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1
Tiroli, Marco. "Fattori prognostici nei carcinomi renali non a cellule chiare. Nostra esperienza". Doctoral thesis, Università Politecnica delle Marche, 2013. http://hdl.handle.net/11566/242681.
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Introduzione: Il carcinoma renale a cellule chiare (ccRCC) è l’istotipo più frequente di tumore
renale (circa l’ 80% di tutti). Ciononostante vi sono anche istotipi meno frequenti. Il carcinoma
renale papillare (pRCC) rappresenta il secondo istotipo per frequenza, nondimeno finora solo pochi
lavori hanno analizzato il suo comportamento in studi osservazionali a lungo termine, con casistiche
consistenti. In questo lavoro sono stati considerati tutti i casi di pRCC operati dal 1997 al 2011
presso il nostro centro. I pazienti sono stati seguiti fino a Dicembre 2012, stratificandoli sulla base
delle condizioni pre-operatorie e sui parametri pre-operatori, considerando le variabili dei
nomogrammi in uso sia per le forme a cellule chiare che per tutte le istologie, valutando la
consistenza di tali nomogrammi per l’istologia papillare.
Pazienti e metodi: Sono stati individuati 468 pazienti, operati dal 1997 al 2011 per neoformazioni
renali. Fra questi, 60 sono stati selezionati, identificati come pRCC. Le caratteristiche cliniche e
parametri patologici sono stati raccolti dai referti di laboratorio, anatomopatologici e dal’imaging
strumentale: età, genere, dimensioni ed estensione del tumore, tipo di chirurgia, invasione
capsulare, del tessuto adiposo, linfonodale; parametri laboratoristici: leucociti, neutrofili e linfociti,
emoglobina, LDH, sodiemia, potassiemia, calcemia. Sono stati testati i nomogrammi disponibili,
per valutare la loro validità ed estendibilità all’istotipo papillare. Il tempo alla recidiva/progressione
è stato scelto come variabile di outcome. E’ stata eseguita analisi della sopravvivenza con metodo di
Kaplan-Meier e regressione di Cox sulla coorte di studio. I risultati sono stati confrontati con i dati
in letteratura.
Risultati:Fra tutte le variabili esaminate, solo lo stadio T (raggruppato) e l’invasione del grasso
ilare sono risultati significativi all’analisi univariata, mantenendo tale significatività al modello
multivariabile. Fra i nomogrammi, solo lo scoring di Karakiewicz ha dimostrato ruolo quale
predittore indipendente. Nessun parametro laboratoristico ha dimostrato un ruolo come variabile
predittiva.
Discussione e Conclusioni: Nonostante le dimensioni della coorte, questa può essere considerata al
di sopra della media degli studi finora condotti. Solo un gruppo limitato di parametri pre- o intraoperatori
si è dimostrato valido come predittore di tempo alla recidiva per il pRCC, sia
autonomamente che quale variabile all’interno di nomogrammi. Per lo staging, comunque, solo un
raggruppamento di più stadi è risultato significativo, a suggerire la necessità di rivedere l’attuale
classificazione in relazione ai differenti istotipi. Sarebbe comunque raccomandabile l’esecuzione di
studi multicentrici con casistiche più ampie, per definire meglio i caratteri di questa patologia.Introduction: Clear cell histology (ccRCC) represents the most common subtype of renal cell carcinoma, accounting for almost 80% of all renal malignancies. Nevertheless, other less common entities can be met during surgical removal of renal masses. Papillary renal cell carcinoma (pRCC) is the second most common histology, nevertheless only few works investigated its behavior in long-time observations with consistent case series. In this work all cases of pRCC operated from 1997 to 2011 at our clinic were collected. Surgical and clinical outcome were followed-up until December 2012, matched with pre-operative patients’ conditions and with laboratory parameters already considered in survival nomograms currently in use for clear cells type, in order to test the consistency of the results for a different histology. Patients and methods: 468 patients were collected, operated at our center from 1997 to 2011 for renal masses. Among these, 60 were selected, by whom a papillary histology resulted at the pathological examination. Clinical and laboratory pre-operative features were collected from patients clinical reports and histological and surgical features collected from pathological reports and imaging diagnostics: age at intervention, gender, tumor dimensions, tumor extension, type of surgery, fat invasion, lymph nodes invasion; laboratory parameters: leucocytes, neutrophils and lymphocytes count, hemoglobin, LDH, sodium, potassium, calcium. Currently available nomograms for different histological subtypes were tested to assess their validity on pRCC. Time to progression/recurrence was chosen as outcome variable. Survival analysis with Kaplan-Meier method and Cox-regression analysis were performed on the whole cohort of cases and the results were compared with the data obtained from the literature. Results: Of all variables tested, only cumulative T-staging and hilar fat invasion were significant at univariate analysis, keeping their significance as independent predictors at the multivariable model, while only Karakiewicz score resulted as independent significant variable among the different models tested. No role could be determined for any of the pre-operative laboratory parameters tested in our series. Discussion and Conclusions: Despite the small dimensions of our cohort study, it can be considered over the average of the studies so far performed on this pathology. Only a limited group of pre- /intra-operative parameters usually considered when considering ccRCC, as themsevews or within predictive nomograms could find a role as predicting parameters for pRCC. For staging parameters, only grouped variables were significant, suggesting that a revision in the classification should be considered, according to the different subtypes. Anyway, further studies considering wider case series, even from multicentric groups would be advisable.
2
MOROSI, LAVINIA. "Studi di proteomica subcellulare nelle patologie renali: carcinoma renale e nefropatia diabetica". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/28933.
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ABSTRACT
Renal cell carcinoma (RCC) is among the 10 leading causes of cancer-related deaths worldwide and its incidence is increasing steadily. At the time of diagnosis, 30% of patients have metastases and another third will develop metastatic disease within 10 years. Moreover metastatic RCC is radio- and chemotherapy resistant. Diabetic nephropathy (DN) is a common diabetic complication that causes a renal massive functional deficit making dialysis or transplantation essential for the survival of patients and it is associated with alterations in the expression of several renal proteins. Therefore, it is important to identify differentially expressed proteins to be used as potential diagnostic and/or prognostic markers in RCC and DN. A promising strategy is comparative subcellular proteomics of urinary exosomes, membranous vesicles released from cells and membrane microdomains, lipid arfts and caveolae.
About 30 ml of urines were collected from 29 clear cell RCC patients and 28 healthy matched controls and stored at -80°C, after antiproteases addition. Diabetes was induced in 10 Sprague Dawley rats by streptozotocin injection. Control rats (n=4) underwent only buffer injection. Out of 10 diabetic rats, 4 were chronically treated with insulin. After 3 months, 24 hours urines were collected. In both cases (RCC patients and diabetic rats with their healthy controls respectively) exosomes were then isolated from total urines by ultracentrifugation after cells and debris clearing.
As regards RCC esults show that the protein profile of urinary exosomes is peculiar: the most abundant urinary proteins of plasmatic origin (i.e. albumin) are markedly reduced, while the Tamm Horsfall protein (THP) is highly enriched and affected by a significant biological variability. Moreover, protein profiles of exosomal fractions isolated from urine of ccRCC and matched controls show some difference. Mass spectrometry analysis of two pools of exosomes isolated from CTRL and RCC patients urines permits the identification of 261 proteins in CTRL and 187 proteins in RCC. Some of these protein Aquaporin-1, Matrix Metallo-protease 9 and Carbonic Anhydrase 9, display differential amount in ccRCC patient urine exosomes by EF/WB.
Moreover subcellular fractions were prepared by differential centrifugation from surgical samples of RCC and adjacent normal kidney (ANK). MD were isolated from plasma-membrane-enriched fractions after treatment with Triton X-100 and sucrose density gradient ultracentrifugation. MD derived from RCC and ANK tissues of 7 patients were pooled, and proteins separated by 4-12% and 12% gel electrophoresis. After Coomassie Blue staining, bands were excised and analyzed by LC-MS/MS after trypsin digestion.
We identified 83 proteins from microdomains isolated from RCC tissue, and 95 proteins from ANK. About 60% of the identified proteins are membrane-associated and about half of these resulted microdomain-associated. GRAVY scores assignment shows that most identified proteins (about 70%) are in the hydrophobic range. From a functional point of view, we found proteins involved in signal transduction (Ras related proteins), channels (Aquaporin-1), carriers (P-glycoprotein) and cytoskeleton structural constituents (Spectrin). We chose some promising proteins such as Renal dipeptidase (identified only in ANK MD) or Emmprin (overexpressed in RCC tissue) and investigated their differential expression of by WB
About DN study, protein profiles of exosomes obtained from the three groups of rat (healthy controls CTRL, diabetic D and diabetic treated with insulin DI) show differences, mainly at low molecular weights. Some differential bands were excised and analyzed by LC-MS/MS after digestion by tripsin. In particular we identified the Major Urinary Proteins, known as MUPs from CTRL and DI gels, while these proteins are not present in the same bands excised from D gels. MUPs regulate glucose and lipid metabolism suggesting an involvement in hyperglycemia, insulin resistance and/or glucose intolerance in diabetes.
3
Reis, Mário Marques de Oliveira. "Carcinoma renal : Estudo anatomoclínico". Doctoral thesis, Universidade do Porto. Reitoria, 1989. http://hdl.handle.net/10216/10169.
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Reis, Mário Marques de Oliveira. "Carcinoma renal : Estudo anatomoclínico". Tese, Universidade do Porto. Reitoria, 1989. http://hdl.handle.net/10216/10169.
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BIANCONI, MARISTELLA. "Il profilo angiogenico nel carcinoma renale metastatico: implicazioni prognostiche e terapeutiche". Doctoral thesis, Università Politecnica delle Marche, 2018. http://hdl.handle.net/11566/253118.
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Il trattamento del carcinoma renale avanzato è radicalmente cambiato nell’ultimo decennio. Le opzioni disponibili sono per la maggior parte dirette contro la via dell’angiogenesi. Nonostante questo i pazienti trattati sperimentano outcome molto diversi tra di loro e, al momento, non possediamo fattori predittivi. Sulla scorta delle nostre precedenti analisi dei polimorfismi di VEGF e VEGFR nel carcinoma renale avanzato in pazienti trattati in prima linea con sunitinib o pazopanib, abbiamo voluto analizzare l’eventuale influenza di tali polimorfismi per quanto concerne la seconda linea.
Dei pazienti trattati per carcinoma renale avanzato, 63 sono risultati eleggibili per l’analisi in correlazione alla seconda linea. Su questi pazienti sono stati analizzati un gruppo di polimorfismi di VEGF e VEGFR correlandoli con la PFS e la OS, i pazienti sono stati divisi in due gruppi in base al trattamento (anti-VEGF vs anti-mTOR).
Il polimorfismo rs2010963 di VEGF A mostra un vantaggio in termini di PFS per il genotipo GG o GC nel gruppo anti-VEGF (7,5 vs 3,3 mesi) e nel gruppo trattato con anti-mTOR (6,3 vs 2,9 mesi) (p<0,0001); questo vantaggio persiste in OS sia nel gruppo trattato con anti-VEGF (26,4 vs 10,8 mesi) sia in quello trattato con anti-mTOR (13,2 vs 3,4 mesi) (p=0,0006). Il polimorfismo di VEGFR-3 rs6877011 si è dimostrato vantaggioso in PFS per il genotipo CC nel gruppo anti-VEGF (7,6 vs 3,2 mesi) e per GG o GC nel gruppo trattato con anti-mTOR (10,3 vs 3,7 mesi) (p=0,0018). Per quanto riguarda la OS la presenza di C evidenzia un vantaggio nel gruppo trattato con anti-VEGF (26,4 vs 3,7 mesi) mentre in quello trattato con anti-mTOR il vantaggio si ha con l’espressione di GG o GC (12,9 vs 8,9 mesi) (p=0,0045).
Dalle nostre analisi sembra evidenziarsi un profilo angiogenico con i polimorfismi rs833061, rs2010963, rs699947 e rs6877011 che sia in grado di predire la scelta del farmaco in prima linea e indirizzare la scelta della seconda linea di trattamento.The treatment of advanced renal cell carcinoma has radically changed in the last decade. The options available are for the most part directed against the angiogenic pathway. Despite this, the treated patients experience very different outcomes and we do not have predictive factors so far. Based on our previous analysis of the polymorphisms of VEGF and VEGFR in advanced renal cell carcinoma in patients treated in the first line with sunitinib or pazopanib, we analyzed the possible influence of these polymorphisms in correlation with the second line. Of patients treated for advanced renal cell carcinoma, 63 were eligible for second-line treatment analysis. On these patients a group of polymorphisms of VEGF and VEGFR were analyzed correlating them with the PFS and the OS, the patients were divided into two groups based on the treatment (anti-VEGF vs anti-mTOR). The rs2010963 polymorphism of VEGF A shows an advantage in terms of PFS for the GG or GC genotype in the anti-VEGF group (7.5 vs 3.3 months) and in the anti-mTOR group (6.3 vs 2.9 months) (p <0.0001); this advantage persists in OS both in the group treated with anti-VEGF (26.4 vs 10.8 months) and in the group treated with anti-mTOR (13.2 vs 3.4 months) (p = 0.0006). The polymorphism of VEGFR-3 rs6877011 was shown to be incremental in PFS for the CC genotype in the anti-VEGF group (7.6 vs 3.2 months) and for GG or GC in the anti-mTOR group (10.3 vs 3 , 7 months) (p = 0.0018). As regards the OS the presence of C allele shows an advantage in the group treated with anti-VEGF (26.4 vs. 3.7 months) while in the one treated with anti-mTOR the advantage is with the expression of GG or GC ( 12.9 vs 8.9 months) (p = 0.0045). From our analysis, an angiogenic profile appears with the polymorphisms rs833061, rs2010963, rs699947 and rs6877011 that is able to predict the choice of the drug in the first line and direct the choice of the second line.
6
Lima, Marcela Sampaio. "Expressão de Ciclina D1 em Carcinoma de Células Renais". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17143/tde-21102013-215129/.
