Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD-1/PD-L1 axis blockade via Id1 downregulation.

BACKGROUND: The identification of novel therapeutic strategies to overcome resistance to the MEK inhibitor trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a challenge. This study analyzes the effects of trametinib on Id1 protein, a key factor involved in the KRAS oncogenic pathway, and investigates the role of Id1 in the acquired resistance to trametinib as well as the synergistic anticancer effect of trametinib combined with immunotherapy in KRAS-mutant LUAD. METHODS: We evaluated the effects of trametinib on KRAS-mutant LUAD by Western blot, RNA-seq and different syngeneic mouse models. Genetic modulation of Id1 expression was performed in KRAS-mutant LUAD cells by lentiviral or retroviral transductions of specific vectors. Cell viability was assessed by cell proliferation and colony formation assays. PD-L1 expression and apoptosis were measured by flow cytometry. The anti-tumor efficacy of the combined treatment with trametinib and PD-1 blockade was investigated in KRAS-mutant LUAD mouse models, and the effects on the tumor immune infiltrate were analyzed by flow cytometry and immunohistochemistry. RESULTS: We found that trametinib activates the proteasome-ubiquitin system to downregulate Id1 in KRAS-mutant LUAD tumors. Moreover, we found that Id1 plays a major role in the acquired resistance to trametinib treatment in KRAS-mutant LUAD cells. Using two preclinical syngeneic KRAS-mutant LUAD mouse models, we found that trametinib synergizes with PD-1/PD-L1 blockade to hamper lung cancer progression and increase survival. This anti-tumor activity depended on trametinib-mediated Id1 reduction and was associated with a less immunosuppressive tumor microenvironment and increased PD-L1 expression on tumor cells. CONCLUSIONS: Our data demonstrate that Id1 expression is involved in the resistance to trametinib and in the synergistic effect of trametinib with anti-PD-1 therapy in KRAS-mutant LUAD tumors. These findings suggest a potential therapeutic approach for immunotherapy-refractory KRAS-mutant lung cancers.

Polymeric nanocapsules loaded with poly(I:C) and resiquimod to reprogram tumor-associated macrophages for the treatment of solid tumors.

Background: In the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer. Toll-like receptors (TLRs) ligands, such as poly(I:C) or resiquimod (R848) are able to reprogram TAMs towards M1-like antitumor effector cells. The objective of our work has been to develop and evaluate polymeric nanocapsules (NCs) loaded with poly(I:C)+R848, to improve drug stability and systemic toxicity, and evaluate their targeting and therapeutic activity towards TAMs in the TME of solid tumors. Methods: NCs were developed by the solvent displacement and layer-by-layer methodologies and characterized by dynamic light scattering and nanoparticle tracking analysis. Hyaluronic acid (HA) was chemically functionalized with mannose for the coating of the NCs to target TAMs. NCs loaded with TLR ligands were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry, using primary human monocyte-derived macrophages. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry and multispectral immunophenotyping. Results: We have developed polymeric NCs loaded with poly(I:C)+R848. Among a series of 5 lead prototypes, protamine-NCs were selected based on their physicochemical properties (size, charge, stability) and in vitro characterization, showing good biocompatibility on primary macrophages and ability to stimulate their production of T-cell attracting chemokines (CXCL10, CCL5) and to induce M1-like macrophages cytotoxicity towards tumor cells. In mouse tumor models, the intratumoral injection of poly(I:C)+R848-protamine-NCs significantly prevented tumor growth and lung metastasis. In an orthotopic murine lung cancer model, the intravenous administration of poly(I:C)+R848-prot-NCs, coated with an additional layer of HA-mannose to improve TAM-targeting, resulted in good antitumoral efficacy with no apparent systemic toxicity. While no significant alterations were observed in T cell numbers (CD8, CD4 or Treg), TAM-reprogramming in treated mice was confirmed by the relative decrease of interstitial versus alveolar macrophages, having higher CD86 expression but lower CD206 and Arg1 expression in the same cells, in treated mice. Conclusion: Mannose-HA-protamine-NCs loaded with poly(I:C)+R848 successfully reprogram TAMs in vivo, and reduce tumor progression and metastasis spread in mouse tumors.

