Treatment Of Clear Cell Renal Carcinoma Research Articles

NFS-07. RESPONSE OF A CENTRAL NERVOUS SYSTEM (CNS) HEMANGIOBLASTOMA TO BELZUTIFAN IN A PEDIATRIC PATIENT WITH VON HIPPEL-LINDAU DISEASE (VHL)

Abstract BACKGROUND VHL is a rare cancer predisposition syndrome which affects many organ systems, leading to renal clear cell carcinoma (RCC), pheochromocytoma, retinal angiomas and CNS hemangioblastomas. Surgical resection has traditionally been the mainstay of treatment of VHL-associated tumors. In 2021, belzutifan, a Hypoxia Inducible Factor 2-alpha inhibitor was approved by the Food and Drug Administration for the treatment of VHL-associated RCC based on efficacy in adults. There is a paucity of data in pediatric VHL patients with hemangioblastoma treated with this novel agent. Herein we present such a case. CASE A 15-year-old male, diagnosed with VHL caused by a de novo germline mutation at the age of 12, was found to have a left craniocervical junction lesion consistent with a hemangioblastoma on surveillance MRI. The lesion demonstrated growth upon serial imaging but remained asymptomatic. Due to location, the patient was started on medical treatment using once daily oral belzutifan (120mg) continuously, sperm banking was performed prior to initiation of therapy. Hematologic and metabolic laboratory values were monitored, in addition to regular physical examinations including blood oxygen saturation recordings. The first MRI on therapy (3 months after treatment started) demonstrated a major radiologic response using RANO criteria. Treatment has been overall very well tolerated with few treatment-related toxicities limited to CTCAE v5 grade 1 fatigue and grade 2 anemia. No dose reductions or interruptions were required. The patient remains on therapy and has completed 11 months of treatment with further reduction in the size of this target lesion. CONCLUSION Hemangioblastomas are preponderantly characterized by their highly vascular nature making surgical resection in some cases arduous depending on location. This unique pediatric case adds to the growing evidence that therapy with belzutifan may be a safe and efficacious option for VHL-associated CNS Hemangioblastomas. Prospective studies in children are needed.

LA INMUNOTERAPIA EN EL MANEJO DEL CÁNCER RENAL METASTÁSICO: EN TRATAMIENTO CON INHIBIDORES DE CHECKPOINT PD-L1 Y/O ANTI-CTLA-4. A

Renal cell carcinoma (RCC) represents approximately 15%, presenting as advanced or metastatic, where surgery is not curative. The prognosis of patients with advanced or metastatic CRC can vary from a few months to a few years, depending on the clinical, pathological and radiological characteristics of the disease. Currently, anti-monoclonals are being used, which is based on immunotherapy-based as checkpoint inhibitors in the initial systemic therapy of advanced treatment of clear cell RCC. This research presents a clinical case where immunotherapy plays a role through the use of anti-monoclonals for the approach of a male patient with metastatic kidney disease who presents a clinical response after surgical treatment and immunotherapy for two years without evidence of oncological disease to date.

Kinase activity profiling in renal cell carcinoma, benign renal tissue and in response to four different tyrosine kinase inhibitors.

Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip® technology. The aim of this study was to identify differences in PTK activity between normal and malignant kidney tissue obtained from the same patient, and to investigate the inhibitory effects of TKIs frequently used in the clinics: sunitinib, pazopanib, cabozantinib and tivozanib. Briefly, our results showed that 36 kinase substrates differs (FDR < 0.05) between normal and cancer kidney tissue, where members of the Src family kinases and the phosphoinositide-3-kinase (PI3K) pathway exhibit high activity in renal cancer. Furthermore, ex vivo treatment of clear cell RCC with TKIs revealed that pathways such as Rap1, Ras and PI3K pathways were strongly inhibited, whereas the neurotrophin pathway had increased activity upon TKI addition. In our assay, tivozanib and cabozantinib exhibited greater inhibitory effects on PTK activity compared to sunitinib and pazopanib, implying they might be better suitable as TKIs for selected RCC patients.

DUSP4 promotes the carcinogenesis of CCRCC via negative regulation of autophagic death.