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Carcinoma de Células Renais (CCR) representa uma família de tumores distintos com evolução clínica imprevisível. Uma variedade de moléculas tem sido avaliada como marcadores prognósticos para CCR. Ciclina D1, uma proteína reguladora do ciclo celular, encontra-se superexpressa em vários tumores primários. Nosso objetivo é avaliar sua expressão como marcador prognóstico em CCR. Antes disso, traçamos um perfil clínico e histopatológico da amostra e verificamos sua relação com os fatores prognósticos considerados clássicos pela literatura. 109 espécimes de pacientes diagnosticados com CCR foram obtidos entre 2005 e 2010 no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto USP e submetidos à análise imunoistoquímica juntamente com 07 amostras de tecido renal normal. A maior parte das características epidemiológicas e clínicas de nossa amostra foi similar àquelas descritas na literatura mundial. Houve predomínio do gênero masculino, da raça branca, com idade próxima a 60 anos, frequência de pacientes assintomáticos em torno de 36% e grande prevalência do CCR de células claras (71,55%). A mortalidade específica da doença foi de 13,76%, sendo o CCR de células claras o tipo mais frequente entre os óbitos e casos metastáticos. Os casos que exibiram má evolução clínica, definida pela ocorrência de metástase e/ou óbito por CCR (22,01%), estiveram associados à presença de sintomas ao diagnóstico, maior tamanho tumoral, grupo de estágio alto (III ou IV), grau nuclear de Fuhrman alto (3 ou 4), presença de necrose e de diferenciação sarcomatóide no tumor, além de outros fatores histológicos desfavoráveis (p < 0,01). Isso indica que as variáveis utilizadas na avaliação de prognóstico em países desenvolvidos podem ser aplicadas aos nossos pacientes. Não houve expressão imunoistoquímica de Ciclina D1 nos casos de tecido renal normal. Observou-se heterogeneidade de marcação nuclear intratumoral no total de casos e menor expressão proteica entre os CCR papilífero e cromófobo. Pacientes com tumores com Ciclina D1baixa (até 30% de células positivas) apresentaram má evolução clínica (p = 0,03), maior tamanho tumoral (p = 0,01), presença de sintomas ao diagnóstico (p = 0,04), grau nuclear alto (p = 0,001), presença de necrose (p = 0,004) e de diferenciação sarcomatóide (p = 0,04) no tumor, além de menor sobrevida sem metástase e/ou óbito por CCR (p = 0,03). Após análise multivariada, a expressão de Ciclina D1 não apresentou valor prognóstico independente para má evolução clínica, embora tenha aumentado levemente a acurácia prognóstica do modelo adotado. Em todas as análises realizadas para o CCR de células claras isoladamente, observamos significância estatística semelhante à do total de casos (CCR). Nosso estudo demonstrou que: a proteína Ciclina D1 encontra-se superexpressa em CCR; os tipos de CCR parecem exibir diferentes padrões de marcação imunoistoquímica da Ciclina D1; alta marcação da proteína (acima de 30% de células positivas) esteve associada à boa evolução clínica e à maioria dos fatores prognósticos favoráveis bem estabelecidos na literatura. Novas investigações são necessárias para descobrir que mecanismos levam a seu acúmulo nas células neoplásicas e quais outros eventos podem estar contribuindo para a progressão da doença.Renal Cell Carcinoma (RCC) is a family of distinct tumors with unpredictable clinical outcome. A variety of molecules have been evaluated as prognostic markers for RCC. Cyclin D1, a cell cycle regulatory protein, is overexpressed in several primary tumors. Our purpose is to evaluate its expression as a prognostic marker in RCC. Before that, we drew a clinical and histopathological profile of the sample and verified its relationship with prognostic factors regarded as classics in literature. 109 specimens from patients diagnosed with RCC were obtained between 2005 and 2010 at Hospital das Clínicas - Ribeirão Preto School of Medicine USP and submitted to immunohistochemical analysis, along with 07 normal kidney tissue samples. Most epidemiological and clinical characteristics of our sample were similar to those described in the literature. There was a predominance of male, Caucasian, aged about 60 years, the frequency of asymptomatic patients around 36%, and high prevalence of clear cell RCC (71.55%). The disease-specific mortality was 13.76%, being the clear cell RCC the most frequent type among deaths and metastatic cases. Cases that exhibited poor clinical outcome, defined by the occurrence of metastasis and/or death by RCC (22.01%), were related to the presence of symptoms at diagnosis, larger tumor size, high stage group (III or IV), high Fuhrman nuclear grade (3 or 4), presence of necrosis and sarcomatoid differentiation in the tumor and other unfavorable histological factors (p < 0.01). This indicates that the variables used in the assessment of prognosis in developed countries can be applied to our patients. There was no immunohistochemical expression of Cyclin D1 in cases of normal kidney tissue. There was intratumoral heterogeneity in nuclear staining in all cases and lower protein expression among papillary and chromophobe RCC. Patients with Cyclin D1low tumors (up to 30% positive cells) showed poor clinical outcome (p = 0.03), larger tumor size (p = 0.01), presence of symptoms at diagnosis (p = 0.04), high nuclear grade (p = 0.001), presence of necrosis (p = 0.004) and sarcomatoid differentiation (p = 0.04) in the tumor and lower survival without metastasis and/or death by RCC (p = 0.03). After multivariate analysis, the expression of Cyclin D1 showed no independent prognostic value for poor clinical outcome, although it has slightly increased the prognostic accuracy of the model adopted. In all analyzes performed for clear cell RCC alone, we observed statistical significance similar to that of the total cases (RCC). Our study showed that: Cyclin D1 protein is overexpressed in RCC; RCC types seem to exhibit different patterns of immunohistochemical staining for Cyclin D1; high protein expression (over 30% positive cells) was related to good clinical outcome and to most favorable prognostic factors well established in the literature. Further investigations are necessary to reveal which mechanisms lead to its accumulation in neoplastic cells and what other events might be contributing to the progression of the disease.
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Silvestre, Cristina. "Meccanismi di immunosorveglianza nella carcinogensei dei reni affetti da end-stage renal disease". Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424488.
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Background- Chronic kidney disease (CKD) and replacement therapies (dialysis or transplantation) increase the risk of native kidneys cancer. Acquired multicystic kidney disease in dialysis patients and immunosuppressive therapy in transplant recipients might be relevant factors for the development of renal cancer.
International guidelines do not clearly recommend specific screening protocols for these categories of patients, although the early diagnosis could lead to an excellent prognosis.
Objectives- To retrospectively analyze the cases of renal neoplasms of the native kidneys in chronic renal failure patients and renal transplant recipients that underwent nephrectomy at the Kidney and Pancreas Transplant Center at Hospital-University of Padua.
The histological type of the tumor, grading, stage at diagnosis and prognosis of these patients were evaluated and compared with the data reported in the literature in uremic patients and in the general population.
In the prospective phase of the study: the histopathological analysis and the flow cytometry of the kidneys have been addressed to study the expression of costimulatory molecules at the level of renal epithelial cells, to determine their function as non-professional APC (Antigen Presenting Cell). The activation status of intraepitelial lymphocyte population have been evaluated.
Methods- From April 2007 to June 2013, 18 patients with chronic kidney disease (CKD) and/or kidney transplant recipients underwent nephrectomy because of renal tumor at the Kidney and Pancreas Transplant Center at Hospital-University of Padua. Were analyzed: the cause of the CKD, the type of replacement therapy, the timing of kidney transplantation, immunosuppressive therapy, the histological type of the tumor, the Fuhrman grade, and patient outcomes.
Thereafter, between December 2014 and December 2015, 16 patients (5F/11M). were enrolled in the study. Indications for nephrectomy were: polycystic disease (APKD) 13 patients, suspected malignancy of the native kidney 3 patients, 1 patient underwent trasnsplantectomy of his kidney, performed for the detection of an aneurysm of the renal artery. Histological examination showed: neoplasms 2 cell carcinomas (Furhman Furhman 4 and 2 respectively), 1 papillary carcinoma
Results- The average age of the patients at the time of nephrectomy was 53.4 ± 11.2 years. Six patients were receiving dialysis (hemodialysis in 2 and 4 on peritoneal dialysis), while 12 patients had a kidney transplant and 1 had previously pancreas and kidney transplantation. One patient developed 2 bilateral metacronous neoplasia and 1 benign tumor. Histological examination showed 17 cases of malignancy (9 clear cell carcinomas and 8 papillary carcinomas) and 3 benign tumors (2 papillary adenoma and a renal oncocytoma). The stage at diagnosis was: in 16 cases T1, and in 1 case T2. All patients underwent nephrectomy: 12 laparoscopically, 5 with laparotomy and 2 by lombotomic approach. All patients were asymptomatic at diagnosis, which took place during ultrasound performed for other reasons and subsequently confirmed at the CT-scan with contrast and / or MRI. After a mean follow-up of 22 ± 20 months, two patients died of causes unrelated to renal cancer and there were no local or distant recurrence of the tumor, in the absence of adjuvant treatment.
The flow cytometry seems to show a greater expression of CD80, HLAABCm, HLAABCr; HLADRm and HLADRr; where HLAABCm and HLADRm represent the average intensity of fluorescence per cell, while HLAABCr and HLADRr represent the percentage of cells that exceed the gate and are therefore classified as positive. The expression of MCHC seems to increase in transplant recipient than in non-transplant patients; probably because immunosuppressive therapy, preventing rejection, leads an inhibition of T cell.
Conclusions- The diagnosis of kidney cancer which is carried out within the program of follow-up in kidney transplant patients and screening in uremic patients allows to detect cancer in its early stages, improving outcomes and reducing the need for adjuvant therapy.
The expression of costimulatory molecule CD80 in patients with renal carcinoma might suggest an activation of immunosurveillance in the carcinogenesis of the kidney. Further studies are needed to clarify the role of immunosuppressive therapy in the immunosurveillance.Introduzione- L’insufficienza renale cronica (IRC) e specialmente la terapia sostitutiva (dialisi e trapianto), aumentano il rischio di riscontrare tumori dei reni nativi. I fattori che possono essere implicati sono la malattia renale multicistica acquisita nei dializzati e la terapia immunosoppressiva nei pazienti trapiantati. Nelle linee guida internazionali mancano tuttavia delle chiare indicazioni sulla tipologia di screening a cui sottoporre questi pazienti , benché in caso di diagnosi precoce la prognosi di queste neoplasie possa risultare ottima. Scopo dello studio- nella fase retrospettiva dello studio è stata analizzata la casistica di neoplasie renali dei reni nativi in pazienti affetti da insufficienza renale cronica e in pazienti trapiantati di rene e sottoposti a nefrectomia presso l’U.O.C. Trapianti di Rene e Pancreas dell’Azienda Ospedale-Università di Padova. L’istotipo del tumore, il grading, lo stadio alla diagnosi e la prognosi di questa tipologia di pazienti sono stati valutati e confrontati con i dati riportati in letteratura relativi a pazienti uremici e nella popolazione generale. Nella fase prospettica: l'analisi istopatologica e citofluorimetrica dei reni sono state indirizzate allo studio dell'espressione delle molecole di costimolazione a livello delle cellule epiteliali renali, per determinare la loro funzione di antigen presenting cell non professionali. Sono state inoltre analizzate le sottopopolazioni linfocitarie T residenti ed il loro stato di attivazione. Materiali e metodi: Da Aprile 2007 a Giugno 2013, 18 pazienti affetti da IRC e/o trapiantati di rene sono stati sottoposti a nefrectomia per riscontro di neoplasia renale presso la U.O.C. Trapianti Rene e Pancreas dell’Azienda Ospedale- Università di Padova. Sono stati analizzati: la causa dell’IRC, il tipo di terapia sostitutiva, il timing del trapianto di rene, la terapia immunosoppressiva, l’istotipo della neoplasia, il grado Fuhrman, e l’outcome dei pazienti. Successivamente tra dicembre 2014 e dicembre 2015, sono stati arruolati nello studio 16 pazienti (5F/11M). Le indicazioni all’intervento di nefrectomia sono state malattia policistica dell’adulto (APKD) 13 pazienti, sospetta neoplasia del rene nativo 3 pazienti, 1 paziente è stata sottoposta ed espianto di autotrapianto di rene, effettuato per il riscontro di un’aneurisma dell’arteria renale primitiva. Sono state riscontrate le seguenti neoplasie renali 2 carcinomi a cellule chiare (Furhman 4 e Furhman 2 rispettivamente), 1 carcinoma papillare. Risultati- L’età media dei pazienti al momento della nefrectomia era 53.4±11.2 anni. Sei pazienti erano in trattamento dialitico (2 in emodialisi e 4 in dialisi peritoneale), mentre 11 pazienti erano trapiantati di rene e 1 era trapiantato di pancreas e rene. Un paziente ha presentato due neoplasie maligne bilaterali metacrone ed un tumore benigno. L’esame istologico ha evidenziato 17 casi di neoplasia maligna (9 carcinomi a cellule chiare e 8 carcinomi papillari) e 3 di tumore benigno (due adenomi papillari e un oncocitoma renale). Lo stadio alla diagnosi era: in 16 casi T1 ed in un caso T2. Tutti i pazienti sono stati sottoposti a nefrectomia: 12 per via laparoscopica, 5 per via laparotomica e 2 per via lombotomica. Tutti i pazienti erano asintomatici alla diagnosi, che è avvenuta in corso di ecografia eseguita per altre ragioni e successivamente confermata all’esame TAC con mezzo di contrasto e/o RM. Dopo un follow-up medio di 22±20 mesi, due pazienti sono deceduti per cause non collegate alla neoplasia renale e non si sono verificate recidive locali o a distanza della neoplasia, in assenza di trattamento adiuvante. L’analisi puramente descrittiva della citofluorimetria sembra evidenziare una maggiore espressione di CD80, HLAABCm, HLAABCr; HLADRm e HLADRr; dove HLAABCm e HLADRm rappresentano l'intensità media della fluorescenza per cellula, mentre HLAABCr e HLADRr rappresentano la percentuale di cellule che superano il gate e sono quindi catalogate come positive. L’espressione di MCHC aumenta nei pazienti trapiantati rispetto ai non trapiantati in quanto il rene trapiantato sta esprimendo antigeni in modo non tollerigeno in quanto organo non self, la terapia immunosoppressiva determina un’inibizione del linfociti T a valle del CD80, impedendo il rigetto. Conclusioni- La diagnosi delle neoplasie renali che viene effettuata nell’ambito di programma di follow-up nel paziente trapiantato di rene e di screening nel paziente uremico consente di individuare neoplasie in stadio precoce, migliorandone l’outcome e riducendo la necessità di terapie adiuvanti. Sembra esserci un’attivazione nel processo di immunosorveglianza suggerito dall’ elevata espressione della molecola di costimolazione CD80 nei pazienti affetti da neoplasie renali. Rimane da chiarire il ruolo della terapia immunosoppressiva nell’immunosorveglianza.
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Rashidkhani, Bahram. "Diet and renal cell carcinoma /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-163-6/.
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Fallah, Abdul Karim. "Genomic studies in renal cell carcinoma". Thesis, Manchester Metropolitan University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528380.
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Al-Sharhan, Mouza Abdulla. "Prognostic factors in renal cell carcinoma". Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285788.
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Ronkainen, H. L. (Hanna-Leena). "Novel prognostic biomarkers for renal cell carcinoma". Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789514297731.
