RESUMO
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.
Assuntos
Carcinoma de Células Renais , Interferon gama , Neoplasias Renais , Células Matadoras Naturais , Macrófagos Associados a Tumor , Células Matadoras Naturais/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Interferon gama/metabolismo , Interferon gama/imunologia , Humanos , Animais , Camundongos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Progressão da Doença , Linhagem Celular Tumoral , Microambiente Tumoral/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor de Morte Celular Programada 1/metabolismoRESUMO
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.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/terapia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Neoplasias Renais/terapia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores de Células Matadoras NaturaisRESUMO
Introduction: Ejaculatory dysfunction is a common complication of surgeries for benign prostatic obstruction. It causes a clear deterioration in quality of life. Techniques have been developed to attempt to preserve antegrade ejaculation (AE). Our objective was to analyze results of ejaculatory function using an AE preservation technique during anatomical vaporization with XPS 180-W. Methods: Between 2017 and 2019, sexually active patients were treated using this technique by the same surgical team. A questionnaire (MSHQ-EjD Short Form) was mailed, patients who did not answer were contacted by phone or personally during follow-up. Responses were analyzed. Voiding function was evaluated using International Prostatic Symptoms Score (IPSS), Qmax, and postvoid residual volume. t-Test for paired samples was used to compare conformity of patients with and without AE and voiding results. A p < 0.05 was considered statistically significant. Results: In total, 77 of 112 patients (68.8%) completed questionnaires and were included. Mean age was 64.1 years (standard deviation [SD] 6.9) and median prostate size was 57.2 g (interquartilic range 30-85). A total of 68 of 77 (88.3%) patients reported AE. Of these, 58 (85.3%) reported AE always or most of the time and 10 (14.7%) reported AE half of the time. In total, 42 (61.7%) patients had preserved strength or slightly less than before the procedure, and 33 (48.5%) reported the same or slightly less volume than before. In terms of satisfaction, the average response values of patients with preserved AE and ejaculatory disfunction were 0.97 (SD 1.12) and 2.7 (SD 1.78), respectively (p = 0.000). Pre- and postoperative variables were as follows: mean Qmax was 11.6 mL/sec vs 19.6 (p = 0.00), mean IPSS was 13.8 vs 8.9 (p = 0.000), and mean postvoiding residual urine was 125.3 vs 33.1 mL (p = 0.00), respectively. Conclusion: It is feasible to perform the AE preservation technique with anatomical vaporization XPS 180-W. In our medium size prostate series, we had a satisfactory patient perception of the ejaculatory function and satisfactory voiding function results.
Assuntos
Terapia a Laser , Doenças Prostáticas , Hiperplasia Prostática , Ejaculação , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Qualidade de Vida , Resultado do TratamentoRESUMO
OBJECTIVE: The prostate-specific antigen density (PSAD) is an accessory tool when suspecting prostate cancer. Multiparametric magnetic resonance imaging (mpMRI) of the prostate has a high rate of false negatives. The aim of this study is to evaluate the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) when adding the PSAD and negative or equivocal mpMRI. MATERIAL AND METHODS: A retrospective study that included prostate biopsies performed using a transperineal approach and guided by ultrasound between 2015 and 2019 was conducted. Clinically significant prostate cancer (csPCa) was defined as Gleason score ≥3+4. The population was divided into groups according to the PSAD level-≤0.15 and >0.15. Sensitivity, specificity, NPV, and PPV of mpMRI were calculated. RESULTS: A total of 292 patients were included; 12.1% (4/33 patients) of the negative mpMRI group presented csPCa, and only 7 in the equivocal mpMRI group presented csPCa. NPV and sensitivity were 91.15% and 90.5%, respectively. In the positive mpMRI group, 53.7% (96/179) had csPCa, with a PPV of 53.6% and specificity of 55.3%. Of the patients with PSAD ≤0.15, 23 (16.54%) presented csPCa. All of them presented a positive mpMRI. All patients with a negative or equivocal mpMRI and a PSAD ≤0.15 presented a clinically non-significant tumor or benign result. The addition of this tool to mpMRI resulted in 100% sensitivity, 69% specificity, and 34.8% PPV. CONCLUSION: In our series, PSAD ≤0.15 increased the NPV in negative or equivocal mpMRI, and through this unnecessary prostate biopsies could be avoided.
