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Incidence and prognostic significance of second primary cancers in renal cell carcinoma.

ABSTRACT: The survival of patients with renal cell carcinoma (RCC) has improved in recent years. However, data on the risk of developing a second cancer after a diagnosis of RCC is limited. We used the data available in the Surveillance Epidemiology and End Results (SEER) database to estimate the risk of second metachronous primary cancers in patients diagnosed with RCC between 1973 and 2006. Furthermore, we also investigated the effect of the second primary cancers (SPCs) on the survival of RCC patients.A total of 3795 cases of SPCs were registered in the SEER between 1973 and 2006. The ratio of observed/expected number of SPCs in RCC was 1.18, which was significantly greater than expected. Solid tumors comprised 90% of all second malignancies in RCC patients, with the most second cancers reported in the prostate gland and the digestive and respiratory systems. The overall risk of second primaries was highest in patients aged over 30 years at the time of diagnosis. The site-specific risk of second cancers varied with the age at diagnosis, sex, race of the patient, size of the primary renal tumor, and history of radiation therapy. Patients with second primaries had a significantly longer overall survival than those without second malignancies. An interval of <1 year between the diagnosis of RCC and the second primary was the strongest predictor of poor overall survival in RCC patients with a second malignancy.Patients with RCC are at a significantly higher risk of developing a second malignancy, suggesting the need for careful surveillance for their early detection and management.

SUBMITTER: Chakraborty S

PROVIDER: S-EPMC3383896 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Incidence and prognostic significance of second primary cancers in renal cell carcinoma.

Chakraborty Subhankar S Tarantolo Stefano R SR Batra Surinder K SK Hauke Ralph J RJ

American journal of clinical oncology 20130401 2

<h4>Background</h4>The survival of patients with renal cell carcinoma (RCC) has improved in recent years. However, data on the risk of developing a second cancer after a diagnosis of RCC is limited. We used the data available in the Surveillance Epidemiology and End Results (SEER) database to estimate the risk of second metachronous primary cancers in patients diagnosed with RCC between 1973 and 2006. Furthermore, we also investigated the effect of the second primary cancers (SPCs) on the surviv ...[more]

PMID: 22441339

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Project description:CD73-adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5'-nucleotidase (NT5E), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1)) and A2 adenosine receptor (A2AR; ADORA2A) transcript levels with markers of angiogenesis and antitumor immune response. Patients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73negative (CS=0), CD73low or CD73high (< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and high NT5E, ENTPD1 and ADORA2A gene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared between NT5E, ENTPD1 and ADORA2A expression groups. Among the 138 patients eligible for inclusion, 'any' CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73high tumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73negative group (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, high NT5E expression was associated with significantly worse 5-year OS (p=0.008). NT5E and ENTPD1 expression correlated with higher regulatory T cell (Treg) signature, while ADORA2A expression was associated with increased Treg and angiogenesis signatures. High CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73-adenosine pathway in RCC.

Project description:BackgroundSecond primary cancers (SPCs) are increasing due to improving survival in first primary cancers. Previous studies on SPCs in renal cell carcinoma (RCC) have focused on treatment and other risk factors, but data of RCC as an SPC are scarce.ObjectiveIn this study, we want to elucidate the risk for any SPC after RCC, and in reverse order, for RCC as an SPC after any cancer. We additionally consider how family histories influence the risks.Design setting and participantsPatient data were obtained from the Swedish Cancer Registry from years 1990 through 2015, and family data were obtained from the Multigeneration Register.Outcome measurements and statistical analysisWe employed standardized incidence ratios to estimate bidirectional relative risks of subsequent cancer associated with RCC.Results and limitationsWe identified 17 587 RCCs (60% in male patients). The highest increases for SPCs were observed for nervous system hemangioblastoma (HB; 26.8), adrenal (12.09) tumors, and renal pelvic cancer (6.32). In the reverse order, RCC as an SPC, nervous system HB (17.01), and adrenal tumors (15.34) were associated with the highest risks. Risks for many other sites (12 sites and subsites) were increased bidirectionally. For women, a total of seven sites and subsites were increased bidirectionally, and many were shared with men. The only significant sex difference in SPCs was the higher lung cancer risk in women (2.41) than in men (1.28). Patients with a family history of HBs or of prostate, colorectal and lung cancers showed high risks of these cancers as SPCs after RCC. Family history accounted for 30% of prostate cancers after RCC.ConclusionsThe bidirectional study design was able to suggest risk factors for SPCs and offered a clinical take-home message urging to consider strategies for early detection and prevention of SPCs. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits.Patient summaryClose to 10% of kidney cancer patients develop another cancer. The cause for these other cancers may not depend on kidney cancer.

