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BACKGROUND: To assess predictors, indicators and medical necessity of readmissions after neoadjuvant chemotherapy (NAC) and radical cystectomy in order to identify opportunities for reducing readmission rates. METHODS: Records for patients treated with cisplatin-based NAC followed by radical cystectomy between 2007 and 2017 were reviewed for 90-day complications and readmission. Readmissions were classified as necessary vs. discretionary based on independent clinician review. The association between postoperative complications and necessary or discretionary readmission were examined with adjusted regression models. RESULTS: Among a total of 250 patients, 76 patients (30.4%) were readmitted within 90 days of surgery (19 discretionary and 57 necessary). Age, insurance coverage, and comorbidity were similar between readmitted and non-readmitted patients. Readmission was more likely after neobladder than ileal conduit (39% vs. 23%, p=0.02). Major (grade ≥ 3) complications within 90-day of surgery including index admission and post-discharge period were significantly more common among re-admitted patients compared to patients who were not readmitted (40% in necessary, 21% in discretionary, 3% in none, p

Cancer-associated fibroblasts (CAF) are highly prevalent cells in the tumor microenvironment in clear cell renal cell carcinoma (ccRCC). CAFs exhibit a pro-tumor effect in vitro and have been implicated in tumor cell proliferation, metastasis, and treatment resistance. Our objective is to analyze the geospatial distribution of CAFs with proliferating and apoptotic tumor cells in the ccRCC tumor microenvironment and determine associations with survival and systemic treatment. Pre-treatment primary tumor samples were collected from 96 patients with metastatic ccRCC. Three adjacent slices were obtained from 2 tumor-core regions of interest (ROI) per patient, and immunohistochemistry (IHC) staining was performed for αSMA, Ki-67, and caspase-3 to detect CAFs, proliferating cells, and apoptotic cells, respectively. H-scores and cellular density were generated for each marker. ROIs were aligned, and spatial point patterns were generated, which were then used to perform spatial analyses using a normalized Ripley’s K function at a radius of 25 μm (nK(25)). The survival analyses used an optimal cut-point method, maximizing the log-rank statistic, to stratify the IHC-derived metrics into high and low groups. Multivariable Cox regression analyses were performed accounting for age and International Metastatic RCC Database Consortium (IMDC) risk category. Survival outcomes included overall survival (OS) from the date of diagnosis, OS from the date of immunotherapy initiation (OS-IT), and OS from the date of targeted therapy initiation (OS-TT). Therapy resistance was defined as progression-free survival (PFS) &lt, 6 months, and therapy response was defined as PFS &gt, 9 months. CAFs exhibited higher cellular clustering with Ki-67+ cells than with caspase-3+ cells (nK(25): Ki-67 1.19, caspase-3 1.05, p = 0.04). The median nearest neighbor (NN) distance from CAFs to Ki-67+ cells was shorter compared to caspase-3+ cells (15 μm vs. 37 μm, respectively, p &lt, 0.001). Multivariable Cox regression analyses demonstrated that both high Ki-67+ density and H-score were associated with worse OS, OS-IT, and OS-TT. Regarding αSMA+CAFs, only a high H-score was associated with worse OS, OS-IT, and OS-TT. For caspase-3+, high H-score and density were associated with worse OS and OS-TT. Patients whose tumors were resistant to targeted therapy (TT) had higher Ki-67 density and H-scores than those who had TT responses. Overall, this ex vivo geospatial analysis of CAF distribution suggests that close proximity clustering of tumor cells and CAFs potentiates tumor cell proliferation, resulting in worse OS and resistance to TT in metastatic ccRCC.