DUSP4 is considered as an oncogenic gene. However, the effect of DUSP4 on the carcinogenesis of clear cell Renal cell carcinoma (CCRCC) is still unclear. In this study, DUSP4 mRNA levels were significantly increased in CCRCC tissues and cell lines. Furthermore, DUSP4 overexpression promotes the proliferation, migration, and tumorigenicity of CCRCC cells while DUSP4 silencing showed the opposite effects. Importantly, both autophagic activity (LC3 conversion rate and LC3 puncta formation) and total death level promoted by DUSP4 silencing were reversed by treatment with 3-MA in CCRCC cells. Moreover, the proliferation and migration of CCRCC cells inhibited by DUSP4 silencing were also recovered by suppression of autophagy with 3-MA. In conclusion, DUSP4 serves as an oncogenic gene in CCRCC carcinogenesis due to its inhibitory effect on autophagic death, indicating the potential value of DUSP4 in the diagnosis and treatment of CCRCC.

Phase II trial of lenvatinib (LEN) at two starting doses + everolimus (EVE) in patients (pts) with renal cell carcinoma (RCC): Results by independent imaging review (IIR) and prior immune checkpoint inhibition (ICI).

307 Background: LEN 18 mg + EVE 5 mg is approved for advanced RCC following anti-angiogenic therapy. Study 218 was a phase II study evaluating LEN 14 mg vs LEN 18 mg, both in combination with EVE 5 mg, for the treatment of clear cell RCC following treatment with a VEGF-targeted therapy. We have previously reported that the LEN 14 mg arm did not demonstrate noninferiority vs the LEN 18 mg arm for objective response rate (ORR) as of wk 24 by investigator assessment, the primary endpoint of the study. In this exploratory analysis of Study 218 data, we evaluated the efficacy of LEN 14 mg vs LEN 18 mg, both in combination with EVE 5 mg, per IIR assessment and by prior ICI status per investigator assessment. Methods: Pts with measurable clear cell RCC (1 prior VEGF-targeted therapy; prior PD-1/PD-L1 therapy permitted) were randomly assigned 1:1 to LEN 14 mg or 18 mg (starting dose) + EVE 5 mg daily. 115 pts in the LEN 14 mg arm were titrated to LEN 18 mg at cycle 2 as they did not experience intolerable grade 2 or any grade ≥3 TEAEs requiring dose reduction within cycle 1. We analyzed ORR and PFS by IIR per RECIST v1.1; additionally, efficacy endpoints (ORR, PFS, and OS) were analyzed by investigator assessment per RECIST v1.1 by prior ICI status. Results: 311 pts (LEN 14 mg arm, n=156; LEN 18 mg arm, n=155) were included in the efficacy analysis and 341 pts (LEN 14 mg arm, n=173; LEN 18 mg arm, n=168) were included in the summary safety analysis. ORR by IIR (LEN 14 mg arm: 39.7%, 95% CI 32.1–47.4; LEN 18 mg arm: 38.7%, 95% CI 31.0–46.4) was similar between treatment arms. PFS by IIR was numerically longer in the LEN 18 mg arm (median 12.9 mos, 95% CI 9.2–17.1) vs the LEN 14 mg arm (median 11.0 mos, 95% CI 9.3–12.9). OS was numerically longer in the LEN 18 mg arm (median not evaluable [NE], 95% CI 23.8–NE) vs the LEN 14 mg arm (median 27.0 mos, 95% CI 18.3-NE) (previously reported). In 82 pts with prior ICI, for the LEN 14 mg (n=43) vs 18 mg (n=39) arms (95% CI): ORR was 30.2% (17.2–46.1) vs 51.3% (34.8–67.6) by investigator assessment, respectively; median PFS was 12.0 mos (8.9–16.7) vs 12.9 mos (8.4–NE) by investigator assessment, respectively; and median OS was 17.1 mos (10.6–NE) vs 18.0 mos (13.1–NE), respectively. Endpoints were generally numerically improved in the LEN 18 mg arm in pts without prior ICI (data will be presented). As previously reported, the safety profile was similar in both treatment arms: 71.7% of pts in the LEN 14 mg arm and 76.8% of pts in the LEN 18 mg arm had grade 3/4 TEAEs. Conclusions: ORR was similar between treatment arms and PFS was numerically longer in the LEN 18 mg arm per IIR. Efficacy outcomes were generally numerically improved for the LEN 18 mg arm compared with the LEN 14 mg arm, regardless of prior ICI. As previously reported, safety was similar in both treatment arms. These results further support starting pts with RCC at the higher 18 mg dose of LEN + EVE 5 mg. Clinical trial information: NCT03173560 .