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Abstract Background and aims: Stage and grade are the most widely used prognostic parameters for renal cell carcinoma (RCC). The clinical course of this disease is not, however, always predictable by traditional prognostic factors. In the era of new molecular targeted therapies a more accurate prognostication of RCC patient survival is important for the individualization of treatment and follow-up of patients. Despite exhaustive research there are still no prognostic biomarkers for RCC in clinical practice. In order to find novel prognostic tissue markers for RCC, we examined the expression of 14 biomarkers involved in carcinogenesis and clarified their prognostic significance in RCC. Material and methods: Out of 189 consecutive patients who underwent surgery for kidney cancer at Oulu University Hospital in the 1990s, 152 patients with histologically verified RCC were included in this study. The stage distribution was 70 (46%), 12 (8%), 51 (34%) and 19 (12%) patients with stages I-IV, respectively. The majority of the tumours (83 tumours, 55%) were nuclear grade II and 5 (3%), 40 (27%) and 22 (15%) of the tumours were grades I, III and IV, respectively. Clinical and follow-up data were obtained from patient records, the Finnish Cancer Registry and on demand from the Population Register Centre of Finland. The biomarkers studied included markers of the oxidative and neuroendocrine systems as well as proteins related to cell adhesion and migration, invasion, metastasis, inflammation and immune responses. The expression of various biomarkers was characterized via immunohistochemical tests of archival tumour material. The staining intensity was compared to clinicopathological parameters and patient RCC-specific survival. Results: The 5-year RCC-specific survival was 77%. The expression of Toll-like receptor 9 (TLR9) was an independent marker of favourable RCC-specific survival whereas cytoplasmic myosin VI expression was found to be an independent prognostic factor of poor RCC-specific survival. Cell culture experiments showed how cyclooxygenase-2 (COX-2) expression is regulated by HuR in RCC. HuR and COX-2 immunoexpression were also related to decreased RCC-specific survival. Immunostaining of Keap1 was associated with advanced RCC and a marker of a poorer RCC-specific prognosis. The expression of different neuroendocrine markers was evaluated but we could not establish any prognostic value for them. Conclusions: In particular, TLR9, HuR and myosin VI can be regarded as promising novel prognostic biomarkers in RCC. Stage, however, is the most important single prognostic factor for RCCTiivistelmä Munuaissyöpä on vuosikymmenten ajan jatkuvasti yleistynyt. Vaikka se diagnosoidaan nykyisin useimmiten sattumalöydöksenä vatsan alueen kuvantamistutkimuksissa ja hoitomenetelmät ovat viime vuosikymmenten aikana kehittyneet, munuaissyöpäkuolleisuus ei ole laskenut. Munuaissyövän ennusteen määrittäminen voi olla haasteellista. Perinteiset ennustetekijät, levinneisyys ja erilaistumisaste, eivät riitä selittämään kaikkien potilaiden taudinkulkua, eikä munuaissyövälle vielä ole kliinisessä käytössä ennusteellista merkkiainetta. Munuaissyöpähoitojen kehittyessä taudinkulun ennustaminen on yhä tärkeämpää, jotta potilaiden hoito ja seuranta voidaan yksilöidä. Tämän väitöskirjatyön tarkoituksena oli etsiä uusia ennusteellisia kudosmerkkiaineita munuaissyöpäkasvaimille. Väitöskirjatutkimus perustuu 1990-luvulla Oulun yliopistollisessa sairaalassa leikatun 152 munuaissyöpäpotilaan aineistoon. Lähes puolet aineiston kasvaimista edusti levinneisyysluokkaa I, ja yli puolet munuaissyöpäkasvaimista oli hyvin erilaistuneita (tumagradus I ja II). Tutkimuspotilaista kerättiin kattavat seurantatiedot. Leikkauksessa poistettujen munuaissyöpäkasvainten arkistomateriaalista tutkittiin eri merkkiaineiden ilmenemistä. Tutkitut merkkiaineet käsittivät oksidatiivisen ja neuroendokriinisen järjestelmän merkkiaineita sekä valkuaisaineita, jotka liittyvät keskeisiin syövän ominaisuuksiin, kuten solujen välisiin liitoksiin ja solujen liikkumiseen sekä etäpesäkkeiden syntymiseen. Lisäksi tutkittiin merkkiaineita, jotka liittyvät tulehdusreaktioihin ja immuunipuolustukseen. Väitöskirjatutkimus paljasti useita uusia kudosmerkkiaineita, joiden ilmeneminen munuaissyöpäkasvaimessa on yhteydessä potilaan ennusteeseen. Näistä merkittävimpiä ovat myosiini VI, joka liittyy syöpäkasvainten metastasointiin, sekä immuunipuolustuksessa vaikuttava Tollin kaltainen reseptori 9 (Toll-like receptor 9, TLR9). Molemmat merkkiaineet osoittautuivat itsenäisiksi ennustetekijöiksi munuaissyövässä. Muita ennusteeseen vaikuttavia merkkiaineita ovat tutkimuksen mukaan oksidatiivista stressiä aistiva Keap1 sekä immunologisiin reaktioihin liittyvä syklo-oksigenaasi 2 (COX-2) ja sen ilmenemistä säätelevä HuR
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Lawrentschuk, Nathan Leo. "Hypoxia and angiogenesis in renal cell carcinoma". Connect to thesis, 2009. http://repository.unimelb.edu.au/10187/6790.
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Hypoxia is one of the hallmarks of cancer. It was first postulated to occur in solid tumours by Thomlinson and Gray in 1955.1 The presence of hypoxia has been demonstrated in different types of solid tumours.2 Intratumoral hypoxia is caused by the lack of functional blood vessels in proliferating tumour tissue, resulting in low intratumoral oxygen concentrations. If hypoxia is severe or prolonged, cell death occurs.3 Malignant cells can undergo genetic and adaptive changes that allow them to escape from dying of oxygen deprivation. These changes are associated with a more aggressive malignant phenotype 4,5 conferring resistance to radiation 6,7 and chemotherapeutic agents.3,8,9 Hence hypoxia is known to be a key factor responsible for tumour resistance in humans.Invasive polarographic oxygen sensor measurements have demonstrated hypoxia in solid tumours and it is generally defined to occur at an oxygen tension less than ten mmHg.10 Perhaps of more importance is that hypoxia has been demonstrated to be a prognostic indicator for local control after treatment with radiotherapy in glioma, head and neck and cervical cancers.11-13 It has also been able to predict for survival and the presence of distant metastases in soft tissue sarcomas.14 Finally, the significance of hypoxia in the activation and induction of functional molecules such as hypoxia inducible factors (HIFs) and VEGF, the modulation of gene expression (e.g. carbonic anhydrase IX), increased proto-oncogene levels, activation of nuclear factors and accumulation of other proteins (e.g. TP53) although progressing, is yet to be defined.15,16
Thus, it is of clinical interest to understand the levels of hypoxia and numbers of hypoxic cell populations in tumours, particularly those resistant to radiation and chemotherapy. In doing so clinicians and researchers may formulate more accurate prognostic information and develop treatments targeting hypoxic cells. Renal cell carcinoma (RCC) is a tumour resistant to radiation and chemotherapy that is yet to have its oxygen status investigated.
Although the “gold standard” of oxygen tension measurement is the Polarographic Oxygen Sensor (POS or Eppendorf pO2 histograph), non-invasive means of measuring oxygen status via imaging, immunohistochemistry or serum tumour markers are more practical. As highlighted by Menon and Fraker, it is imperative that reliable, globally usable, and technically simplistic methods be developed to yield a consistent, comprehensive, and reliable profile of tumour oxygenation. Until newer more reliable techniques are developed, existing independent techniques or appropriate combinations of techniques should be optimized and validated using known endpoints in tumour oxygenation status and/or treatment outcomes.17
Hanahan and Weinberg 18 surmised that the field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them- a focus that has produced an extraordinary body of knowledge. Looking forward in time, they believe that progress in cancer research would come from regarding tumours as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types (endothelial cells, immune cells, fibroblasts) to serve as active collaborators in their neoplastic agenda. The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.18
Essentially, the background outlined here not only highlights the core aim of this thesis: to better understand the oxygen status of renal cell carcinoma and the relationship of this to angiogenesis so that better targeted therapies may be pursued in the future; but it also places this research in the context of the future proposed by Hanahan and Weinberg,18 by clearly focusing on collaborators in the neoplastic agenda, rather than just tumour cells themselves, to better understand RCC.
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Turner, Kevin. "The regulation of angiogenesis in renal carcinoma". Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394017.
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Morrissey, Catherine. "The molecular pathology of renal cell carcinoma". Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420407.
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Laird, Alexander. "Molecular prognostic markers in renal cell carcinoma". Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/17873.
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Renal cell carcinoma (RCC) is the most deadly of urological malignancies. While metastatic disease affects one third of patients at diagnosis, a further third of patients who undergo extirpative surgery with curative intent subsequently develop metastatic disease. Inconsistency in the clinical course ensures predicting subsequent metastasis is notoriously difficult, despite the routine use of prognostic clinico-pathological parameters in risk stratification. With greater understanding of pathways involved in disease pathogenesis, a number of biomarkers have been proposed to be of prognostic significance; however there are currently no molecular prognostic markers in clinical use. Genetic intra-tumoural heterogeneity (genetic ITH) has been described in clear cell RCC (ccRCC) and may limit the clinical translation of biomarkers. There has been no assessment of ITH at other molecular levels. The aim of this work was to define and compare proteomic, transcriptomic and DNA methylation ITH in ccRCC, and identify potential prognostic biomarkers. Using reverse phase protein arrays to study protein expression in multiple spatially separate regions of primary and metastatic ccRCC, proteomic ITH was demonstrated for the first time. Interestingly there was no significant difference in proteomic ITH in metastatic ccRCC tumour deposits compared to primary tumours. However, on analysis of differential protein expression between primary and metastatic ccRCC tissue using a tissue microarray and automated analysis of immunofluorescence, there was significantly greater expression of Ki67, p53, VEGFR1, SLUG and SNAIL in the metastases compared to the primary tumours. Subsequent profiling of gene expression and DNA methylation in multiple areas of the same primary tumours confirmed transcriptomic and methylomic ITH. On comparison of this multimolecular ITH, significantly greater proteomic ITH was seen compared to gene expression and DNA promoter methylation heterogeneity. Recent evidence suggests DNA methylation may be prognostically important in RCC and given the lower methylomic ITH in ccRCC, the identification of prognostic DNA methylation changes in ccRCC were pursued using the Infinium HumanMethylation450K Beadchip. Following development of an analysis pipeline, identification and validation of prognostic differentially methylated regions (DMR) was performed on an experimental cohort and published dataset respectively. Five DMRs, which were associated with disease recurrence in ccRCC, were identified. NEFM gene promoter methylation was the only DMR associated with cancer specific survival, independent of TNM stage and nuclear grade on multivariate analysis, which was confirmed on a third independent published dataset. This thesis therefore demonstrates multi-molecular ITH in ccRCC for the first time. Despite this, NEFM promoter methylation may be a useful independent prognostic marker of cancer specific survival.
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Scherr, Adolfo José de Oliveira 1979. "Terapia adjuvante pós tratamento cirúrgico no carcinoma renal : revisão sistemática da literatura com meta-análise". [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313866.
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Orientadores: André Deeke Sasse, Carmen Silvia Passos LimaDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Pacientes com câncer renal localmente avançado são de alto risco para recidiva após ressecção cirúrgica com intuito curativo. Muitos estudos têm sido realizados na tentativa de se descobrir alguma intervenção adjuvante capaz de reduzir este risco. No entanto, até o momento não foi observado nenhum benefício clínico nas intervenções avaliadas nos estudos. O objetivo desta revisão sistemática foi avaliar o exato papel da terapia adjuvante nos pacientes com câncer renal localmente avançado após cirurgia. Foram selecionados estudos clínicos randomizados que comparavam terapia adjuvante (quimioterapia, vacinas, imunoterapia, bioquimioterapia, hormonioterapia) versus nenhum tratamento ativo após cirurgia em pacientes com câncer renal. Os desfechos clínicos avaliados foram sobrevida global (SG), sobrevida livre de doença (SLD) e toxicidades severas. A análise dos dados extraídos foi realizada no programa estatístico Review Manager 5.0 (RevMan 5; Cochrane Collaboration Software). As diferentes estratégias de tratamento adjuvante foram avaliadas em conjunto e separadamente. Dez estudos (2609 pacientes) foram incluídos. Terapia adjuvante não mostrou benefício em termos de SG (HR 1.07; IC95% 0.89 a 1.28; P = 0.48 I2= 0%) ou SLD (HR 0,96; IC95% 0.83 a 1.10; P =0.52 I2= 36%) quando comparado a nenhum tratamento adjuvante. Nenhuma análise de subgrupo (imunoterapia,vacinas, bioquimioterapia) atingiu resultado relevante. A avaliação de toxicidades mostrou uma frequencia significativamente maior de eventos adversos graves no grupo tratado (OR 73.86; IC 95% 28,32 a 192,62; P < 0,00001 I2 = 37%). O resultado final da análise não forneceu nenhum suporte para a hipótese de que os agentes estudados forneçam qualquer benefício clínico para pacientes com câncer renal no contexto adjuvante, além de aumentarem o risco de efeitos adversos graves. Estudos clínicos randomizados que avaliam o uso de terapias-alvo no cenário adjuvante estão em andamento e podem abrir uma nova fronteira terapêutica para estes pacientes. Até que os resultados destes estudos sejam conhecidos e se mostrem efetivos, nenhuma terapia adjuvante pode ser recomendada para pacientes com câncer de células renais após ressecção cirúrgica curativa
Abstract: Many adjuvant trials have been undertaken in an attempt to reduce the risk of recurrence among patients who undergo surgical resection for locally advanced renal cancer. However, no clear benefit has been identified to date. This systematic review was conducted to examine the exact role of adjuvant therapy in renal cancer setting. Randomized controlled trials were searched comparing adjuvant therapy (chemotherapy, vaccine, immunotherapy, biochemotherapy, hormone therapy) versus no active treatment after surgery among renal cell cancer patients. Clinical outcomes were overall survival (OS), disease-free survival (DFS), and severe toxicities. The extracted data was performed using the statistical software Review Manager 5.0 (RevMan 5; Cochrane Collaboration Software).Different strategies of adjuvant treatment were evaluated together and separately. Ten studies (2,609 patients) were included. Adjuvant therapy provided no benefits in terms of OS (HR 1.07; 95%CI 0.89 to 1.28; P = 0.48 I2 = 0%) or DFS (HR 0,96; CI 95% 0.83 to 1.10; P =0.52 I2 = 36%) when compared to no treatment. No subgroup analysis (immunotherapy, vaccines, biochemotherapy) had relevant results. Toxicity evaluation depicted a significantly higher frequency of serious adverse events in the adjuvant group(OR 73.86; CI 95% 28,32to 192,62; P < 0,00001 I2 = 37%).The result of the analysis provided no support for the hypothesis that the agents studied provide any clinical benefit for renal cancer patients in the adjuvant setting, in addition to increasing the risk of serious adverse events. Randomized trials are underway to test targeted therapies in adjuvant setting, which might open a new therapeutic frontier for these patients. Until these trials yield results, no adjuvant therapy can be recommended for patients who undergo surgical curative resection for renal cell cancer
Mestrado
Clinica Medica
Mestre em Clinica Medica
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Exertier, Prisca. "Rôle des kinésines mitotiques Eg5 et MKLP-2 dans l’angiogenèse physiologique et pathologique". Thesis, Bordeaux 1, 2012. http://www.theses.fr/2012BOR14621/document.