BackgroundIt is highly contested whether cytoreductive nephrectomy for treating advanced renal cell carcinoma (RCC) with sarcomatoid features (sRCC) benefits overall survival. Patients with sRCC are known to have a poor prognosis, and these tumors have a more aggressive biology than those without sarcomatoid features.MethodsPatients with clear cell RCC or non–clear cell RCC underwent cytoreductive nephrectomy in efforts to improve overall survival (OS). Patients were stratified by presence or absence of histologic sarcomatoid features within tumor samples.ResultsOf 167 patients who underwent cytoreductive nephrectomy, 127 had clear cell RCC, of whom 14 had sarcomatoid features, and 40 had non–clear cell RCC, of whom 13 had sarcomatoid features. Median age of the cohort was 62 years (range, 56.5–69 years). The cohort included 119 male (71.3%) and 48 (28.7%) female patients. Among all patients with advanced RCC, having sRCC had a significantly worse OS after cytoreductive nephrectomy (30 vs 8 months; hazard ratio [HR], 2.88; P P =0.00016). For patients with clear cell RCC, having sRCC conferred a significantly poorer survival (30 vs 9 months; HR, 2.82; P=0.0035). Patients with non–clear cell sRCC also had significantly worse outcomes compared to patients whose tumors did not have sarcomatoid features (30 vs 6.5 months; HR, 3; P =0.009). When patients with sRCC were stratified by whether there was >10% or ≤10% sarcomatoid features present within the sample, there was no significant difference in OS (8 vs 8.5 months; P =0.32).ConclusionsSarcomatoid features within tumor histology confer significantly poor prognosis. Patients with sRCC, regardless of clear cell vs non–clear cell histology, have significantly shorter OS. Even among patients with 10% or less sarcomatoid features, there was no OS benefit to cytoreductive nephrectomy. Based on our findings, there appears to be a limited to no role of cytoreductive nephrectomy if sRCC is identified on pretreatment biopsy. The role of radiomics and pre-operative biopsies may confer significant benefit in this patient population.

Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular density and cellular clustering for myeloid cell markers in 129 regions of interest from 55 samples from 35 patients with metastatic ccRCC. CD68+ cells were found to be clustered with tumor cells and dispersed from stromal cells, while CD163+ and CD206+ cells were found to be clustered with stromal cells and dispersed from tumor cells. CD68+ density was not associated with OS, while high tumor/CD68+ cell clustering was associated with significantly worse OS. These novel findings would not have been identified if immune infiltrate was assessed using cellular density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors.SIGNIFICANCEIncreased clustering of CD68+ TAMs and tumor cells was associated with worse overall survival for patients with metastatic ccRCC. This effect would not have been identified if immune infiltrate was assessed using cell density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors.

Background Emerging evidence from studies in sarcoma and melanoma immune checkpoint blockade(ICB) trials demonstrated enhanced efficacy in tumors harbouring tertiary lymphoid structures(TLS)1–3 - lymph node like aggregates in the tumor microenvironment postulated to recruit lymphocyte infiltration and coordinate tumor antigen presentation and lymphocyte priming. Previously, our group described a 12-chemokine metagene signature that reflects strong intratumoral chemotactic signalling and accurately predicts the presence of TLS in colorectal carcinoma.4 Grounded in these works, we attempted to correlate high 12CK signature with TLS formation in the context of muscle invasive bladder cancer(MIBC), and then sought to define its prognostic implications and its ability to predict response to ICB. Methods A total of 130 MIBC samples were arrayed on Affymetrix microarrays and 12CK scores were assessed. Scores were normalized using 12CK>1 to denote 12CK-High(n=24). We then investigated the the presence of TLS with the associated immune cellular infiltration evaluated by immunohistochemistry and gene signature deconvolution method (xCell).5 12CK scores were also correlated with survival in our institutional cohort and validated using data from TCGA. Finally, 12CK scores were extracted from the IMVIGOR210 study to examine its ability to predict response to ICB.6 Results Type III TLS, consisting of germinal center-like structures and discrete T-cell zones were found in 7/22 12CK-High vs. 0/21 12CK-Low tumors (p=0.009) (figure 1a). Additionally, a more robust immuno-environment was seen in 12CK-High tumors, consisting of increased infiltration of CD4+ T lymphocytes (p=0.1), CD8+ T lymphocytes (p=0.02), activated dendritic cells (p=0.047), and B lymphocytes (p=0.006) on immunohistochemistry (figure 1b). Furthermore, on xCell deconvolution, M1 macrophage, NK cells, CD8+ Tem, CD4+ Tem, and memory B cells were enriched in 12CK-High tumors, suggesting both a heightened innate and adaptive immune response (figure 1c, d). Kaplan-Meier survival analyses of our internal cohort revealed improved PFS (HR 0.25, p=0.003 ), CSS (HR 0.25, p=0.003), and OS (HR 0.55, p=0.03) amongst 12CK-High patients (figure 2a-c). From the TCGA, similar improvements were found in PFS (HR 0.55, p=0.007), CSS (HR 0.40, p=0.002), and OS (HR 0.59, p=0.01) in 12CK-High patients (figure 2d-f). From the IMVIGOR 210 study, complete responders exhibited significantly higher 12-CK scores than all other groups (figure 2g). Strikingly, the 12CK-High signature conferred a median overall survival benefit of almost 1 year in the atezolizumab-treated patients (figure 2h). Conclusions In muslce invasive bladder cancer, 12CK-High scores corresponded with formation of TLS in the TME; favourable prognosis in surgically treated MIBC patients; and CR in atezolizumab-treated patients. References Cabrita R, Lauss M, Sanna A, et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 2020;577(7791):561–565. Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 2020;577(7791):549–555. Petitprez F, de Reynies A, Keung EZ, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 2020;577(7791):556–560. Aran D, Hu Z, Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome biology 2017;18(1):220. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (London, England). 2016;387(10031):1909–1920.

