Up-regulation of GINS1 highlighted a good diagnostic and prognostic potential of survival in three different subtypes of human cancer / A regulação positiva de GINS1 destacou um bom potencial diagnóstico e prognóstico de sobrevivência em três subtipos diferentes de câncer humano

Abstract Cancer is a fatal malignancy and its increasing worldwide prevalence demands the discovery of more sensitive and reliable molecular biomarkers. To investigate the GINS1 expression level and its prognostic value in distinct human cancers using a series of multi-layered in silico approach may help to establish it as a potential shared diagnostic and prognostic biomarker of different cancer subtypes. The GINS1 mRNA, protein expression, and promoter methylation were analyzed using UALCAN and Human Protein Atlas (HPA), while mRNA expression was further validated via GENT2. The potential prognostic values of GINS1 were evaluated through KM plotter. Then, cBioPortal was utilized to examine the GINS1-related genetic mutations and copy number variations (CNVs), while pathway enrichment analysis was performed using DAVID. Moreover, a correlational analysis between GINS1 expression and CD8+ T immune cells and a the construction of gene-drug interaction network was performed using TIMER, CDT, and Cytoscape. The GINS1 was found down-regulated in a single subtypes of human cancer while commonly up-regulated in 23 different other subtypes. The up-regulation of GINS1 was significantly correlated with the poor overall survival (OS) of Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), and Kidney renal clear cell carcinoma (KIRC). The GINS1 was also found up-regulated in LIHC, LUAD, and KIRC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GINS1 in two diverse pathways, while few interesting correlations were also documented between GINS1 expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted few drugs that could be used in the treatment of LIHC, LUAD, and KIRC by regulating the GINS1 expression. The expression profiling of GINS1 in the current study has suggested it a novel shared diagnostic and prognostic biomarker of LIHC, LUAD, and KIRC.

Resumo O câncer é uma doença maligna fatal e sua crescente prevalência mundial exige a descoberta de biomarcadores moleculares mais sensíveis e confiáveis. Investigar o nível de expressão de GINS1 e seu valor prognóstico em cânceres humanos distintos, usando uma série de abordagens in silico em várias camadas, pode ajudar a estabelecê-lo como um potencial biomarcador de diagnóstico e prognóstico compartilhado de diferentes subtipos de câncer. O mRNA de GINS1, a expressão da proteína e a metilação do promotor foram analisados ​​usando UALCAN e Human Protein Atlas (HPA), enquanto a expressão de mRNA foi posteriormente validada via GENT2. Os valores prognósticos potenciais de GINS1 foram avaliados por meio do plotter KM. Em seguida, o cBioPortal foi utilizado para examinar as mutações genéticas relacionadas ao GINS1 e as variações do número de cópias (CNVs), enquanto a análise de enriquecimento da via foi realizada usando DAVID. Além disso, uma análise correlacional entre a expressão de GINS1 e células imunes T CD8 + e a construção de uma rede de interação gene-droga foi realizada usando TIMER, CDT e Cytoscape. O GINS1 foi encontrado regulado negativamente em um único subtipo de câncer humano, enquanto comumente regulado positivamente em 23 outros subtipos diferentes. A regulação positiva de GINS1 foi significativamente correlacionada com a sobrevida global pobre (OS) de Carcinoma Hepatocelular de Fígado (LIHC), Adenocarcinoma de Pulmão (LUAD) e Carcinoma de Células Claras Renais de Rim (KIRC). O GINS1 também foi encontrado regulado positivamente em pacientes LIHC, LUAD e KIRC de diferentes características clínico-patológicas. A análise de enriquecimento de vias revelou o envolvimento de GINS1 em duas vias diversas, enquanto poucas correlações interessantes também foram documentadas entre a expressão de GINS1 e seu nível de metilação do promotor, nível de células imunes T CD8 + e CNVs. Além disso, também previmos poucos medicamentos que poderiam ser usados ​​no tratamento de LIHC, LUAD e KIRC, regulando a expressão de GINS1. O perfil de expressão de GINS1 no estudo atual sugeriu que é um novo biomarcador de diagnóstico e prognóstico compartilhado de LIHC, LUAD e KIRC.

Lesiones metastásicas a glándula tiroides. Una serie de casos / Metastatic lesions to the thyroid gland. Case series

Las lesiones metastásicas representan hasta un 3 % de los tumores malignos de la glándula tiroides. La mayoría de los casos se originan de tumores de células renales y de pulmón. El abordaje diagnóstico implica una alta sospecha clínica en pacientes con primarios conocidos, sin embargo, puede ser la manifestación inicial de una enfermedad maligna extensa no diagnosticada hasta en un 20 % a 40 % de los pacientes. La biopsia por aguja fina ha demostrado buen rendimiento para el diagnóstico de los nódulos metastásicos. El pronóstico y la opción del tratamiento quirúrgico dependen del control local del primario y del estado de la enfermedad sistémica asociada, por lo tanto, debe ser individualizado. Por lo general, hasta un 80 % de los pacientes con compromiso de la tiroides tienen enfermedad metastásica multiorgánica, y la intención del tratamiento quirúrgico es con fines paliativos para prevenir las complicaciones derivadas de la extensión local de la enfermedad a las estructuras del tracto aerodigestivo superior en el cuello. Se presenta a continuación, una serie de seis casos de pacientes con lesiones metastásicas a glándula tiroides con primarios en riñón, mama y de melanomas

