Tumor-associated macrophages impair NK cell IFN-γ production and contribute to tumor progression in clear cell renal cell carcinoma.

Tumor-associated macrophages (TAM) are abundant in several tumor types and usually correlate with poor prognosis. Previously, we demonstrated that anti-inflammatory macrophages (M2) inhibit NK cell effector functions. Here, we explored the impact of TAM on NK cells in the context of clear-cell renal cell carcinoma (ccRCC). Bioinformatics analysis revealed that an exhausted NK cell signature strongly correlated with an M2 signature. Analysis of TAM from human ccRCC samples confirmed that they exhibited an M2-skewed phenotype and inhibited IFN-γ production by NK cells. Moreover, human M0 macrophages cultured with conditioned media from ccRCC cell lines generated macrophages with an M2-skewed phenotype (TAM-like), which alike TAM, displayed suppressive activity on NK cells. Moreover, TAM depletion in the mouse Renca ccRCC model resulted in delayed tumor growth and reduced volume, accompanied by an increased frequency of IFN-γ-producing tumor-infiltrating NK cells that displayed heightened expression of T-bet and NKG2D and reduced expression of the exhaustion-associated co-inhibitory molecules PD-1 and TIM-3. Therefore, in ccRCC, the tumor microenvironment polarizes TAM toward an immunosuppressive profile that promotes tumor-infiltrating NK cell dysfunction, contributing to tumor progression. In addition, immunotherapy strategies targeting TAM may result in NK cell reinvigoration, thereby counteracting tumor progression.

The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology.

NKG2D is a major natural killer (NK) cell-activating receptor that recognizes eight ligands (NKG2DLs), including MICA, and whose engagement triggers NK cell effector functions. As NKG2DLs are upregulated on tumor cells but tumors can subvert the NKG2D-NKG2DL axis, NKG2DLs constitute attractive targets for antibody (Ab)-based immuno-oncology therapies. However, such approaches require a deep characterization of NKG2DLs and NKG2D cell surface expression on primary tumor and immune cells. Here, using a bioinformatic analysis, we observed that MICA is overexpressed in renal cell carcinoma (RCC), and we also detected an association between the NKG2D-MICA axis and a diminished overall survival of RCC patients. Also, by flow cytometry (FC), we observed that MICA was the only NKG2DL over-expressed on clear cell renal cell carcinoma (ccRCC) tumor cells, including cancer stem cells (CSC) that also coexpressed NKG2D. Moreover, tumor-infiltrating leukocytes (TIL), but not peripheral blood lymphoid cells (PBL) from ccRCC patients, over-expressed MICA, ULBP3 and ULBP4. In addition, NKG2D was downregulated on peripheral blood NK cells (PBNK) from ccRCC patients but upregulated on tumor-infiltrating NK cells (TINK). These TINK exhibited impaired degranulation that negatively correlated with NKG2D expression, diminished IFN-γ production, upregulation of TIM-3, and an impaired glucose intake upon stimulation with cytokines, indicating that they are dysfunctional, display features of exhaustion and an altered metabolic fitness. We conclude that ccRCC patients exhibit a distorted MICA-NKG2D axis, and MICA emerges as the forefront NKG2DL for the development of targeted therapies in ccRCC.

[Risk factors for contrast extravasation in renal colic]. / Factores de riesgo para extravasación de contraste en cólico renal.

INTRODUCTION: Non-traumatic ruptureof the pyeloureterocaliceal system (PUC) is anuncommon clinical entity. The most frequent cause isureteral obstruction due to lithiasic pathology, whichis present in up to 75%. To our knowledge, there isno description in the literature of the possible factorsassociated with this event. Our objective is to analyzethe variables associated with intravenous contrastextravasation in patients with renal colic due to singleureteral lithiasis. MATERIALS AND METHODS: We performed aretrospective, descriptive analysis of a series ofpatients who, in the context of renal colic, presentedendovenous contrast extravasation throughthe urinary system in computed tomography (CT).Patients with single ureteral lithiasis without otherassociated pathology were included. A comparisonof the samples from the group with contrast leakage(group 1) with an equal number of consecutiveCT scans without contrast leakage (group 2) in patientswith renal colic lithiasis was performed in alogistic regression model to identify risk factors forcontrast leakage. RESULTS: There were 117 cases of contrast leakagefrom January 2013 to July 2018. Eighty-sixpercent of the lithiases were 5 mm and 79% werelocated in the lower ureter. 72% of patients presentedwith intrarenal pelvis. In the univariate analysisboth location in lower ureter, lithiasis 5 mm, andintrarenal pyelic anatomy increased the probabilityof extravasation. In multivariate model, 5 mmlithiasis increased five times the risk of extravasationcompared to larger ones, the location in distalureter increased three times and the anatomy withintrarenal pelvis increased two times compared toother location and extrarenal pelvis, respectively, ina statistically significant way the risk of presentingcontrast leakage. CONCLUSION: In this series, we found an increasedrisk of contrast leakage in a lithiasic renalcolic in patients with intrarenal pelvic anatomy,with lithiasis less than or equal to 5 mm and locatedin the lower ureter.

