SNF'ing out antitumor immunity: Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745

AGRO100, also known as AS1411, is an experimental anticancer drug that recently entered human clinical trials. It is a member of a novel class of antiproliferative agents known as G-rich oligonucleotides (GRO), which are non-antisense, guanosine-rich phosphodiester oligodeoxynucleotides that form stable G-quadruplex structures. The biological activity of GROs results from their binding to specific cellular proteins as aptamers. One important target protein of GROs has been previously identified as nucleolin, a multifunctional protein expressed at high levels by cancer cells. Here, we report that AGRO100 also associates with nuclear factor-κB (NF-κB) essential modulator (NEMO), which is a regulatory subunit of the inhibitor of κB (IκB) kinase (IKK) complex, and also called IKKγ. In the classic NF-κB pathway, the IKK complex is required for phosphorylation of IκBα and subsequent activation of the transcription factor NF-κB. We found that treatment of cancer cells with AGRO100 inhibits IKK activity and reduces phosphorylation of IκBα in response to tumor necrosis factor-α stimulation. Using a reporter gene assay, we showed that AGRO100 blocks both tumor necrosis factor-α-induced and constitutive NF-κB activity in human cancer cell lines derived from cervical, prostate, breast, and lung carcinomas. In addition, we showed that, in AGRO100-treated cancer cells, NEMO is coprecipitated by nucleolin, indicating that both proteins are present in the same complex. Our studies suggest that abrogation of NF-κB activity may contribute to the anticancer effects of AGRO100 and that nucleolin may play a previously unknown role in regulating the NF-κB pathway. [Mol Cancer Ther 2006;5(7):1790–9]

Objective: To compare the perioperative outcomes of robotic partial nephrectomy ( RPN ) with laparoscopic PN ( LPN ) performed for small renal masses ( SRM s), in a large multi‐institutional series and to define a new composite outcome measure, termed ‘optimal outcome’ for the RPN group. Patients and Methods: Retrospective review of 2392 consecutive cases of RPN and LPN performed in five high‐volume centres from 2004 to mid‐2013. We limited our study to SRMs and cases performed by surgeons with significant expertise with the technique. The Trifecta was defined as negative surgical margin, zero perioperative complications and a warm ischaemia time of ≤25 min. The ‘optimal outcome’ was defined as achievement of Trifecta with addition of 90% estimated glomerular filtration rate preservation and no chronic kidney disease stage upgrading. Univariable and multivariable analysis were used to identify factors predicting Trifecta and ‘optimal outcome’ achievement. Results: In all, 1185 RPN and 646 LPN met our inclusion criteria. Patients in the RPN group were older and had a higher median Charlson comorbidity index and higher R.E.N.A.L . nephrometry score. The RPN group had lower warm ischaemia time (18 vs 26 min), overall complication rate (16.2% vs 25.9%), and positive surgical margin rate (3.2% vs. 9.7%). There was a significantly higher Trifecta rate for RPN (70% vs 33%) and the rate of achievement of ‘optimal outcome’ for the RPN group was 38.5%. Conclusions: In this large multi‐institutional series RPN was superior to LPN for perioperative surgical outcomes measured by Trifecta. Patients in the RPN group had better outcomes for all three components of Trifecta compared with their LPN counterparts. Our more strict definition for ‘optimal outcome’ might be a better tool for assessing perioperative and functional outcomes after minimally invasive PN . This tool needs to be externally validated.

Understanding the degree of phenotypic heterogeneity in a small renal mass may have implications for interpreting renal mass biopsy data. In this study we quantify nuclear grade heterogeneity in small renal masses. Our institutional renal mass database was queried for patients with T1a (less than 4 cm) renal masses stratified by the criteria of imaging diameter less than 2 cm or 2 cm or greater, clear cell or papillary histology, low grade (Fuhrman 1-2) or high grade (Fuhrman 3-4) with tissue available for review. Four consecutive specimens were chosen from each of the 8 strata for a total of 32. All specimens were reanalyzed and the highest Fuhrman grade present in each 10× powered field was recorded. A case was classified as heterogeneous if multiple grades were present and as discordant if the highest Fuhrman grade was present in less than 50% of the specimen. A median of 5 slides (IQR 3.5-7.5) and 59, 10× powered fields (IQR 34-109) were examined per patient. Overall 26 samples (81.3%) were heterogeneous, including 15 of 16 (93.8%) high grade specimens. Among all cases 10 (31.3%) were discordant and of high grade specimens 4 (25%) were discordant. Median fraction of low grade tissue in high grade specimens was 38.9% (IQR 12.2-57.2). The majority of small renal masses demonstrated considerable nuclear grade heterogeneity. The greatest degree of heterogeneity and discordance was observed in high grade tumors. One should consider these findings when interpreting renal mass biopsy data as the risk of under sampling high grade tumors may not be insignificant.