RCC represents more than 90% of these malignant renal tumours . The three main histologic types are clear cell, papillary and chromophobe RCC . Risk factors include tobacco smoking, obesity, hypertension and a positive family history for renal cancer . A protective effect has been reported for a diet rich in fruit and vegetables  as well as for moderate alcohol consumption . There are a number of genetic cancer syndromes associated with RCC, such as Von-Hippel-Lindau disease, hereditary papillary renalcellcarcinoma, hereditary leiomyomatosis and renalcell cancer and Birt-Hogg-Dubé syndrome .
Summary Interleukin 10 (IL-10) is an immunosuppressive factor and has been detected in tumour cell cultures of renalcellcarcinoma and of malignant melanoma. IL-10 has been described as a cytokine of the Th2 response; it is able to suppress antigen-presenting cells (APCs) and may lead to down-regulation of HLA class I and II molecules on dendritic cells and to anergy of T-lymphocytes. We evaluated pretreatment serum levels of soluble IL-10 and various clinical parameters to determine their prognostic value in 80 advanced renalcellcarcinoma patients seen at our institution between May 1990 and April 1996. For statistical evaluation we used both univariate and multivariate Cox proportional hazards models. An elevated pretreatment serum level of IL-10 was a statistically independent predictor of unfavourable outcome (P < 0.0028), in addition to the well-known clinical and biochemical risk factors. These data support risk stratification for future therapeutic trials and identify a predictor which needs to be validated in prospective studies and may potentially influence decision making in palliative management of patients with metastatic renalcellcarcinoma. These data also suggest a potential role of IL-10 in the development of advanced renalcellcarcinoma and in the future design of therapeutic strategies.
Renalcellcarcinoma is the 9 th and the 14 th most common cancer in men and women worldwide, respectively. Clear cell histology is the most common subtype of renalcellcarcinoma, which accounts for about 70-75% of all cases. The pathogenesis of renalcellcarcinoma is not well clarified and various factors are reported to be associated with kidney cancer. Identifying novel clinical and pathological features associated with the diagnosis, prognosis and targeted therapies of ccRCC patients is an essential task. Interleukin-22 (IL-22) belongs to the IL-10 family of cytokine and is produced by several subsets of lymphocytes. IL-22 plays an important role in sustaining the integrity of several organs and it prevents injury due to invading pathogens and the subsequent inflammatory response. Moreover, IL-22 has been reported to be associated with cancers in several organs. IL-22 mediates its biological effect by binding to the heterodimeric transmembrane complex of IL-22RA1 and IL-10R2.
Background. Real-world data are essential to accurately assessing ef ﬁcacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to con ﬁrm the real-world safety and efﬁcacy of pazo- panib in patients with advanced renalcellcarcinoma (RCC). Subjects, Materials, and Methods. Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eli- gible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment out- comes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, de ﬁned using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible
I, [Hongbiao, Lu] certify under penalty of perjury by my own signature that I have submitted the thesis on the topic [Diagnostic and prognostic potential of circulating cell-free genomic and mitochondrial DNA fragments in clear cellrenalcellcarcinoma patients] I wrote this thesis independently and without assistance from third parties, I used no other aids than the listed sources and resources.
Background: Treatment decisions in routine clinical practice are based on reports of clinical trials, which represent highly selected populations. Limited studies reported real-world evidences representing routine clinical practices in patients with renal-cellcarcinoma (RCC) in Europe. The aim of this retrospective, noninterventional chart review was to collect data on the treatment landscape for patients with advanced/metastatic RCC in routine clinical practice in a broader patient population in Austria. Patients and Methods: Patients with advanced/metastatic RCC receiving systemic treatment between June 2010 and June 2016 across 12 centers in Austria were included. Parameters were entered into an electronic case report form from the participating sites via the application Hermesoft electronic data capture system. Progression-free survival (PFS) and overall survival (OS) were the 2 primary end points. Results: The
Background: Sunitinib, a tyrosine kinases inhibitor, is a well-established treatment for metastatic renalcellcarcinoma (mRCC). Based on the results of the pivotal trial, it has been recommended at a dose of 50 mg per day in a 4 weeks on/2 weeks off schedule; with growing clinical experience and in an attempt to improve tolerability, other treatment schedules, e.g. 2 weeks on-1 week off have been established. After a median treatment duration of 11 months, resistance to sunitinib eventually occurs. Results from studies conducted in xenografts revealed that dose escalation of sunitinib could overcome resistance. We translated these findings into clinical practice and studied the concept of dose escalation in patients with acceptable toxicity profile at the time point of disease progression and resistance to sunitinib Methods: A single-centred retrospective study was conducted to analyse the efficacy of sunitinib dose escalation in mRCC patients who were treated at the Medical University of Vienna during January 2011 and Mai 2016. The primary endpoint was time on dose escalated treatment. Other endpoints were response rate, overall survival, progression free survival and toxicity.
