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Introducción. El cáncer de riñón es la undécima neoplasia maligna más común en los Estados Unidos Mexicanos. El carcinoma de células claras de riñón (CCR) es considerado la estirpe más frecuente y representa el 2-3 % de todos los cánceres a nivel mundial. En el contexto de la enfermedad metastásica, por lo general se identifica un tumor renal primario y las metástasis se localizan en pulmón, hueso, hígado, cerebro y, raramente, en tejidos blandos. Los pacientes con metástasis a tejidos blandos no tienen síntomas en las etapas iniciales y generalmente se identifican sólo cuando las lesiones aumentan de tamaño o durante el estudio de la pieza de resección quirúrgica. Caso clínico. Se presenta el caso de una paciente en la séptima década de la vida, con una metástasis en tejidos blandos de la región sacra, de 10 años de evolución posterior a una nefrectomía secundario a CCR. Resultados. Hallazgos clínicos e imagenológicos de un tumor bien delimitado. Se realizó resección quirúrgica de la lesión, bajo anestesia regional, con extirpación completa. Conclusión. Se recomienda que los pacientes con un sitio metastásico resecable y solitario sean llevados a resección quirúrgica con márgenes libres, como fue el caso de nuestra paciente, por su fácil acceso y ser una lesión única. En el CCR, además de su tratamiento quirúrgico inicial, es indispensable una estrecha vigilancia con examen físico e imágenes transversales, para detectar la presencia de metástasis y con ello evitar tratamientos tardíos.
Introduction. Kidney cancer is the eleventh most common malignancy in the United States of Mexico. Carcinoma renal cell (CRC) is considered the most frequent type and represents 2-3% of all cancers worldwide. In the setting of metastatic disease, a primary renal tumor is usually identified, and metastases are located in the lung, bone, liver, brain, and rarely in soft tissue. Patients with soft tissue metastases do not have symptoms in the initial stages and are generally found only when the lesions increase in size or during the study of the surgical resection piece. Clinical case. In this case, we report a female patient in the seventh decade of life with a soft tissue metastasis located in the sacral region, 10 years after a nephrectomy secondary to CRC. Results. Clinical and radiological findings of a well-defined tumor. Surgical resection of the lesion is performed under regional anesthesia with complete excision. Conclusions. It is recommended that patients with a resectable and solitary metastatic site be candidates for surgical resection with free margins, as was the case with our patient due to its easy access and single lesion. In CRC, in addition to its initial surgical treatment, close surveillance with physical examination and cross-sectional images is essential to monitor the presence of metastases and thus avoid late treatments.
Subject(s)
Humans , Carcinoma, Renal Cell , Kidney Neoplasms , Neoplasm Seeding , Soft Tissue Neoplasms , Diagnosis, Differential , Neoplasm MetastasisABSTRACT
SUMMARY: We investigated the expression and clinical significance of miR-15b-5p in clear cell renal cell carcinoma (RCC) through bioinformatics analysis and experimental verification. The differentially expressed miRNAs were screened in the GEO database. Venn diagram showed that there were 5 up-regulated miRNAs (has-miR-210, has-miR-142-3p, has-miR-142-5p, has-miR-15b-5p, and has-miR-193a-3p) and only 1 down-regulated miRNA (has-miR-532-3p) that were commonly expressed between GSE189331 and GSE16441 datasets. This was further confirmed in TCGA. Further analysis showed that the has-miR-193a-3p, has-miR-142-3p, has- miR-142-5p, and has-miR-15b-5p were closely related to tumor invasion, distant metastasis and survival probability. The expression of miR-15b-5p in ccRCC tissues was significantly higher than that in adjacent normal kidney tissues (P0.05). Following inhibition of miR-15b-5p expression, RCC cells had attenuated proliferation, increased apoptosis, and attenuated migration and invasion. has-miR-15b-5p-WEE1, has-miR-15b-5p-EIF4E, has-miR-15b-5p-PPP2R1B may be three potential regulatory pathways in ccRCC. miR-15b-5p is highly expressed in cancer tissues of ccRCC patients. It may promote proliferation, inhibit apoptosis and enhance cell migration and invasion of RCC cells. The has-miR-15b-5p-WEE1, has-miR-15b-5p-EIF4E, and has-miR-15b-5p-PPP2R1B may be three potential regulatory pathways in ccRCC.
Investigamos la expresión y la importancia clínica de miR-15b-5p en el carcinoma de células renales (CCR) de células claras mediante análisis bioinformático y verificación experimental. Los miARN expresados diferencialmente se examinaron en la base de datos GEO. El diagrama de Venn mostró que había 5 miARN regulados positivamente (has-miR-210, has-miR-142-3p, has-miR-142-5p, has-miR-15b-5p y has-miR-193a-3p). ) y solo 1 miARN regulado negativamente (has-miR-532-3p) que se expresaron comúnmente entre los conjuntos de datos GSE189331 y GSE16441. Esto fue confirmado aún más en TCGA. Un análisis más detallado mostró que has-miR-193a-3p, has-miR-142-3p, has- miR-142-5p y has-miR-15b-5p estaban estrechamente relacionados con la invasión tumoral, la metástasis a distancia y la probabilidad de supervivencia. La expresión de miR-15b-5p en tejidos ccRCC fue significativamente mayor que la de los tejidos renales normales adyacentes (P 0,05). Tras la inhibición de la expresión de miR-15b-5p, las células RCC tuvieron una proliferación atenuada, un aumento de la apoptosis y una migración e invasión atenuadas. has-miR-15b-5p-WEE1, has- miR-15b-5p-EIF4E, has-miR-15b-5p-PPP2R1B pueden ser tres posibles vías reguladoras en ccRCC. miR-15b-5p se expresa altamente en tejidos cancerosos de pacientes con ccRCC. Puede promover la proliferación, inhibir la apoptosis y mejorar la migración celular y la invasión de células RCC. has-miR-15b-5p-WEE1, has- miR-15b-5p-EIF4E y has-miR-15b-5p-PPP2R1B pueden ser tres posibles vías reguladoras en ccRCC.
