Thioredoxin 1 (Trx1) is associated with poor prognosis in clear cell renal cell carcinoma (ccRCC): an example for the crucial role of redox signaling in ccRCC

Abstract Purpose Thioredoxins are major regulatory proteins of oxidative signaling. Trx1 is the most prominent thioredoxin and, therefore, the current study sought to evaluate the prognostic role of Trx1 in ccRCC. Methods and patients A tissue micro-array (TMA) study was carried out to evaluate the association of Trx1 with clinicopathological features and survival outcome. Data from the Cancer Genome Atlas (TCGA) were evaluated for the association of characteristics in the Trx1 gene with clinicopathological features and survival outcome. Results In the TMA, patients with ccRCC that had high Trx1 levels had lower T stages (p < 0.001), less often distant metastases (p = 0.018), lower nuclear grades (p < 0.001), and less often tumor necrosis (p = 0.037) or sarcomatoid features (p = 0.008). Patients with a combined score of ≥ 10 had better DSS than patients with a low combined score of < 10 (HR 95% CI 0.62 (0.39–0.98)). Interestingly, the survival outcome is compartment specific: ccRCC patients whose tumors had exclusively Trx1 expression in the cytoplasm had the worst survival outcome (HR 3.1; 95% CI 1.2–8.0). Genomic data from the TCGA demonstrated that patients with ccRCCs that had Trx1 losses had more advanced clinicopathological features and worse survival outcome in disease specific (p < 0.001), overall (p = 0.001), and progression free survival (p = 0.001) when compared to patients with ccRCCs without copy number variations (CNV) or gains. Conclusion The current study suggests a possible role of Trx1 in the tumor biology of ccRCC and thus, the current study strongly advises in depth investigations of redox signaling pathways in ccRCC.

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The role of architectural patterns and cytologic features in the prognosis of clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.632 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 632-632

Author(s):

Qi Cai ◽

Alana Christie ◽

Qinbo Zhou ◽

Ellen Araj ◽

Jeffrey A Cadeddu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Tumor Biology ◽

Disease Free Survival ◽

Cell Renal Cell Carcinoma ◽

Clinical Prognosis ◽

Architectural Patterns

632 Background: Clear cell renal cell carcinoma (ccRCC) exhibits a spectrum of clinical behavior and intratumoral heterogeneity histologically. Pathologic grading for ccRCC is primarily based on nucleolar size. Sarcomatoid and rhabdoid changes are known to be associated with aggressive behavior, the significance of the histopathologic heterogeneity occurring in ccRCC remains largely unknown. We evaluated the prognostic role of architectural patterns and cytologic features in ccRCC. Methods: We identified sequential ccRCC cases at our institution between 2006 and 2015 for which follow-up information was available beyond 1.5 years, excepting those who died sooner. Architectural patterns and cytologic features were predefined and quantitated in nephrectomy specimen slides, which were reviewed by an experienced GU pathologist. Nine novel architectural patterns and ten cytologic features were correlated with disease-free survival (DFS) and overall survival (OS). Kaplan-Meier curves were generated to visualize survival distributions. Results: 549 cases met selection criteria and were comprehensively reviewed including 16 grade 1 (2.9%), 278 grade 2 (50.6%), 201 grade 3 (36.6%) and 54 grade 4 (9.8%). Pathologic tumor stage distribution included 63.9% pT1 (n = 351), 6.0% pT2 (n = 33), 27.5% pT3 (n = 151), and 2.6% pT4 (n = 14). Microcystic, tubular, bleeding follicles, and small compact nest patterns (n = 309), were associated with better DFS and OS. In contrast, large nests, thick trabecular, solid sheet, alveolar or papillary/pseudopapillary patterns (n = 240) were associated with worse DFS and OS (p < 0.0001). In addition to multinucleated giant cells, and sarcomatoid and rhabdoid changes, cytologic features including large intracytoplasmic eosinophilic inclusions, voluminous cytoplasm, cytoplasmic spindling, a giant nucleus with perinuclear halo, and a wrinkled nucleus with perinuclear halo were associated with worse DFS and OS (p < 0.0004). Conclusions: Architectural patterns and cytologic features observed in ccRCC predict tumor behavior and are associated with clinical prognosis. Evaluation of histopathologic heterogeneity may shed light on tumor biology and complement prognostic models.

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Coronary Intervention with the Excimer Laser: Review of the Technology and Outcome Data

Interventional Cardiology Review ◽

10.15420/icr.2016.11.01.27 ◽

2016 ◽

Vol 11 (1) ◽

pp. 27

Author(s):

John Rawlins ◽

◽

...

