8,091 research outputs found

    Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program

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    Background: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval. Methods: Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model. Results: A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis. Conclusions: The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab

    Chromogranin A: From Laboratory to Clinical Aspects of Patients with Neuroendocrine Tumors

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    Background. Neuroendocrine tumors (NETs) are characterized by having behavior and prognosis that depend upon tumor histology, primary site, staging, and proliferative index. The symptoms associated with carcinoid syndrome and vasoactive intestinal peptide tumors are treated with octreotide acetate. The PROMID trial assesses the effect of octreotide LAR on the tumor growth in patients with well-differentiated metastatic midgut NETs. The CLARINET trial evaluates the effects of lanreotide in patients with nonfunctional, well-, or moderately differentiated metastatic enteropancreatic NETs. Everolimus has been approved for the treatment of advanced pancreatic NETs (pNETs) based on positive PFS effects, obtained in the treated group. Sunitinib is approved for the treatment of patients with progressive gastrointestinal stromal tumor or intolerance to imatinib, because a randomized study demonstrated that it improves PFS and overall survival in patients with advanced well-differentiated pNETs. In a phase II trial, pasireotide shows efficacy and tolerability in the treatment of patients with advanced NETs, whose symptoms of carcinoid syndrome were resistant to octreotide LAR. An open-label, phase II trial assesses the clinical activity of long-acting repeatable pasireotide in treatment-naive patients with metastatic grade 1 or 2 NETs. Even if the growth of the neoplasm was significantly inhibited, it is still unclear whether its antiproliferative action is greater than that of octreotide and lanreotide. Because new therapeutic options are needed to counter the natural behavior of neuroendocrine tumors, it would also be useful to have a biochemical marker that can be addressed better in the management of these patients. Chromogranin A is currently the most useful biomarker to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy

    Tumoral CD105 is a novel independent prognostic marker for prognosis in clear-cell renal cell carcinoma

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    International audienceBackground: Angiogenesis is essential for tumour growth and metastasis. There are conflicting reports as to whether microvessel density (MVD) using the endothelial marker CD105 (cluster of differentiation molecule 105) in clear-cell renal cell carcinomas (ccRCC) is associated with prognosis. Recently, CD105 has been described as a RCC cancer stem cell marker.Methods: A total of 102 ccRCC were analysed. Representative tumour sections were stained for CD105. Vascularity (endothelial CD105) was quantified by MVD. The immunohistochemistry analysis detected positive (if present) or negative (if absent) CD105 tumoral staining. This retrospective population-based study was evaluated using Kaplan–Meier method, t-test and Cox proportional hazard model.Results: We found that the expression of endothelial CD105 (MVD) negatively correlated with nuclear grade (P<0.001), tumour stage (P<0.001) and Leibovitch score (P<0.001), whereas the expression of tumoral CD105 positively correlated with these three clinicopathological factors (P<0.001). In multivariate analysis, tumoral CD105 was found to be an independent predictor of poor overall survival (P=0.002).Conclusions: We have shown for the first time that tumoral CD105 is an independent predictive marker for death risk and unfavourable prognosis in patients with ccRCC after curative resection

    Identifying mRNA targets of microRNA dysregulated in cancer: with application to clear cell Renal Cell Carcinoma

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    BACKGROUND. MicroRNA regulate mRNA levels in a tissue specific way, either by inducing degradation of the transcript or by inhibiting translation or transcription. Putative mRNA targets of microRNA identified from seed sequence matches are available in many databases. However, such matches have a high false positive rate and cannot identify tissue specificity of regulation. RESULTS. We describe a simple method to identify direct mRNA targets of microRNA dysregulated in cancers from expression level measurements in patient matched tumor/normal samples. The word "direct" is used here in a strict sense to: a) represent mRNA which have an exact seed sequence match to the microRNA in their 3'UTR, b) the seed sequence match is strictly conserved across mouse, human, rat and dog genomes, c) the mRNA and microRNA expression levels can distinguish tumor from normal with high significance and d) the microRNA/mRNA expression levels are strongly and significantly anti-correlated in tumor and/or normal samples. We apply and validate the method using clear cell Renal Cell Carcinoma (ccRCC) and matched normal kidney samples, limiting our analysis to mRNA targets which undergo degradation of the mRNA transcript because of a perfect seed sequence match. Dysregulated microRNA and mRNA are first identified by comparing their expression levels in tumor vs normal samples. Putative dysregulated microRNA/mRNA pairs are identified from these using seed sequence matches, requiring that the seed sequence be conserved in human/dog/rat/mouse genomes. These are further pruned by requiring a strong anti-correlation signature in tumor and/or normal samples. The method revealed many new regulations in ccRCC. For instance, loss of miR-149, miR-200c and mir-141 causes gain of function of oncogenes (KCNMA1, LOX), VEGFA and SEMA6A respectively and increased levels of miR-142-3p, miR-185, mir-34a, miR-224, miR-21 cause loss of function of tumor suppressors LRRC2, PTPN13, SFRP1, ERBB4, and (SLC12A1, TCF21) respectively. We also found strong anti-correlation between VEGFA and the miR-200 family of microRNA: miR-200a*, 200b, 200c and miR-141. Several identified microRNA/mRNA pairs were validated on an independent set of matched ccRCC/normal samples. The regulation of SEMA6A by miR-141 was verified by a transfection assay. CONCLUSIONS. We describe a simple and reliable method to identify direct gene targets of microRNA in any cancer. The constraints we impose (strong dysregulation signature for microRNA and mRNA levels between tumor/normal samples, evolutionary conservation of seed sequence and strong anti-correlation of expression levels) remove spurious matches and identify a subset of robust, tissue specific, functional mRNA targets of dysregulated microRNA.Cancer Institute of New Jersy; New Jersey Commission for Cacner Research; Lineberger Comprehensive Cancer Center Tissue Procurement and Genomics Core Facility; Crawford Fun