Subject(s)
Humans , Male , Female , Carcinoma, Renal Cell/pathology , MicroRNAs , Kidney Neoplasms/pathology , Carcinoma, Renal Cell/genetics , Survival Analysis , Cell Movement , Computational Biology , Real-Time Polymerase Chain Reaction , Kidney Neoplasms/genetics , Neoplasm Invasiveness , Neoplasm MetastasisABSTRACT
Renal cell carcinoma (RCC) is the most common subtype of adult renal tumors, and its detection rate in the early stages has been increased in the dawn of advanced imaging modalities. Nephrectomy is the mainstay of treatment; determination of tumor category and staging is the primary concern of oncopathologists. Non-neoplastic renal parenchyma is overlooked majority of times and thus misses the opportunity to detect concomitant medical renal diseases which also predict the renal outcome in the postoperative era. Although any kind of glomerular or extraglomerular pathology may be encountered, vascular changes in the form of arterionephrosclerosis are the commonest one. Here, we take the opportunity to report an unusual association of heavy chain deposition disease (HCDD) with clear cell subtypes of renal cell carcinoma in a 48-year-old male of Indian ethnicity.
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Oral cavity metastatic tumors derived from primary tumors from other corporal regions are rare, representing barely 1 % of all malignant tumors. Differential diagnosis of these lesions is challenging due to the wide spectrum of lesions with similar clinical presentation and especially when the presence of a primary tumor goes undetected. We present the case of a 55-year-old male with a painless tumor in the anterior maxillary region, vestibular gingiva and palate, with a 2-month evolution. Anatomopathological diagnosis was malignant clear cell tumor, highly suggestive of clear cell renal carcinoma metastasis, and the oral lesion constituted the first sign of illness.
Los tumores metastásicos de cavidad oral derivados de tumores primarios de otras regiones corporales son raros, representando apenas el 1 % de todos los tumores malignos. El diagnóstico diferencial de estas lesiones es desafiante debido al amplio espectro de lesiones con presentación clínica similar y especialmente cuando la presencia de un tumor primario pasa desapercibida. Presentamos el caso de un varón de 55 años con una tumoración indolora en región maxilar anterior, encía vestibular y paladar, de 2 meses de evolución. El diagnóstico anatomopatológico fue de tumor maligno de células claras, altamente sugestivo de metástasis de carcinoma renal de células claras, y la lesión bucal constituyó el primer signo de enfermedad.
Subject(s)
Humans , Male , Middle Aged , Mouth Neoplasms/secondary , Carcinoma, Renal Cell/diagnosis , Kidney Neoplasms/diagnosisABSTRACT
Background: CXCL13, B-lymphocyte chemoattractant, has been associated with many diseases and cancers. One of the malignancies that CXCL13 has been investigated is clear cell renal cell carcinomas which are the most common subtype of renal cancers. Aims and Objectives: The aim of this study is to evaluate the immunohistochemical staining patterns of CXCL13 in clear cell renal cell carcinomas and to determine its relationship with pathological tumor stage, risk factors, and prognostic parameters. Materials and Methods: In this study, 99 patients who underwent partial/radical nephrectomy diagnosed with clear cell renal cell carcinoma were included. Four micron sections were taken from paraffin embedded blocks containing sufficient tumor and kidney tissue. Samples were immunohistochemically stained with CXCL13 antibody. During microscopic examination, CXCL13 positive stained cells in ten high magnification fields were counted and evaluated using a semiquantitative H score: 3 × strongly stained + 2 × moderately stained + 1 × weakly stained. The cut-off value was set as 40 for values between 0 and 300. The low and high stained groups were compared with prognostic parameters and risk factors. Statistics: The difference of continuous variables between the two groups was examined with the t test and the distribution of categorical variables with the Chi-square test. A value of P < 0.05 was considered to be statistically significant. Results: The number of lymphocytes stained with CXCL13 in the tumor was higher than in the normal kidney parenchyma (p = 0.07). Intratumoral lymphocytes were highly stained with CXCL13 in 57.5% of pT3 cases and 31.7% of pT1 cases. The amount of intratumoral lymphocytes stained with CXCL13 increased in advanced pathological stages (p = 0.05). Nonsmoking cases were mostly in the low staining group (p = 0.06). Conclusion: The relationship we found between advanced pathological stage and intratumoral CXCL13 staining in our study suggests that CXCL13 has a prognostic value in this cancer.