Keyword(s):

Excimer Laser ◽

Coronary Intervention ◽

Outcome Data ◽

Boston Scientific ◽

Technical Aspects ◽

Safety And Efficacy ◽

Percutaneous Coronary ◽

Short Period ◽

Complex Lesions

Excimer laser coronary atherectomy (ELCA) is a long-established adjunctive therapy that can be applied during percutaneous coronary intervention (PCI). Technical aspects have evolved and there is an established safety and efficacy record across a number of clinical indications in contemporary interventional practice where complex lesions are routinely encountered. The role of ELCA during PCI for thrombus, non-crossable or non-expandable lesions, chronic occlusions and stent under-expansion are discussed in this review. The key advantage of ELCA over alternative atherectomy interventions is delivery on a standard 0.014-inch guidewire. Additionally, the technique can be mastered by any operator after a short period of training. The major limitation is presence of heavy calcification although when rotational atherectomy (RA) is required but cannot be applied due to inability to deliver the dedicated RotaWire™ (Boston Scientific), ELCA can create an upstream channel to permit RotaWire passage and complete the case with RA – the RASER technique.

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Role of TWEAK and Fn14 in tumor biology

Frontiers in Bioscience ◽

10.2741/2270 ◽

2007 ◽

Vol 12 (1) ◽

pp. 2761 ◽

Cited By ~ 32

Author(s):

Jeffrey, A. Winkles

Keyword(s):

Tumor Biology

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Comprehensive Analyses of Copy Number Variations In DNA Repair Genes Reveal the Role of Poly(ADP-Ribose) Polymerase in Longevity in Trees

SSRN Electronic Journal ◽

10.2139/ssrn.3751787 ◽

2020 ◽

Author(s):

Yuta Aoyagi Blue ◽

Junko Kusumi ◽

Akiko Satake

Keyword(s):

Dna Repair ◽

Copy Number ◽

Copy Number Variations ◽

Dna Repair Genes ◽

Repair Genes

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Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

Metabolites ◽

10.3390/metabo11030180 ◽

2021 ◽

Vol 11 (3) ◽

pp. 180

Author(s):

Christina Mertens ◽

Matthias Schnetz ◽

Claudia Rehwald ◽

Stephan Grein ◽

Eiman Elwakeel ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Tumor Cells ◽

Cancer Progression ◽

Lung Metastases ◽

Expression Profiles ◽

The Cancer Genome Atlas ◽

Lipocalin 2 ◽

Tumor Associated Macrophages

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

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Differential Expression of a Panel of Ten CNTN1-Associated Genes during Prostate Cancer Progression and the Predictive Properties of the Panel towards Prostate Cancer Relapse

Genes ◽

10.3390/genes12020257 ◽

2021 ◽

Vol 12 (2) ◽

pp. 257

Author(s):

Yan Gu ◽

Mathilda Jing Chow ◽

Anil Kapoor ◽

Xiaozeng Lin ◽

Wenjuan Mei ◽

...

Keyword(s):

Prostate Cancer ◽

Differential Expression ◽

Cancer Progression ◽

Lncap Cell ◽

Endocrine Resistance ◽

Gene Panel ◽

The Cancer Genome Atlas ◽

Cancer Center ◽

Poor Overall Survival ◽

Cell Renal Cell Carcinoma

Contactin 1 (CNTN1) is a new oncogenic protein of prostate cancer (PC); its impact on PC remains incompletely understood. We observed CNTN1 upregulation in LNCaP cell-derived castration-resistant PCs (CRPC) and CNTN1-mediated enhancement of LNCaP cell proliferation. CNTN1 overexpression in LNCaP cells resulted in enrichment of the CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_3 gene set that facilitates endocrine resistance in breast cancer. The leading-edge (LE) genes (n = 10) of this enrichment consist of four genes with limited knowledge on PC and six genes novel to PC. These LE genes display differential expression during PC initiation, metastatic progression, and CRPC development, and they predict PC relapse following curative therapies at hazard ratio (HR) 2.72, 95% confidence interval (CI) 1.96–3.77, and p = 1.77 × 10−9 in The Cancer Genome Atlas (TCGA) PanCancer cohort (n = 492) and HR 2.72, 95% CI 1.84–4.01, and p = 4.99 × 10−7 in Memorial Sloan Kettering Cancer Center (MSKCC) cohort (n = 140). The LE gene panel classifies high-, moderate-, and low-risk of PC relapse in both cohorts. Additionally, the gene panel robustly predicts poor overall survival in clear cell renal cell carcinoma (ccRCC, p = 1.13 × 10−11), consistent with ccRCC and PC both being urogenital cancers. Collectively, we report multiple CNTN1-related genes relevant to PC and their biomarker values in predicting PC relapse.