Metastatic lesions represent up to 3% of malignant tumors of the thyroid gland. Most cases originate from lung and renal cell tumors. The diagnostic approach implies a high clinical suspicion in patients with known primaries, however, it can be the initial manifestation of an extensive undiagnosed malignant disease in up to 20% to 40% of patients. Fine-needle biopsy has shown good performance for the diagnosis of metastatic nodules. The prognosis and the option of surgical treatment depend on the local control of the primary condition and the state of the associated systemic disease, therefore it must be individualized. In general, up to 80% of patients with thyroid involvement have multi-organ metastatic disease and surgical treatment is intended to be palliative to prevent complications resulting from local extension of the disease to structures of the upper aerodigestive tract in the neck. A case series of six patients with metastatic lesions to the thyroid gland with primaries in the kidney, breast and melanomas is presented below

Robotic-assisted nephrectomy with level II IVC thrombectomy using Rummel Tourniquets

ABSTRACT Background: Inferior vena cava (IVC) invasion from renal cell carcinoma (RCC) occurs at a rate of 4-10% (1). IVC thrombectomy (IVC-TE) can be an open procedure because of the need for handling of the IVC (2). The first reported series of robotic management of IVC-TE started in 2011 for the management of Level I - II thrombi with subsequent case reports in recent years (2-5). Materials and Methods: The following is a patient in his 50's with no significant medical history. Magnetic resonance imaging and IR venogram were performed preoperatively. The tumor was clinical stage T3b with a 4.3cm inferior vena cava thrombus. The patient underwent robotic assisted nephrectomy and IVC-TE. Rummel tourniquets were used for the contralateral kidney and the IVC. The tourniquets were created using vessel loops, a 24 French foley catheter and hem-o-lock clips. Results: The patient tolerated the surgical procedure well with no intraoperative complications. Total surgical time was 274 min with 200 minutes of console time and 22 minutes of IVC occlusion. Total blood loss in the surgery was 850cc. The patient was discharged from the hospital on post-operative day 3 without any complications. The final pathology of the specimen was pT3b clear cell renal cell carcinoma Fuhrman grade 2. The patient followed up post-operatively at both four months and six months without disease recurrence. The patient continues annual follow-up with no recurrence. Conclusions: Surgeon experience is a key factor in radical nephrectomy with thrombectomy as patients have a reported 50-65% survival rate after IVC-TE (4).

MiR-744-5p inhibits the proliferation, invasion, and migration of clear-cell renal cell carcinoma cells by targeting CCND1 / 南方医科大学学报

OBJECTIVE@#To explore the role of miR-744-5p/CCND1 axis in clear-cell renal cell carcinoma (ccRCC).@*METHODS@#We examined the expression levels of miR-744-5p in 65 pairs of ccRCC and adjacent tissue specimens and in 5 ccRCC cell lines and human renal tubular epithelial (HK2) cells using qRT-PCR. The ccRCC cell lines 786-O and OSRC2 were transfected with miR-744-5p mimic, CCND1 mimic, or their negative control mimics, and the changes in cell proliferation, migration, and invasion were evaluated with CCK-8, wound healing, and Transwell assays. The downstream target molecules of miR-744-5p were predicted by bioinformatics analysis, and the expression level of CCND1 in ccRCC cells was verified by qRT-PCR and Western blotting. The relationship between miR-744-5p and CCND1 was further validated by dual luciferase reporter assay, and the role of the miR-744-5p/CCND1 axis in ccRCC was explored by rescue experiments.@*RESULTS@#MiR-744-5p was significantly downregulated in ccRCC tissues and cell lines (all P < 0.05), and its overexpression inhibited the proliferation, migration, and invasion of ccRCC cells (all P < 0.05). Bioinformatics analysis and dual luciferase reporter assay showed that CCND1 was a downstream target of miR-744-5p. The results of rescue experiments showed that upregulation of CCND1 could partially reverse the inhibitory effect of miR-744-5p overexpression on ccRCC cell proliferation, migration, and invasion (all P < 0.05).@*CONCLUSION@#MiR-744-5p inhibits the malignant phenotype of ccRCC cells by targeting CCND1, and the miR-744-5p/CCND1 axis may be a novel target for diagnosis and treatment of ccRCC.

Eosinophilic vacuolated tumor of the kidney: clinicopathological and molecular characteristics / 中华病理学杂志

Objective: To study the clinicopathological features, immunophenotype, molecular changes, differential diagnosis and prognosis of eosinophilic vacuolated tumor (EVT) of the kidney. Methods: Four cases were collected retrospectively from 2014 to 2020 at Ningbo Diagnostic Pathology Center. The clinicopathologic features and immunophenotypic profile were studied by light microscopy and immunohistochemistry. Targeted next-generation sequencing (NGS) panel was used to detect cancer-associated mutation. Follow-up and literature review were also performed. Results: Among the 4 patients studied,2 were males and 2 were females. The age of the patients ranged from 44 to 63 years (the mean age: 51 years).Tumor size ranged from 1.5 to 4.2 cm (mean: 2.3 cm). Microscopically, tumors were well-circumscribed, unencapsulated. Thick-walled vessels and entrapped renal tubules were found within or at the periphery of the tumors. The tumors were predominantly composed of nest pattern, and focal tubular pattern. The tumor cells exhibited abundant, eosinophilic, granular cytoplasm and conspicuous, large nucleoli. Prominent intracytoplasmic vacuoles were seen. These cytoplasmic vacuoles varied in size and frequently coalesced into a large space. Loose fibromatous or hyaline stroma was focally noted. Immunohistochemically, the tumor cells in all cases exhibited a CD117+/CK7-phenotype. All cases were positive for CD10 and p504s. MTOR, S6 and cathepsin K were positive in 4 cases. TFE3, CA9, Melan A and HMB45 were negative in all cases. SDHB retained expression. NGS demonstrated MTOR mutations in all cases, and TSC2 mutation in 2 cases. Conclusions: EVT is a rarely oncocytic renal tumor with unique morphology, immunohistochemical phenotype, molecular profile and an indolent behavior. Recognition of the characteristics of this novel but rare entity will allow for better classification of renal tumors.