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Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a newly emerging distinct and rare morphologic variant of renal cell carcinoma (RCC). Morphological, immunohistochemical, and molecular data have shown that BSARCC is closely related to papillary RCC type 1. We report a case of Biphasic squamoid alveolar renal cell carcinoma with a rare presentation as cutaneous metastases. This variant tends to show an aggressive behavior. Hence, accurate histopathological diagnosis can help in effective treatment and for close follow-up of the patients.
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Context: TFE3 translocation renal cell carcinoma (RCC) is a rare tumor that represents approximately 1% of RCC. It was classifed as a member of MiT family translocation RCCs by the World Health Organization in 2016. It is characterized by Xp11 translocation gene fusions involving TFE3. The diagnosis of TFE3 translocation RCC is based on immunohistochemical analysis and TFE3 break apart probes in FISH analysis, rather than histological characteristics and imaging examination. Aims: To determine the clinico-pathological, immuno-phenotypic, and cytogenetic characteristics of TFE3 translocation RCC. Methods and Materials: The clinical data of a 52-year-old-female patient with TFE3 translocation RCC exhibiting rare morphological characteristics was analyzed, and the tumor tissues were probed using histopathological staining, immunohistochemistry, and fluorescence in situ hybridization (FISH). In addition, the relevant literature was reviewed. Results: This case is a TFE3 translocation RCC with rare morphological features. It composed of two types of tumor cells. TFE3 and pax-8 were diffusely and strongly expressed in both tumor cells, and they were partially positive for CAIX, RCC, CK, EMA, CD10, Vim, Melan-A, and p504s. Only 2% of the cells were positive for the proliferation marker Ki-67, and the tumor was negative for CK7, CD117, Inhibin-?, HBM45, and p53. FISH showed a positive signal for TFE3 translocation. Conclusions: This case was a TFE3 translocation RCC with rare morphological features. Through this case report, we emphasize the importance of in situ detection of TFE3 gene translocation and protein in TFE3 translocation RCC.
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Background: Renal cell carcinoma (RCC) presents with inferior vena cava (IVC) thrombus in 10%�% cases and surgical management forms the mainstay of the treatment. The objective of this study is to assess the outcomes of the patients undergoing radical nephrectomy with IVC thrombectomy. Methods: A retrospective analysis of patients undergoing open radical nephrectomy with IVC thrombectomy between 2006 till 2018 was done. Results: A total of 56 patients were included. The mean (眘tandard deviation) age was 57.1 (�.2) years. The number of patients with levels I, II, III, and IV thrombus were 4, 29,10, and 13, respectively. The mean blood loss was 1851.8 mL, and the mean operative time was 303.3 minutes. Overall, the complication rate was 51.7%, while the perioperative mortality rate was 8.9%. The mean duration of hospital stay was 10.6 � 6.4 days. The majority of the patients had clear cell carcinoma (87.5%). There was a significant association between grade and stage of thrombus (P = 0.011). Using Kaplan朚eier survival analysis, the median overall survival (OS) was 75 (95% confidence interval [CI] = 43.5�6.5) months, and the median recurrence-free survival (RFS) was 48 (95% CI = 33.1�.3) months. Age (P = 0.03), presence of systemic symptoms (P = 0.01), radiological size (P = 0.04), histopathological grade (P = 0.01), level of thrombus (P = 0.04), and invasion of thrombus into IVC wall (P = 0.01) were found to be significant predictors of OS. Conclusion: The management of RCC with IVC thrombus poses a major surgical challenge. Experience of a center along with high-volume and multidisciplinary facility particularly cardiothoracic facility provides better perioperative outcome. Though surgically challenging, it offers good overall-survival and recurrence-free survival
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Background: The aim of this study was to investigate the application value of laparoscopic ultrasound (LU) in retroperitoneal radical nephrectomy for renal cell carcinoma with Type II inferior vena cava tumor thrombectomy (RRN-RCC-TII-IVCTT). Methods: The clinical data (operative time, length of tumor thrombus, tumor length, intraoperative bleeding, clinical stage, histological type, residual tumor tissue, and postoperative follow-up) of 6 patients who underwent LU-guided RRN-RCC-TII-IVCTT were retrospectively analyzed, and the intraoperative experience of LU was also summarized. Results: All 6 patients recovered well with liver and kidney functions returning to normal, and no tumor recurrence, metastasis, or vena cava tumor thrombus. Conclusions: LU-guided RRN-RCC-TII-IVCTT is a feasible treatment option, which locates the tumor accurately by retroperitoneal approach and provides the additional benefit of reduced intraoperative bleeding and shortened operative time, also achieving the much sought-after goal of precision.