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Rôle des kinésines mitotiques Eg5 et MKLP-2 dans l’angiogenèse physiologique etpathologique.L’angiogenèse est un phénomène biologique complexe qui correspond à la formation de nouveauxvaisseaux à partir de vaisseaux préexistants. Ce processus essentiel est régulé par des nombreuxfacteurs, dont le plus puissant est le facteur de croissance de l’endothélium vasculaire (VEGF).Des inhibiteurs du VEGF sont actuellement utilisés dans le traitement de nombreux cancerssolides. Leur efficacité est constatée dans plusieurs études mais des résistances contre cesmolécules sont fréquemment observées. Afin d’identifier de nouvelles cibles thérapeutiques dansla voie de signalisation de VEGF, nous avons utilisé le modèle de la membrane chorioallantoïdienne(CAM) de l’embryon de poulet. Les CAM traitées au VEGF pendant 24hdéveloppent de nombreux vaisseaux. Ces tissus ont été isolés pour effectuer une analysetranscriptomique. En dehors des gènes endothéliaux déjà connus pour être régulés par le VEGF,de nouveaux gènes ont été identifiés. Nous avons focalisé notre recherche sur des gènes codantpour les kinésines mitotiques KIF11/Eg5 et KIF20A/MKLP-2 qui ont été fortement induites.Nous avons démontré qu’Eg5 et MKLP-2 sont fortement exprimées au niveau de l’endothéliumdans des tissus sains et dans des cancers solides. Des inhibiteurs chimiques spécifiques d’Eg5(dimethylenastron et ispinesib mesylate) et MKLP-2 (paprotrain) bloquent les étapes clés de laformation des vaisseaux sanguins (prolifération, adhérence et migration des cellules endothéliales),la prolifération des cellules tumorales ainsi que la formation de néo-vaisseaux dans des culturesd’anneaux aortiques. De plus, sur la CAM et chez la souris, l’inhibition de cette même kinésinediminue significativement la croissance et la vascularisation des modèles tumoraux utilisés lors dece projet (le glioblastome et le carcinome rénal). En conclusion, Eg5 et MKLP-2 pourraient descibles potentielles dans les thérapies anti-angiogéniques.Mots clés : Eg5, MKLP-2, angiogenèse, kinésine, ispinesib, dimethylenastron, glioblastome,cancer rénalRole of the mitotic kinesins Eg5 and MKLP-2 in physiologic and pathologic angiogenesis.Angiogenesis is a complex biological phenomenon which corresponds to the formation of newblood vessels from pre-existing vessels. This process is regulated by a plethora of differentmolecules with vascular endothelial growth factor (VEGF) being one of the most important ones.VEGF inhibitors are currently used in the treatment of numerous solid cancers. Even though theefficacy of such treatment is prouven by numerous studies, resistance to anti-angiogenic therapy isa common feature. To identify new therapeutic targets downstream of VEGF, we modelized itsaction on the chick chorioallantoic membrane (CAM). VEGF-treated CAMs develop a densevascular network 24h after application. We used chick microarrays to monitor global geneexpression changes in VEGF-induced CAMs. Beside a consistent number of genes alreadydescribed to be regulated by VEGF, numerous unknown genes have been identified. We havefocused our work on the characterization of Eg5/KIF11 and MKLP-2/KIF20A, members of thekinesin family, both strongly upregulated by VEGF.We demonstrated that Eg5 and MKLP-2 are strongly expressed by blood vessels in normal andcancer tissue sections. KIF20A is involved in the proliferation and migration of endothelial cellsin vitro. We showed that chemical inhibitors specific for KIF11/Eg5 (dimethylenastron andispinesib mesylate) affect key steps in the formation of blood vessels (proliferation, adhesion andmigration of endothelial cells) and proliferation of tumor cells (glioma and renal cancer).Furthermore, in experimental glioblastoma and renal cell carcinoma models (CAM and orthotopicimplantation in mice), anti-Eg5 treatment strongly reduces tumor angiogenesis and growth. Inconclusion, Eg5 and MKLP-2 could be potential targets in anti-angiogenic therapies.Keywords: Eg5, MKLP-2, angiogenesis, kinesin, ispinesib, dimethylenastron, glioblastoma, renalcell cancer
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Suzigan, Sueli. "Angiogênese em neoplasias epiteliais corticais renais: estudo de 41 casos". Faculdade de Medicina de São José do Rio Preto, 2002. http://bdtd.famerp.br/handle/tede/43.
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Previous issue date: 2002-05-03Introduction. Tumor growth and metastasis depend greatly on angiogenesis. There are several angiogenic growth factors able to induce new vessels in renal tumors, but the most important are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF). The aim of our study was to investigate expression of b-FGF and to quantify microvessel density (MVD) in oncocytomas and renal cell carcinomas (RCCs) and to relate these parameters of tumor vascularity to other clinicopathological features. Material and Methods. b-FGF and CD31 immunostaining were performed on formalin-fixed paraffin-embedded archival tissues from Larpac Laboratories files, including 36 RCCs (10 conventional, 10 papillary, 8 sarcomatoid, and 8 chromophobe) and 5 oncocytomas. Angiogenesis was quantified microscopically by two independent observers. Results. b-FGF was positive in all five oncocytomas and only in seven of 36 RCCs: 5 of conventional type, 1 papillary, and 1 chromophobe. All sarcomatoid carcinomas were negative. The expression of b-FGF was not related to tumor size, grade, stage, or short survival in either group. MVD mean value was 124.16 ± 50.1 in oncocytomas and 91.54 ± 52.4 in RCCs. The pattern of vascularization observed in oncocytomas was characterized by a fine vascular network around groups of tumor cells although in RCCs the microvessels tended to be more disorganized. When analyzing only carcinomas, patients who died within 12 months after the diagnosis had a tumoral MVD mean value significantly higher (124.12 ± 75.2) than that observed in patients who were still alive one year after diagnosis (80.34 ± 37.8). ix Conclusion. We demonstrate that b-FGF is expressed more often in oncocytomas than in RCCs but MVD is similar in both groups of tumors. The high expression of b-FGF in oncocytomas may reflect the peculiar pattern of vascularization of these tumors. High MVD in rapidly lethal RCCs is an indication that angiogenesis may be correlated with the degree of malignancy of these tumors.
O desenvolvimento dos tumores e das suas metastases dependem em grande parte da angiogenese tumoral. Existem varios fatores de crescimento capazes de induzir à neoformação vascular nas neoplasias renais, porém, os mais importantes são o fator de crescimento do entotélio vascular (vegf) e o fator de crescimento fibroblástico básico (bfgf). O objetivo deste estudo foi o de investigar a expressão do b-fgf e a densidade microvascular (dmv) nos oncocitomas e nos carcinomas de células renais (ccrs) e correlacionar estes parâmetros da vascularização tumoral com outros ascpectos clínico-patológicos. Material e métodos. O estudo imunohidtoquímico para o b-fgf e o cd31 (densidade microvascular) foi realizado em material fixado em formalina e incluído em parafina de 36 casos de ccrs (10 convencionais, 10 papilíferos, 8 sarcomatóides e 8 cromófobos) e 5 oncocitomas, oriundos de exames anátomo-patológicos por dois observadpres independentes. Resultados. Nota de Resumo Foi encontrada positividade para o b-fgf em todos os 5 casos de oncocitomas e em 7 dos 36 casos de ccrs: 5 do tipo convencional, um papilífero, e um cromófobo. Todos os carcinomas sarcomatóides mostraram-se negativos. A expressão tumoral do b-fgf não apresentou correlação com tamanho tumora, grau histológico, estadio patológico, ou sobrevida a curto prazo em nenhum dos grupos. O valor médio da dvm foi de 124,16 +/- 50,1 nos oncocitomas e de 91,54 +/- 52,4 nos ccrs. O padrão de vascularização observado nos oncocitomas era caracterizado por um delicado leito vascular envolvendo grupos de celulas tumorais, enquanto que nos ccrs a microvascularização se apresentou de forma mais organizada. Entre os carcinomas, os tumores que se mostraram letais nos 12 primeiros meses após o diagnóstico, apresentaram um ídice angiogênico significativamente maior (124,12 +/- 75,2) em relação aos pacientes que ainda permaneciam vivos um ano após o diagnóstico (80,34 +/- 37,8). Conclusão. Demostramos que o b-fgf está expresso mais freqüentemente nos oncocitomas do que nos ccrs. Nota de Resumo Apesar de as dmv ser semelhante em ambos os grupos tumorais, observou-se um padrão de vascularização característico nos oncocitomas. Uma dvm mais elevada nos ccrs, rapidamente letais é indicativo de que a angiogenese possa estar correlacionada com grau de malignidade destes tumores.
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Lidgren, Anders. "Hypoxia inducible factor-1α in renal cell carcinoma". Doctoral thesis, Umeå universitet, Kirurgisk och perioperativ vetenskap, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1462.
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Hypoxia Inducible Factor-1α in Renal Cell Carcinoma Departments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden Background: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all human cancers. A distinguished feature of RCC is vascularisation and among the three dominating RCC types conventional RCC (cRCC) generally is more vascularised than papillary RCC (pRCC) and chromophobe RCC (chRCC). Angiogenesis is a critical step in tumour progression controlled by a balance involving molecules that have positive and negative regulatory activity. A balance distorted by metabolic stress such as hypoxia, acidosis, and inflammation. Hypoxia-Inducible Factor 1α (HIF-1α) is a key transcription factor in angiogenesis and tumour progression, targeting more than a 100 genes involved in vascular growth and regulation, iron metabolism and erythropoesis, collagen matrix formation, regulation of extracellular pH, glucose uptake and metabolism, proliferation, apoptosis, differentiation, and cell viability. Methods: Tumour tissue and corresponding kidney cortex from nephrectomised RCC patients was used in order to characterize HIF-1α expression and one of its target genes, Glucose Transporter 1 (GLUT-1). All tumour samples were thoroughly described regarding tumour type, TNM stage, nuclear grade, tumour size, vein invasion, and patient survival. Utilizing RT-PCR, Westen Blot and Tissue micro array (TMA) we studied HIF-1α mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters. Results: Using Western Blot, HIF-1α protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1α was an independent prognostic factor for favourable prognosis. TMA is a useful method to analyze HIF-1α protein expression in RCC. HIF-1α levels were significantly lower in locally aggressive cRCC and patients with high levels of HIF-1 tended to have a better prognosis. GLUT-1 levels were higher in cRCC than in other RCC types and for cRCC a correlation to HIF-1α was seen. HIF-1α mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1α protein expression and mRNA levels was observed. Summary: These results demonstrate a discrepancy between RCC types, highlighting the need to separately evaluate biological events in different RCC types. Overexpression of HIF-1α protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.
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Menezes, Ravi. "Physical activity and risk of renal cell carcinoma". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0020/MQ53351.pdf.
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Jacobsen, Jan. "Vascular endothelial growth factor in renal cell carcinoma". Doctoral thesis, Umeå : Kirurgisk och perioperativ vetenskap, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-713.
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Alimov, Andrei. "Molecular genetic aspects of renal cell carcinoma development /". Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-559-X/.
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Lelarge, Virginie. "Rôle de la lysyl oxidase-like-2 endothéliale et tumorale au cours de l’angiogenèse dans le carcinome du rein à cellules claires". Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066421/document.
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L’angiogenèse est un processus majeur intervenant au cours du remodelage du microenvironnement tumoral, induit par l’hypoxie et le VEGF. La lysyl oxydase like-2 (LOXL2) appartient à la famille des lysyl oxydases, impliquée dans le pontage de constituants matriciels. Notre équipe a montré que l’induction de LOXL2 par l’hypoxie conduit à sa sécrétion par les cellules endothéliales et son accumulation dans la matrice extracellulaire endothéliale. Nous avons montré que LOXL2 joue un rôle dans l’angiogenèse au cours du développement. Des études ont montré que LOXL2 est surexprimée dans de nombreux cancers et que l’inhibition de LOXL2 extracellulaire empêche la formation d’un microenvironnement tumoral. Mon travail de thèse a porté sur l’étude du rôle de LOXL2, exprimée par les cellules endothéliales et tumorales, au cours de l’angiogenèse dans le carcinome du rein à cellules claires (ccRCC) humain. Nous avons montré que LOXL2 est exprimée à la fois par les cellules stromales et tumorales dans le ccRCC humain, mais aussi que LOXL2 pourrait jouer un rôle spécifique en fonction de son origine cellulaire dans ces tumeurs. L’étude de la contribution de LOXL2 endothéliale nous a permis de démontrer que LOXL2 promeut l’angiogenèse in vitro et in vivo dans le ccRCC, avec une implication partielle de son activité catalytique dans ce processus. Nous avons montré que LOXL2 sécrétée par les cellules tumorales stimule l’angiogenèse in vitro et in vivo, avec la participation de son activité catalytique, notamment en modulant la prolifération des cellules endothéliales. LOXL2 endothéliale et tumorale promeuvent l’angiogenèse dans le ccRCC, dépendamment ou non de son activité catalytiqueAngiogenesis is a major process in microenvironment remodeling which is mainly induced by hypoxia and VEGF. Lysyl oxidase like-2 (LOXL2) belongs to lysyl oxidase family involved in extracellular matrix crosslinking. Our team previously described that LOXL2 is a hypoxia-target, which is secreted by endothelial cells and accumulated into endothelial extracellular matrix. We also demonstrated that LOXL2 stimulates developmental angiogenesis. Moreover, several studies showed that LOXL2 is overexpressed in many cancers and inhibition of extracellular LOXL2 impedes the formation of a tumor microenvironment. My PhD work focused on the contribution of LOXL2 secreted by stromal cells (endothelial cells and cancer associated fibroblasts) and tumor cells in clear cell renal cell carcinoma (ccRCC) angiogenesis. ccRCC is a highly vascularized and metastatic tumor. We showed that LOXL2 is expressed both by stromal and tumor cells in ccRCC and might play a specific role depending on its cellular origin in these tumors. Then we demonstrated that LOXL2 secreted by endothelial cells promotes angiogenesis in vitro and in vivo with a partial contribution of its catalytic activity. We also demonstrated that LOXL2 secreted by tumor cells stimulates angiogenesis in vitro and in vivo and that LOXL2 catalytic activity is involved in this process, notably modulating endothelial cells proliferation. Moreover, we showed that endothelial and tumor LOXL2 regulate several signaling pathways implicated in different steps of the angiogenic process.Both tumor and endothelial LOXL2 are involved in angiogenesis of ccRCC, in a dependent or independent catalytic activity manner
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Spandidos, Athanasia. "Proteomic methods applied to renal cell carcinomas". Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620561.