Survival and perioperative morbidity of totally laparoscopic versus open gastrectomy for early gastric cancer: analysis from a single latin american centre / Comparação da sobrevida e morbidade perioperatória da gastrectomia totalmente laparoscópica vs. laparotômica para tratamento do câncer gástrico precoce em um centro latino-americano

ABSTRACT Background: Laparoscopic gastrectomy has numerous perioperative advantages, but the long-term survival of patients after this procedure has been less studied. Aim: To compare survival, oncologic and perioperative outcomes between completely laparoscopic vs. open gastrectomy for early gastric cancer. Methods: This study was retrospective, and our main outcomes were the overall and disease-specific 5-year survival, lymph node count and R0 resection rate. Our secondary outcome was postoperative morbidity. Results: Were included 116 patients (59% men, age 68 years, comorbidities 73%, BMI 25) who underwent 50 laparoscopic gastrectomies and 66 open gastrectomies. The demographic characteristics, tumour location, type of surgery, extent of lymph node dissection and stage did not significantly differ between groups. The overall complication rate was similar in both groups (40% vs. 28%, p=ns), and complications graded at least Clavien 2 (36% vs. 18%, p=0.03), respiratory (9% vs. 0%, p=0.03) and wound-abdominal wall complications (12% vs. 0%, p=0.009) were significantly lower after laparoscopic gastrectomy. The lymph node count (21 vs. 23 nodes; p=ns) and R0 resection rate (100% vs. 96%; p=ns) did not significantly differ between groups. The 5-year overall survival (84% vs. 87%, p=0.31) and disease-specific survival (93% vs. 98%, p=0.20) did not significantly differ between the laparoscopic and open gastrectomy groups. Conclusion: The results of this study support similar oncologic outcome and long-term survival for patients with early gastric cancer after laparoscopic gastrectomy and open gastrectomy. In addition, the laparoscopic approach is associated with less severe morbidity and a lower occurrence of respiratory and wound-abdominal wall complications.

RESUMO Racional: A gastrectomia laparoscópica tem numerosas vantagens perioperatórias, mas a sobrevivência em longo prazo após este procedimento tem sido menos estudada. Objetivo: Comparar resultados de sobrevivência, oncológica e perioperatória entre a gastrectomia completamente laparoscópica vs. aberta para câncer gástrico precoce. Método: Este estudo foi retrospectivo e os principais resultados foram a sobrevivência global e específica de cinco anos, contagem de linfonodos e taxa de ressecção R0. Resultado secundário foi a morbidade pós-operatória. Resultados: Foram incluídos 116 pacientes (59% homens, idade 68 anos, comorbidades 73%, IMC 25) que foram submetidos a 50 gastrectomias laparoscópicas e 66 gastrectomias abertas. As características demográficas, a localização do tumor, o tipo de operação, a extensão da dissecção dos linfonodos e do estágio não diferiram significativamente entre os grupos. A taxa geral de complicações foi semelhante em ambos os grupos (40% vs. 28%, p=ns) e complicações classificadas Clavien 2 (36% vs. 18%, p=0,03), respiratórias (9% vs. 0%, p=0,03) e as da parede abdominal (12% vs. 0%, p=0,009) foram significativamente menores após a gastrectomia laparoscópica. A contagem de linfonodos (21 contra 23, p=ns) e a taxa de ressecção R0 (100% vs. 96%; p=ns) não diferiram significativamente entre os grupos. A sobrevida global de cinco anos (84% vs. 87%, p=0,31) e a sobrevida específica (93% vs. 98%, p=0,20) não diferiram significativamente entre os grupos de gastrectomia laparoscópica e aberta. Conclusão: Estes resultados suportam resultados oncológicos similares e sobrevida em longo prazo para pacientes com câncer gástrico precoce após gastrectomia laparoscópica e gastrectomia aberta. Além disso, a abordagem laparoscópica está associada com morbidade menos grave e menor ocorrência de complicações respiratórias e da parede abdominal.