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Nephrectomy, histopathological examination, neoplastic, renal cell carcinomaBackground: Nephrectomy either partial or radical has become a common procedure in surgical and urological practice. In this study pathological reports were interpreted for the following parameters: age, gender, pathological diagnosis. An indication of nephrectomy depends on type of lesion, extent of damage, general condition of patient and status of contralateral kidney. Method: The present ambiceptive data analysis has been carried out in Department of Pathology in tertiary care centre under Maharashtra University of Health Sciences by histopathological examination of nephrectomy specimens. A Results: total of 59 nephrectomy cases were included in the study. Non neoplastic and neoplastic cases were 44 (75%) and 15 (25%) respectively. Among non-neoplastic lesions, total of 32 cases (72%) were diagnosed as Chronic pyelonephritis with End Stage Renal Disease(ESRD) . Others Chronic Xanthogranulomatous Pyelonephritis with ESRD 9 cases (21%) and Chronic Glomerulonephritis with ESRD 3 cases (7%). Neoplastic lesions constitutes 15 cases with peak in 6th decade. Renal Cell Carcinoma(RCC) is the most common neoplastic lesion. The distribution among the neoplastic lesions include: Clear cell RCC (40%), Papillary RCC (13.34%), Mixed RCC (13.34%), Chromophobe RCC (13.34%), Multicystic nephroma (6.67%), Collecting duct carcinoma (6.67%) and Renal Medullary carcinoma (6.67%). Fuhrman's nuclear grade II is the most common among the RCC. Rare case such as Collecting Duct carcinoma, Renal Medullary carcinoma and Sarcomatoid RCC were diagnosed during the study period. On IHC, Collecting Duct carcinoma is positive for HMW CK, PAX8 and Renal medullary carcinoma is positive for Vimentin. The histopathological Conclusion: examination is essential to differentiate between benign and malignant neoplastic lesions and in grading of malignant lesions which help in treatment and further management of patients.
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OBJECTIVE@#To compare the performance of Clear Cell Likelihood Score (ccLS) v1.0 and v2.0 in diagnosing clear cell renal cell carcinoma (ccRCC) from small renal masses (SRM).@*METHODS@#We retrospectively analyzed the clinical data and MR images of patients with pathologically confirmed solid SRM from the First Medical Center of the Chinese PLA General Hospital between January 1, 2018, and December 31, 2021, and from Beijing Friendship Hospital of Capital Medical University and Peking University First Hospital between January 1, 2019 and May 17, 2021. Six abdominal radiologists were trained for use of the ccLS algorithm and scored independently using ccLS v1.0 and ccLS v2.0. Random- effects logistic regression modeling was used to generate plot receiver operating characteristic curves (ROC) to evaluate the diagnostic performance of ccLS v1.0 and ccLS v2.0 for ccRCC, and the area under curve (AUC) of these two scoring systems were compared using the DeLong's test. Weighted Kappa test was used to evaluate the interobserver agreement of the ccLS score, and differences in the weighted Kappa coefficients was compared using the Gwet consistency coefficient.@*RESULTS@#In total, 691 patients (491 males, 200 females; mean age, 54 ± 12 years) with 700 renal masses were included in this study. The pooled accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ccLS v1.0 for diagnosing ccRCC were 77.1%, 76.8%, 77.7%, 90.2%, and 55.7%, as compared with 80.9%, 79.3%, 85.1%, 93.4%, 60.6% with ccLS v2.0, respectively. The AUC of ccLS v2.0 was significantly higher than that of ccLS v1.0 for diagnosis of ccRCC (0.897 vs 0.859; P < 0.01). The interobserver agreement did not differ significantly between ccLS v1.0 and ccLS v2.0 (0.56 vs 0.60; P > 0.05).@*CONCLUSION@#ccLS v2.0 has better performance for diagnosing ccRCC than ccLS v1.0 and can be considered for use to assist radiologists with their routine diagnostic tasks.
Subject(s)
Female , Male , Humans , Adult , Middle Aged , Aged , Carcinoma, Renal Cell/diagnosis , Retrospective Studies , Kidney , Carcinoma , Kidney Neoplasms/diagnosisABSTRACT
OBJECTIVE@#To explore the effect of curcumin on the proliferation of renal cell carcinoma and analyze its regulation mechanism.@*METHODS@#In RCC cell lines of A498 and 786-O, the effects of curcumin (2.5, 5, 10 µ mo/L) on the proliferation were analyzed by Annexin V+PI staining. Besides, A498 was inoculated into nude mice to establish tumorigenic models, and the model mice were treated with different concentrations of curcumin (100, 200, and 400 mg/kg), once daily for 30 days. Then the tumor diameter was measured, the tumor cells were observed by hematoxylin-eosin staining, and the protein expressions of miR-148 and ADAMTS18 were detected by immunohistochemistry. In vitro, after transfection of miR-148 mimics, miR-148 inhibitor or si-ADAMTS18 in cell lines, the expression of ADAMTS18 was examined by Western blotting and the cell survival rate was analyzed using MTT. Subsequently, Western blot analysis was again used to examine the autophagy phenomenon by measuring the relative expression level of LC3-II/LC3-I; autophagy-associated genes, including those of Beclin-1 and ATG5, were also examined when miR-148 was silenced in both cell lines with curcumin treatment.@*RESULTS@#Curcumin could inhibit the proliferation of RCC in cell lines and nude mice. The expression of miR-148 and ADAMTS18 was upregulated after curcumin treatment both in vitro and in vivo (P<0.05). The cell survival rate was dramatically declined upon miR-148 or ADAMTS18 upregulated. However, si-ADAMTS18 treatment or miR-148 inhibitor reversed these results, that is, both of them promoted the cell survival rate.@*CONCLUSION@#Curcumin can inhibit the proliferation of renal cell carcinoma by regulating the miR-148/ ADAMTS18 axis through the suppression of autophagy in vitro and in vivo. There may exist a positive feedback loop between miR-148 and ADAMTS18 gene in RCC.