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Faria, Denise Heidrich. "Efeitos citotóxicos do teniposide, um derivado semi-sintético das epipodofilotoxinas, sobre linhagens celulares de carcinoma renal humano". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2000. http://hdl.handle.net/10183/2913.
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O câncer renal corresponde a aproximadamente 3% dos tumores malignos do adulto, sendo a terceira malignidade urológica mais comum. Os tratamentos sistêmicos disponíveis para pacientes portadores de carcinoma renal avançado são, via de regra, pouco eficazes e sem um impacto definido na sobrevida. Portanto, torna-se imperioso que novos agentes e/ou estratégias terapêuticas para esta enfermidade sejam desenvolvidas. O derivado das epipodolofilotoxinas, etoposide, tem sido utilizado com sucesso no tratamento de vários tipos de tumores sólidos e hematológicos. Este agente exerce a sua ação antitumoral através da inibição da enzima nuclear topoisomerase II. Estudos recentes demonstraram que o efeito citotóxico in vitro deste agente é bem mais pronunciado quando as linhagens tumorais são expostas à droga por um tempo mais prolongado. Isto vem sendo confirmado em estudos clínicos, nos quais foi documentado um aumento significativo no percentual de respostas tumorais objetivas em pacientes com câncer avançado tratados com etoposide em doses repetidas diárias de forma continuada, comparativamente a pacientes que receberam pulsos de doses altas da droga a intervalos mais longos. Infelizmente, estudos iniciais com etoposide não revelaram uma atividade antitumoral significativa em pacientes com câncer renal avançado. Por esta razão, os estudos preliminares explorando o potencial terapêutico de seu análogo teniposide nesta doença também não receberam a devida atenção na literatura. Entretanto, este análogo possui potenciais vantagens terapêuticas em relação ao etoposide, uma vez que apresenta um tempo de retenção intracelular mais prolongado em linhagens de tumores sólidos in vitro. Estas observações nos estimularam a reconsiderar o estudo do potencial citotóxico do teniposide em modelos experimentais de câncer renal avançado. Nesta dissertação, foram estudados vários protocolos de administração de teniposide em linhagens de câncer renal humano, uma vez que esta neoplasia carece de drogas ativas disponíveis no armamentário terapêutico. Foram utilizadas as linhagens celulares RXF-393, A-498 e TK-10, as quais foram incubadas com teniposide em concentrações pré-determinadas e tempos de incubação variáveis. Além disto, foram feitos experimentos em que protocolos de administração de teniposide como agente único foram comparados a protocolos em que o mesmo foi combinado com agentes que bloqueiam a ação da glicoproteína P, responsável pelo efluxo ativo da droga do interior da célula tumoral. Além disso, foram também estudados protocolos incluindo a associação de teniposide com agentes que interferem com a síntese do DNA. Para os estudos de avaliação de citotoxicidade dos agentes quimioterápicos, os mesmos foram pré-incubados por 24 h na ausência ou presença do inibidor da DNA polimerase α afidicolina glicinada (0,2 µM) ou do inibidor da ribonucleotídeo redutase hidroxiuréia (200 µM) e após incubados por diferentes tempos de exposição com diluições seriadas de teniposide. Os efeitos citotóxicos foram avaliados através do método colorimétrico com sulforodamina B (SRB). Os protocolos de exposição prolongada das células ao teniposide mostraram um aumento significativo na sua citotoxicidade nas linhagens RXF-393, A-498 e TK-10, sugerindo que a citotoxicidade do teniposide é dependente de tempo de administração. Neste sentido, uma maior taxa de dano no DNA foi observada nas células expostas ao teniposide por tempos de administração mais prolongados. Curiosamente, os diferentes tempos de exposição ao teniposide não influenciaram de forma clara na formação de complexos DNA-topoisomerase II, nem nas medidas da atividade desta enzima. O uso concomitante de agentes moduladores da glicoproteína P como o verapamil, a ciclosporina A e o tamoxifeno não produziu potencialização do efeito antiproliferativo do teniposide. Por sua vez, os tratamentos com agentes que interferem na síntese de DNA, como a afidicolina glicinada ou a hidroxiuréia, potencializaram a citotoxicidade do teniposide em todas as linhagens estudadas, seguindo as características intrínsecas de cada linhagem. Em conclusão, os resultados apresentados nesta dissertação sugerem que o teniposide apresenta um maior efeito citotóxico em protocolos de administração prolongada em combinação com agentes inibidores da síntese de DNA. Frente a estes resultados iniciais, o teniposide será testado nos protocolos de administração acima mencionados em um painel contendo um maior número de linhagens tumorais in vitro. Uma vez confirmadas as observações acima descritas, serão iniciados estudos em modelos tumorais in vivo. Estes estudos servirão de base nas decisões quanto à reavaliação clínica do teniposide em ensaios de fase I em pacientes com neoplasias avançadas refratárias.
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Lee, Wing-sang y 李榮生. "The prognostic significance of DJ-1 in patients with renal cell carcinoma of clear cell type". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42925095.
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Lee, Wing-sang. "The prognostic significance of DJ-1 in patients with renal cell carcinoma of clear cell type". Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B42925095.
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Handa, Kiren. "Dietary patterns and the risk of renal cell carcinoma". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq45404.pdf.
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Chagnon, Fanny. "A dendritic cell vaccine for murine renal cell carcinoma". Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=19400.
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Renal Cell Carcinoma (RCC) has a very high rate of mortality since it does not respond to conventional therapies such as chemotherapy and radiation therapy. Furthermore, in the majority of cases, metastases are already present at the time of diagnosis. The objective of our study is to develop a noval treatment for RCC, using a dendritic cell (DC) vaccine. An animal model of RCC, RENCA, was used to develop the vaccine.
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Young, Alison Claire. "Significance of VHL changes in sporadic renal cell carcinoma". Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581867.
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The von Hippel-Lindau (VHL) tumour suppressor gene is central to the development of sporadic conventional clear cell renal cell carcinoma (ccRCC). The role VHL plays as part of a ubiquitin ligase targeting HIF-a for proteasomal degradation underpins many changes seen in ccRCC but the importance of other VHL functions and the clinical significance of specific genetic/epigenetic changes are not clear. Genetic and epigenetic analysis of VHL gene in 86 tumours from patients with ccRCC was carried out, adding to the 96 tumours already analysed in an ongoing study within the group. Overall, loss of heterozygosity (LOH) was found in 89.2%, mutation in 74.6% and methylation in 30.9%. Evidence of biallelic inactivation (LOH and mutation or methylation alone) was "found in 84.9% whilst no involvement of VHL was found in only 4% of samples, consistent with VHL involvement in the majority of conventional ccRCCs. Associations between mutation and gender (p=0.0189), LOH and grade (p=0.0097) and methylation and grade (p=0.0159) were found with a possible association between methylation and gender (p=0.0835). There was a suggestion of LOH and mutation correlating with a better overall survival compared to patients with no VHL involvement and a similar relationship was seen with methylation; however sample numbers were small in the no VHL group and neither reached statistical significance.
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Chen, Dong. "Identification of new prognostic markers in renal cell carcinoma". Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-168397.
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The clinical course of renal cell carcinoma (RCC) shows a high variability. Prognostic markers are essential to enable an individualized therapeutic strategy. The objective of this study was the identification of novel independent prognostic markers and potential therapeutic targets in RCC. The focus was on genes involved in epithelial-mesenchymal transition (EMT) and cancer stem cell biology.
EMT enhances tumor cell motility and hence plays a critical role in invasion and metastasis in various carcinomas. A set of transcription factors acts as master regulators of EMT. Whether EMT is important for tumor progression in clear cell renal cell carcinoma (RCC) is unknown. Therefore, EMT-related genes were selected from the literature, and their role and prognostic relevance in RCC were analyzed. The known cancer stem cell marker CXCR4 and the associated TPBG gene were also analyzed in this project. Additionally, a novel filter strategy was used to analyze RCC oligonucleotide microarray data for identification of potential prognostic markers: genes with increasing expression during tumor progression (normal kidney < primary tumor < metastases) were selected for outcome analysis because they could be crucial for RCC biology.
Expression of 46 EMT-related genes was analyzed using oligonucleotide microarrays and gene set enrichment analysis (GSEA) in tissue samples from normal kidney and G1 and G3 primary RCC, 14 samples each. Expression of selected EMT genes was validated by real-time polymerase chain reaction (PCR) in normal kidney, primary RCC and metastases in an independent cohort of 112 patients and then combined with follow-up data for survival analysis. Immunohistochemistry, Western blot and flow cytometry were performed to further examine the expression of CXCR4 and co-expression of CXCR4 and TPBG on the surface of RCC cells. GSEA and dChip software were used for microarray data analysis.
The EMT gene set was preferentially expressed in primary tumors compared to normal tissue (false discovery rate FDR=0.01), but no difference between G1 and G3 tumors was found. Quantitative RT-PCR showed down-regulation of critical EMT genes like CDH2 and ZEB1 in metastases which suggests reversal of EMT during metastasis. Kaplan-Meier analysis demonstrated a significant better outcome for patients with low CXCR4, vimentin, fibronectin and TWIST1 mRNA levels. Multivariate analysis revealed that CXCR4 and vimentin up-regulation represent independent prognostic markers for poor cancer-specific survival of RCC patients. The microarray approach using filtering and further RT-PCR validation of progression-associated genes revealed that ATAD2, TET3, HELLS and TOP2A are independent and previously unknown predictors of poor outcome in RCC patients.
Taken together, this study provides strong evidence that EMT occurs in RCC. Modulation of EMT in RCC, therefore, might represent a future therapeutic option. Expression levels of a number of EMT-related genes (like the genes encoding the cancer stem cell marker CXCR4 and vimentin) could be identified as independent prognostic markers. Using a novel filtering approach on array data, additional novel prognostic markers could be identified. These findings contribute to a better risk stratification of RCC patients that can support an individualized and optimized therapeutic strategy.Der klinische Verlauf des Nierenzellkarzinoms (RCC) zeigt eine hohe Variabilität. Prognostische Marker sind unerlässlich, um eine individuelle Therapiestrategie zu ermöglichen. Das Ziel dieser Studie war die Identifizierung neuer unabhängiger prognostischer Marker und potentieller therapeutischer Targets beim RCC. Der Schwerpunkt lag auf Genen, die bei der Epithelial-Mesenchymalen Transition (EMT) und Tumorstammzellenbiologie beteiligt sind. EMT steigert die Beweglichkeit von Tumorzellen und spielt eine entscheidende Rolle bei der Invasion und Metastasierung bei verschiedenen Karzinomen. Eine Reihe von Transkriptionsfaktoren fungiert als die Hauptregulatoren von EMT. Ob EMT wichtig ist für die Tumorprogression beim klarzelligen Nierenzellkarzinom (RCC), ist unbekannt. Daher wurden EMT-Gene aus der Literatur ausgewählt und ihre Rolle und prognostische Relevanz bei RCC wurden analysiert. Der bekannte Tumorstammzellmarker CXCR4 und das damit assoziierte TPBG-Gen wurden auch in diesem Projekt analysiert. Zusätzlich wurde eine neuartige Filter-Strategie bei RCC-Microarray-Daten verwendet, um mögliche prognostische Marker zu identifizieren: Gene mit zunehmender Expression während der Tumorprogression (normale Niere < Primärtumor < Metastasen) wurden für die Outcome-Analyse ausgewählt, weil sie entscheidend für die RCC-Biologie sein könnten. Die Expression von 46 EMT-Genen wurde mit Oligonukleotid-Microarrays und Gene Set Enrichment Analysis (GSEA) an Gewebeproben von normaler Niere und G1 und G3 Primärtumoren (jeweils 14 Proben) analysiert. Die Expression von ausgewählten EMT-Genen wurde mittels RT-PCR in normaler Niere, primärem RCC und Metastasen an einer unabhängigen Kohorte von 112 Patienten validiert und dann mit Follow-up-Daten für die Survivalanalyse kombiniert. Immunhistochemie, Western Blot und Durchflusszytometrie wurden durchgeführt, um die Expression von CXCR4 und die Co-Expression von CXCR4 und TPBG auf der Oberfläche von RCC-Zellen weiter zu untersuchen. Die Software GSEA und dChip wurde für die Analyse der Microarray-Daten verwendet. Das EMT-gene set wurde bevorzugt in Primärtumoren exprimiert, verglichen mit dem Normalgewebe (false discovery rate FDR = 0,01), es wurde aber kein Unterschied zwischen G1- und G3-Tumoren gefunden. Quantitative RT-PCR zeigte Herunterregulation von kritischen EMT-Genen wie CDH2 und ZEB1 in Metastasen, was eine Umkehrung der EMT während der Metastasierung vermuten lässt. Die Kaplan-Meier-Analyse zeigte signifikant bessere Ergebnisse für die Patienten mit niedriger CXCR4, Vimentin, Fibronectin und TWIST1 mRNA Expression. Die multivariate Analyse zeigte, dass eine Hochregulierung von CXCR4 und Vimentin unabhängige prognostischer Marker darstellen für ein schlechtes tumorspezifisches Überleben von RCC-Patienten. Der Microarray-Ansatz mit Filtern und weiterer RT-PCR-Validierung der Progressions-assoziierten Gene ergab, dass ATAD2, TET3, HELLS und TOP2A unabhängige und bisher unbekannte Prädiktoren für schlechtes Outcome bei RCC-Patienten sind. Insgesamt liefert diese Studie deutliche Hinweise, dass EMT bei RCC vorkommt. Die Modulation von EMT bei RCC könnte daher eine zukünftige therapeutische Option darstellen. Die Expressionsstärke einiger EMT-Gene (z.B. die Gene für den Tumorstammzellmarker CXCR4 und Vimentin) konnten als unabhängige prognostische Marker identifiziert werden. Mit Hilfe eines neuartigen Filter-Ansatzes bei Array-Daten konnten zusätzliche neue prognostische Marker identifiziert werden. Diese Ergebnisse tragen bei zu einer besseren Risikostratifizierung von RCC-Patienten, was eine individualisierte und optimierte Therapiestrategie unterstützen kann.