Anaplastic lymphoma kinase-translocation renal cell carcinoma: clinical and pathological analysis / 中华病理学杂志

Objective: To investigate the clinicopathological features, molecular characteristics, differential diagnosis and prognosis of anaplastic lymphoma kinase (ALK)-translocation renal cell carcinoma. Methods: Two cases of ALK-translocation renal cell carcinoma diagnosed from January 2011 to December 2020 were retrospectively analyzed to characterize their morphological features, immunohistochemical expression and prognosis. Multiple molecular studies including fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and next-generation sequencing were performed to characterize the genetic alterations. Results: Two patients included one male and one female, with 59 and 57 years old, respectively. Morphologically, case 1 resembled collecting duct carcinoma or renal medullary carcinoma, which demonstrated tubular, microcapsule and reticular structures, with a remarkable myxoid background and lymphocytes infiltration; case 2 resembled Xp11.2 translocation renal cell carcinoma or type 2 papillary renal cell carcinoma, which demonstrated tubular papillary and focal solid structures, with flocculent cytoplasm and many foamy histiocytes, but without myxoid background and lymphocytes infiltration. Immunohistochemistry showed strongly positive expression of ALK. CK7, E-cadherin, vimentin, PAX8 and CD10 showed various degrees of expression, and other antibodies were nonreactive. A variety of molecular assays showed definite ALK gene translocation, with rare VCL-ALK gene fusion (VCL exon and 16-ALK exon 20) in case 1, and EML4-ALK gene fusion (EML4 exon and 2-ALK exon 20) in case 2. Conclusions: ALK-translocation renal cell carcinoma is rare with various morphological features, and is easy to miss and misdiagnose. The characteristic ALK expression and molecular detection of ALK translocation are helpful for diagnosing this type of renal cell carcinoma.

Papillary renal neoplasm with reverse polarity: a clinicopathological analysis / 中华病理学杂志

Objective: To study the clinical pathological characteristics, immunophenotype, molecular changes and prognosis of the papillary renal neoplasm with reverse polarity (PRNRP). Methods: Nine cases of PRNRP, diagnosed from 2013 to 2019, were retrieved from the Department of Pathology of Nanjing Jinling Hospital, Nanjing University School of Medicine. Histomorphology, immunophenotype and molecular genetics were analyzed with review of the literatures. Results: There were five male and four female patients, aged from 49 to 70 years, with an average age of 60.1 years. During a mean follow-up of 29 months, one patient died for other cause, and the others survived without disease. Microscopically, the tumor cells arranged in papillary structure with a fibrovascular core, the surface of which was covered with a single layer of cuboidal or columnar cells. The most prominent feature was that the tumor nuclei located at the top of the cytoplasm far from the basement membrane, and they were monotonous in size and arranged neatly with no or few nucleoli. Immunohistochemically, all nine cases of PRNRP showed diffuse positive expression of CK7 and E-cadherin, various degrees of P504s expression, and no expression of CD10 and CD117, with a Ki-67 index of 1%-3%. Unlike other papillary renal cell carcinoma, the nine cases of PRNRP all showed characteristic positive expression of GATA3. The fluorescence in situ hybridization assay showed that the majority of PRNRPs (8/9) did not have triploids on chromosomes 7 and 17. The sequencing of the KRAS gene confirmed the presence of a nonsense KRAS mutation in 8 of the 9 cases. Conclusions: PRNRP is a subtype of papillary renal cell carcinoma with characteristic morphological, immunophenotypic and molecular features, and indolent behaviors. More data are needed to define PRNRP as "carcinoma", and a definitive diagnosis of PRNRP is of great significance for proper treatment choice and accurate prognostication.

Succinate dehydrogenase-deficient renal cell carcinoma:a clinicopathological, ultrastructural and molecular analysis / 中华病理学杂志

Objective: To investigate the clinicopathological features, immunophenotype, ultrastructure, genetic alterations and prognosis of succinate dehydrogenase-deficient renal cell carcinoma (SDH RCC). Methods: A total of 11 SDH RCCs, diagnosed from 2010 to 2019, were selected from the Department of Pathology of Nanjing Jingling Hospital, Nanjing University School of Medicine for clinicopathologic, immunohistochemical (IHC), ultrastructural investigation and follow-up. The molecular features of seven cases were analyzed by the panel-targeted DNA next generation sequencing (NGS). Results: There were seven males and four females, with ages ranging from 24 to 62 years (mean 41.4 years, median 41 years). Microscopically, SDH RCC was mainly composed of solid and tubular structures with local cystic change. Four cases showed nested or trabecular structure distributed in a loose hypocellular connective tissue or around scar, similar to oncocytoma. The neoplastic cells demonstrated flocculent eosinophilic cytoplasm with typical intracytoplasmic vacuoles. Immunohistochemically, eight cases were negative for SDHB; three cases showed focal and weak expression, whereas normal renal tubular and vascular endothelial cells demonstrated strong cytoplasmic staining. NGS of DNA targeted-panel detected pathogenic mutations of SDHB gene in seven cases (including three cases with equivocal IHC expression of SDHB), without any mutations in other SDH related genes. There were four cases of SDHB missense mutation, one case of frameshift mutation, one case of splicing mutation, and one case of acquired stop codon mutation. Conclusions: SDH RCC is a distinct variant of RCCs with genetic tendency or with hereditary cancer syndrome. NGS is recommended to detect the related gene mutations for a definitive diagnosis. The patients should be closely followed up.