Subject(s)
Animals , Mice , Carcinoma, Renal Cell/metabolism , Curcumin/therapeutic use , MicroRNAs/metabolism , Mice, Nude , Cell Line, Tumor , Kidney Neoplasms/metabolism , Autophagy , Cell Proliferation , Gene Expression Regulation, Neoplastic , ADAMTS Proteins/metabolismABSTRACT
OBJECTIVE@#To investigate and analyze the risk factors of massive hemorrhage in patients with renal cell carcinoma and venous tumor thrombus undergoing radical nephrectomy and removal of venous tumor thrombus.@*METHODS@#From January 2014 to June 2020, 241 patients with renal cancer and tumor thrombus in a single center of urology at Peking University Third Hospital were retrospectively analyzed. All patients underwent radical nephrectomy and removal of venous tumor thrombus. The relevant preoperative indicators, intraoperative conditions, and postoperative data were statistically analyzed by using statistical software of SPSS 18.0. The main end point of the study was intraoperative bleeding volume greater than 2 000 mL. Logistic regression analysis was used to determine the relevant influencing factors. First, single factor Logistic regression was used for preliminary screening of influencing factors, and variables with single factor Logistic regression analysis P < 0.05 were included in multivariate Logistic regression. In all statistical analyses, P < 0.05 is considered statistically significant.@*RESULTS@#Among the 241 patients included, there were 60 cases of massive hemorrhage, 48 males and 12 females, with a median age of 62 years. The number of non-massive hemorrhage was 181. There were 136 males and 45 females, with a median age of 59 years. Univariate analysis showed that the clinical symptoms (both systemic and local symptoms, OR 2.794, 95%CI 1.087-7.181, P=0.033), surgical approach (open surgery, OR 9.365, 95%CI 4.447-19.72, P < 0.001), Mayo grade (Mayo 3-4, OR 5.257, 95%CI 2.806-10.886, P < 0.001), American Society of Anesthesiologists (ASA) score (ASA level 3, OR 2.842, 95%CI 1.338-6.036, P=0.007), preoperative hemoglobin (OR 0.978, 95%CI 0.965-0.991, P=0.001), preoperative platelet count (OR 0.996, 95%CI 0.992-1.000, P=0.037), maximum tumor thrombus width (OR 1.061, 95%CI 1.033-1.091, P < 0.001), Complicated with bland thrombus (OR 4.493, 95%CI 2.264-8.915, P < 0.001), adrenalectomy (OR 3.101, 95%CI 1.614-5.958, P=0.001), segmental resection of the inferior vena cava (OR 2.857, 95%CI 1.395-5.852, P=0.004). There was a statistically significant difference in these aspects(P < 0.05). Multivariate Logistic regression analysis showed that there was a statistically significant difference in surgical approach (open surgery, OR 6.730, 95%CI 2.947-15.368;P < 0.001), Mayo grade (Mayo 3-4, OR 2.294, 95%CI 1.064-4.948, P=0.034), Complicated with bland thrombus (OR 3.236, 95%CI 1.492-7.020, P=0.003).@*CONCLUSION@#Combining the results of univariate and multivariate Logistic regression analysis, the surgical approach, Mayo grade, and tumor thrombus combined with conventional thrombus were associated risk factors for massive hemorrhage during surgery for renal cell carcinoma with tumor thrombus. Patients who undergo open surgery, high Mayo grade, and tumor thrombus combined with conventional thrombus are at a relatively higher risk of massive hemorrhage.
Subject(s)
Male , Female , Humans , Middle Aged , Carcinoma, Renal Cell/pathology , Retrospective Studies , Thrombosis/etiology , Kidney Neoplasms/pathology , Vena Cava, Inferior/surgery , Nephrectomy/methods , Thrombectomy/methods , Risk Factors , HemorrhageABSTRACT
OBJECTIVE@#To explore the potential mechanism of resistance to axitinib in clear cell renal cell carcinoma (ccRCC), with a view to expanding the understanding of axitinib resistance, facilitating the design of more specific treatment options, and improving the treatment effectiveness and survival prognosis of patients.@*METHODS@#By exploring the half maximum inhibitory concentration (IC50) of axitinib on ccRCC cell lines 786-O and Caki-1, cell lines resistant to axitinib were constructed by repeatedly stimulated with axitinib at this concentration for 30 cycles in vitro. Cell lines that were not treated by axitinib were sensitive cell lines. The phenotypic differences of cell proliferation and apoptosis levels between drug resistant and sensitive lines were tested. Genes that might be involved in the drug resistance process were screened from the differentially expressed genes that were co-upregulated in the two drug resistant lines by transcriptome sequencing. The expression level of the target gene in the drug resistant lines was verified by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). The expression differences of the target gene in ccRCC tumor tissues and adjacent tissues were analyzed in the Gene Expression Profiling Interactive Analysis (GEPIA) public database, and the impact of the target gene on the prognosis of ccRCC patients was analyzed in the Kaplan-Meier Plotter (K-M Plotter) database. After knocking down the target gene in the drug resistant lines using RNA interference by lentivirus vector, the phenotypic differences of the cell lines were tested again. WB was used to detect the levels of apoptosis-related proteins in the different treated cell lines to find molecular pathways that might lead to drug resistance.@*RESULTS@#Cell lines 786-O-R and Caki-1-R resistant to axitinib were successfully constructed in vitro, and their IC50 were significantly higher than those of the sensitive cell lines (10.99 μmol/L, P < 0.01; 11.96 μmol/L, P < 0.01, respectively). Cell counting kit-8 (CCK-8) assay, colony formation, and 5-ethynyl-2 '-deoxyuridine (EdU) assay showed that compared with the sensitive lines, the proliferative ability of the resistant lines decreased, but apoptosis staining showed a significant decrease in the level of cell apoptosis of the resistant lines (P < 0.01). Although resistant to axitinib, the resistant lines had no obvious new replicated cells in the environment of 20 μmol/L axitinib. Nuclear protein 1 (NUPR1) gene was screened by transcriptome sequencing, and its RNA (P < 0.0001) and protein expression levels significantly increased in the resistant lines. Database analysis showed that NUPR1 was significantly overexpressed in ccRCC tumor tissue (P < 0.05); the ccRCC patients with higher expression ofNUPR1had a worse survival prognosis (P < 0.001). Apoptosis staining results showed that knockdown ofNUPR1inhibited the anti-apoptotic ability of the resistant lines to axitinib (786-O, P < 0.01; Caki-1, P < 0.05). WB results showed that knocking downNUPR1decreased the protein level of B-cell lymphoma-2 (BCL2), increased the protein level of BCL2-associated X protein (BAX), decreased the protein level of pro-caspase3, and increased the level of cleaved-caspase3 in the resistant lines after being treated with axitinib.@*CONCLUSION@#ccRCC cell lines reduce apoptosis through theNUPR1 -BAX/ BCL2 -caspase3 pathway, which is involved in the process of resistance to axitinib.