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Volk, Andreas, Stephan Kersting, Ralf Konopke, Frank Dobrowolski, Stefan Franzen, Detlef Ockert, Robert Grützmann, Hans Detlev Saeger y Hendrik Bergert. "Surgical Therapy of Intrapancreatic Metastasis from Renal Cell Carcinoma". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136489.
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Background: Pancreatic métastases from renal cell carcinoma (RCC) are clinically rare but highly resectable. The aim of this article is to identify patients who profit from pancreatic resection of RCC despite the invasiveness of the surgery. Methods: Between January 1996 and December 2007, data from 744 patients were collected in a prospective pancreatic surgery database, and patients with metastasis into the pancreas from RCC were identified. Results: Resective surgery was performed in 14 patients with metastasis to the pancreas from RCC. Most patients were clinically asymptomatic. The median interval between primary treatment of RCC and occurrence of pancreatic metastasis was 94 months (range 32–158). The morbidity rate was 42.8%. Patients with a metastasis size <2.5 cm had a much better survival after resection (100 months) than those with a metastasis size >2.5 cm (44 months). Moreover, the number of métastases predicts the survival after resection. Conclusions: In patients with pancreatic métastases from RCC who have only limited disease, complete resection of all lesions can be successfully performed with a low rate of complications. Thus, patients with a history of RCC should be monitored for more than 10 years after nephrectomy to detect recurrenceDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Fröhner, Michael, Andreas Manseck, Arndt Lossnitzer y Manfred P. Wirth. "Late Local and Pulmonary Recurrence of Renal Cell Carcinoma". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-133953.
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Locally recurrent renal cell carcinoma and multiple pulmonary metastases were successfully resected in a patient 20 years after nephrectomyDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Foster, Keith. "Molecular genetic analysis of non-familial renal cell carcinoma". Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289811.
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Jafri, Mariam. "Molecular characterisation of renal cell carcinoma and related disorders". Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6996/.
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Over the last two decades genetic advances have provided novel insights into the molecular basis of familial and sporadic cancers and provided the basis for the development of novel therapeutic approaches. For example, the identification of the gene for von Hippel Lindau disease provided seminal insights into its role in most clear cell renal carcinomas (RCC) and led to new treatments for RCC. In this thesis I investigated three related genetic aspects of neoplasia. Firstly, I analyzed the results of genetic testing for inherited phaeochromocytoma and investigated how clinical features could be used to stratify patients and improve the cost effectiveness of genetic testing. Secondly, I sought to identify novel causes of inherited neoplasia. Through exome sequencing of familial RCC kindreds, \(CDKN2B\) was identified as a novel familial RCC gene. The role of \(CDKN2B\) mutations in neoplasia was evaluated in familial and sporadic RCC and phaeochromocytoma. \(In\) \(vitro\) assays confirmed that germline \(CDKN2B\) mutations associated with inherited RCC caused an abrogation of tumour suppressor function. Finally, I explored how a gene-based strategy might be used to identify novel therapeutic strategies, Thus, using a siRNA library screen, in RCC cells with inactivated \(VHL\), potential candidate targets (e.g. \({PLK1/STK}\)-\(10\)) were identified for selectively decreasing the viability of RCC cells with inactivated \(VHL\).
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Qayyum, Tahir. "The role of Src kinase in renal cell carcinoma". Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5600/.
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Renal cancer is a malignancy which is not only increasing in incidence but there has also been an increase in mortality rates. There are various prognostic factors in renal cell cancer. We have demonstrated that some of these such as nuclear grading, tumour necrosis and systemic inflammatory response can be further refined to aid in prognosis but cannot be utilised at present to assess which would benefit from therapeutic agents when recurrence occurs. We investigated if SFK members are expressed in renal cancer. Eight SFK members were found to be expressed in renal cancer and were present to varying degrees. Furthermore, expression differed in organ confined disease and metastatic disease. Immunohistochemistry was employed to assess protein expression and activation of c-Src and SFK activity as well as the downstream marker FAK Y861. Analysis demonstrated that c-Src expression was associated with improved survival and expression of the downstream marker FAK Y861 was associated with poor survival and demonstrated a positive relationship with known prognostic factors. This would suggest that another SFK member was associated with poor survival. Dasatinib, a SFK inhibitor was utilised on renal cell lines, demonstrating a dose dependant reduction on cellular metabolic activity as well an increase in apoptotic rates. This would support that Dasatinib may be a useful therapeutic drug for RCC. Treatment with Dasatinib also demonstrated that expression of c-Src, SFK activity and FAK Y861 reduced in a dose dependant manner. It was necessary to further assess that another SFK member was responsible for poor prognosis and this was undertaken by silencing c-Src. Cellular metabolic activity rates increased following silencing c-Src and assessment of SFK activity (Src Y416) and FAK Y861 on cell pellets demonstrated no change suggesting that another SFK member is responsible for the phosphorylation of FAK Y861 and therefore responsible for poor survival. This would suggest that another SFK inhibitor and not c-Src inhibitors may play a role in the treatment of renal cell cancer and further work is required to ascertain which SFK member is responsible so that this can be targeted for treatment.
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Fröhner, Michael, Andreas Manseck, Arndt Lossnitzer y Manfred P. Wirth. "Late Local and Pulmonary Recurrence of Renal Cell Carcinoma". Karger, 1998. https://tud.qucosa.de/id/qucosa%3A27552.
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Locally recurrent renal cell carcinoma and multiple pulmonary metastases were successfully resected in a patient 20 years after nephrectomy.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Volk, Andreas, Stephan Kersting, Ralf Konopke, Frank Dobrowolski, Stefan Franzen, Detlef Ockert, Robert Grützmann, Hans Detlev Saeger y Hendrik Bergert. "Surgical Therapy of Intrapancreatic Metastasis from Renal Cell Carcinoma". Karger, 2009. https://tud.qucosa.de/id/qucosa%3A27708.
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Background: Pancreatic métastases from renal cell carcinoma (RCC) are clinically rare but highly resectable. The aim of this article is to identify patients who profit from pancreatic resection of RCC despite the invasiveness of the surgery. Methods: Between January 1996 and December 2007, data from 744 patients were collected in a prospective pancreatic surgery database, and patients with metastasis into the pancreas from RCC were identified. Results: Resective surgery was performed in 14 patients with metastasis to the pancreas from RCC. Most patients were clinically asymptomatic. The median interval between primary treatment of RCC and occurrence of pancreatic metastasis was 94 months (range 32–158). The morbidity rate was 42.8%. Patients with a metastasis size <2.5 cm had a much better survival after resection (100 months) than those with a metastasis size >2.5 cm (44 months). Moreover, the number of métastases predicts the survival after resection. Conclusions: In patients with pancreatic métastases from RCC who have only limited disease, complete resection of all lesions can be successfully performed with a low rate of complications. Thus, patients with a history of RCC should be monitored for more than 10 years after nephrectomy to detect recurrence.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Mastrandrea, Nicholas Joseph. "Pentoxifylline As An Adjuvant Treatment In Renal Cell Carcinoma". Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/337293.
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Cyclin D1, a proto-oncogene, is required for progression from the G1 phase into the S phase of the cell cycle. Over-expression of cyclin D1 causes an increase in cell cycle progression and cell proliferation, implicating it in a variety of cancers including renal cell carcinoma (RCC). The rodent RCC cell model, QTRRE, and human RCC cell models, ACHN, 786-O and Caki-2, exhibit elevated levels of cyclin D1. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, is an FDA-approved hemorheologic agent used to treat intermittent claudication, stemming from peripheral vascular diseases, as well as other diseases involving defective locoregional blood flow. Treatment of QTRRE, ACHN, 786-O and Caki-2 with PTX caused a time- (0-24 hrs) and dose- (0-1.0 mg/mL) dependent decrease of cyclin D1 protein and p-Rb levels in whole cell lysate as well as cytosolic and nuclear fractions, albeit, to different extents within the models. Concomitant with cyclin D1 and p-Rb decrease, enhanced G1 phase cell cycle arrest was observed in the RCC models. Mechanistic studies in these RCC cell models were carried out to determine PTXs mechanism of action with regard to cyclin D1 protein level decrease. RT-PCR analysis showed no significant changes in cyclin D1 mRNA copy number in time- (0-24 hrs) and dose- (0-1.0 mg/mL) dependent PTX treatments. However, such treatments caused decrease in p-4EBP1 (Ser65), p-4EBP1 (Thr70), and p-4EBP1 (Thr37/46). Because PTX's ability to decrease cyclin D1 protein was prevented in the presence of the proteasome inhibitor, MG-132, studies were performed to determine whether cyclin D1 stability was decreased during PTX treatment. Cyclin D1 degradation is initiated by phosphorylation of residue Thr286 by GSK-3β. Inhibition of GSK-3β with LiCl or knockdown via siRNA in the presence of PTX failed to block cyclin D1 decrease. Moreover, PTX treatment in the presence of MG-132 revealed no significant increase in cyclin D1 p-Thr286 compared to control. Finally, using the protein synthesis inhibitor, CHX, PTX caused no significant decrease in cyclin D1 t₁/₂ (wt-HA and T286A-HA) compared to control. Sorafenib, a broad-spectrum (cRAF, bRAF, KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β) kinase inhibitor, is FDA-approved for the treatment of RCC. Studies with sorafenib and PTX in the ACHN cell model were carried out to determine PTXs possible adjuvant role in inhibiting cell growth via cyclin D1 decrease and G1 phase arrest. MTS data showed PTX potentiates the anti-proliferative effects of sorafenib. PTX pre-treatment for 24 hrs was also lowered the effective dose of sorafenib from 50 μM to 5 μM. Further, ACHN xenograft tumor volumes from mice treated with PTX and sorafenib displayed significantly higher tumor growth inhibition compared to either drug treatment alone or vehicle. Finally, drug treated ACHN xenograft tissue displayed significantly lower cyclin D1, p-RB and p-4EBP1 levels. These results demonstrate a novel anti-cancer property of PTX and suggest its use as a possible adjuvant therapy in RCC treatment should be further explored.
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Winegard, Billie. "Renal Cell Carcinoma in Arizona American Indians/Alaska Natives". Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/221595.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.OBJECTIVE – This study assesses trends in the incidence of cancers of the kidney and renal pelvis (K&RP) with focus on renal cell carcinoma (RCC) from 1995-2009 among American Indian/Alaska Natives (AI/AN) residing in Arizona. RESEARCH DESIGN AND METHODS – Using the Arizona Cancer Registry (ACR), we obtained the total number of new cases of cancers of the K&RP from 1995 through 2009. The incidence rates of these cancers, as well as the sub-group of RCC, were age-adjusted to the 2000 U.S. population for comparison between populations. Comparisons between demographic and tumor characteristics were also completed between AI/AN and non-Hispanic white cases. RESULTS – Between 1995 and 2009, 502 cases of K&RP were diagnosed in AI/AN in Arizona, with a majority of these cases (463, 92.23% of cases) being RCC of the kidney parenchyma. Over the study period, the age-adjusted incidence per 100,000 population was 19.18 for all tumors of the K&RP and 17.65 for RCC. Comparing the average age-adjusted rate over the first third (1995-1999) of the study period versus the last third (2005-2009), the rate of RCC among AI/AN increased 12.30% from 16.55 to 18.58 per 100,000 population. When this rate was stratified by sex, AI/AN males showed the most striking increase - 54.56% (19.22 to 29.70 cases of RCC per 100,000 population). While AI/AN females showed a decrease in the rate of 28.24% (14.20 to 10.19 cases per 100,000 population). CONCLUSIONS – The incidence rate of RCC has increased dramatically in Arizona AI/AN males. Research looking at this disease in this group is needed to determine which risk factors may be associated and to determine if any steps can be taken toward prevention or if there is a need for screening in this population.
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Bulmer, Bronwyn. "Prostate specific antigen-like expression in renal cell carcinoma". Thesis, Queensland University of Technology, 2002.
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Vilella-Arias, Santiago Andrés. "Estudo de candidatos a biomarcadores moleculares de prognóstico em carcinoma renal de células claras". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-20032014-075848/.
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O carcinoma de células renais (CCR) é o tumor mais agressivo que afeta o rim de pessoas adultas. O CCR é uma doença heterogênea, com diferentes alterações moleculares e variados patrões histológicos e clínicos que apresentam evolução diferente. Atualmente apenas variáveis anatomopatológicas clássicas são utilizadas para determinar o prognóstico dos pacientes. Utilizando uma plataforma de microarranjos de DNA, nosso grupo identificou em um trabalho anterior um conjunto de genes que se encontram diferencialmente expressos em tumores de rim. Neste estudo, nove candidatos foram selecionados para avaliação como marcadores de prognóstico no CCR. Foi confirmada a alteração na expressão dos genes ARNTL, ACTN4 e EPAS1 (p < 0,05) em amostras tumorais de CCR através de PCR em tempo real. Adicionalmente, foi observada a alteração da expressão dos genes ARNTL, EPAS1 e CASP7 em linhagens celulares imortalizadas derivadas de tumores renais, recapitulando por tanto, as alterações observadas nos tumores obtidos de pacientes. Posteriormente investigamos o padrão de expressão proteica destes candidatos por imunohistoquímica utilizando microarranjos de tecidos. Foi detectada a diminuição significativa (p < 0,05) da expressão das proteínas ACTN4, ARNTL, CASP7 e EPAS1 em tumores de pacientes com CCR relativamente ao tecido renal não tumoral. Além disso, foi possível determinar valores de imunomarcação capazes de estratificar pacientes com CCR em diferentes grupos de risco quanto à sobrevida câncer-específica, que adicionalmente apresentaram associação significativa com parâmetros anatomopatológicos utilizados na clínica. As imunomarcações de ACTN4, ARNTL, e EPAS1 se mostraram parâmetros independentes de prognóstico de sobrevida dos pacientes. A imunomarcação de CASP7 foi capaz de identificar subgrupos de pacientes com pior prognóstico dentro de um conjunto de pacientes de baixo risco em função do estadio clinico, além de identificar pacientes com menor risco de morte pelo câncer entre aqueles apresentaram recorrência em até 5 após a cirurgia. O conjunto de resultados obtidos aponta para um novo conjunto de biomarcadores moleculares com potencial relevância para auxiliar no prognóstico de pacientes com carcinoma de células renais.The renal cell carcinoma (RCC) is the most aggressive tumor that affects the kidney in adult people. The RCC is a heterogeneous disease, with many different molecular alterations and varied histological and clinical patterns with different outcome. Currently, only classic anatomopathological variables are used to determine patients\' prognosis. Using a DNA microarray platform, our group identified in a previous work a set of genes differentially expressed in renal tumors. In this study, nine candidates were selected for evaluation as prognostic biomarkers in RCC. Alteration of the gene expression in RCC tumor samples was confirmed for ARNTL, ACTN4 and EPAS1 (p < 0.05) by real time PCR. Additionally, gene expression changes of ARNTL, EPAS1 and CASP7 were also observed in immortalized cell lines derived from renal tumors, recapitulating the expression changes detected in the patients\' tumors. Next, we used tissue microarrays to investigate the protein expression of the selected candidates by immunohistochemistry. Expression of the proteins ACTN4, ARNTL, CASP7 and EPAS1 was detected as significantly downregulated (p < 0.05) in patients´ tumors relative to non-tumor renal tissue. Furthermore, immunostaining patterns of the selected candidates were able to stratify patients with RCC in different risk groups according to cancer-specific survival, which also showed significant associations with anatomopathological parameters used in the clinics. ACTN4, ARNTL and EPAS1 immunostaining resulted as independent prognostic parameters of patient survival. CASP7 immunostaining was able to identify subgroups of patients with worse prognosis in a set of low risk patients as determined by their clinical stage, and also identified patients with lower risk of death from cancer amongst patients that relapsed within 5 years after surgery. Overall, these results point to a new set of molecular biomarkers with potential relevance to help in the prognosis of patients with renal cell carcinoma.
