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PurposeThe COVID-19 pandemic has led to the cancellation or deferment of many elective cancer surgeries. We performed a systematic review on the oncological effects of delayed surgery for patients with localised or metastatic renal cell carcinoma (RCC) in the targeted therapy (TT) era.MethodThe protocol of this review is registered on PROSPERO(CRD42020190882). A comprehensive literature search was performed on Medline, Embase and Cochrane CENTRAL using MeSH terms and keywords for randomised controlled trials and observational studies on the topic. Risks of biases were assessed using the Cochrane RoB tool and the Newcastle–Ottawa Scale. For localised RCC, immediate surgery [including partial nephrectomy (PN) and radical nephrectomy (RN)] and delayed surgery [including active surveillance (AS) and delayed intervention (DI)] were compared. For metastatic RCC, upfront versus deferred cytoreductive nephrectomy (CN) were compared.ResultsEleven studies were included for quantitative analysis. Delayed surgery was significantly associated with worse cancer-specific survival (HR 1.67, 95% CI 1.23–2.27, p < 0.01) in T1a RCC, but no significant difference was noted for overall survival. For localised ≥ T1b RCC, there were insufficient data for meta-analysis and the results from the individual reports were contradictory. For metastatic RCC, upfront TT followed by deferred CN was associated with better overall survival when compared to upfront CN followed by deferred TT (HR 0.61, 95% CI 0.43–0.86, p < 0.001).ConclusionNoting potential selection bias, there is insufficient evidence to support the notion that delayed surgery is safe in localised RCC. For metastatic RCC, upfront TT followed by deferred CN should be considered.

Background/ Introduction:Kidney cancer accounts for approximately 2-3% of all cancers worldwide. Renal cell carcinoma (RCC) is the commonest malignant renal tumour with 7,500 cases diagnosed annually resulting in over 3,700 deaths in the UK. The only curative treatment is surgery for the 50% presenting with early-stage disease. Patients with metastatic disease have a 5 year survival rate less than 10%, due to chemo-radiotherapy resistance. Newer drugs, so-called ‘targeted’ agents such as temsirolimus, sunitinib and sorafenib, have shown some activity against metastatic RCC. However, this is not longstanding and tumours inevitably progress.A key mechanism in RCC chemoresistance is the ability of RCC cells to efflux chemotherapeutic agents via multidrug resistant pumps (MDR), where MDR expression has been correlated with tumour progression and poor prognosis. It has recently been shown that RCC specimens contain a side population (SP), as defined by the constituent cell’s ability to efflux Hoechst 33342 dye and cytotoxic agents. The SP is enriched for cancer stem-like cells. The hypothesis tested herein is that the cells resident within the SP are the root cause of chemoresistance, and that characterisation of these cells will facilitate the understanding of the biology of this process and in addition, help to develop novel therapeutic approaches. Moreover, recent reports have suggested that the ‘targeted’ agents used in metastatic RCC may also affect MDR function, which forms the basis of these studies.Methods:Eight primary and metastatic human RCC lines (2220R, 2245R, 2246R, 2247R, ACHN, A498, Caki-1 and Caki-2) were assessed for the presence of Hoechst 33342 SP subpopulations and their growth characteristics were determined in vitro. Candidate renal subpopulations were sub-fractionated using Hoechst 33342 incubation and FACS- based separation, and treated with the chemotherapeutic agents docetaxel, paclitaxel, adriamycin, cisplatin, 5-fluorouracil and etoposide. IC50 values were determined by SRB assay and drug efflux by FACS and fluorescence microscopy. The novel targeted agents (temsirolimus, sunitinib and sorafenib) in RCC were interrogated as potential MDR modulator agents using FACS and SRB assays in combination with selected chemotherapy agents. Western blot experiments were performed to define the dosing strategy. qRT-PCR experiments investigated MDR expression levels in the SP compared to the NSP. Key signalling pathways involved in the conventional mechanism of action of the various targeted agents defined the doses where activity was demonstrated i.e. mTOR inhibition.Results:Characteristic verapamil sensitive SPs were seen in 5 of the 8 human RCC cell lines. The 2245R cell line had the highest SP (6.0±4.6%), and was chosen for further studies. The IC50 values for the SP, compared to the NSP, were significantly higher with docetaxel, paclitaxel, etoposide and adriamycin (5.4 vs. 3.3nM, 41.8 vs. 13.4nM, 11.6 vs. 8.8µM and 89.6 vs. 47.3nM respectively). There was no difference seen in these subpopulations treated with cisplatin or 5-fluorouracil (which are not MDR pump substrates). Retention of adriamycin fluorescence following treatment was significantly lower in the SP when measured both quantitatively using FACS, and assessed qualitatively using microscopy (p<0.0001), confirming that efflux is important in adriamycin resistance.