26. McDermott, D.F.; Motzer, R.J.; Rini, B.I.; Aren Frontera, O.; George, S.; Powles, T.; Donskov, F.; Harrison, M.; Rodriguez-Cid, J.; Ishii, Y.; et al. ChechMate214 retrospective analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renalcellcarcinoma with sarcomatoid features. In Proceedings of the Seventeenth International Kidney Cancer Symposium, Miami, FL, USA, 2–3 November 2018.
low/high grade renalcellcarcinoma specimens (Anastassiou et al, 1995). Another example for a possible relevance of cell adhesion molecule expression in the course of malignant disease is the fact that endothelial and leucocyte expression of PECAM-1 has shown impact on leucocyte infiltration of the tumour tissue and on patient survival (Anastassiou et al, 1995). However, it remains unclear whether serum levels of the soluble isoforms are of prognostic value. To test this hypothesis in advanced renalcellcarcinoma, we examined sera from 99 patients for pretreatment serum levels of sICAM-1, sVCAM-1 and sELAM-1.
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 cellrenalcellcarcinoma (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.
CD8 T-cells. They differentiate from bone-marrow derived progenitor cells that migrate via the blood into lymphoid and non-lymphoid organs. Immature DC constantly sample antigens from their surroundings, but only undergo maturation upon pathogenic antigen uptake and stimulation. The complex process of maturation includes antigen presentation on MHC molecules on their surface, the down regulation of pro- inflammatory chemokine receptors, and the expression of CCR7 which facilities migration towards lymph nodes, cytokine production and finally T-cell activation . While acting as a link between innate and adaptive immune system, DC also induce tolerance towards self-antigens and maintain tissue homeostasis. Simplified there are two broad subtypes of DC, plasmacytoid DC (pDC) and myeloid or conventional DC (mDC/cDC). Phenotypically all DC express high levels of MHC II (HLA-DR), but no hematopoietic lineage markers CD3, 14, 15, 19, 20, and 56 . pDC are CD11c − CD123 + DC, which are able to produce high amounts INF-a upon virus recognition via TLR7 and TLR9, and can induce T H 1 and T H 2, and cross-present antigens to CTL .
For statistical analysis we used IBM-SPSS 22.0 and Microsoft Excel 2013. Expression results were quantified and presented as relative units. Significances of tissue specimen analyses were calculated by using the Log Rank test in relation to lymph node metastasis and over- all survival. Regression analyses were performed by using a Pearson correlation. All other results using RCC cell lines were presented in % of control cells. Differences in expression levels, activity levels, apoptosis rates, adhe- sion and migration potential were performed using the Student’s T-test. Statistical significance was assumed at a p-value of < 0.05.
Until the present day, one of the most successful treatments of mRCC patients has been accomplished with IL-2 and IFN- . One possible mechanism for the positive outcome is that treatment with cytokines from the interferon type I family activates antigen-presenting cells to perform better T cell stimulation . Additionally, the expression of tumor antigens can be modulated through upregulation of transporter associated with antigen presentation (TAP)-1 . To test whether IFN- or IFN- would regulate the pMHC ligand recognized by TCR53, target cells were cultured for 48 h with IFN- or IFN- containing medium or medium without cytokines. Then, HLA-A2 expression was determined by flow cytometry and the cells were cocultured with B3Z-TCR53m cells. RCC-26, which was well recognized by B3Z-TCR53m and RCC-53, which was weakly recognized, were used to investigate whether the different IFNs would differentially modulate the expression of the TCR53-pMHC ligand and, consequently, the response of B3Z-TCR53m cells. NKC-49, a primary normal kidney cell line, and RCC-1.26, a RCC cell line that expresses HLA-A2 endogenously but did not stimulate B3Z-TCR53m (Table 2 and Table 1, respectively) were used to monitor whether the IFNs would induce de novo TCR53 pMHC-ligand expression enough for TCR53m recognition. Induced recognition of normal kidney cultures would be undesirable because it would suggest that TCR53-pMHC ligand expression could be induced on normal kidney tissues by inflammatory conditions (such as IFN- ), raising concern about TCR53-associated autoreactivity in the clinical application.