INTRODUCCIÓN: La ruptura no traumaticadel sistema pieloureterocalicial (PUC) es una entidadclínica poco común. La causa más frecuente esla obstrucción ureteral por patología litiásica, que sepresenta hasta en un 75%. A nuestro conocimiento, noexiste en la literatura una descripción de los posiblesfactores asociados con este evento. Nuestro objetivo esanalizar las variables asociadas con la extravasaciónde contraste endovenoso en pacientes con cólico renalpor litiasis ureteral única.MATERIALES Y MÉTODOS: Se realizó un análisis retrospectivo,descriptivo, de una serie de pacientes que,en contexto de cólico renal, presentaron extravasaciónde contraste endovenoso por el sistema urinario entomografía computada (TC). Se incluyeron pacientescon litiasis ureteral única sin otra patologia asociada.Se realizó una comparación de las muestras del grupocon fuga de contraste (grupo 1) con igual número detomografías consecutivas sin fuga de contraste (grupo2) en paciente con cólico renal litiásico, en un modelode regresión logística para identificar factores de riesgode fuga de contraste. RESULTADOS: Se registraron 117 casos de fuga decontraste desde enero de 2013 hasta julio de 2018. El86% de los litos fueron ≤ 5 mm y el 79 % se ubicaronen uréter inferior. El 72% de los pacientes presentópelvis intrarrenal. En el análisis univariado tanto ubicaciónen uréter inferior, litiasis ≤ 5 mm, como anatomíapielica intrarrenal aumentaron la probabilidad deextravasación. En el modelo multivariado, litiasis ≤ 5mm aumentaron cinco veces el riesgo de extravasacióncomparado con las mayores, la ubicación en uréterdistal aumentó en tres veces y la anatomía con pelvisintrarrenal aumentó en dos veces comparado conotra ubicación y pelvis extrarrenal, respectivamente,de manera estadísticamente significativa el riesgo depresentar fuga de contraste.CONCLUSIÓN: En esta serie, encontramos aumentode riesgo de fuga de contraste en un cólico renal litiásicoen pacientes con anatomía piélica intrarrenal,con litos menores o iguales a 5 mm y ubicados enuréter inferior.

Factores de riesgo para extravasación de contraste en colico renal / Risk factors for contrast extravasation in renal colic

INTRODUCCIÓN: La ruptura no traumatica del sistema pieloureterocalicial (PUC) es una entidad clínica poco común. La causa más frecuente esla obstrucción ureteral por patología litiásica, que sepresenta hasta en un 75%. A nuestro conocimiento, noexiste en la literatura una descripción de los posiblesfactores asociados con este evento. Nuestro objetivo esanalizar las variables asociadas con la extravasaciónde contraste endovenoso en pacientes con cólico renalpor litiasis ureteral única.MATERIALES Y MÉTODOS: Se realizó un análisis retrospectivo, descriptivo, de una serie de pacientes que,en contexto de cólico renal, presentaron extravasaciónde contraste endovenoso por el sistema urinario entomografía computada (TC). Se incluyeron pacientescon litiasis ureteral única sin otra patologia asociada.Se realizó una comparación de las muestras del grupocon fuga de contraste (grupo 1) con igual número detomografías consecutivas sin fuga de contraste (grupo2) en paciente con cólico renal litiásico, en un modelode regresión logística para identificar factores de riesgo de fuga de contraste. RESULTADOS: Se registraron 117 casos de fuga decontraste desde enero de 2013 hasta julio de 2018. El86% de los litos fueron ≤ 5 mm y el 79 % se ubicaronen uréter inferior. El 72% de los pacientes presentópelvis intrarrenal. En el análisis univariado tanto ubicación en uréter inferior, litiasis ≤ 5 mm, como anatomía pielica intrarrenal aumentaron la probabilidad deextravasación. En el modelo multivariado, litiasis ≤ 5mm aumentaron cinco veces el riesgo de extravasación comparado con las mayores, la ubicación en uréter distal aumentó en tres veces y la anatomía con pelvis intrarrenal aumentó en dos veces comparado conotra ubicación y pelvis extrarrenal, respectivamente,de manera estadísticamente significativa el riesgo depresentar fuga de contraste.