Curcumin Inhibits Viability of Clear Cell Renal Cell Carcinoma by Down-Regulating ADAMTS18 Gene Methylation though NF-κ B and AKT Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To investigate the effect of curcumin on viability of clear cell renal cell carcinoma (ccRCC) and analyze its possible mechanism.@*METHODS@#In cell lines of A498 and 786-O, the effects of curcumin (1.25, 2.5, 5 and 10 μ mol/L) on the viability of ccRCC were analyzed at 24, 48 and 72 h by MTT assay. The protein expression levels of ADAMTS18 gene, p65, phosphorylation p65 (pp65), AKT, phosphorylation AKT (pAKT) and matrix metallopeptidase 2 (MMP-2) before and after curcumin (10 μ mol/L) treatment were examined by Western blotting. Real-time PCR and methylation specific PCR (MSP) were applied to analyze the expression and methylation level of ADAMTS18 gene before and after curcumin treatment (10 μ mol/L).@*RESULTS@#Curcumin significantly inhibited the viability of A498 and 786-O cell lines in a dose- and time-dependent manner (P<0.01). Up-regulation of ADAMTS18 gene expression with down-regulation of ADAMTS18 gene methylation was reflected after curcumin treatment, accompanied by down-regulation of nuclear factor κ B (NF-κ kB) related protein (p65 and pp65), AKT related protein (AKT and pAKT), and NF-κ B/AKT common related protein MMP-2. With ADAMTS18 gene overexpressed, the expression levels of p65, AKT and MMP2 were downregulated, of which were conversely up-regulated in silenced ADAMTS18 (sh-ADAMTS18). The expression of pp65, pAKT and MMP2 in sh-ADAMTS18 was down-regulated after being treated with PDTC (NF-κ B inhibitor) and LY294002 (AKT inhibitor).@*CONCLUSIONS@#Curcumin could inhibit the viability of ccRCC by down-regulating ADAMTS18 gene methylation though NF-κ B and AKT signaling pathway.

Analysis of phenotype and FH gene variation in a pedigree affected with hereditary leiomyomatosis and renal cell carcinoma syndrome / 中华医学遗传学杂志

OBJECTIVE@#To analyze clinical phenotype and genetic variants in a Chinese pedigree of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.@*METHODS@#Whole exome sequencing was carried out for the proband from the pedigree. Suspected FH gene variants were validated by Sanger sequencing. Clinical manifestation and histopathological examination were used to analyze the pedigree comprehensively.@*RESULTS@#The pedigree met the clinical diagnostic criteria for HLRCC syndrome. The whole exome sequencing showed that the FH gene of the proband had a heterozygous missense variant of c.1490T>C (p.F497S), which was consistent with the Sanger sequencing. The mother, daughter and son of the proband all had the heterozygous missense variant of c.1490T>C (p.F497S). According to the American Society of Medical Genetics and Genomics Classification Standards and Guidelines for Genetic Variations, c.1490T>C (p.F497S) (PM2+PP1-M+PP3+PP4) was a possible pathogenic variant. Based on our literature search, this variant was a new variant that had not been reported.@*CONCLUSION@#The FH gene missense variant of c.1490T>C (p.F497S) may be the cause of the HLRCC syndrome pedigree, which provides a basis for the genetic diagnosis and genetic counseling of the HLRCC syndrome.

Immunotherapy Based on Tumor Microenvironment in Renal Cell Carcinoma / 中国医学科学院学报

Renal cell carcinoma (RCC) is a common lethal urological cancer,the distant metastasis of which is the leading cause of death.Although targeted agents have remarkably improved the overall prognosis of RCC patients,nearly all the patients eventually acquire therapeutic resistance.With the advent of immune checkpoint inhibitors,immunotherapy based on tumor microenvironment (TME) has shown a broad scope in clinical application.The deepening understanding of TME leads to the changes of therapeutic strategies for advanced RCC,and the combination of targeted therapy and immunotherapy is exhibiting a promising prospect.Herein,we reviewed the TME characteristics,candidate predictive biomarkers,and possible targets for future development of drugs against RCC.

Metástasis oral de carcinoma de células renales. A propósito de un caso y revisión de la literatura / Oral metastasis of renal cell carcinoma. A Case report and literature review / Metástase oral de carcinoma de células renais. Relato de um caso e revisão da literatura

Los tumores metastásicos en cavidad oral son pocos frecuentes, representan el 1% de las neoplasias malignas orales, son relativamente más frecuentes en los maxilares, respecto a aquellos localizados en los tejidos blandos orales. Se describe el caso de una paciente de 75 años de edad, con antecedentes de carcinoma renal de células claras, que consulta por la aparición repentina de una lesión tumoral en reborde alveolar superior izquierdo. Se realizó la biopsia exéresis con diagnóstico presuntivo de tumor metastásico o posible lesión reactiva. El informe anátomo - patológico confirma el diagnóstico de metástasis de un carcinoma renal. Las metástasis orales tienen un pronóstico generalmente malo, compromete la sobrevida, por lo que es importante realizar un exhaustivo estudio del paciente y considerar sus antecedentes, ya que en ocasiones son diagnosticadas tardíamentete.