Subject(s)
Humans , Carcinoma, Renal Cell/metabolism , Axitinib/pharmacology , Kidney Neoplasms/metabolism , bcl-2-Associated X Protein , Nuclear Proteins , Cell Line, Tumor , Apoptosis , Cell ProliferationABSTRACT
Renal cell carcinoma is one of the common tumors in the urinary system. Despite the high incidence of renal cell carcinoma worldwide, progress has been made in cancer control and patients' survival profits from advances in laparoscopic technology and the application of targeted drugs. Recent studies have confirmed that the progression of renal cell carcinoma is related to cellular metabolism in the tumor microenvironment. Therefore, based on the existing surgical treatment and immunotherapy, exploring new metabolic therapies that target the metabolic pathway of tumor cells and interfere with the microenvironment of tumor cells will provide a unique treatment for renal cell carcinoma.
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Fumarate hydratasedeficient renal cell carcinoma(FH-RCC)is s a rare and highly aggressive and metastatic form of renal cell carcinoma. Clinical diagnosis is relatively challenging, and there is a lack of recognized systemic treatment options. Therefore, in clinical practice, it is necessary to have a deeper understanding of this disease and fully integrate family history, imaging findings, and pathological manifestations for clinical identification, and genetic testing shoule be conducted when necessary. Improved patient prognosis can be achieved through the selection of appropriate curative surgery or systemic treatment strategies.
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Objective:To investigate the treatment efficacy of adjuvant anti-VEGF/VEGFR targeted therapy in patients with non-metastatic (cM 0) non-clear cell renal cell carcinoma and tumor thrombus (nccRCC-VTT). Methods:This retrospective study enrolled 26 patients who underwent radical nephrectomy combined with inferior vena cava tumor thrombectomy at Peking University Third Hospital from January 2014 to July 2021. Patients were divided into adjuvant therapy group (10 cases) and control group (16 cases)based on the use of postoperative targeted therapy. The distribution of baseline clinical characteristics in the adjuvant therapy group and the control group were as follows: gender (6 males and 4 females in the adjuvant therapy group, 12 males and 4 females in the control group, P=0.66), age (56.2±18.5 years old in the adjuvant therapy group; 54.6±14.5 years old in the control group; P=0.80), BMI(24.0±3.5 in the adjuvant therapy group; 24.3±3.3 in the control group; P=0.80), presence of clinical symptoms (8 cases in the adjuvant therapy group; 15 cases in the control group; P=0.54), tumor laterality(6 cases on the left and 4 cases on the right in the adjuvant therapy group; 6 cases on the left and 10 cases on the right in the control group; P=0.42), location of tumor thrombus (2 cases with renal vein tumor thrombus and 8 cases with inferior vena cava tumor thrombus in the adjuvant therapy group; 2 cases with renal vein tumor thrombus and 14 cases with inferior vena cava tumor thrombus in the control group; P=0.67), ASA classification (2 cases in ASA class 1 and 8 cases in ASA class 2 in the adjuvant therapy group; 2 cases in ASA class 1 and 14 cases in ASA class 2 in the control group; P=0.63), surgical approach (7 minimally invasive surgeries and 3 open surgeries in the adjuvant therapy group; 9 minimally invasive surgeries and 7 open surgeries in the control group; P=0.68), conversion to open surgery (2 cases in the adjuvant therapy group; 2 cases in the control group; P=0.63), operation time [287.5(222.2, 456.0) minutes in the adjuvant therapy group; 344.0(287.8, 482.5) minutes in the control group; P=0.34), blood loss [400.0(250.0, 600.0)ml in the adjuvant therapy group; 575.0(175.0, 800.0)ml in the control group; P=0.63), Clavien-Dindo classification of postoperative complications (8 cases with no postoperative complications, 2 cases with level 1-2 complications, and 0 cases with level ≥3 complications in the adjuvant therapy group; 10 cases with no postoperative complications, 4 cases with level 1-2 complications, and 2 cases with level ≥3 complications in the control group; P=0.68), postoperative hospital stay (8.5 [5.5, 11.5] days in the adjuvant therapy group; 7.5 [6.0, 13.0] days in the control group; P=1.00), maximum tumor diameter[ (9.2±2.7)cm in the adjuvant therapy group; (8.9±3.3)cm in the control group; P=0.81], sarcomatoid differentiation (0 cases in the adjuvant therapy group; 1 case in the control group; P=1.00), perinephric fat invasion (2 cases in the adjuvant therapy group; 7 cases in the control group; P=0.40), tumor necrosis (6 cases in the adjuvant therapy group; 5 cases in the control group; P=0.23), pathological subtype (1 case of PRCC type 1, 6 cases of PRCC type 2, and 3 cases of TFE3 rearrangement