Although established cell lines represent effective models for in vitro studies, these models often significantly differ from in vivo situations due to tumor clone selection and missing communication within the tumor microenvironment. Therefore, we further focused our investigations on primary tumor tissues from patients. Due to the much stronger cell–cell contacts, the extraction and purification of exosomes from tissues poses a great challenge. To date, there are only few data on the isolation of exosomes from kidney tissue. Zieren et al. reported the isolation of exosomes based on collagenase treatment, differential centrifugation, and filtration with 800 nm and 450 nm filters, followed by ultracentrifugation [ 46 ]. In contrast, our protocol was based on a density gradient without mechanical filters. To the best of our knowledge, this is the first report on successful exosome isolation from tumor and normal kidney tissues samples based on ultracentrifugation combined with a sucrose gradient. By applying a sucrose gradient to deplete the contaminants present in kidney tissues, we successfully isolated the corresponding exosomes at a high concentration and purity, as confirmed by Western blot, TEM, and NTA. Thereby, we found 1.3 M sucrose to be the optimal concentration. The comparison with exosomes from cell culture revealed differences between the expressions of the tumor-specific marker proteins.
It has been acknowledged for several years now that pediatric RCC can be classified into a variety of histologic subtypes. These included papillary type RCC, RCC not otherwise specified, clear cell-type RCC and chromophobe RCC. A worldwide classification was, however, not available. Since the 2004 WHO classification system, MiT-RCC was officially recognized as a separate entity [ 12 ]. In addition, the recently discovered succinate dehydrogenase (SDH)-deficient RCC, fumarate hydratase (FDH)-deficient RCC and anaplastic lymphoma kinase (ALK)-rearranged RCC have been recognized as separate entities and are increasingly reported [ 13 , 68 ]. Fortunately, we have the 2016 WHO classification, which now enables worldwide comparison of registered cases in the future [ 31 ].
188.8.131.52 Specific Immunotherapy
The first step in rational design of cancer immunotherapy is the identification of a suitable antigen. The more antigens known for a particular cancer the better. Targeting of a single antigen may lead to tumor escape by selection of antigen loss variants. Therefore, the aim should be to immunize not only with one or two but with a number of different antigens simultaneously. However, the quality of the antigen with regard to tumor rejection is also important. The potency of a tumor rejection antigen depends not only on the strength of immune response induced but also the vaccination protocol used. Weak tumor antigens can record as strong rejection antigens when used in protocols that favour the induction of CTL responses plus Th-1 CD4 + T cell responses. Avidity and frequency of cognate T cells to a particular antigen are also important parameters. Several studies have shown that whereas low-avidity CTL can be readily detected by standard immunological assays, only high-avidity CTL exert biological function in vivo (Speiser et al 1992, Zeh et al 1999). A high frequency of responding T cells would conceivably be able to offset low avidity and thus result in an effective antitumor immune response. It is thought that the best tumor rejection antigens are those that are either patient-specific, tumor-specific or highly restricted shared antigens (such as the CT antigens) as these antigens are more likely to have been previously ignored by the immune system. However, there is a case for non-mutated self antigens when used in the correct context. Nishikawa et al (2001) have shown that combined vaccination of mice with a known tumor rejection antigen plus a non-mutated self antigen results in increased antitumoral activity as compared to vaccination with the tumor rejection antigen alone. Once a tumor rejection antigen has been identified and selected, the next question is what strategy to use to elicit an effective antitumor response. There are a number of different strategies such as loading of denritic cells (DCs) with peptides, lentiviral transduction of DCs, monoclonal antibodies, and gene therapy.
Osteopontin (OPN) is a glycoprotein, which is present in all body fluids including plasma. Due to the presence of arginine-glycine-aspartic acid sequence (RGD) in its structure OPN is capable of binding to cell integrin receptors and promoting adhesion, proliferation, and survival in various cell types including tumor cells. Its involvement in tumor progression and metastasis has been indicated in a number of studies. For example, tumor cells with high invasive properties or obtained from metastatic lesions show elevated OPN expression and, moreover, OPN expression in tissue correlates with tumor stage and size as well as survival of cancer patients. All these findings suggest that elevation of OPN levels in blood could also reflect tumor progression towards metastasis and poor prognosis for cancer patients. In addition, OPN is abundantly distributed in bone tissue and involved in the regulation of bone turnover. This indicates that OPN in plasma could also be a sensitive indicator of skeletal metastasis, since the latter alters finely balanced processes of bone turnover. The PubMed literature review has shown that reports on plasma OPN in prostate cancer (PCa) are very limited whereas in renalcellcarcinoma (RCC) no studies have been done so far. Therefore, the aim of this study was to evaluate the clinical usefulness of plasma OPN in patients suffering from PCa and RCC. Diagnostic and prognostic significance of plasma OPN was compared with the established bone formation markers: N-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (bALP) and the bone resorption marker: cross-linked carboxyterminal telopeptide of type I collagen (ICTP).