INTRODUCTION: Non-traumatic rupture of the pyeloureterocaliceal system (PUC) is anuncommon clinical entity. The most frequent cause isureteral obstruction due to lithiasic pathology, whichis present in up to 75%. To our knowledge, there isno description in the literature of the possible factorsassociated with this event. Our objective is to analyzethe variables associated with intravenous contrastextravasation in patients with renal colic due to singleureteral lithiasis. MATERIALS AND METHODS: We performed aretrospective, descriptive analysis of a series ofpatients who, in the context of renal colic, presented endovenous contrast extravasation throughthe urinary system in computed tomography (CT).Patients with single ureteral lithiasis without otherassociated pathology were included. A comparisonof the samples from the group with contrast leakage (group 1) with an equal number of consecutiveCT scans without contrast leakage (group 2) in patients with renal colic lithiasis was performed in alogistic regression model to identify risk factors forcontrast leakage.RESULTS: There were 117 cases of contrast leakage from January 2013 to July 2018. Eighty-sixpercent of the lithiases were 5 mm and 79% werelocated in the lower ureter. 72% of patients presented with intrarenal pelvis. In the univariate analysisboth location in lower ureter, lithiasis 5 mm, andintrarenal pyelic anatomy increased the probability of extravasation. In multivariate model, 5 mmlithiasis increased five times the risk of extravasation compared to larger ones, the location in distalureter increased three times and the anatomy withintrarenal pelvis increased two times compared toother location and extrarenal pelvis, respectively, ina statistically significant way the risk of presentingcontrast leakage.CONCLUSION: In this series, we found an increased risk of contrast leakage in a lithiasic renalcolic in patients with intrarenal pelvic anatomy with lithiasis less

[Partial nephrectomy in mesorrenal tumors greater than 4 cm: 15 years of experience.] / Nefrectomia parcial en tumores mesorrenales mayores de 4 cm: experiencia de 15 años.

OBJECTIVES: Mesorenal tumors (those located in the renal middle line or between both poles) are complex cases for partial nephrectomy (PN). Our objective is to evaluate oncological and perioperative results of PN in these patients with mesorenal tumors greater than 4 cm, mesophytic or endophytic. METHODS: A review of the medical records of patients with tumors with these characteristics operated between January 2016 and June 2016 was performed. RESULTS: 36 cases were included. The mean age was 54.2 years (24-79) with 12 cases of male gender. Mean surgical time: 139 minutes (120-280); 30 cases with complete clamping with mean ischemia of 19 minutes (10-90) and 6 compression of the parenchyma. Mean estimated bleeding: 280 ml (100-900). Mean tumor diameter: 4.3 cm (4.0 to 7.6). Preoperative and postoperative mean glomerular filtration rate 89 ml/min and 76 ml/min (p=0.32) respectively. Median length of stay: 3.8 days (2-21). There were 2 (6.5%) complications (II and IIIb). One case (3.3%) presented positive margin. One patient died due to progression at 14 months. With a median follow-up of 52.1 months (10-168) no recurrences were observed. CONCLUSIONS: We consider that mesorenal tumors, with significant penetration within the renal parenchyma and greater than 4 cm, PN presents both oncological and satisfactory results.

OBJETIVO: Los tumores mesorrenales (aquellos ubicados en la línea media renal o entre ambos polos) son casos complejos para una nefrectomía parcial. Nuestro objetivo es evaluar resultados oncológicos y perioperatorios de NP (nefrectomía parcial) en estos pacientes con tumores mesorrenales mayores a los 4 cm, mesofiticos o endofiticos. METODOS: Se realizó una revisión de las historias clínicas de pacientes con tumores con estas características operados entre enero de 2011 y junio de 2016 y se analizaron distintas variables. RESULTADOS: Se obtuvieron 36 casos. La edad media fue 54,2 años (24-79) con 12 casos de sexo masculino. Tiempo quirúrgico medio: 139 minutos (120- 280); 30 casos con clampeo completo con isquemia media de 19 minutos (10-90) y 6 compresión del parénquima. Sangrado promedio estimado: 280 ml (100-900). Diámetro tumoral medio: 4,3 cm (4,0 a 7,6). Tasa media de filtrado glomerular preoperatoria y posoperatoria 89 ml/min y 76 ml/min (p=0,32) respectivamente. Mediana de internación: 3,8 días (2-21). Hubo 2 (6,5%) complicaciones (II y IIIb). Un caso (3,3%) presentó margen positivo. Un paciente falleció por progresión a los 14 meses. Con una mediana seguimiento de 52,1 meses (10-168) no se observaron recidivas. CONCLUSION: Consideramos que en los tumores mesorrenales, con penetración significativa dentro del parénquima renal y mayores a los 4 cm, la NP presenta resultados tanto oncológicos como funcionales satisfactorios.

