[PubMed] [Google Scholar] 36

[PubMed] [Google Scholar] 36. indicate Isoliquiritigenin a central role for mTOR in nccRCC; a therapy that targets this ubiquitous regulator of cellular signaling could prove efficacious across various tumor subtypes. Results from recent studies exploring targeted therapies as both monotherapy and combination therapy have provided early indications of efficacy in patients with nccRCC. Exploratory analyses support further research with the mTOR inhibitors everolimus and temsirolimus in patients with nccRCC. Current clinical practice guidelines support the use of mTOR inhibitors in patients with nccRCC; however, these recommendations are based on low levels of evidence. Further results from randomized, controlled clinical trials are needed to determine the optimal choice of therapy for patients with nccRCC. Results from ongoing clinical trials of mTOR inhibitors and other agents in nccRCC, as well as their impact on the nccRCC treatment paradigm, are eagerly awaited. Translocation RCCs A subtype of RCCs characterized by various translocations involving chromosome Xp11.2, resulting in gene fusions involving the gene, has been recognized by the WHO [14]. Most Xp11 translocation RCCs occur in pediatric patients, but cases in adults have also been reported [18]. In one study of 28 patients aged >20 years with Xp11 translocation RCC, 14 patients presented with stage 4 Xp11 translocation RCC [18]. Lymph nodes were resected in 13 patients and 11 contained metastases [18]. Of 6 patients followed up for at least 1 year, 5 patients developed hematogenous metastases and 2 died within a year of diagnosis [18]. In a study of 54 patients with various translocation RCCs, patients with the fusion gene appeared to have the most aggressive form of cancer: both patients with the fusion gene developed distant metastases compared with 1 of 11 patients with other fusion genes [19]. Prognosis Many factors influence the prognosis of nccRCC. The tumor, node, metastasis (TNM) staging system can be used to assess tumor size, localization, adrenal involvement, and lymph node metastasis [12]. Histologic factors, RHOA such as Fuhrman grade, tumor subtype, sarcomatoid features, and microvascular invasion, may also provide critical information on potential outcomes. The widely accepted Fuhrman nuclear grade is a four-tier classification system based on nuclear morphology [20]. Clinical factors such as performance status, symptoms, cachexia, anemia, and platelet count can indicate disease impact for individual patients, providing a more specific disease profile [12]. Several prognostic systems and nomograms have been developed, combining various individual predictive factors to provide additional accuracy to TNM or Fuhrman grading alone. However, despite a multitude of studies, the use of molecular markers (e.g., single-nucleotide polymorphisms and and reduced activation of MET and impaired signaling to mTOR [28]. Thus, in patients with papillary RCC, overexpression of may lead to increased mTOR Isoliquiritigenin signaling via increased MET activation. Immunohistochemical studies suggest that patients with Xp11 translocation carcinomas have higher levels of phosphorylated S6 kinase, an indicator of increased mTOR pathway activation [29]. Small studies have suggested that mTOR inhibitors may have clinical efficacy in these patients [30, 31]. Finally, increased levels of p70S6K and reduced Akt expression are reported in sporadic non-TSC-related angiomyolipomas, indicating increased mTOR activity. Several studies indicate efficacy of mTOR inhibitors in TSC-related angiomyolipoma and lymphangiomyomatosis [32C34]. Clinical Experience with Targeted Therapies in Metastatic nccRCC Treatment of nccRCC of Any Subtype VEGF-Targeted Agents The North American Advanced Renal Cell Carcinoma Sorafenib expanded-access study was a nonrandomized, open-label expanded-access program providing sorafenib to patients with ccRCC or nccRCC [35]. The median progression-free survival (PFS) was 24 weeks for both the overall population (= 1,891; 95% confidence interval [CI]: 22C25 weeks) and the subpopulation of patients with ccRCC (excluding 202 patients with nccRCC; = 1,689; 95% CI: 22C25 weeks), suggesting that sorafenib has similar efficacy Isoliquiritigenin in patients with nccRCC and ccRCC [35]. Comparable results were observed in the parallel European Advanced Renal Cell Carcinoma Sorafenib study, with a median PFS of 6.6 months for the overall population (= 1,150; 95% CI: 6.1C7.4 months) and a slightly longer median PFS (7.4 months) for patients with ccRCC (= 909) [36]. Patients with nccRCC were also enrolled in an expanded-access program of sunitinib (= 588, 13% of the total study population) [37]. Median PFS for these patients was 7.8 months (95% CI: 6.3C8.3 months) compared with 10.9 months (95% CI: 10.3C11.2 months) for the overall population; median overall survival (OS) was 13.4 months (95% CI: 10.7C14.9 months) and 18.4 months (95% CI: 17.4C19.2 months), respectively [37]. Of 437 patients with nccRCC evaluable for response, 48 patients had an objective response (11%; 2 complete responses and 46 partial responses) and 250 patients (57%) had stable disease for 3 months [37]. Overall, VEGF-targeted agents have some efficacy for nccRCC, although probably.