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CIMADAMORE, ALESSIA. "Biomarkers of angiogenesis and clinical outcomes to Cabozantinib and Everolimus in Patients with Metastatic Renal Cell Carcinoma from the Randomized Phase III METEOR Trial". Doctoral thesis, Università Politecnica delle Marche, 2022. https://hdl.handle.net/11566/295826.
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Gli inibitori del recettore anti-angiogenico VEGF (VEGFR) sono stati approvati per il trattamento di pazienti con carcinoma renale (RCC) metastatico e la loro efficacia è maggiore nei tumori con elevata angiogenesi. Dato che Cabozantinib inibisce multipli recettori tirosin-chinasici, incluso VEGFR, l'obiettivo dello studio è quello di valutare se marcatori di angiogenesi, ovvero la densità microvascolare (MVD) e la densità dei mastociti (MCD), sono predittivi di risposta alla terapia con cabozantinib versus everolimus. Sono stati utilizzati campioni istologici di carcinomi renali di pazienti arruolati nel METEOR trial. MVD e MCD sono state studiate in 430 pazienti (cabozantinib = 216, everolimus = 214) con tecnica immunoistochimica per CD31 (marcatore endoteliale) e triptasi (marcatore delle mast cell) valutate con analisi di immagine su slides digitali. I risultati sono stati correlati con la progression-free survival (PFS), overall survival (OS), tasso di risposta (ORR) e controllo della malattia (DCR).
La densità microvascolare è positivamente correlata con la densità delle mast cells. Considerando tutti i pazienti inclusi nello studio, un'elevata MVD è associata con più lunga PFS e elevata MCD con più lunga PFS e OS. La terapia con Cabozantinib è associata con migliore PFS, OS, ORR e DCR rispetto a everolimus, indipendentemente da i livelli di mast cells. Per la PFS e OS, l'effetto di cabozantinib rispetto a everolimus è stato maggiore nei pazienti con inferiore MCD. In conclusione, alti livelli di MVD e MCD sono associati con migliore outcome nei pazienti RCC metastatici, ma non sono risultati predittivi di risposta alla terapia con cabozantinib versus everolimus. La maggiore efficacia di cabozantinib rispetto a everolimus nei tumori con bassi livelli di angiogenesi suggerisce che la sua attività antitumorale non è mediate principalmente dall'inibizione di VEGFR.Purpose: Anti-angiogenic VEGF-receptor (VEGFR) inhibitors are approved for metastatic renal cell carcinoma (RCC) and their efficacy is higher in high angiogenic tumors. As cabozantinib inhibits multiple tyrosine kinase receptors, including VEGFR, we tested whether markers of angiogenesis, including microvascular density (MVD) and mast cell density (MCD), could predict benefit from cabozantinib versus everolimus, using RCC samples from the METEOR (NCT01865747) trial. Experimental design: MVD and MCD were studied in 430 patients (cabozantinib = 216, everolimus = 214) by double immunohistochemistry for CD31 (vascular marker) and tryptase (mast cell marker) coupled with automated image analysis. Results from evaluable cases (MVD = 360, MCD =325) were correlated with progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR). Results: MVD was positively correlated with MCD. In the whole cohort, high MVD was associated with longer PFS and high MCD was associated with longer PFS and OS. Cabozantinib was associated with improved PFS, OS, ORR and DCR compared to everolimus, irrespective of MVD levels. Cabozantinib was also associated with improved ORR and DCR compared to everolimus, irrespective of MCD levels. For PFS and OS, the treatment effect for cabozantinib versus everolimus tended to be greater in tumors with low MCD. Conclusions: High MVD and high MCD are associated with improved outcome in metastatic RCC, but fail to predict benefit to cabozantinib versus everolimus. The high efficacy of cabozantinib in tumors with low angiogenic markers suggests that its anti-tumor activity in RCC is not predominantly mediated by VEGFR inhibition.
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Cadillo, Chávez Ronald Germán. "Manejo del Trombo en Cava por Cancer Renal". Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2002. https://hdl.handle.net/20.500.12672/2503.
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Se realizo un estudio retrospectivo en un total 23 pacientes de cáncer renal con presencia de trombo tumoral en la vena renal atendidos y tratados quirúrgicamente en el Hospital Nacional Edgardo Rebagliatti Martins en el período de 1995 – 2001.
El presente trabajo se ha realizado se realizo con el objetivo de conocer los resultados del tratamiento quirúrgico empleado en pacientes con cáncer renal y compromiso por trombo tumoral en la vena renal.
Se encontró que el sexo masculino (67%) es el mas afectado en una proporción de 2:1 , la edad mas frecuente es en mayores de 50años (89,4%).
Asi mismo se encontró que no existe relación entre el tamaño tumoral y la presencia de compromiso por trombo tumoral en la vena cava, el estadio 3b fue el mas frecuente con 87%. La sobrevida de los pacientes fue a 1 año de 78% y a 5 años de 42%
Las complicaciones postoperatorias más frecuentes fueron la infección de herida operatoria (8,7%), neumonia (4,4%).
El mayor tiempo de estancia hospitalaria fue de 5 – 7 dias (73,9%).
Por los resultados obtenidos vemos que el tratamiento quirúrgico del trombo tumoral en la vena cava por cáncer renal es un tratamiento efectivo y que ofrece a dichos pacientes una mejor sobrevida.Tesis de segunda especialidad
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Campos, Eurico Cleto Ribeiro de. "Análise do perfil de hipermetilação do gene PTEN e correlação com fatores clínicos anatomopatológicos no carcinoma de células renais". Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-23082011-144223/.
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Introdução: Apesar da identificação de fatores prognósticos clínicos e patológicos, muitos pacientes portadores de carcinoma de células renais (CCR) apresentam metástases ao diagnóstico e outros irão desenvolver recorrência local ou à distância durante o seguimento. Novos fatores prognósticos e de origem molecular têm sido avaliados no CCR, destacando-se o PTEN como um dos principais genes envolvidos na carcinogênese renal. Objetivos: Avaliar os fatores clínicos e anatomopatológicos mais significativos nas taxas de sobrevida, identificar a frequência de hipermetilação do gene PTEN através da técnica do pirosequenciamento, o impacto da hipermetilação do gene nas taxas de sobrevida global (SG) e livre de doença (SLD), como também, a associação da presença de hipermetilação com os principais fatores prognóticos. Material e métodos: Foram avaliados 137 pacientes portadores de CCR submetidos a tratamento cirúrgico do tumor primário entre 1997 e 2009. Foram considerados os dados epidemiológicos, clínicos, anatomopatológicos, de estadiamento (TNM 2004) e os obtidos da reação de pirosequenciamento. Resultados: O tempo de seguimento médio foi de 32,3 meses e mediana de 28,8 meses. Considerando o estadimento clínico, foram fatores independentes para a SG: idade (p<0,01), ASA (p=0,02), margens cirúrgicas (p=0,04), grau de Fuhrman (p=0,01), estádio clínico (p<0,001) e subtipo histológico (p<0,01). No modelo múltiplo a SLD foi influenciada únicamente pelo estádio clínico (p<0,001). Dos 137 casos analisados, hipermetilação do gene foi detectada em cinco casos (3,6%). Devido a baixa freqüência detectada optou-se por não realizar a associação da metilação do PTEN com os fatores prognósticos. Em relação às taxas de SG e SLD, de acordo com o perfil de hipermetilação do PTEN, não houve a ocorrência de nenhum evento, ou seja, morte, morte por CCR ou recorrência da doença para os cinco casos que apresentavam hipermetilação. Conclusões: A hipermetilação do xv PTEN foi detectada com baixa frequência, sugerindo a participação de outros genes ou mecanismos moleculares diferentes da metilação na inativação deste gene frequentemente envolvido na carcinogênese renal. As taxas de sobrevida não foram influenciadas pelo perfil de hipermetilação do PTEN, permanecendo o estadiamento clínico do TNM como a principal variável determinante da evolução e do risco de recidiva pelo CCRIntroduction: Despite the identification of clinical and pathological prognostic factors, many patients with renal cell carcinoma (RCC) have metastases at diagnosis and others will develop local or distant recurrence during follow-up. New prognostic factors and of molecular origin have been evaluated in RCC, highlighting PTEN, one of the main genes involved in renal carcinogenesis. Objetives: To assess the most significant clinical and pathological factors in survival rates, and identify the frequency of hypermethylation of the PTEN gene by the pyrosequencing technique, the impact of gene hypermethylation on overall survival (OS) rates and disease free interval (DFS), as well as associating presence of hypermethylation with main prognostic factors. Methods: We evaluated 137 patients with RCC that underwent surgical treatment of primary tumor between 1997 and 2009. We considered the epidemiological, clinical, pathological, staging (TNM 2004) data and those obtained from pyrosequencing. Results: Mean follow-up was of 32.3 months and the median of 28.8 months. Considering the clinical TNM stage, the OS was influenced in the multiple model by age (p < 0.01), ASA (p = 0.02), surgical margins (p = 0.04), Fuhrman´s grade (p = 0,01), clinical stage (p <0.001) and cell subtype (p < 0.01). DFS were influenced in multivariate analysis only by presence of clinical stage (p <0.001). Of the 137 cases examined, gene hypermethylation was detected in five cases (3,6%). Because of this low frequency perceived, we elected not to carry out the association of PTEN methylation with prognostic factors. Regarding OS and DFS rates, according to the hypermethylation of PTEN profile, no event occurred, that is to say death, death from RCC or disease recurrence in the five cases with hypermethylation. Conclusions: Hypermethylation of PTEN was detected with low frequency suggesting involvement of other genes or different molecular mechanisms of methylation upon inactivation of this gene, frequently involved in renal xvii carcinogenesis. Survival rates were not influenced by the hypermethylation of PTEN profile, with clinical TNM staging remaining as the main determinant for development and risk of RCC recurrence
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GUIDA, ANNALISA. "Decifrare la risposta immunitaria ai checkpoint inibitori e ricerca di nuovi biomarcatori nel carcinoma renale metastatico". Doctoral thesis, Università degli studi di Modena e Reggio Emilia, 2020. http://hdl.handle.net/11380/1201007.
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Nivolumab rappresenta attualmente uno standard per il trattamento di seconda linea del carcinoma renale metastatico (mRCC). E’ un anticorpo monoclonale IgG4 diretto contro programmed death-1 (PD-1) ed agisce inibendo il legame tra PD-1 e il suo ligando. Nella maggior parte dei pazienti, il farmaco ripristina la risposta immunitaria antitumorale T-mediata, migliorando la sopravvivenza e il tasso di rispsote obiettive. Tuttavia, in un certo numero di pazienti non si osserva una risposta al trattamento, motivando la crescente necessità di predire e incrementare il numero di pazienti responsive al trattamento con inibitori dei checkpoint immunitari. Il sistema immunitario rappresenta quindi un mediatore dell’attività del farmaco, suggerendo che l’equilibrio tra agenti regolatori positivi e negativi del sistema immunitario possono avere un ruolo chiave nell’efficacia terapeutica. Oggetto di attenzione sono fattori solubili coinvolti nel reclutamento e nella regolazione delle cellule T effettrici, i sottotipi di cellule T regolatorie e il rapporto tra cellule T effetrici e regolatorie.
L’obiettivo principale del progetto è identificare biomarcatori sierici e immunitari in pazienti affetti da mRCC e trattati con Nivolumab per predire quali pazienti possono beneficiare del trattamento.
E’ uno studio prospettico, longitdinale, su pazienti affetti da mRCC trattati con Nivolumab nella normale pratica clinica. Lo studio indaga le variazioni nei principali parametri immunitari nella popolazione in esame, attraverso l’analisi di prelievi ematici al basale e a distanza di 1, 2, 3, 6 ed eventualmente 12 mesi. Vengono prelevati 30 mL di sangue periferico da cui sono estratte le cellule perferiche mononucleate. Le cellule vengono conservate in azoto liquido. Vengono testati i seguenti anticorpi: CD3, CD4, CD8, CD25, CD127, FoxP3, ICOS, CXCXR6, CXCR3, CD95, CD45RA, CCR7, CD95, HLA-DR, CD38, CD28, CD27, CD71, CD87, CD39, TIM3, TIGIT, CCR4, Glycoforin, PD-1/IgG4, CD57, KI-67. Questa citometria a flusso multicolor viene analizzata in collaborazione con il Dr. Lugli (Humanitas Milano). I campioni vengono ottenuti attraverso un citometro a flusso BD Symphony. Per l’analisi dei dati viene utilizzato FlowJo 9.6 per MacOSX.
Da gennaio 2016 a ottobre 2018 sono stati arruolati 21 pazienti. L’età media è di 60 anni (33-79). La maggiro parte dei pazienti ha un’istologia a cellule chiare (90%). Il Nivolumab è stato somministrato come terapia di seconda linea nel 59% dei casi e di terza linea nel 27% dei casi. Secondo International Metastatic Renal Cell Carcinoma Database Consortium Score (IMDC score) il 72% ha un rischio prognostico intermedio e il 14% ha un rischio prognostico sfavorevole. Con un follow up mediano di 14 mesi (min 2 max 31), il tasso di sopravvivenza a 6 e 12 mesi è rispettivamente del 74% (95%CI 48-88) e del 47% (95%CI 22-68). La mediana di sopravvivenza libera da progressione è di 4.2 mesi (95%CI 3-10). Un controllo di malattia è stato registrato in 8 pazienti (40%) definiti responder (R). Al momento dell’analisi il trattamento era in corso di 4 pazienti. Dati preliminari mostrano che KI67, marker di proliferazione, aumenta dopo 15 giorni di trattamento. Coerentemente anche HLA-DR e CD38 sono aumentati.