Nefrectomia parcial en tumores mesorrenales mayores de 4 cm: experiencia de 15 años / Partial nephrectomy in mesorrenal tumors greater than 4 cm: 15 years of experience

Objetivo: Los tumores mesorrenales (aquellos ubicados en la línea media renal o entre ambos polos) son casos complejos para una nefrectomía parcial. Nuestro objetivo es evaluar resultados oncológicos y perioperatorios de NP (nefrectomía parcial) en estos pacientes con tumores mesorrenales mayores a los 4 cm, mesofiticos o endofiticos. Metodos: Se realizó una revisión de las historias clínicas de pacientes con tumores con estas características operados entre enero de 2011 y junio de 2016 y se analizaron distintas variables. Resultados: Se obtuvieron 36 casos. La edad media fue 54,2 años (24-79) con 12 casos de sexo masculino. Tiempo quirúrgico medio: 139 minutos (120- 280); 30 casos con clampeo completo con isquemia media de 19 minutos (10-90) y 6 compresión del parénquima. Sangrado promedio estimado: 280 ml (100-900). Diámetro tumoral medio: 4,3 cm (4,0 a 7,6). Tasa media de filtrado glomerular preoperatoria y posoperatoria 89 ml/min y 76 ml/min (p = 0,32) respectivamente. Mediana de internación: 3,8 días (2-21). Hubo 2 (6,5%) complicaciones (II y IIIb). Un caso (3,3%) presentó margen positivo. Un paciente falleció por progresión a los 14 meses. Con una mediana seguimiento de 52,1 meses (10-168) no se observaron recidivas. Conclusión: Consideramos que en los tumores mesorrenales, con penetración significativa dentro del parénquima renal y mayores a los 4 cm, la NP presenta resultados tanto oncológicos como funcionales satisfactorios

Objectives: Mesorenal tumors (those located in the renal middle line or between both poles) are complex cases for partial nephrectomy (PN). Our objective is to evaluate oncological and perioperative results of PN in these patients with mesorenal tumors greater than 4 cm, mesophytic or endophytic. Methods: A review of the medical records of patients with tumors with these characteristics operated between January 2016 and June 2016 was performed. Results: 36 cases were included. The mean age was 54.2 years (24-79) with 12 cases of male gender. Mean surgical time: 139 minutes (120-280); 30 cases with complete clamping with mean ischemia of 19 minutes (10-90) and 6 compression of the parenchyma. Mean estimated bleeding: 280 ml (100-900). Mean tumor diameter: 4.3 cm (4.0 to 7.6). Preoperative and postoperative mean glomerular filtration rate 89 ml/min and 76 ml/min (p = 0.32) respectively. Median length of stay: 3.8 days (2-21). There were 2 (6.5%) complications (II and IIIb). One case (3.3%) presented positive margin. One patient died due to progression at 14 months. With a median follow-up of 52.1 months (10-168) no recurrences were observed. Conclusions: We consider that mesorenal tumors, with significant penetration within the renal parenchyma and greater than 4 cm, PN presents both oncological and satisfactory results

Synthetic Renal Capsule Tailoring: A Novel Renorrhaphy Technique After Subcapsular Dissection of Renal Tumors with Severe Adherent Perirenal Fat During Laparoscopic Partial Nephrectomy.

BACKGROUND: Multiple factors can account for surgical complexity during laparoscopic partial nephrectomy (LPN); severe adhesion of perirenal fat (PRF) is a crucial one. Consequent renal decapsulation can deem renorrhaphy a very challenging task. We propose a novel technique (synthetic renal capsule tailoring [SYRCT]) to facilitate renorrhaphy in decapsulated kidneys and suggest early decapsulation as a safe option in cases with severe PRF. MATERIALS AND METHODS: We retrospectively analyzed perioperative results of this novel technique performed in cases with severe PRF. All cases were classified as high grade in the Mayo Adhesive Probability (MAP) score. RESULTS: A total of six cases were performed with the SYRCT technique. All patients were male with a mean age of 70 years (62-76 years) and mean body mass index of 30 kg/m2 (23.66-33.86). Of the six cases, five were T1a and 1 T1b. Mean tumor size was 2.83 cm (range 1.2-6 cm). Mean operative time was 121 minutes (range 74-150 minutes); mean warm ischemia time was 17.2 minutes (range 13-25 minutes). Mean operative bleeding was 128 mL (range 50-250 mL). Mean hospital stay was 2.3 days. There were no surgical complications greater or equal to Clavien II. CONCLUSION: Performing complete renal decapsulation with subcapsular dissection and SYRCT in cases with high MAP score and severe PRF is safe and reproducible. Using this novel technique, we were able to obtain perioperative results comparable to the ones we found in LPN with normal PRF.