 1996, año en que por determinación conjunta se decidió la terminación del convenio Colegio Mayor de Nuestra Señora del Rosario-Hospital de San José. En 1996 la Sociedad de Cirugía de Bogotá se hizo cargo académica y administrativamente de los posgrados del Hospital de San José, como unidades dependientes de la Fundación Universitaria de Ciencias de la Salud, bajo la dirección del doctor Roberto Jaramillo Uricoechea. Por ley de la república para funcionar los programas de posgrado deberían estar adscritos a una facultad de medicina que tuviera el programa de pregrado. Las condiciones estaban dadas en un hospital de III nivel, con una reconocida rayectoria de los docentes y con las garantías suficientes para un excelente programa de pregrado en medicina.

Nueva fuente de quinoles, la superficie foliar de Pentacalia ledifolia y Pentacalia corymbosa y sus propiedades antifúngicas / Nova fonte de quinóides, a superficie foliar de Pentacalia lediflora e Pentacalia corymbosa e suas propriedades antifúngicas / New source of quinols, the surface of Pentacalia ledifolia and Pentacalia corymbosa leaves and its antifungal activity

Foi demonstrada a ação antifúngica do extrato clorofórmico e de duas substâncias isoladas da superfície foliar de Pentacalia ledifolia (H.B.K.) Cuatr. e P. corymbosa (Benth) Cuatr. frente aos fungos fitopatógenos Fusarium oxysporum e Botrytis cinerea, cultivados em BDA (batata-dextrose-ágar). Destes extratos foram isolados, além de cumarinas já identificadas em estudos anteriores, dois derivados quinóides: (1-hidroxi-4-oxo-2,5-ciclohexadienil) acetato de metila ou jacaranona e (1-hidroxi-4-oxo-2,5-ciclohexadienil) acetato de etila ou metiljacaranona. Para o (1-hidroxi-4-oxo-2,5-ciclohexadienil) acetato de etila foi calculado CI50 de 650 μg/mL para os dois tipos de fungos e o (1-hidroxi-4-oxo-2,5-ciclohexadienil) acetato de metila teve um CI50 de 660 μg/mL.

Quinols identified in the surface waxes of Pentacalia ledifolia (H.B.K.) Cuatr and P. corymbosa (Benth) Cuatr. leaves, possess antifungal activity against Fusarium oxysporum and Botrytis cinerea, cultured on PDA (potato-dextrose-agar) medium. These extracts were prepared by dipping fresh leaves in chloroform for 5 min, and afforded ethyl-(1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl) acetate and methyl-(1-hydroxy-4-oxocyclohexa-2,5-dien-1-yl) acetate, the major surface compounds.

Diseño de una propuesta educativa para prevención de la violencia intrafamiliar en el departamento del Huila / Design of one educative proposal for domestic violence prevention in the Huila department

Frente a la evidencia de un marcado incremento de la violencia intrafamiliar en el Departamento del Huila y por ende de una prevalencia de agresiones en mujeres y niños se realiza este estudio de investigación que a la vez establece un diagnóstico de los diferentes tipos de violencia intrafamiliar y la forma como se genera y desarrolla; plantea además el diseño de un modelo educativo para prevenir la violencia donde las mismas familias implicadas en el hecho violento, a partir de un proceso reflexivo producto de su propia violencia, establecen las bases para la construcción de una estrategia educativa que prevenga la violencia y promueva la convivencia pacífica. El documento está organizados en dos secciones; uno donde se desarrolla la fase cuantitativa de tipo descriptiva exploratoria mediante el cual se hace el diagnóstico de la situación de violencia en el departamento del Huila con sus determinantes y factores de riesgo a partir de las fuentes de información previamente seleccionadas y otra donde se plantean los elementos metodológicos y conceptuales del diseño educativo para ser discutido, analizado, devuelto y socializado con las familias con el fin de hacer una recomprensión de la situación de violencia encontrada, enriquecer, ajustar y modificar el diseño y proceder a construír conjuntamente una propuesta más consolidada y ajustada a las necesidades del medio. El estudio por lo tanto está enfocado a producir conocimiento y plantea una estrategia educativa