    Surgically treated renal cell carcinoma : Prognostic factors and outcomes of treatment

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    Background Kidney cancer is the 12th most common malignancy worldwide, accounting for over 400,000 new cases in 2018 (1). As renal cell carcinoma (RCC) incidence and mortality, as well as treatment patterns, vary widely in Europe, to plan strategies for the future, we need to comprehend the current situation in Finland. Accurate prognostic tools are essential for detecting cancers amongst the tumours noted in imaging studies and choosing optimal treatment for cancer patients. The Tumor, Node, Metastasis (TNM) staging system and International Society of Urologic Pathology (ISUP)/Fuhrman grading system are the most commonly used prognostic parameters for RCC. Currently, risk stratification relies on prognostic nomograms or risk stratification tools combining clinical, anatomical and histopathological data. However, these models have well-known limitations. Treatment for RCC is changing. Over the last decades, more incidental RCCs were found, and more minor lesions were operated on using less invasive techniques. At the opposite end of the disease spectrum, selected metastatic RCC patients receive a combined treatment consisting of nephrectomy, metastasectomy and oncologic therapies. Surgery for locally advanced and metastasised tumours must be justified by the prospect of an improved outcome or quality of life. Decisions to operate on metastatic RCCs are currently based on expert opinions and nomograms designed for targeted therapy survival estimations only. Thus, better prognostic markers and diagnostic tools are needed. Aims The aims of this PhD study were to evaluate the current changes in the clinical picture, treatment and outcomes of RCC in Helsinki University Hospital district. Further analysis was done to determine the clinical outcomes of surgically treated RCC with tumour thrombus and metastasised RCC (mRCC). The authors aimed to externally validate the performance of the Leuven-Udine (LU) prognostic group model for mRCC and to evaluate the prognostic value of serum concentration of tumour-associated trypsin inhibitor (TATI). The performance of renal tumour diameter and parenchymal invasion depth was compared with more complex classifications to assess their accuracy in predicting the nephrectomy performed. Patients and methods All patients studied were either suspected to have RCC or had RCC, and the majority of patients underwent nephrectomy at the Helsinki University Hospital (HUH). There were 1,719 patients with tumours suspected of RCC evaluated in four periods from 2006 to 2016 for clinical characteristics and treatments offered. From 2006–2014, 142 RCC patients with tumour thrombus (TT) were operated on at HUH. In total, using computed tomography (CT) or magnetic resonance imaging (MRI) images of 915 patients, tumour maximum diameter, depth of invasion, Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score and Renal Tumour Invasion Index (RTII) were estimated. There were 97 patients with metastatic RCC undergoing surgery for metastases. Preoperative and postoperative serum levels of tumour associated trypsin inhibitor (S-TATI) of 132 RCC patients were determined by time-resolved immunofluorescence assay in 2006-2010. Main results and conclusions During the study period, the proportions of frail and co-morbid patients increased significantly as did the percentage of small (diameter ≤4 cm) and asymptomatic tumours. The use of surveillance as treatment increased significantly while the use of cytoreductive nephrectomies (CNs) decreased to 54%. However, CN combined with tyrosine kinase inhibitors remained the primary option in patients with metastatic RCC. However, the changing landscape of RCCs has already affected and will increasingly affect the treatments given. For RCC patients with TT, no statistically significant difference in survival was found amongst the different levels of the venous extension. The prognosis for operated RCC patients with TT was good in the absence of papillary histology of primary tumour, lymphoid or distant metastases. Surgery also remains a feasible option for selected patients in the era of modern oncologic therapy. In predicting the type of nephrectomy, partial or radical, the simple measurements of tumour diameter and parenchymal invasion, were superior to the more complex classification. Hence, all of them were