La riattivazione del sistema immunitario è l’obiettivo del trattamento con Nivolumab. Auspichiamo di individuare marker facilmente misurabili predittivi di risposta al trattamento. Un follow up più lungo sarà necesario per confermare i dati preliminari.Nivolumab represents the new second-line treatment for metastatic renal cell carcinoma (mRCC). This drug is a fully human IgG4 against PD-1 and his role is to inhibits programmed death-1 (PD-1)/PD-1 ligand 1 (PD-L1) immune checkpoint. In the majority of patients, this drug is able to restore the patient’s tumour-specific T-cell-mediated response thus improving both overall survival and objective response rate. However, a lack of clinical response occurs in a number of patients, raising questions about how to predict and increase the number of patients who receive long-term clinical benefit from immune checkpoint therapy. The requirement for the immune system as a mediator of the drug's activity suggests that the balance of positive and negative regulators of the immune response at the time of therapy may be critical for therapy efficacy. Of particular interest are soluble factors involved in the recruitment and regulation of effector T cells, the frequency of different subsets of regulatory T cells and the ratio between effector T cells and regulatory T cells. The main aim of this project is to identify immune and serum biomarkers that are modulated in patients with metastatic renal cell carcinoma during and treated with immune checkpoint inhibitors and that can discriminate patients who most likely benefit from such therapy. This is a prospective, longitudinal, study on patients with mRCC who will receive Nivolumab in standard clinical practice. The project investigates changes in main immune parameters in patients with mRCC treated with nivolumab by analysing blood samples at baseline and after 1, 2, 3, 6 and eventually 12 months. Thirty mL of blood were collected and peripheral blood mononuclear cells (PBMC) were isolated according to standard procedures. PBMC were stored in liquid nitrogen. Then, PBMC were thawed according to standard procedures and stained with a viability probe and the following antibodies recognizing: CD3, CD4, CD8, CD25, CD127, FoxP3, ICOS, CXCXR6, CXCR3, CD95, CD45RA, CCR7, CD95, HLA-DR, CD38, CD28, CD27, CD71, CD87, CD39, TIM3, TIGIT, CCR4, Glycoforin, PD-1/IgG4, CD57, KI-67. This 28-color multicolour flow cytometry panel was set up in collaboration with Dr. Lugli (Humanitas, Milan). Samples were acquired by using a BD Symphony flow cytometer. Compensation was set using single stained controls and gating strategy was checked by using FMO. Data analysis was performed using FlowJo 9.6 under Mac OSX. From January 2016 until October 2018 we enrolled 21 patients. The median age was 60 years (33-79). The majority of patients had clear cell histology (90%). Nivolumab was given as second-line therapy in 57% of patients, as third line therapy in 29% of cases. According with International Metastatic Renal Cell Carcinoma Database Consortium Score (IMDC score) 72% of patients were in the intermediate prognostic risk group and 14% in poor risk. With a median follow-up of 14 months (min: 2 max: 31), 6-months and 12-months survival rate were 74% (95%CI 48-88) and 47% (95%CI 22-68), respectively. Median progression-free survival (PFS) was 4.2 months (95% 3-10). Disease control was achieved in 8 patients (40%), defined responder (R). At time of analysis treatment was ongoing in 4 patients. Preliminary data on PBMC show that Ki-67, a marker of cell proliferation, is increased after 15 days of therapy in some patients. Accordingly, the expression of HLA-DR and CD38 are increased. Reactivation of the immune system is one of the main goals of nivolumab. We expect to identify easily measurable immune biomarkers that predict the responsiveness to nivolumab. Finding novel biomarkers that predict the response to therapy with nivolumab and monitor its efficacy can be of great benefit for the success of treatment. Longer follow up is required to assess preliminary immunological data.
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Giraldo-Castillo, Nicolas. "The Immune Microenvironment in Clear Cell Renal Cell Carcinoma : The heterogeneous immune contextures accompanying CD8+ T cell infiltration in clear cell Renal Cell Carcinoma". Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066321/document.
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Dans cette étude, nous avons tenté de décrypter les mécanismes reliant l’augmentation de lymphocytes infiltrant les tumeurs (LIT) T CD8+ et un pronostic clinique défavorable dans le cancer du rein à cellules claires (ccRCC). Pour cela, nous avons déterminé 1) la relation entre le pronostic associé à l'expression d’immune checkpoints et l’infiltrat de cellules dendritiques (DC) et de LT CD8+ et 2) les caractéristiques phénotypiques des LIT T CD8+. L’expression des immune checkpoints a été déterminée par immunohistochimie dans une cohorte de 135 ccRCC. Nous avons constaté que les densités des cellules exprimant CD8, PD-1 et LAG-3 sont corrélées, et associées à une diminution de PFS et OS. Egalement, les patients dont les tumeurs présentent des densités élevées de cellules PD-1+ et PD-L1 et/ou PD-L2 +, ont le taux de survie le plus faible. Des densités élevées de DC immatures isolées dans le stroma tumoral sont associées à une forte expression d’immune checkpoints et à un faible taux de survie chez ces patients. En revanche, les patients présentant un taux de survie prolongé ont une densité élevée de lymphocytes CD8+, des DC matures au sein de structures lymphoïdes tertiaires, ainsi qu’une faible expression d’immune checkpoints. Nous avons analysé les LIT T CD8+ chez 21 patients ccRCC par Cytométrie de Flux. On a trouvé un groupe de patients (8/21) dont les tumeurs sont caractérisées par la surexpression de marqueurs inhibiteurs (PD1 et TIM3) et de d'activation (CD69 et CD38), par l'expansion des cellules T CD8 + mémoires effectrices et un plus grand potentiel d’agressivité. En résumé, nous avons démontré qu’une densité élevée de LIT T CD8+ dans les ccRCC est accompagnée d’une forte expression d’immune checkpoints et d’une réponse immunitaire mal coordonnée dans un sous-groupe de tumeurs agressivesTo decipher the potential mechanisms linking increased CD8+ T cell infiltration with an adverse clinical outcome in ccRCC, in this study we determined: 1) the prognosis associated with the expression of immune checkpoints and its coordination with dendritic cell (DC) and CD8+ cell infiltration, and 2) the phenotypic traits of CD8+ tumor infiltrating lymphocytes. The prognosis associated with CD8+ and DC infiltrations, in addition to the expression of immune checkpoints were investigated in a cohort of 135 ccRCC by quantitative immunohistochemistry. We found that the densities of CD8+, PD-1+ and LAG-3+ cells were closely correlated, and independently associated with decreased PFS and OS. In addition, patients whose tumors presented both high densities of PD-1+ cells and PD-L1+ and/or L2+ tumor cells, displayed the worst clinical outcome. High densities of immature DC isolated in the tumour stroma were associated with high expression of immune checkpoints and patients’ poor clinical outcome. In contrast, the presence of mature DC within Tertiary Lymphoid Structures identified, among the tumours with high CD8+-TIL densities, those with low expression of immune checkpoints and prolonged survival. We also investigated the phenotype of freshly isolated CD8+TIL in 21 ccRCC by flow cytometry. We found a group tumors (8/21) characterised by the over-expression of inhibitory (PD-1 and TIM-3) and activation markers (CD69 and CD38), the expansion of the effector memory cell subpopulation (CCR7-CD45RA-), and a trend toward more aggressive features. In summary, we demonstrated that the infiltration with CD8+ TIL in ccRCC is accompanied by the enhanced expression of immune checkpoints and a poorly coordinated immune response in a subgroup of aggressive tumors
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Bartrolí, Comellas Mariona. "Prognostic markers and therapeutic targets for metastatic renal cell carcinoma". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/664198.
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Targeting cancer metastasis has gained considerable importance in the recent years when aiming to increase patients’ overall survival. In Renal Cell Carcinoma (RCC), the discovery of metastatic biomarkers and targets is still required, as most patients present metastatic disease at the time of diagnosis.
Therefore, the aim of this thesis is the discovery of new biomarkers and targets of metastatic RCC using two variants of a patient-derived orthoxenograft (PDOX) animal model of clear cell RCC (ccRCC). Indeed, PDOX models have recently gained significant relevance for studying the progression of cancer and metastasis, due to their better mimicking of the histology, the metastatic capacity and treatment responses of human cancers. To this purpose, previous results had sequenced the two variants of this PDOX model, both at DNA and at RNA level, and had performed a FISH analysis.
Firstly, Carboxypeptidase E (CPE), which was one of the highest expressed genes in the metastatic variant, has demonstrated to play a role in invasion when it is secreted to the medium, even though its overexpression alone is not sufficient to generate metastasis in vivo. In addition, it has showed a clear association to ccRCC and an inverse correlation with the overall survival of these patients. Secondly, we have studied two molecules of the coagulation pathway due to its relevance as one of the most upregulated pathways at RNA level. On the one hand, Factor XIII (FXIII or F13) has shown to be related to CPE in vivo, despite the overexpression of both molecules is not sufficient to develop all the metastatic cascade. However, it also affects the overall survival of ccRCC patients, highlighting these two molecules as possible biomarkers for this type of cancer. On the other hand, Coagulation Factor II Thrombin Receptor (F2R or PAR1) has demonstrated to play a role in metastasis, since its inhibition reduces both the early and late phases of this process. With the use of F2R inhibitors and the clinical association of the coagulation pathway to worse prognosis, this thesis opens new opportunities for the treatment of metastasis and cancer malignization.
In summary, we have discovered new metastatic biomarkers and targets which, together with further validations, especially in the clinical setting, are proposed to be useful for RCC patients in the future.Recentment, l’estudi de la metàstasi ha guanyat importància amb l’objectiu d’augmentar la supervivència dels pacients amb càncer. En el càncer renal (RCC), el descobriment de biomarcadors metastàtics i dianes terapèutiques és necessari degut a que la majoria de pacients presenten metàstasi en el moment del diagnòstic. L’objectiu d’aquesta tesi ha estat el descobriment de nous biomarcadors i dianes terapèutiques pel càncer renal metastàtic a través de dues variants d’un model animal orthoxenograft (PDOX) de RCC de cèl·lula clara (ccRCC). Els models PDOX han guanyat molta importància en l’estudi de la progressió del càncer i la metàstasi, ja que mimetitzen la histologia, la capacitat metastàtica i la resposta als tractaments. Prèviament, s’havien seqüenciat les dues variants d’aquest model PDOX tant a nivell de DNA com de RNA, juntament amb un anàlisi FISH. En primer lloc, la Carbxoxipeptidasa E (CPE), un dels gens més expressats en la variant metastàtica, ha demostrat ser important en la invasió quan és secretada al medi, tot i no ser suficient per generar metàstasi in vivo. A més, s’ha associat amb el ccRCC i anti-correlacionat amb la supervivència d’aquests pacients. En segon lloc, hem estudiat dues molècules de la cascada de coagulació, una de les més alterades en nivells de RNA. Hem demostrat que el Factor XIII (FXIII o F13) està relacionat amb CPE in vivo, malgrat que l’expressió de les dues molècules no és suficient per a que es desenvolupi la metàstasi. Tot i així, el F13 afecta la supervivència de pacients amb ccRCC, suggerint aquestes dues molècules com a possibles biomarcadors d’aquest tipus de càncer. A més, la inhibició del Receptor del Factor de Coagulació II (F2R) ha demostrat reduir les fases inicials i finals del procés metastàtic. Així doncs, l’ús d’inhibidors de F2R, juntament amb el fet que la cascada de coagulació es relaciona amb el pronòstic dels pacients, fa que aquesta tesi obri noves oportunitats per al tractament de la metàstasi i la malignització del càncer. En resum, hem descobert nous biomarcadors i dianes terapèutiques que, juntament amb futures validacions, sobretot en clínica, poden ser útils per als pacients metastàtics de ccRCC.
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Carter, Jessica. "Epigenetic basis for Tensin3 dysregulation in human renal cell carcinoma". Thesis, University of Portsmouth, 2013. https://researchportal.port.ac.uk/portal/en/theses/epigenetic-basis-for-tensin3-dysregulation-in-human-renal-cell-carcinoma(e39a962d-9c23-4265-8318-bf5fd296148c).html.
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The Tensins are a family of intracellular cytoskeleton interacting proteins that are involved in the regulation of cell motility and migration. Downregulation of Tensins has been observed in several cancers, indicating that it may be advantageous for tumour progression. In this study, an epigenetic basis for the observed downregulation of Tensin3 in human renal cell carcinoma (RCC) has been investigated, specifically the methylation state of the TNS3 gene promoter. The aims of this study were to: 1. Identify and validate a functional promoter for the human TNS3 gene that contains a CpG island within it; 2. quantify the methylation level of this region in RCC; 3. determine whether expression of Tensin3 could be altered through DNA demethylation treatment. Bioinformatic analysis revealed there to be a putative promoter for the human TNS3 gene, housing an 826-bp CpG island. A luciferase reporter assay demonstrated a functional minimal promoter activity for a 2000 bp sequence containing this island. For quantification of methylation in the TNS3 promoter, genomic DNA from RCC patients (tumour and adjacent non tumour) and a normal control group were analysed by bisulphite conversion followed by pyrosequencing analysis. This enabled quantitative determination of DNA methylation of individual CpG dinucleotides within the TNS3 gene promoter, out of a total of 43 analysed. Across the entire CpG stretch, RCC DNA showed significantly higher methylation level than non-tumour kidney DNA and normal control DNA (tumour n=12, non-tumour n=3; normal n=12; P<0.01, tumour vs. non-tumour; P<0.0001, tumour vs. normal). Out of the CpGs analysed, two CpG dinucleotides, CpGs 2 and 8, showed the most pronounced increases in methylation in tumour samples (P<0.0001). Furthermore, CpG 2 methylation negatively correlated with Tensin3 gene expression levels in RCC samples (P<0.005). In addition, pharmacological demethylation of cultured HK2 kidney cells with 5-aza-2’deoxycytidine caused a threefold upregulation of Tensin3 expression as measured by qRT-PCR. In conclusion, these results reveal a differential methylation pattern in the TNS3 promoter region occurring in human RCC, suggesting at least in part an epigenetic basis for the observed aberrant downregulation of Tensin3 in this disease.
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Sandlund, Johanna. "Angiogenesis in human renal cell carcinoma : hypoxia, vascularity and prognosis". Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1331.
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