Metastatic tumors to the oral cavity are rare, representing only 1% of malignant oral neoplasms. These metastatic tumors occur more frequently in the jaws than in soft oral tissues. This article describes the case of a 75-year-old patient with a history of clear cell renal carcinoma who seeks care because of the sudden appearance of a tumor lesion in the upper left alveolar ridge. An excision biopsy was performed with a presumptive diagnosis of a metastatic tumor or potential reactive lesion. The pathology report confirmed the diagnosis of renal cell carcinoma metastasis. Oral metastatic tumors usually present a bad prognosis with a low survival rate. It is important to examine patients thoroughly and consider their medical records, as they are sometimes diagnosed late.

Os tumores metastásicos na cavidade oral são raros, representam 1% das neoplasias malignas orais, sendo relativamente mais frequentes nos ossos maxilares enquanto aos localizados nos tecidos moles orais. Descreve-se o caso de uma mulher de 75 anos com história de carcinoma renal de células claras, que consultou com queixa de lesão tumoral localizada na crista alveolar superior esquerda. Uma biópsia foi feita com diagnóstico clínico presuntivo de tumor metastático ou possível lesão reativa. O laudo anátomopatológico confirmou o diagnóstico de metástase de carcinoma renal. As metástases orais geralmente têm um prognóstico ruim, com baixa sobrevivência, portanto é importante fazer um estudo exaustivo do paciente e tomar em conta sua história, já que às vezes o diagnóstico é tardio.

Análise do perfil de mRNAs diferencialmente traduzidos no carcinoma renal de células claras / Analysis of differentially translated mRNA profile in clear cell renal cell carcinoma

O carcinoma renal de células claras (CRCC) é o tipo de neoplasia renal com maior incidência, cerca de 80%. A maioria dos casos são curados após cirurgia, porém, cerca de um terço dos pacientes apresentam recidiva da doença com metástase à distância. O tratamento para este tumor evoluiu muito nas últimas duas décadas, entretanto, pacientes metastáticos ainda apresentam baixas taxas de resposta aos tratamentos devido a resistência adquirida pelo tumor para escapar da terapia alvo. Identificar os mecanismos moleculares associados à carcinogênese do CRCC é essencial para entender as características tumorais que estão associadas a progressão da doença e resistência aos tratamentos. Entre as alterações mais frequentes no CRCC está a perda do gene VHL, um supressor tumoral e principal regulador da resposta à hipóxia. VHL tem dois principais alvos, o fator induzido por hipóxia 1α (HIF-1α) e o fator induzido por hipóxia α (HIF-2α). Em normóxia, VHL é responsável pela degradação das subunidades de HIF. Em hipóxia, VHL deixa de reconhecer e marcar HIF-1α e HIF-2α para degradação e, uma vez estabilizadas, ativam vias de sinalização associadas a sobrevivência celular. As informações sobre alterações encontradas em tumores normalmente são estudadas a partir do sequenciamento da população total de mRNAs, oferecendo uma visão do transcriptoma. Nossa abordagem metodológica coleta e analisa apenas a população de mRNAs ativamente traduzidos, oferecendo uma visão mais próxima da expressão proteica final. A via de mTOR regula o início da tradução de mRNAs e está frequentemente mutada em CRCC. A hipóxia afeta a expressão de genes tanto via transcrição quanto via tradução. Alterações no controle traducional em CRCC afetam a expressão gênica contribuindo para a formação do tumor e progressão da doença. Assim, nosso objetivo principal foi identificar o perfil de genes diferencialmente traduzidos dependendo do status de VHL e da via de mTOR. Para isso utilizamos um modelo celular de CRCC deficiente em VHL e sua contraparte onde VHL foi restituído. Realizamos o perfil polissomal em modelos celulares de CRCC para separar e coletar a população de mRNAs ativamente traduzidos que foram posteriormente sequenciados. Nossos dados mostraram perfis distintos de tradução entre as células VHL- deficientes e VHL-proficientes. Além disso, após a inibição de mTOR, ambas as células também apresentaram respostas diferentes ao tratamento. Além disso, observamos alterações na resposta imune e aumento do ciclo celular na ausência de VHL, que podem contribuir para a progressão tumoral. Em modelo com tecido tumoral congelado, nossos resultados parciais indicam que alterações na tradução global podem interferir principalmente no estadiamento clínico de pacientes com CRCC. Por fim, também analisamos a expressão de HIF-2α, um dos alvos de VHL, em tecidos de pacientes com CRCC. Nossos resultados mostram que HIF-2α pode ser utilizado na estratificação de pacientes com maior risco de recidiva, dependendo do estadiamento clínico.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal neoplasia with 80% of incidence. Most cases are cured after surgery, however, one third of all patients will have disease recurrence with distant metastasis. ccRCC treatment had evolved in the past two decades, however, metastatic patients still have low response rates due to tumor resistance. The identification of molecular mechanisms associated with ccRCC carcinogenesis is essential to understand the characteristics associated with disease progression and treatment resistance. The most frequent alteration in ccRCC is the loss of VHL gene, a tumor suppressor and the main regulator in response to hypoxia. VHL has two main target, hypoxia-induced factor 1 α (HIF-1 α) and hypoxia-induced factor α (HIF-2 α). In normoxic conditions, VHL can lead HIF subunits to degradation. In hypoxia, HIF-1α and HIF-2α stabilize and activate cell survival associated signaling pathways. Studies about tumor alterations usually provides a view of the transcriptome. Our approach is based on the actively translated mRNAs collection and analysis, which provides a closer view from protein expression. mTOR pathway regulates translation initiation and is frequently mutated in ccRCC. Hypoxia affects gene expression in both transcriptional and translational regulation. Alteration in translational control in ccRCC affect gene expression which contributes to tumor progression. Our main objective was to identify the differentially translated gene profile depending on VHL status and mTOR pathway activation. To assess this, we used a VHL-deficient and a VHL-proficient ccRCC cell line. We used the polysome profiling technique to separate and collect the population of mRNAs actively translated that were subsequently sequenced. Our data showed distinct translation profiles between VHL-deficient and VHL-proficient cells. In addition, after mTOR inhibition, both cells showed different responses to treatment. We observed changes in immune response and increased cell cycle pathways in VHL deficient cells, which may contribute to tumor progression. In tumor tissue, our polysome profiling analysis indicate that changes in global translation may interfere in clinical staging of ccRCC patients. Finally, we analyzed the expression of HIF-2α, a VHL target, in ccRCC patient's tissues. Our results showed that HIF-2α can distinct patients at higher recurrence risk depending on clinical staging.