RCC in the adjuvant therapy group; 2 cases of PRCC type 1, 10 cases of PRCC type 2, and 1 case each of oncocytic PRCC, TFE3 rearrangement RCC, FH-deficient RCC, and unclassified RCC in the control group; P=0.72), WHO/ISUP nuclear grade (10 cases of grades 3-4 in the adjuvant therapy group; 4 cases of grades 1-2 and 12 cases of grades 3-4 in the control group; P=0.14), invasion of tumor thrombus into the vessel wall (5 cases in the adjuvant therapy group; 5 cases in the control group; P=0.43), T stage (1 case of T 3a, 3 cases of T 3b, 5 cases of T 3c, and 1 case of T 4 in the adjuvant therapy group; 1 case of T 3a, 4 cases of T 3b, 10 cases of T 3c, and 1 case of T 4 in the control group; P=1.00), and positive lymph nodes metastasis(3 cases in the adjuvant therapy group; 0 cases in the control group; P<0.05). The recommended doses for sunitinib, axitinib, and pazopanib are 50mg qd, 5mg q12h, and 800mg qd, respectively. The primary endpoint of this study was disease-free survival (DFS), and the secondary endpoint was overall survival (OS). Statistical analyses were performed using R v4.2.2. Confounding factors were adjusted using propensity score weighting. Results:The median follow-up time for DFS was 29 months in the adjuvant therapy group and not reached in the control group, while median follow-up time for OS was 28 and 26 months, respectively. In the univariate Cox regression analysis, there were no statistically significant difference in the impact of all baseline characteristics and exposure factors on DFS and OS between the two groups. In survival analysis, there were no significant difference between DFS and OS curves of patients in the adjuvant therapy group and the control group (DFS, P=0.62; OS, P=0.74). The median DFS of patients in the adjuvant therapy group and the control group were 17 and 19 months, respectively, while the median OS was 43 and 27 months. After adjusting for confounding factors, the median DFS of patients in the adjuvant therapy group and the control group were 26 and 12 months, respectively, and the median OS remained 43 and 27 months, with no significant difference (DFS, P=0.81; OS, P=0.40). Conclusion:There is currently a lack of definitive evidence for survival benefit from adjuvant anti-VEGF/VEGFR targeted therapy in patients with cM0 nccRCC-VTT after surgery.
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Objective:To investigate the safety and prognosis of partial nephrectomy (PN) in the treatment of highly malignant non-clear renal cell carcinoma (nccRCC).Methods:Clinical data of 47 patients with cT 1N 0M 0 high malignant nccRCC treated in Changhai Hospital from March 2016 to March 2022 were retrospectively analyzed. All patients received PN. There were 34(72.3%) males and 13(27.7%) females. The mean age was (53.5±15.0) years, and average BMI, was(23.7±3.4)kg/m 2.The maximum tumor diameter was (29.8±12.6) mm, and R. E.N.A.L. score was 7(5-9), with 37(78.7%) cases of T 1a and 10(21.3%) cases of T 1b. The mean estimated glomerular filtration rate (eGFR) before surgery was (96.3±25.5) ml/ (min·1.73m 2). All patients underwent PN, including 1 patient (2.1%) undergoing open surgery, 29 patients (61.7%) undergoing laparoscopic surgery, and 17 patients (36.2%) undergoing robotic surgery. There were a total of 22(46.8%) cases of papillary cell carcinoma(pRCC)type Ⅱ, 4(8.5%) cases of collecting duct carcinoma (cdRCC), 9(19.1%) cases of MiT family translocated renal cell carcinoma (tRCC), 5(10.6%) cases of mucoid tubular and spindle cell carcinoma (mtSCC)and 7(14.9%) cases of unclassified renal cell carcinoma (uRCC). The surgical conversion rate, positive margin rate, operative time, intraoperative blood loss, complications, and postoperative hospital stay were analyzed. Preoperative and postoperative eGFR were analyzed, and overall survival (OS) and cancer specific survival (CSS) were calculated. Results:All the operations were successfully completed. No radical operation or open operation was performed, with operation time of(100±60) min and intraoperative blood loss of(100±59) ml. There were no intraoperative complication and 1 case (2.1%) suffered from postoperative complication. Postoperative hospital stay were 5 (4-6) days. The mean eGFR after surgery was (86.5±27.1) ml/(min·1.73m 2), and the difference was statistically significant ( P=0.041). In this study, the mean follow-up time was (45.7±20.9)months, and no adjuvant therapy was used after surgery. During the follow-up period, 2 patients died, who all of them were kidney cancer-related death, and both OS and CSS were 95.7% (45/47). Conclusions:PN is safe, feasible and has a good prognosis in the treatment of high malignant T 1 nccRCC. For tumors with clear imaging boundaries and complete envelope, complete tumor resection is more likely, postoperative follow-up should be strict, and no remedial radical or systemic treatment was required.