RESUMO
Objetivos: La detección del cáncer de próstata requiere una biopsia prostática para su confirmación histopatológica. Actualmente, las biopsias prostáticas por vía transrectal guiadas por ecografía (BpTR) son el procedimiento de elección, mientras que las biopsias prostáticas por vía transperineal (BpTP) han sido usualmente recomendadas para rebiopsias de pacientes con biopsias previas negativas. El objetivo de este estudio es comparar los resultados y complicaciones postoperatorias obtenidos utilizando ambas técnicas y la efectividad para hallar tumores con score de Gleason ≥ a 7. Materiales y métodos: Se realizó un estudio retrospectivo, analizando todas las biopsias prostáticas realizadas en el servicio de urología del Hospital Alemán de Buenos Aires, en un período comprendido entre el año 2011 y 2016. Los pacientes fueron divididos en cuatro grupos. El primer grupo fue el cual pertenecían aquellos pacientes a los cuales se les realizó una BpTR sin resonancia magnética prostática previa (RMNp). El segundo grupo lo formaron aquellos pacientes a los cuales se les realizó una RMNp, previa a la BpTR, donde se practicó una biopsia standard, asociada a una biopsia del área sospechosa. dirigida por estimación visual. El tercer grupo corresponde a aquellos pacientes donde se realizó una BpTP con RMNp previa. Por último, el cuarto grupo agrupó a los pacientes que fueron sometidos a una BpTP sin RMNp previa. Se puso especial interés en la capacidad de hallar tumores con un score de Gleason ≥ a 7. A su vez, se evaluaron la tasa de complicaciones postoperatorias (ITU y RAO. Resultados: Se compararon las vías de abordaje, enfrentando los resultados obtenidos de BpTP frente a BpTR, tanto si presentaban o no RMNp previa. En primer lugar, los resultados obtenidos entre BpTR sin RMNp y BpTP sin RMNp. Se calculó Chi2 (X²) de 8,77, con un resultado de p=0,003 (estadísticamente significativa). Por último, se comparó aquellos pacientes con RMNp previa, es decir BpTP y BpTR con RMNp. Se volvió a calcular Chi2 (X²) de 4,6032, con un resultado de p = 0,003. En cuanto a las complicaciones postoperatorias, el grupo de pacientes sometidos a una BpTP presentó menor porcentaje de ITU o RAO, y al comparar estadísticamente estos valores, fue estadísticamente significativo (p=0,0247) cuando se evaluaron las ITU de ambos grupos. Conclusiones: En este estudio retrospectivo las biopsias prostáticas por vía transperineal permitieron hallar un número significativamente mayor de tumores prostáticos con score de Gleason ≥ a 7 que el abordaje transrectal, con o sin RMNp previa. En cuanto a las complicaciones postoperatorias, las BpTP presentaron un menor porcentaje, siendo significativas cuando se compararon las infecciones del tracto urinario. (AU)
Objectives: Currently, the transrectal ultrasound-guided prostate biopsies (TRUS) are the standard-procedure, while transperineal prostatic biopsies (TP) have usually been recommended for re-biopsies of patients with previous negative biopsies. The aim of this study is to compare the results and postoperative complications obtained using both techniques and the effectiveness to find tumors with a Gleason score ≥7. Materials and methods: A retrospective study was carried out, analyzing all the prostatic biopsies performed in the Urology Service of the Hospital Aleman, between 2011 and 2016. The patients were divided into four groups. The first and second group were those patients in whom a TRUS biopsy was performed without a previous multiparametric magnetic resonance of the prostate (mp-MRI) and those who underwent a mp-MRI before the TURS-biopsy (guided by visual estimation), respectively. The third and fourth group were those patients where a TP-biopsy with previous and without mp-MR, respectively. Special interest was placed on the ability to find tumors with a Gleason score ≥7. Furthermore, the rate of postoperative complications (urinary tract infections and acute urinary retention) were evaluated. Results: The approaches were compared, comparing the results obtained with TRUS and TP biopsies, whether or not they had previous mp-MRI. First, the results obtained between TRUS-biopsy without mp-MRI and TP-biopsy without mp-MRI. Chi2 (X²) of 8.77 was calculated, with a result of p=0.003 (statistically significant). Finally, we compared those patients with previous mp-MRI. It was recalculated Chi2 (X²) of 4.6032, with a result of p=0.003. Regarding postoperative complications, the group of patients submitted to a TP-biopsy had a lower percentage of UTI or AUR, and when statistically comparing these values, it was statistically significant (p=0.0247) when the UTIs of both groups were evaluated. Conclusions: In this retrospective study, transperineal prostatic biopsies allowed to find a significantly higher number of prostate tumors with a Gleason score ≥7 than the transrectal approach, with or without previous mp-MRI. Regarding the postoperative complications, the TP-biopsy presented a lower percentage, being significant when the urinary tract infections were compared. (AU)