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The Role of CD1a expression in the diagnosis of cutaneous leishmaniasis, its relationship with Leishmania species and clinicopathological features

Dermatologic Therapy ◽

10.1111/dth.14977 ◽

2021 ◽

Author(s):

Yasemin Yuyucu Karabulut ◽

Funda KuŞ Bozkurt ◽

Ümit Türsen ◽

Gül Bayram ◽

Gülhan Örekeci Temel ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Leishmania Species ◽

Clinicopathological Features

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Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920977117 ◽

2020 ◽

Vol 12 ◽

pp. 175883592097711

Author(s):

Xia Ran ◽

Jinyuan Xiao ◽

Yi Zhang ◽

Huajing Teng ◽

Fang Cheng ◽

...

Keyword(s):

Clinical Trial ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Checkpoint Inhibitors ◽

Simulated Data ◽

The Cancer Genome Atlas ◽

Intratumor Heterogeneity ◽

Cell Renal Cell Carcinoma ◽

Immune Activity

Background: Intratumor heterogeneity (ITH) has been shown to be inversely associated with immune infiltration in several cancers including clear cell renal cell carcinoma (ccRCC), but it remains unclear whether ITH is associated with response to immunotherapy (e.g. PD-1 blockade) in ccRCC. Methods: We quantified ITH using mutant-allele tumor heterogeneity, investigated the association of ITH with immune parameters in patients with ccRCC ( n = 336) as well as those with papillary RCC (pRCC, n = 280) from The Cancer Genome Atlas, and validations were conducted in patients with ccRCC from an independent cohort ( n = 152). The relationship between ITH and response to anti-PD-1 immunotherapy was explored in patients with metastatic ccRCC from a clinical trial of anti-PD-1 therapy ( n = 35), and validated in three equal-size simulated data sets ( n = 60) generated by random sampling with replacement based on this clinical trial cohort. Results: In ccRCC, low ITH was associated with better survival, more reductions in tumor burden, and clinical benefit of anti-PD-1 immunotherapy through modulating immune activity involving more neoantigens, elevated expression of HLA class I genes, and higher abundance of dendritic cells. Furthermore, we found that the association between the level of ITH and response to PD-1 blockade was independent of the mutation status of PBRM1 and that integrating both factors performed better than the individual predictors in predicting the benefit of anti-PD-1 immunotherapy in ccRCC patients. In pRCC, increased immune activity was also observed in low- versus high-ITH tumors, including higher neoantigen counts, increased abundance of monocytes, and decreased expression of PD-L1 and PD-L2. Conclusions: ITH may be helpful in the identification of patients who could benefit from PD-1 blockade in ccRCC, and even in pRCC where no genomic metrics has been found to correlate with response to immune checkpoint inhibitors.

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Pancreatic ductal adenocarcinoma concomitant with pancreatic metastases of clear-cell renal cell carcinoma: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-021-02768-8 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Lena Haeberle ◽

Melanie Busch ◽

Julian Kirchner ◽

Georg Fluegen ◽

Gerald Antoch ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Pancreatic Ductal Adenocarcinoma ◽

Renal Cell ◽

Clear Cell ◽

Ductal Adenocarcinoma ◽

Special Role ◽

Cell Renal Cell Carcinoma ◽

Pancreatic Metastases

Abstract Background Metastatic spread to the pancreas is a rare event. Renal cell carcinoma represents one possible site of origin of pancreatic metastases. Renal cell carcinoma often metastasizes late and exclusively to the pancreas, suggesting a special role of renal cell carcinoma among primaries metastasizing to the pancreas. Even rarer, renal cell carcinoma may occur simultaneously with pancreatic ductal adenocarcinoma. Case presentation We present the case of a 78-year-old male Caucasian patient with a history of clear-cell renal cell carcinoma treated with oncological left nephrectomy 20 years before. The patient was diagnosed with pancreatic ductal adenocarcinoma by fine-needle aspiration cytology. At our institution, he received neoadjuvant therapy with folic acid, fluorouracil, irinotecan, oxaliplatin for borderline-resectable pancreatic ductal adenocarcinoma, and subsequently underwent total pancreatectomy. Upon resection, pancreatic ductal adenocarcinoma as well as two metachronous metastases of clear-cell renal cell carcinoma occurring simultaneously and cospatially with pancreatic ductal adenocarcinoma were diagnosed in the pancreatic body. Conclusions Renal cell carcinoma metastases of the pancreas are rare and often occur decades after the initial diagnosis of renal cell carcinoma. The combination of renal cell carcinoma metastases and pancreatic ductal adenocarcinoma is even rarer. However, the possibility should be considered by clinicians, radiologists, and pathologists. The special role of renal cell carcinoma as a site of origin of pancreatic metastasis should be further elucidated.

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