The Immunotherapy Revolution in Kidney Cancer Treatment: Scientific Rationale and First-Generation Results.

The recent discovery of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, including the treatment for renal cell carcinoma (RCC). Following the eras of cytokines and molecularly targeted therapies including vascular endothelial growth factor-directed agents and mammalian target of rapamycin (mTOR) inhibitors, ICIs have become the latest addition to the RCC armamentarium. To understand the scientific rationale behind this revolution in RCC treatment, we have reviewed the fundamental discoveries underlying the transition from old (cytokines) to new (ICIs) immunotherapies. We summarize the pivotal trials (CheckMate 025, CheckMate 214, KEYNOTE-426, JAVELIN Renal 101, IMmotion151) of checkpoint inhibitors for clear cell RCC in various treatment settings. With the availability of many different combination therapies and many more currently under investigation, clear cell RCC treatment is becoming more complex. Patient preferences, disease volumes, and adverse event profiles are essential in determining which option is the best for an individual patient. In the future, biomarkers currently under development could guide these treatment decisions.

Hsa_circ_0035483 sponges hsa-miR-335 to promote the gemcitabine-resistance of human renal cancer cells by autophagy regulation

Renal clear cell carcinoma (RCC) is the most common pathological type of renal carcinoma and drug resistance often occurs. We studied the effect of hsa_circ_0035483 on gemcitabine sensitivity in RCC, and explored its regulatory effect on downstream hsa-miR-335 and Cyclin B1 (CCNB1). High-throughput sequencing was used to analyze the differentially expressed circRNA in RCC. The expressions of hsa_circ_0035483, hsa-miR-335, CCNB1, and autophagy-related proteins were detected by RT-PCR or Western blot. The target relationships were revealed by RNA pulldown assay and dual luciferase report assay. Autophagy marker LC3 was detected by immunofluorescence. Cell viability was detected by MTT assay. Hsa_circ_0035483 can facilitate gemcitabine-induced autophagy, and enhance the resistance of RCC to gemcitabine. Hsa-miR-335 is the target regulatory point of hsa_circ_0035483. In addition, hsa_circ_0035483 promotes autophagy and tumor growth and enhances gemcitabine resistance in RCC by regulating hsa-miR-335/CCNB1, and silenced hsa_circ_0035483 can enhance gemcitabine sensitivity in vivo. Hsa_circ_0035483 may be the target of gemcitabine resistance in the treatment of RCC.

Preclinical evaluation of an unconventional ruthenium-gold-based chemotherapeutic: RANCE-1, in clear cell renal cell carcinoma.

BackgroundThere are few effective treatments for patients with advanced clear cell renal cell carcinoma (CCRCC). Recent findings indicate that ruthenium‐gold containing compounds exhibit significant antitumor efficacy against CCRCC in vitro affecting cell viability as well as angiogenesis and markers driving those 2 phenomena. However, no in vivo preclinical evaluation of this class of compounds has been reported.MethodsFollowing the dose‐finding pharmacokinetic determination, NOD.CB17‐Prkdc SCID/J mice bearing xenograft CCRCC Caki‐1 tumors were treated in an intervention trial for 21 days at 10 mg/kg/72h of RANCE‐1. At the end of the trial, tumor samples were analyzed for histopathological and changes in protein expression levels were assessed.ResultsAfter 21 days of treatment there was no significant change in tumor size in the RANCE‐1‐treated mice as compared to the starting size (+3.87%) (P = 0.082) while the vehicle treated mice exhibited a significant tumor size increase (+138%) (P < 0.01). There were no signs of pathological complications as a result of treatment. Significant reduction in the expression of VEGF, PDGF, FGF, EGFR, and HGRF, all key to the proliferation of tumor cells and stromal cells serving protumorigenic purposes was observed.ConclusionsThe tumor growth inhibition displayed and favorable pathology profile of RANCE‐1 makes it a promising candidate for further evaluation toward clinical use for the treatment of advanced CCRCC.

KIF20B promotes the progression of clear cell renal cell carcinoma by stimulating cell proliferation.