significant predictors for nephrectomy type. Our results recommend that potential anatomical classifications should be tested against these user-friendly measurements, diameter and parenchymal invasion. Overall survival (OS) was more favourable for patients undergoing complete metastasectomy than patients with non-complete metastasectomy and time to systemic therapy was longer. Patients with skeletal metastases had shorter survival than patients with other metastatic sites whereas patients with lung metastases had the most favourable prognosis. In this study population, the performance of the LU prognostic group model could not be validated. Despite the abundant amount of inauspicious prognostic factors in our patient cohort, survival rates were reasonable. Significant associations with preoperative S-TATI and Chronic Kidney Disease Stage (CKD grade), tumour stage, lymph-node involvement, metastatic status and preoperative C-reactive protein (CRP) level were noted. S-TATI, as a continuous variable, however, significantly predicted OS and cancer-specific survival (CSS). Prognostic significance of S-TATI should be further studied in larger patient cohorts and prospective settings.Munuaissyöpä on iäkkäiden tauti. Munuaiskasvaimet todetaan tavallisesti muista syistä tehtyjen kuvantamistutkimusten takia. Pelkät kuvantamistutkimukset eivät aina riitä taudin luonteen selvittämiseksi. Paikallisen taudin ensisijainen hoito on munuaisen poisto tai kasvaimen osapoisto, ja taudin ennuste on yleensä hyvä. Laskimoihin kasvaintappina edenneitä munuaissyöpiä pyritään ensisijaisesti hoitamaan leikkaushoidolla. Etäpesäkkeistä tautia hoidetaan lääkehoidolla, mutta voidaan valikoiduissa tapauksissa hoitaa myös emokasvaimen poistolla yhdistettynä tarvittaessa etäpesäkkeiden poistoon. Jotta raskaat kirurgiset toimenpiteet levinneessä taudissa tai muuten hauraille potilaille voidaan perustella, tulee olla selvää näyttöä hyödystä joko elinaikalisänä tai parantuneena elämänlaatuna ja oman alueen kirurgiset tulokset ja komplikaatiomäärät tulee tietää. Väitöskirjatutkimus tehtiin Helsingin yliopistosairaalassa leikatuista tai seuratuista potilaista, joilla oli munuaissyöväksi epäilty kasvain tai munuaissyöpä. Potilaita oli 1719, ja heitä oli hoidettu ja seurattu vuosina 2006-2016. Aineistossamme vuosien 2006-2016 välillä selvästi sairaampien ja vanhempien potilaiden sekä pienten todettujen munuaiskasvainten osuudet kasvoivat merkittävästi. Seuranta hoitomuotona lisääntyi, kun taas emokasvainten poistojen määrä etäpesäkkeisessä taudissa väheni. Potilaiden, joilla oli laskimotapillisten munuaissyöpä, ennuste leikkaushoidon jälkeen oli suotuisa. Tosin emokasvaimen papillaarinen histologia ja levinneisyys imusolmukkeisiin tai kauemmas huononsivat leikatun potilaan ennustetta. Täydellinen etäpesäkkeen ja emokasvaimen poisto pidensi eloonjäämisaikaa ja siirsi munuaissyövän lääkehoidon aloitusta pidemmälle verrattuna leikkaukseen, jossa ei saatu kaikkea syöpämateriaalia poistettua, levinnyttä munuaissyöpää sairastavilla potilailla. Keuhkoetäpesäkkeisillä potilailla oli paras ennuste, ja luustoetäpesäkkeisillä huonoin. Yksinkertaiset anatomiset mitat, kasvaimen halkaisija ja kasvusyvyys, ennustivat monimutkaisempia luokituksia paremmin, tehtiinkö paikallisen munuaiskasvaimen hoidoksi munuaisen kokopoisto vai osapoisto. Leikkauksen jälkeen mitattuna seerumin TATI -merkkiaine ennusti kokonaiskuolleisuutta ja syöpäkuolleisuutta aineistomme munuaissyöpäpotilailla. Todellisen ennusteellisen merkityksen selvittämiseksi S-TATIa pitäisi tutkia suuremmassa aineistossa etenevässä tutkimusasetelmassa. Lisää työkaluja kaivataan sekä syöpien löytämiseksi hyvänlaatuisten munuaismuutosten joukosta että valitsemaan oikeat potilaat oikeisiin hoitoihin tai seurantaan ja määrittelemään seurannan tiheyden. Kun entistä vanhemmilla, hauraammilla ja sairaammilla potilailla löytyy aiempaa pienempiä kasvaimia, tulee hoidon hyötyjä ja haittoja punnita tarkasti. Tällä hetkellä syöpäkuoleman ja uusiutumisen riskiä ennustetaan munuaiskasvaimen anatomiasta, histologiasta sekä kliinisistä tiedoista koostetuilla pisteytysjärjestelmillä. Tarkempia ennusteellisia biomarkkereita etsitään kuumeisesti. Parhaat merkkiaineet olisivat esimerkiksi verestä tai virtsasta mitattavia, jotta kajoavia toimenpiteitä ei tarvittaisi –toistaiseksi yhtään tarkkaa ja kliiniseen tai tutkimuskäyttöön sopivaa merkkiainetta ei ole onnistuttu löytämään
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