Project description:BACKGROUND: The aim of this study was to determine whether Src family kinases (SFK) are expressed in renal cell cancer and to assess their prognostic significance. METHODS: mRNA expression levels were investigated for the 8 SFK members by quantitative real-time PCR in 19 clear cell cancer tissue samples. Immunohistochemical staining was utilised to assess expression of Src kinase, dephosphorylated Src kinase at Y(530) (SrcY(530)), phosphorylated Src at Y(419) (SrcY(419)) and the downstream focal adhesion kinase (FAK) marker at the Y(861) site (FAK Y(861)) in a cohort of 57 clear cell renal cancer specimens. Expression was assessed using the weighted histoscore method. RESULTS: Src, Lyn, Hck, Fgr and Fyn were the most highly expressed in renal cancer. All members were more highly expressed in T2 disease, and furthermore expression levels between T2 and T3 disease showed a significant decrease for Lck, Lyn, Fyn, Blk and Yes (P=0.032). Assessment of membrane, cytoplasm and nuclear expression of Src kinase, SrcY(530) and SrcY(419) were not significantly associated with cancer-specific survival. High expression of cytoplasmic FAK Y(861) was associated with decreased cancer-specific survival (P=0.001). On multivariate analysis, cytoplasmic FAK Y(861) was independently associated with cancer-specific survival (hazard ratio 3.35, 95% CI 1.40-7.98, P=0.006). CONCLUSION: We have reported that all SFK members are expressed in renal cell carcinoma. The SFK members had their highest levels of expression before the disease no longer being organ confined. We hypothesise that these SFK members are upregulated before the cancer spreading out-with the organ and given that Src itself is not associated with cancer-specific survival but the presence of FAK Y(861), a downstream marker for SFK member activity is associated with decreased cancer-specific survival, we hypothesise that another SFK member is associated with decreased cancer-specific survival in renal cell cancer.

Project description:PurposeSecond primary malignancy (SPM) is challenging for treatment and long-term survival. We sought to investigate the standardized incidence rate (SIR), risk factors, and survival outcomes for SPM after renal cell carcinoma (RCC) treatment.MethodA nested case-control study was designed, we identified all T1-4N0-1M0 RCC patients diagnosed between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database and followed them for SPM diagnosis for up to 13 years. Patients with SPM diagnosis ≥6 months after treatment of primary T1-4N0-1M0 RCC were identified as the case cohort and SPM-free patients were the control cohort. SIRs and the excess risk were calculated. A competing risks and Cox model were used to evaluate the risk factors of SPM and overall survival (OS).ResultsA cohort of 6,204 RCC patients with SPM were matched with a control group of 31,020 RCC patients without SPM. The median time-to-SPM interval was 54.5 months in RCC patients with SPM diagnosis. Besides, an SPM of T3/4 or/and M1 stage diagnosis was positively associated with a longer time-to-SPM interval. SIR of SPM increased by follow-up time and decreased with age at diagnosis (Pfor all <0.001). SPM in the kidney had the highest SIR (54.6, P <0.001) among all SPMs. Prostate cancer (29.8%) in males and breast cancer (23.5%) in females were the most common SPM. Older age, black ethnicity, male sex, higher family income, papillary RCC, and lower TNM stage were significant risk factors for SPM diagnosis. The proportion of deaths from SPM exceeds that of deaths from RCC 3 years after the first RCC treatment. Patients with SPM and early time-to-SPM interval shortens the OS compared with SPM-free patients. The 5-year OS was 85.9% and 58.9% from the first RCC and the SPM diagnosis, respectively. Besides, patients with low-grade/early-stage SPM could benefit from aggressive surgical treatment for solid tumors.ConclusionsCollectively, our study described the epidemiological characteristics of SPM among RCC survivors and identified the independent predictors of the SPM diagnosis and its survival outcomes. This study highlights the importance of patient education and follow-up after the surgery for RCC.

Project description:Background:Renal cell carcinoma (RCC) is a fatal disease, in which the PI3K/AKT/mTOR signaling pathway serves an important role in the tumorigenesis. Previous studies have reported the prognostic significance of PI3K/AKT/mTOR signaling pathway members in RCC; however, there is insufficient evidence to date to confirm this. Thus, the present study aimed to systematically investigate the prognostic roles of multiple PI3K/AKT/mTOR signaling proteins in clear cell RCC (ccRCC) using online large-scale databases. Methods:The mRNA expression profiles of PI3K/AKT/mTOR signaling pathway proteins PTEN, PIK3CA, PIK3CB, PIK3CD, PIK3CG, AKT1, AKT2, AKT3 and mTOR were investigated using the Gene Expression Profiling Interactive Analysis (GEPIA) and Oncomine databases, and the protein expression levels of PI3K, AKT and mTOR were detected using western blotting (WB) analysis. In addition, the correlation between mRNA or protein expression levels and the prognostic significance was analyzed using the Kaplan-Meier (K-M) plotter (n = 530), the Human Protein Atlas (HPA; n = 528) and The Cancer Protein Atlas (TCPA; n = 445) databases. Results:The GEPIA revealed that the mRNA expression of major PI3K/AKT/mTOR pathway members, including PTEN, PIK3CA, PIK3CB, AKT1, AKT2 and AKT3, were negatively correlated with ccRCC stages (P < 0.05), though most of their mRNA and protein expression levels were notsignificantly different between ccRCC and normal tissues using GEPIA, Oncomine and WB analyses (P < 0.05). Meanwhile, using the K-M plotter and HPA prognostic analysis, it was found that the mRNA expression levels of the majority of the PI3K/AKT/mTOR signaling pathway members, including PTEN, PIK3CA, PIK3CB, PIK3CG, AKT3 and mTOR were positively correlated with overall survival (OS), whereas PIK3CD mRNA expression was negatively correlated with OS (P < 0.05). Furthermore, TCPA prognostic analysis observed that several of the key molecules of the PI3K/AKT/mTOR signaling pathway [PTEN, p-AKT (S473) and p-mTOR (S2448)] were also positively correlated with OS in patients with ccRCC (P < 0.05). In conclusion, the present study suggested that several members of the PI3K/AKT/mTOR signaling pathway, especially PTEN, may be favorable prognostic factors in ccRCC, which indicated that the PI3K/AKT/mTOR signaling pathway may be implicated in ccRCC initiation and progression.

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Incidence and prognostic significance of second primary cancers in renal cell carcinoma.

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Incidence and prognostic significance of second primary cancers in renal cell carcinoma.

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