Renal cell carcinoma (RCC) is a common urinary system cancer with high morbidity and mortality rate. Clear cell renal cell carcinoma (ccRCC) is a highly aggressive and common type of RCC. More and effective therapeutic targets are badly needed for the treatment of ccRCC. Kinesin family protein (KIF)20B, also named M-phase phosphoprotein 1, was reported as a microtubule-associated, plus-end-directed kinesin. KIF20B was involved in multiple cellular processes such as cytokinesis. Multiple studies indicated the oncogenic role for KIF20B in several types of tumors, including breast cancer and bladder cancer. However, the possible role of KIF20B in the progression of renal carcinoma is still unknown. Herein, our study demonstrated that KIF20B was relatively highly expressed in ccRCC tissues. In addition, KIF20B was inversely related to the clinical features including tumor size and T stage. We further found that inhibition of the KIF20B expression by a specific short hairpin RNA obviously reduces proliferation of ccRCC cells both in vitro and in vivo. Our study reveals the involvement of KIF20B in ccRCC progression. Generally, KIF20B is a promising novel therapeutic for the treatment of clear cell RCC.

Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism.

Clear cell renal cell carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advanced stages. The objective of this study was to investigate HMG-CoA reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in three different CC-RCC cell lines with three different lipophilic statins. Inhibition of mevalonate synthesis by statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in VHL-deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Inhibition of Rho and Rho kinase (ROCK) signaling contributes to the synthetic lethality effect, and overactivation of hypoxia-inducible factor signaling resulting from VHL loss is required. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of VHL-deficient CC-RCC. Mol Cancer Ther; 17(8); 1781-92. ©2018 AACR.

Notch 1 is a valuable therapeutic target against cell survival and proliferation in clear cell renal cell carcinoma.

Notch 1 is a key component of the Notch pathway, which performs a crucial role in clear cell renal cell carcinoma (CCRCC) development. The present study aimed to investigate whether Notch 1 could serve as a potential target for CCRCC treatment. Firstly, an association analysis was performed using 52 CCRCC cases and 30 normal controls. The results indicated that Notch 1 protein expression in renal tissues was closely associated with the incidence of CCRCC. In addition, higher Notch 1 expression in CCRCC tissues was positively associated with higher tumor-node-metastasis stage and Fuhrman grade, in addition to larger tumor size. Subsequently, an in vitro study was conducted to examine the biological functions of Notch 1 in CCRCC 786-O cells through inhibiting the Notch 1 expression with Notch 1-specific small interfering RNA (siRNA). As a result, the inhibition of Notch 1 expression by increasing concentrations of Notch 1-specific siRNA dose-dependently decreased cell proliferation and increased cell apoptosis in 786-O cells. Furthermore, B-cell lymphoma-2 and procaspase-3 expression exhibited a dose-dependent decrease accompanied with a dose-dependent inactivation of the Akt/mammalian target of rapamycin (mTOR) signaling pathway in Notch 1 siRNA-treated 786-O cells. These findings demonstrated that Notch 1 was associated with CCRCC carcinogenesis and progression, the underlying mechanism of which was that Notch 1 acted as an activator for cell proliferation and a suppressor for cell apoptosis through the Akt/mTOR signaling-dependent pathway in CCRCC. In conclusion, the present study confirmed that Notch 1 is a valuable target against cell survival and proliferation in CCRCC treatment.

Bilateral renal clear cell carcinoma in the elderly: 38 cases of diagnosis and treatment and related literature review