Utilização de biópsia líquida baseada em detecção de DNA tumoral em urina e plasma em pacientes com carcinoma renal de células claras / Use of liquid biopsy based on detection of tumor DNA in urine and plasma in patients with clear cell renal carcinoma

O carcinoma de células renais (CCR) é o sétimo tipo de câncer mais comum no ocidente e vêm apresentando um aumento em sua prevalência. A classificação histológica dos CCRs é a abordagem mais utilizada para determinar o subtipo da doença, bem como prognosticar o paciente. Cerca de 70-80% dos CCRs é do subtipo células claras (ccRCC), o qual representa o subtipo mais prevalente e agressivo da doença. A escolha do tratamento difere para cada paciente, sendo a ressecção cirúrgica a terapia mais efetiva nos casos de doença localizada. Apesar de ser um tratamento já estabelecido, estudos mostram uma certa heterogeneidade entre massas renais detectadas, onde cerca de 20% apresentam um perfil benigno, 60% são considerados tumores indolentes, sugerindo desta forma que, entender de forma mais detalhada este tumor pode auxiliar na escolha de um tratamento mais direcionado para o paciente. Sendo assim, o presente trabalho buscou selecionar genes potencialmente alterados em CCR com o intuito de customizar um painel multigênico capaz de identificar variantes somáticas, específicas do tumor, e avaliar as variantes específicas do tumor de forma personalizada em amostras de ctDNA (DNA tumoral circulante) extraídas de plasma e dos dois componentes da urina (sedimento e sobrenadante) coletados no momento da cirurgia (baseline). Neste contexto, dentro de nossa proposta, construímos um painel com 28 genes associados com CCR e sequenciamos 89 casos de tumores renais, juntamente com as amostras de leucócitos. Identificamos que dentre os tumores analisados, 59 apresentavam pelo menos uma variante somática, ou seja, o painel customizado apresentou uma sensibilidade para identificar variantes somáticas em 66% dos casos. Com relação aos 45 tumores classificados como ccRCC em 38 casos identificamos pelo menos uma marca tumoral, ou seja, nosso painel foi capaz de detectar variantes somáticas específicas do tumor em 84,4% desses casos. Um total de 105 variantes somáticas foram identificadas, e os genes mais frequentemente mutados nessa coorte de pacientes foram os genes VHL, PBRM1, BAP1, SETD2. Dos 59 casos em que identificamos variante somática, 44 casos foram avaliados as amostras baseline de plasma e 29 casos de urina (sobrenadante e sedimento), e encontramos pelo menos uma marca tumoral em um dos fluidos corpóreos em 11 pacientes, 6 em amostras de plasma e 6 amostras de urina. Através do desenvolvimento deste estudo, confirmamos que o subtipo ccRCC é o CCR mais bem caracterizado genomicamente e que é importante continuar a investigação genômica principalmente nos subtipos não ccRCC. Além disso o estudo demonstra a viabilidade de utilizar biópsia líquida ctDNA tanto no plasma quanto na urina para fins de diagnóstico e prognóstico.

Renal cell carcinoma (RCC) is the seventh most common type of cancer in the West and its prevalence is increasing. The histological classification of RCCs is the most used approach to determine the disease subtype as well as the patient's prognosis. About 70% of RCCs are of the clear cell Renal Cell Carcinoma subtype (ccRCC), which represents the most prevalent and aggressive subtype of the disease. The choice of treatment is different for each patient. Resection is one of the most effective therapies in cases of localized disease. Despite being an established treatment, studies show a certain heterogeneous profile studied. In this profile, up to 20% even present a benign treatment, helping the indolent, thus suggesting that understanding this tumor in detail can help to choose a more targeted treatment for the patient. Therefore, the present work aimed to select potentially altered genes in CCR in order to customize a multigene panel capable of identifying somatic, tumor-specific variants, and to evaluate the tumor-specific variants in a personalized way in ctDNA (circulating tumor DNA) samples extracted from plasma and from two components of urine (sediment and supernatant) collected at the time of surgery (baseline). In this context, within our proposal, we built a panel with 28 genes associated with CCR and sequenced 89 cases of renal tumors, together with leukocyte samples. We identified that among the analyzed tumors, 59 had at least one somatic variant, that is, the customized panel showed sensitivity to identify somatic variants in 66% of cases. Of the 45 classified as ccRCC in 38 cases we identified at least one tumor marker, that is, our panel was able to detect tumor-specific somatic variants in 84.4%. A total of 105 somatic variants were identified, and the genes most frequently mutated in this cohort of patients were the VHL, PBRM1, BAP1, SETD2 genes. Among 59 cases in which we identified somatic variant, 44 cases were evaluated in baseline plasma samples and 29 cases in urine (supernatant and sediment), and we found at least one tumor mark in one of the body fluids in 11 patients, 6 in plasma samples and 6 urine samples. Through the development of this study, we confirm that the ccRCC subtype is the best genomically characterized CCR and that it is important to continue genomic investigation, especially in the non-ccRCC subtypes. Furthermore, the study demonstrates the feasibility of using ctDNA liquid biopsy in both plasma and urine for diagnostic and prognostic purposes.