Gastrectomía totalmente laparoscópica por neoplasias gástricas: Experiencia en un centro público / Totally laparoscopic gastrectomy for the treatment of gastric tumors

Background: The laparoscopic approach for the treatment of gastric tumors has many advantages. Aim: To evaluate the results of a laparoscopic gastrectomy program developed in a public hospital. Patients and Methods: Retrospective review of epidemiological, perioperative and follow-up data of patients who were treated with a laparoscopic gastrectomy due to gastric tumors between 2006 and 2013. A totally laparoscopic technique was used for all cases. Complications were evaluated according to the Clavien-Dindo classification. Results: Fifty one patients, aged 65 (36-85) years, underwent a laparoscopic gastrectomy. In 22 patients a total gastrectomy was performed. Conversion rate to open surgery was 8%. Operative time was 330 (90-500) min and bleeding was 200 (20-500) ml. Median hospital stay was 7 (3-37) days. Postoperative morbidity was present in 17 (33%) patients, 3 (6%) patients had complications grade 3 or higher and one patient died (1.9%). Tumor pathology was adenocarcinoma in 39 patients. A complete resection was achieved in 97%. Twenty nine patients (74%) with gastric adenocarcinoma had early gastric cancer and 84% of patients were in stage one. Median lymph node count was 24. Median follow-up was 26 (1-91) months. There was no cancer related mortality among patients subjected to a curative resection. Overall survival for patients with adenocarcinoma was 92% at 3 years. Conclusions: This study supports the feasibility and safety of a laparoscopic gastrectomy program in a public hospital; with low morbidity, adequate lymph node dissection and long-term survival. This approach must be considered an option for selected patients with gastric cancer.

Lipoma gástrico gigante sintomático tratado con gastrectomía subtotal laparoscópica: caso clínico / Gastric lipoma removed by laparoscopic subtotal gastrectomy: Report of one case

Gastric lipoma is a rare benign gastric tumor. We report a 62-year-old man, who presented with abdominal pain, vomiting and weight loss. An upper gastrointestinal endoscopy showed a gastric antral, submucosal tumor. Abdominal ultrasound and computed tomography revealed a large antral lesion with content of high echogenicity and fat density, measuring 11 x 6 cm. The patient was treated with a laparoscopic distal subtotal gastrectomy, and a Roux-en-Y reconstruction. The patient had no postoperative morbidity, was started on a liquid diet on the third postoperative day and was discharged on the third postoperative day. The pathological study revealed a gastric lipoma with clear margins. This laparoscopic procedure represents a good alternative in the treatment of this benign gastric tumor.

Polimorfismo genético relacionado al metabolismo de la aflatoxina y el riesgo de cáncer vesicular en mujeres chilenas / Aflatoxin metabolism-related genetic polymorphisms and the risk of gallbladder cancer in Chilean women