Objective To investigate the diagnosis, treatment and prognosis of bilateral renal clear cell carcinoma in the elderly. Methods Clinical data from 38 cases of elder patients admitted with bilateral renal clear cell carcinoma in our department from 2010 to 2014 were retrospectively analyzed.Among the total 38 cases diagnosed by B ultrasound and CT, 13 cases(A group)were treated with laparoscopic radical nephrectomy on one side, combined with microwave ablation on the other side; another 25 cases(B group)were treated with microwave ablation on bilateral sides.Patients were followed up for 24-36 months, with regularly checking by B ultrasound, CT and renal function. Results The operations were successful in total 38 cases(A+ B group), and no postoperative complications were found.All cases were diagnosed as pathologically proven bilateral renal clear cell carcinoma.Postoperative renal functions of the cases were decreased at different degrees as compared with preoperative renal functions, but not needing dialysis treatment.The microwave ablation on bilateral sides(B Group)versus A Group, significantly decreased the surgical time cost(P=0.012)and hospital stay(P=0.021). For both A and B group, postoperative renal function were declined in different degree.The damage extents of blood urea nitrogen, creatinine and creatinine clearance rate were less in group B than in group A at one week after surgery(P=0.008, 0.009 and 0.006). Atpostoperative follow-up for 3 month, it was found that the damage extents of blood urea nitrogen, creatinine and creatinine clearance rate were less in group B than in group A(P=0.037, 0.020 and 0.018). At postoperative follow-up for 30 months in average, no local recurrence or metastasis was found.Diagnosis of bilateral kidney clear cell carcinoma in the elderly mainly depended on B ultrasound, CT scan and MRI imaging. Conclusions As to the treatment of elderly patients with early renal clear cell carcinoma, considering both the general healthy condition of patients and tumor therapy and choosing microwave ablation might be good for efficiency and prognoses. Key words: Clear cell carcinoma; Kidney

Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma.

Clear Cell Renal Cell Carcinoma (CC-RCC) is the most lethal of all genitourinary cancers. The functional loss of the von Hippel-Lindau (VHL) gene occurs in 90% of CC-RCC, driving cancer progression. The objective of this study was to identify chemical compounds that are synthetically lethal with VHL deficiency in CC-RCC. An annotated chemical library, the Library of Pharmacologically Active Compounds (LOPAC), was screened in parallel on VHL-deficient RCC4 cells and RCC4VHL cells with re-introduced VHL cDNA. The ROCK inhibitor, Y-27632, was identified and validated for selective targeting of VHL-deficient CC-RCC in multiple genetic backgrounds by clonogenic assays. Downregulation of ROCK1 by siRNA selectively reduced the colony forming ability of VHL-deficient CC-RCC, thus mimicking the effect of Y-27632 treatment, whereas downregulation of ROCK2 had no effect. In addition, two other ROCK inhibitors, RKI 1447 and GSK 429286, selectively targeted VHL-deficient CC-RCC. CC-RCC treatment with ROCK inhibitors is cytotoxic and cytostatic based on BrdU assay, Propidium Iodide (PI) staining, and growth curves; and blocks cell migration based on transwell assay. Importantly, knockdown of Hypoxia Inducible Factor (HIF) β in the VHL-deficient CC-RCC had a protective effect against Y-27632 treatment, mimicking VHL reintroduction. On the other hand, CC-RCCVHL cells were sensitized to Y-27632 treatment in hypoxia (2% O2). These results suggest that synthetic lethality between ROCK inhibition and VHL deficiency is dependent on HIF activation. Moreover, HIF1α or HIF2α overexpression in CC-RCCVHL cells is sufficient to sensitize them to ROCK inhibition. Finally, Y-27632 treatment inhibited growth of subcutaneous 786-OT1 CC-RCC tumors in mice. Thus, ROCK inhibitors represent potential therapeutics for VHL-deficient CC-RCC.

Metastasis of renal cell carcinoma to the parathyroid gland 16 years after radical nephrectomy: A case report.

Renal cell carcinoma (RCC) has a high metastatic potential, and most commonly metastasizes via the bloodstream, although lymphatic metastases also occur. RCC is well-known for its propensity to metastasize to unusual sites, and late metastasis, even after a number of years, is common. The occurrence of RCC metastasis to the head and neck region is uncommon, and occurs primarily in the thyroid gland and in patients with widespread dissemination. Involvement of the parathyroid gland in metastatic carcinoma is extremely rare. In the present report, a case of metastasis confined to the parathyroid gland is described, likely with intrathyroidal localization, arising from a RCC that occurred 16 years after nephrectomy. A 66-year-old man was referred to the Department of Surgery of the University Hospital of Pisa (Pisa, Italy) with a preoperative fine-needle aspiration diagnosis of a follicular lesion in the context of nodular goiter of the thyroid gland. The previous medical history of the patient included a right nephrectomy for the treatment of clear cell RCC in February 1997. No other distant metastases were identified as of the latest follow-up in March 2014. At the time of thyroid surgery, the thyroid and parathyroid function tests were normal. The gross appearance of the surgical specimen was a multinodular goiter with a solid nodule measuring 33 mm on the left lobe of the thyroid gland. Microscopic examination revealed a completely encapsulated lesion consisting of clear cells arranged in a solid pattern and intermixed with fragments of parathyroid tissue. Following immunohistochemical examination, the clear cell lesion was negative for thyroid transcription factor-1 and thyroglobulin and strongly positive for epithelial membrane antigen, cluster of differentiation 10 and vimentin. To the best of our knowledge, this is the second case of metastasis to the parathyroid gland from a RCC reported in the literature.