Radical Nephrectomy in Renal Cell Carcinoma with Venous Tumoral Thrombus: Long-term Outcomes and Overall Survival / Nefrectomía radical en carcinoma de células renales con trombo tumoral venoso: Desenlaces a largo plazo y supervivencia global

Objective To describe the five-year overall survival (OS) and perioperative morbidity of patients with renal cell carcinoma (RCC) with venous tumor thrombus (VTT) treated through radical nephrectomy and thrombectomy. Materials and Methods We evaluated a cohort of 530 patients with a diagnosis of RCC from January 2009 to December 2019, and found VTT in 42 of them; these 42 patients composed the study sample. The patients were stratified according to the Neves Thrombus Classification (NTC). The baseline and perioperative characteristics, as well as the follow-up, were described. The Kaplan-Meier curve and its respective Cox regression were applied to present the 5-year OS and the OS stratified by the NTC. Results The average age of the sample was of 63.19 ± 10.7 years, and there were no differences regarding gender. In total, VTT was present in 7.9% of the patients. According to the NTC, 30.9% of the cases corresponded to level I, 21.4%, to level II, 26.1%, to level III, and 21.4%, to level IV. The 5-year OS was of 88%. For level-I and level-II patients, the 5-year OS was of 100%, and of only 38% among level-IV patients. Complications, mostly minor, occurred in 57% of the cases. Conclusions Radical nephrectomy with thrombectomy is a morbid procedure; however, most complications are minor, and the five-year mortality is null for patients in NTC levels I and II, and low for levels III and IV, and it may be even lower in level-III patients when standardizing transesophageal echocardiogram intraoperatively and routinary extracorporeal bypass. Thus, we recommend considering this surgery as the first-line management in patients with RCC and VTT.

Objetivo Describir la supervivencia global (SG) a los cinco años y la morbilidad perioperatoria de pacientes con carcinoma de células renales (CCR) con trombo tumoral venoso (TTV) tratados por nefrectomía radical y trombectomía. Materiales y Métodos Se evaluó una cohorte de 530 pacientes con diagnóstico de CCR entre enero de 2009 y diciembre de 2019, y se encontró TTV en 42 de ellos; esos 42 pacientes compusieron la muestra de este estudio. Los pacientes fueron estratificados según la clasificación de trombos de Neves (CTN). Se describieron las características basales y perioperatorias de los pacientes, así como el seguimiento. Se aplicaron la curva de Kaplan-Meier y su respectiva regresión de COX para presentar la SG a los 5 años y la SG estratificada por CTN. Resultados La edad promedio de la muestra fue de 63,19 ± 10,7 años, sin diferencia respecto a género. El TTV estuvo presente en el 7,9% de los pacientes. Según la CTN, el 30,9% de los casos correspondía al nivel I, el 21,4%, al nivel II, el 26,1%, al nivel III, y el 21,4%, al nivel IV. La SG a los 5 años fue del 88%. Para los niveles I y II, la SG a los 5 años fue del 100%, y, para el nivel IV del 38%. Las complicaciones, menores en su mayoría, ocurrieron en el 57% de los casos. Conclusiones La nefrectomía radical con trombectomía es un procedimiento mórbido; sin embargo, la mayoría de las complicaciones son menores, y la mortalidad a los 5 años es nula cuando en los pacientes de niveles I y II en la CYN, y baja en los niveles III y IV, y puede ser incluso menor en los pacientes de nivel III al estandarizar el ecocardiograma transesofágico intraoperatorio y el baipás extracorpóreo rutinario. Por ello, recomendamos considerar esta cirugía como manejo de primera línea en pacientes con CCR y TTV.

Sporadic Renal Angiomyolipoma: Can We Adopt a Uniform Management Protocol / Angiomiolipoma renal esporádico: ¿Podemos adoptar un protocolo de tratamiento estándar?

Renal angiomyolipomas (AMLs), formerly known as PEComas (tumors showing perivascular epithelioid cell differentiation) are common benign renal masses composed of a varying ratio of fat, blood vessels, and smooth muscles. They are largely asymptomatic and diagnosed incidentally on imaging. The adipose tissue content is the factor that gives AMLs their characteristic appearance on imaging and makes them easily identifiable. However, the fat-poor or fat-invisible varieties, which are difficult to differentiate radiologically from renal cell carcinomas (RCCs), present a diagnostic challenge. It is thus essential to establish the diagnosis and identify the atypical and hereditary cases as they require more intense surveillance and management due to their potential for malignant transformation. Multiple management options are available, ranging from conservative approach to embolization and to the more radical option of nephrectomy. While the indications for intervention are relatively clear and aimed at a rather small cohort, the protocol for follow-up of the remainder of the cohort forming the majority of cases is not well established. The surveillance and discharge policies therefore vary between institutions and even between individual practitioners. We have reviewed the literature to establish an optimum management pathway focusing on the typical AMLs.