Background/aim: High consumption of red chili pepper has been shown to be a risk factor for gallbladder cancer (GBC) in Chilean women with gallstones (GS). GS are the main cause of GBC, but not all patients with gallstones develop GBC. Since red chili pepper is a widely consumed spice among the Chilean population, the development of GBC in Chilean women cannot be completely explained by the presence of GS and red chili pepper consumption alone. Genetic factors in addition to these and other environmental factors may also be associated with an increased risk of GBC. We aimed to study whether genetic polymorphisms involved in aflatoxin metabolism are associated with the risk of GBC in Chilean women, because we detected aflatoxins B1 and B2 in red chili pepper purchased in Santiago, Chile. Methods: We conducted a hospital-based case-control study whose subjects were 57 patients with GBC, 119 patients with GS, and 70 controls. DNA was extracted from subjects’ blood or paraffin block samples using standard commercial kits. The statuses of the genetic polymorphisms of cytochrome P450 (CYP) 1A2 rs762551 and CYP3A4 rs2740574 were assayed using the TaqMan® SNP Genotyping Assay or the Custom TaqMan® SNP Genotyping Assay, respectively. Results: In the assay for the CYP1A2 polymorphism, of the 57 GBC patients, 23 (40.3 percent) had at least one minor allele (A/C or C/C). However, there were no significant differences in the genotypic or allelic frequencies among the three subject groups. In the assay for the CYP3A4 polymorphism, the minor G/G genotype was not detected in the three groups, and there were no significant differences in the genotypic or allelic frequencies among the three groups. Conclusion: These genetic polymorphisms were not related to the risk of GBC in Chilean women. Further studies including a greater number of controls and cases are needed to confirm this preliminary exploratory result.

Introducción/objetivo: El alto consumo de ají rojo ha demostrado ser un factor de riesgo de cáncer vesicular (CV) en mujeres chilenas con cálculos vesiculares. Los cálculos vesiculares son la causa principal de CV, no obstante, no todos los pacientes con cálculos vesiculares desarrollan CV. Debido a que el ají rojo es una especia ampliamente consumida entre la población chilena, el desarrollo de CV en las mujeres chilenas no puede ser explicado en su totalidad sólo por la presencia de cálculos vesiculares y consumo de ají rojo. Factores genéticos además de éstos y otros factores ambientales, también podrían estar relacionados con un aumento del riesgo de CV. Nuestro objetivo es estudiar si los polimorfismos genéticos involucrados en el metabolismo de la aflatoxina están relacionados con el riesgo de CV en mujeres chilenas, porque detectamos aflatoxinas B1 y B2 en ajíes rojos comprados en Santiago de Chile. Métodos: El estudio caso control, incluyó 57 pacientes con CV, 119 pacientes con cálculos vesiculares, y 70 controles. Se extrajo ADN de la sangre de los sujetos o de bloques de parafina, usando kits comerciales estándar. El estado de los polimorfismos genéticos del citocromo P450 (CYP) 1A2 rs762551 y CYP3A4 rs2740574 fueron estudiados usando el ensayo de genotipo SNP TaqMan® o el ensayo de genotipo SNP Custom TaqMan®, respectivamente. Resultados: En el ensayo para el polimorfismo CYP1A2, de los 57 pacientes con CV, 23 (40,3 por ciento) tuvieron al menos un alelo menor (A/C o C/C). No obstante, no hubo diferencias significativas en las frecuencias genotípicas o alélicas entre los tres grupos. En el ensayo para el polimorfismo CYP3A4, el genotipo menor G/G no fue detectado en los tres grupos, y no hubo diferencias significativas en las frecuencias genotípicas o alélicas entre los tres grupos. Conclusión: Estos polimorfismos genéticos no estaban relacionados con el riesgo de CV en mujeres chilenas...

Resultados actuales de la pancreatoduodenectomía para el tratamiento de los tumores periampulares y análisis de factores pronósticos de sobrevida / Results of pancreaticoduodenectomy in the treatment of periampullary tumors