Expression of long non-coding RNA in renal clear cell carcinoma

Objective To analyze the expression of long non-coding RNA (lncRNA) in renal clear cell carcinoma (RCCC), the association of lncRNA with RCCC, as well as the role of lncRNA in the diagnosis and treatment of RCCC. Methods Forty fresh RCCC tissues and their normal adjacent tissues were collected from March 2012 to June 2013, and total RNA was extracted using Trizol reagents, purified and tested by denaturing agarose gel electrophmesis and NanoDrop 1000. Through Arraystar Human LncRNA Microarray, the different expression of lncRNA between RCCC and normal adjacent tissues was screened. RT-qPCR was used to verify the expression of lncRNA in 40 pair RCCC tissues and normal adjacent tissues. The receiver-operating characteristic (ROC) curve was adopted to verify the diagnostic efficiency of the selected lncRNA. Results LncRNA expression profile showed 1 787 lncRNA with expression alteration in two fold or above, up-regulated and down-regulated candidate lncRNAs were 941 and 846 respectively. Compared with the adjacent tissues, NR_034095 and NR_038974 were up-regulated in RCCC, and ENS0571724 and ENS0566575 were down-regulated, which were consistent with the microarray analysis. By the ROC curves of NR_034095, NR_038974, ENS0571724 and ENS0566575 to discriminate the RCCC from normal adjacent tissue, the area under curve was 0.928 (95%CI 0.873-0.984), 0.759 (95%CI 0.647-0.871), 0.833 (95%CI 0.747-0.919) and 0.887 (95%CI 0.815-0.959), respectively. Conclusions NR_034095, NR_038974, ENS0571724 and ENS0566575 are significantly differently expressed in RCCC. The different expressed lncRNA might be closely related to the process of RCCC, and may be used as a new candidate target for molecular diagnosis and gene therapy of RCCC. Key words: Carcinoma, renal cell; Adenocarcinoma, clear cell; Long non-coding RNA; Gene expression profiling

Netrin-1: The new tumor markers in renal clear cell carcinoma.

To explore the expression of Netrin-1 protein in human renal clear cell carcinoma (RCCC) and the relationships between Netrin-1, pathology and prognosis. 72 cases of RCCC admitted in our hospital from 2008 June to 2009 June and their adjacent tissues were selected for study. They included 30 cases in stage Ⅰ-Ⅱ, 42 cases in stage Ⅲ-Ⅳ; 9 cases in grade Ⅰ, 9 cases in grade Ⅱ, 40 cases in grade Ⅲ and 14 cases in grade Ⅳ. All cases were followed up for more than 5 years. Survival analysis lines were made by Kaplan-Meier method and the difference between groups was tested by the Log-rank test. The expression of Netrin-1 protein was detected by immunohistochemistry staining and its clinical significance was analyzed. Renal clear cell carcinoma: 51 cases in high expression of Netrin-1 and 21 cases in low expression, normal tissues: 12 cases in high expression of Netrin-1 and 60 cases in low expression, the difference between the two groups is significant (χ(2)=42.921, P＜0.01). The difference of the expression of Netrin-1in Fuhrman grade and AJCC clinical stage is significant (χ(2)=8.000, χ(2)=6.203; P＜0.05). The 5-year survival rate in low protein expression group and in high protein expression group was 79％ (17/21) and 62％ (32/51). The survival curve had different trend, with no significant difference between groups ((χ(2)=1.360, P=0.245). Netrin-1 protein plays an important role in the development of RCCC. It might be a new specific tumor marker of RCCC, and might become a new target in treatment of RCCC.