Los angiomiolipomas renales (AML), antes conocidos como PEComas (tumores que muestran epitelioides perivasculares) son masas renales benignas frecuentes compuestas por una proporción variable de grasa, vasos sanguíneos y músculos lisos. Suelen ser asintomáticos y se diagnostican de forma incidental en las pruebas de imagen. El contenido de tejido adiposo es el factor que confiere a los AML su aspecto característico en las imágenes y los hace fácilmente identificables. Sin embargo, las variedades pobres en grasa o invisibles, que son difíciles de diferenciar radiológicamente de los carcinomas de células renales (CCR), suponen un reto diagnóstico. Por lo tanto, es esencial establecer el diagnóstico e identificar los casos atípicos y hereditarios, ya que requieren una vigilancia y un tratamiento más intensos debido a su potencial de malignización. debido a su potencial de transformación maligna. Existen múltiples opciones de tratamiento, que van desde el enfoque conservador hasta la embolización y la opción más radical de la nefrectomía. Si bien las indicaciones para la intervención son relativamente claras y están dirigidas a una cohorte bastante pequeña, el protocolo para el seguimiento del resto de la cohorte que forma la mayoría de los casos no está bien establecido. Por lo tanto, las políticas de vigilancia y alta varían entre instituciones e incluso entre profesionales individuales. Hemos revisado la literatura para establecer una ruta de manejo óptima centrada en los AML típicos.

Vertebral metastasis of renal carcinoma at diagnosis: mechanical and clinical evaluation: surgical management / Metástasis vertebral de carcinoma renal en el momento del diagnóstico: evaluación mecánica y clínica: manejo quirúrgico

Renal cell carcinoma accounts for 2-3% of all malignant neoplasms. Metastatic disease of the spine is common and 50% of bone metastases are already present at the time of primary diagnosis. Bone metastases from renal cell carcinoma are difficult to manage, especially vertebral localization.A 48-year-old woman was diagnosed with renal cell carcinoma in the context of low back pain. The patient presented two skeleton metastases at diagnosis (T11 and 5th rib). The patient received neoadjuvant treatment with cabozantinib, followed by removal of the renal tumor. Radiotherapy was administered for the lumbar lesion. In spite of the radiotherapy treatment, increased low back pain limiting mobility and ambulation. MRI showed an occupation of the spinal canal, without neurological lesion. The SINS scale revealed a score of 14 (vertebral instability). The patient's prognosis was greater than 12 months according to the Tokuhashi score. Based on clinical and mechanical criteria, surgical treatment of the vertebral lesion was decided. T11 vertebrectomy was performed, the reconstruction was made with an expandable cage, and T8 a L2 posterior spinal arthrodesis. A partial resection of the fifth rib was performed in order to remove the whole macroscopic tumor. After 3 months, she was diagnosed with a local infection, treated by irrigation, debridement and antibiotherapy, with good evolution. At 1-year follow-up, she has no low back pain or functional limitation. Follow-up chest-abdomen-pelvis computed CT scan showed absence of disease progression, furthermore, the vertebral arthrodesis shows fusion signs. At the time of this report, there are no clinical or radiological data of infection

El carcinoma de células renales representa el 2-3% de todas las neoplasias malignas. La enfermedad metastásica de la columna vertebral es frecuente y el 50% de las metástasis óseas ya están presentes en el momento del diagnóstico. Las metástasis óseas del carcinoma de células renales son difíciles de manejar, especialmente en localización vertebral.Una mujer de 48 años fue diagnosticada de carcinoma de células renales en el contexto de un dolor lumbar. La paciente presentaba dos metástasis óseas en el momento del diagnóstico (T11 y 5ª costilla). Inicialmente recibió tratamiento neoadyuvante con cabozantinib, seguido de la extirpación quirúrgica del tumor renal. Se administró radioterapia para la lesión lumbar. A pesar del tratamiento radioterápico, aumentó el dolor lumbar con limitación para la movilidad y la deambulación. La RM mostró una ocupación del canal espinal, sin lesión neurológica. La escala SINS reveló una puntuación de 14 (inestabilidad vertebral). El pronóstico de la paciente era superior a 12 meses según la puntuación de Tokuhashi. Basándose en criterios clínicos y mecánicos, se decidió el tratamiento quirúrgico de la lesión vertebral. Se realizó una vertebrectomía de T11, para la reconstrucción se usó una caja extensible, junto con una artrodesis vertebral T8-L2. Se realizó una resección parcial de la quinta costilla para eliminar todo el tumor macroscópico. A los 3 meses de la cirugía la paciente fue diagnosticada de infección local, tratada mediante irrigación, desbridamiento y antibioterapia, con buena evolución. Al año de seguimiento, no presenta dolor lumbar ni limitación funcional. La tomografía computarizada de tórax-abdomen-pelvis de seguimiento mostró ausencia de progresión de la enfermedad, además, la artrodesis vertebral muestra signos de fusión. En el momento de este informe, no hay datos clínicos ni radiológicos de infección.

Surgical insights for the management of variant histology in renal cell carcinoma

ABSTRACT Purpose: To review the current literature regarding variant (non-clear) histology of renal cell carcinoma (RCC) and the clinical management of these renal tumors. Material and Methods: A PubMed database search was performed in May 2020 focusing on variant RCC, its diagnosis and associated syndromes, tumor characteristics, and options for management. Results: A broad range of pathological, clinical and diagnostic characteristics amongst non-ccRCC variants were found to have an impact on the overall management of these tumors. The imaging modalities, frequency of surveillance, and timing for intervention were found to be dependent on the type of genetic alterations, type of histology, and tumor growth rates. The timing and type of surgery as well as the systemic therapy are tailored to the specific tumor type and patient. Conclusion: The findings of this review suggest that clinical management should be considered and adjusted for patients with non-ccRCC histological variants based on tumor subtype and genetic alterations.