Background: The diagnosis and treatment of periampullary tumors represents a challenge for current medicine. Aim: To review the results of pancreaticoduodenectomy (PDD) in the treatment of periampullary tumors and to identify risk factors that impact the long-term survival. Patients and Methods: We performed a retrospective study of patients who underwent a PDD for periampullary tumors between 1993 and 2009. We reviewed perioperative results and long term survival. We performed a multivariate analysis for long-term survival. Results: A PDD was performed in 181 patients aged 58 ± 12 years (98 females). Piloric preservation was done in 53 percent and a pancreatogastric anastomosis was used in 94 percent of cases. Morbidity was 62 percent and postoperative mortality was 5.5 percent. Pancreatic cancer was the most frequent pathological finding in 41 percent, followed by ampullary cancer in 28 percent and distal bile duct cancer in 16 percent. Median survival was 17 months, with a five years survival of 24 percent. Survival for ampullary tumors was 28 months with a five years survival of 32 percent. The median and five years survival were 14 months and 16 percent for bile duct cancer and 11 months and 14 percent for pancreatic cancer. Multivariate analysis identified tumor type (pancreas /bile duct) and lymph node dissemination as independent predictors of mortality. Conclusions: One quarter of patients experienced long term survival. Mortality predictors were tumor type and lymph node dissemination.

Epidemiología del cáncer biliar en Chile: análisis preliminar / Epidemiology of biliary cancer in Chile: preliminary analysis

Toda la evidencia disponible indica que el cáncer biliar en Chile ha tenido un incremento real, importante y mantenido en los últimos 15 años (1970-1984). Por otra parte, no existen elementos de juicio que indiquen que esta tendencia al incremento presente alguna perspectiva de detención o retroceso en el futuro inmediato. El incremento se basaría en aumento del componente vesícula biliar y no tanto en el de vía biliar extra-hepática. Los factores que parecen estar jugando un rol importante en este incremento serían: disminución relativa de la cirugía biliar, aumento de colelitiasis, alto nivel de morbilidad en tifoidea y envejecimiento de la población. El elemento central en la prevención del cáncer biliar debe ser la extirpración de todas las vesículas con colelitiasis, particularmente en los grupos de más riesgo: personas de más de 50 años, mujeres y portadores de tifoidea. Estudios epidemiológicos más completos deberán aportar más información tendiente a evaluar en forma adecuada el riesgo del cáncer biliar en Chile

Perspectivas del cáncer biliar y otros cánceres importantes en Chile / Biliary cancer perspectives and other most common cancers in Chile

Se analiza la mortalidad de los tres principales cánceres en Chile: gástrico, pulmonar y biliar. Mientras el primero disminuye notablemente entre 1970 y 1985 (de 32.7 a 18.6 por 100.000), el pulmonar aumenta en forma moderada (de 7.6 a 10.7) y el biliar lo hace en forma extraordinaria (de 3.7 a 9.4). Las tendencias observadas permiten pronosticar con algún fundamento y en ausencia de programas efectivos de control que dichas tendencias se mantendrán en el próximo decenio, revirtiendo la importancia relativa de estos cánceres y confirmando al cáncer biliar como primera causa de muerte oncológica en Chile por encima del pulmonar y del gástrico en el próximo decenio. Esto empeoraría la situación actual de ser ya el primero en la mujer (desde 1985), por encima del gástrico, cérvico-uterino y mamario

Piometra / Pyometra

Se presentan dos casos clínicos de piometra, atendidos en el servicio de Urgencia de Adultos del Hospital Dr. Sótero del Río, en 1985. No se registran otros en los últimos cinco años. El diagnóstico no fue planteado en el preoperatorio. En una de las pacientes el diagnóstico quirúrgico fue evidente por la complicación de perforación espontánea y peritonitis difusa secundaria. En el otro no se completó la investigación hasta la necropsia, una semana después de la intervención sobre colon, en una enferma en muy malas condiciones. No se efectuó estudio bacteriológico. El orígen del piometra en estas pacientes fue un pólipo cervical benigno con cervicitis crónica en un caso y en el otro un cáncer cérvico uterino. No hubo tratamiento ginecológico en el caso benigno debido al fallecimiento de la paciente (infarto de miocardio) a la semana de una operación sobre colon. En el otro, el cáncer cervico-uterino no se trató con irradiación por estimarse de alto riesgo dados la edad, condiciones generales y peritonitis agregada, además de una supervivencia teórica de muy pocos años. La paciente está relativamente bien, con 8 meses de control