Contemporary external validation of the Leibovich model for prediction of progression after radical surgery for clear cell renal cell carcinoma

Objective.The aim of this study was to externally validate in an up-to-date setting the predictive ability of the model for recurrence after radical treatment of clear cell renal cell carcinoma (CCRCC) published by Leibovich in 2003. Materials and methods. The study included a total of 386 consecutive patients with CCRCC between January 1997 and May 2013, treated with partial or radical nephrectomy. All patients were scored with points between 0 and 11, and further subdivided into low-, intermediate- and high-risk groups according to the original paper. Well-recognized statistical methods for the evaluation of Cox’s proportional hazard-based prognostic models were applied. To validate the discriminative ability, Harrell’s concordance (c) index and hazard ratios (HRs) between risk groups were used, and calibration was graphically explored. Results.The 10 year recurrence-free survival rates for the low-, intermediate- and high-risk groups were 87.3%, 63.8% and 19.8%, respectively Harrell’s c index was 0.864. The HRs across risk groups for the intermediate- and high-risk groups were 5.29 and 21.56, respectively, with the low-risk group as a reference category. A gross comparison of the survival estimates between the patients showed an overall similarity. However, differences within the intermediate- and high-risk groups were seen in the first year of follow-up. Conclusions.The Leibovich model seems to discriminate well between risk groups, but for the intermediate- and high-risk groups the calibration is not optimal. This study validates the model in a present-day Nordic patient population. The model can be used as a risk stratification tool for follow-up after radical treatment of CCRCC.

B7-H4 expression and its role in interleukin-2/interferon treatment of clear cell renal cell carcinoma.

The immunological mechanism mediated by T cells is the main therapeutic target in the treatment of renal cell carcinoma (RCC) with interleukin (IL)-2 and interferon (IFN)-α. The aim of the present study was to evaluate the role of B7-H4 in the IL-2, IFN-α and IFN-γ treatment of clear cell RCC (ccRCC). A total of 154 paraffin-embedded ccRCC tissues were studied using immunohistochemistry, which subsequently indicated that positive B7-H4 expression is associated with adverse clinical features in ccRCC. The effects of IL-2, IFN-α and IFN-γ on B7-H4 expression in a ccRCC cell line were evaluated at the mRNA and protein levels. In addition, the effect of B7-H4 on the killing activity of T cells was detected. B7-H4 expression was identified to be upregulated by IL-2, IFN-α and IFN-γ, of which, IFN-γ was the most capable. Additionally, blocking of B7-H4/B7-H4 ligand interactions may rescue the killing activity of T cells. Altogether, the observations of the current study showed that the immune escape pathway induced by B7-H4 may be one of the most important reasons for the low efficacy of IL-2 and IFN-α and the inability to observe the efficacy of IFN-γ in mRCC. This indicates that B7-H4 may be used as a new molecular biology marker to select treatment options for patients with ccRCC.

Tyrosine Kinase Inhibitor Sorafenib Decreases 111In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti-carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximab-based therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of (111)In-labeled girentuximab. (111)In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of (111)In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single (111)In-girentuximab injection and scintigraphy without any treatment. Distribution of (111)In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue. Treatment with sorafenib resulted in a marked decrease of (111)In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, -38.4%; range, +9.1% to -79.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients. Treatment with sorafenib resulted in a treatment duration-dependent significantly decreased uptake of (111)In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.

The anti-tumor mechanism of tyrosine kinase inhibitors in clear cell renal cell carcinomas: insights from a pathologic assessment

Angiogenesis occurs during tumor development and plays a critical role in the progression of clear cell renal cell carcinoma (CCRCC). Tyrosine kinase inhibitors (TKIs) are multi-target inhibitors of TK receptors that are standard first-line drugs for the treatment of advanced or recurrent CCRCC. Although their efficacy in preventing CCRCC progression is well established, the pathologic features of tumors treated with TKIs are rarely described in the literature. We recently reported that TKIs induced two types of vasculopathy in tumor vessels: type A in large and/or medium-sized vessels, in which there is a concentric intimal thickening that results in the narrowing or occlusion of the lumen; and type B in small vessels, which consist of hyalinized fibrous vessel walls, leading to occlusion of the lumen. TKI-induced vasculopathy was observed in or adjacent to necrotic or degenerative areas in CCRCCs, with tumor vessels showing decreased endothelial cell density; the consequent reduction in the blood supply to CCRCCs had anti-tumorigenic effects. These findings indicate that vasculopathy can serve as a prognostic marker for predicting the effectiveness of TKIs as well as patients outcome, and highlight the relevance of pathologic assessments for pharmaceutical development.