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Objective:To Explore the diagnosis, treatment and prognosis of FH-deficient renal cell carcinoma (FH-deficient RCC) with tumor thrombus, and share surgical experience.Methods:From August 2019 to October 2022, 6 cases of FH-deficient RCC with tumor thrombus were diagnosed and treated in our center, including 4 males and 2 females. The patients were aged 22 to 57 years, with 2 cases younger than 40 years, icluding 5 cases on the left and 1 case on the right. The median maximum diameter of the tumor is 8 (4.8, 14.0) cm. Operations were performed after complete examination (enhanced CT and other related examinations). One case underwent open surgery and palliative resection of the left kidney was performed because of severe adhesion of the inferior vena cava. Among the remaining 5 cases, 1 case underwent retroperitoneal laparoscopic right radical nephrectomy with inferior vena cava thrombectomy, 1 case underwent transabdominal laparoscopic left radical nephrectomy with inferior vena cava thrombectomy, and 3 cases underwent robot assisted laparoscopic left radical nephrectomy with inferior vena cava thrombectomy.Results:The median surgical time was 293 (185, 366) min, with blockage of the vena cava for 13 min and 28 min in 2 of 6 cases, respectively. The pathological report of renal tumor and tumor thrombus was FH-deficient renal carcinoma. The pathological features were as follows: the gross section of the specimen was gray yellow solid, often accompanied by necrosis, and the cystic cavity could be seen locally. Microscopically, the tumor extensively involved the renal parenchyma, with papillary, cribriform and tubular cystic structures. Immunohistochemistry showed FH (-), 2SC (+ ). The median postoperative hospital stay was 8 (4, 15) days. The median follow-up time was 13 (4, 27) months. One patient undergoing palliative resection of the left kidney underwent targeted therapy and radiotherapy after surgery (died 15 months after surgery due to gastrointestinal perforation). During the follow-up process, 4 cases experienced metastasis and received systematic treatment, with 1 death 27 months after surgery. Uterine leiomyomas were found in the remaining 1 case during follow-up.Conclusions:FH-deficient RCC with tumor thrombus is very rare. This disease is highly invasive, difficult to be diagnosed preoperatively and poor clinically prognostic. Operation combined with systemic therapy is an effective way to treat FH-deficient RCC with tumor thrombus.
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Objective:To evaluate the efficacy of first-line tyrosine kinase inhibitors (TKI) plus immune checkpoint inhibitors (ICI) in metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC).Methods:The data of 87 metastatic FH-deficient RCC patients from West China Hospital ( n=44), Renji Hospital ( n=27) and Sun Yat-sen University Cancer Center (n=16) from Mar 2019 to Aug 2022 were retrospectively analyzed. The median age was 37(30, 47) years, the male to female ratio was 1.9∶1. The median size of tumor was 7.5(5.0, 10.0) cm. Sixty-one patients (70.1%) had germline FH mutations, and 26 patients (29.9%) had somatic FH mutations. Forty-nine patients (56.3%) metastasis disease at initial diagnosis, and 38 patients (43.7%) had metachronous metastasis. The most common site of metastasis was lymph node (41/87, 47.1%), followed by bone (33/87, 37.9%), liver (22/87, 25.3%), and lung (14/87, 16.1%). Fifteen patients (17.2%) had weak expression of FH protein and 59 patients (67.8%) had positive PD-L1 expression. The most common treatments were sintilimab plus axitinib (52/87, 59.8%), followed by pembrolizumab plus cabozantinib (7/87, 8.0%), tirelizumab plus axitinib (6/87, 6.9%), pembrolizumab plus axitinib (5/87, 5.7%), and toripalimab plus axitinib (4/87, 4.6%). Thirteen patients (13/87, 14.9%) received other ICI plus TKI combination treatments. Statistical analysis was conducted using R 4.2.3 software. Kaplan Meier survival curve was used to evaluate survival data, and log-rank test was used to compare differences between treatment groups. Results:The overall objective response rate (ORR) and disease control rate (DCR) of first-line TKI + ICI were 39.1% and 89.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 16.5 months and 71.0 months, respectively. For first-line sintilimab plus axitinib, the ORR and DCR were 44.2% and 92.3%, respectively. The median PFS was 17.3 months and the median OS was not reached for this combination treatment. The efficacy of first-line tirelizumab plus axitinib was inferior to other treatment strategies (median PFS: 4.0 vs. 16.6 months, P<0.001; median OS: 22.0 vs. 71.0 months, P=0.043). Subgroup analyses further showed that the efficacy of ICI+ TKI combination therapy was consistent in patients with different clinicopathologic and genomic features. However, patients with liver metastasis had shorter OS than those without liver metastasis (median OS: 26.3 vs. 71.0 months, P=0.021). Conclusion:First-line TKI + ICI is effective for metastatic FH-deficient RCC and can significantly prolong the survival of the patients.