PURPOSE: Although neoadjuvant chemotherapy is associated with a survival advantage in pure urothelial, muscle invasive bladder cancer, the role of neoadjuvant chemotherapy is less clear in variant histology or urothelial carcinoma with divergent differentiation. We compared chemotherapy response and survival outcomes of patients with nonpure urothelial carcinoma histology who were managed with neoadjuvant chemotherapy followed by cystectomy vs cystectomy alone. MATERIALS AND METHODS: We analyzed 768 patients with clinical muscle invasive bladder cancer (cT2–4N0M0) who were treated with cystectomy at a tertiary care center from 2007 to 2017. Patients were stratified by histology and treatment strategy. Adjusted logistic and Cox regression models were used to evaluate pathological downstaging, cancer specific survival and overall survival. RESULTS: The cohort consisted of 410 patients (53%) with pure urothelial carcinoma, 185 (24%) with urothelial carcinoma with divergent differentiation and 173 (23%) with variant histology. Overall, 314 patients (41%) received neoadjuvant chemotherapy prior to cystectomy. There were similar rates of complete (18% to 30%) and partial (37% to 46%) pathological downstaging with neoadjuvant chemotherapy across all histological subgroups (p=0.30 and p=0.40, respectively). However, while patients with pure urothelial carcinoma experienced an overall survival benefit (HR 0.71, 95% CI 0.51–0.98, p=0.0013) and those with variant histology experienced a cancer specific survival benefit (HR 0.55, 95% CI 0.30–0.99, p=0.0495) with neoadjuvant chemotherapy, patients with urothelial carcinoma with divergent differentiation did not experience overall or cancer specific survival benefits with the use of neoadjuvant chemotherapy prior to cystectomy. CONCLUSIONS: Among patients with muscle invasive bladder cancer those with nonpure urothelial carcinoma histology with variant histology achieved nearly equivalent response rates and survival benefits with the use of neoadjuvant chemotherapy as those with pure urothelial carcinoma, while patients with urothelial carcinoma with divergent differentiation experienced significantly worse survival outcomes regardless of the use of neoadjuvant chemotherapy prior to cystectomy.

Therapy for early stage testicular seminoma has changed radically over the past several decades. Given high cure rates and clinical trials supporting less active therapy in most cases, close observation after radical orchiectomy is now considered standard of care for clinical stage (CS) IA/IB seminoma, with either radiation therapy (RT) or chemotherapy salvage options possible. For CS IIA/IIB seminoma characterized by non-bulky retroperitoneal lymph node involvement (≤5 cm in greatest dimension), RT or combination chemotherapy are the standard of care. Given high comparable survival rates, preventing treatment-related toxicity and second malignancy, and limiting quality of life deficits associated with intense treatment has gained much greater importance. Clinical trials are currently testing the feasibility of retroperitoneal lymph node dissection (RPLND) for low volume CS IIA/IIB metastatic testicular seminoma to this end. Likewise, one cycle of chemotherapy is being evaluated as an adjuvant approach to reduce recurrence rates in CS I disease with unfavorable risk factors. Moreover, recent genomic and molecular studies have recently identified novel signatures and a potential biomarker for testicular seminoma. In this review, we first summarize the evolution of early stage seminoma management and discuss the effectiveness and drawbacks of contemporary treatment strategies. We further outline future perspectives and potential challenges in management of early stage testicular seminoma.

Parkinson's disease is a debilitating movement disorder characterized by altered levels of alpha(6)beta(2) * ( * indicates the possible presence of additional subunits) nicotinic acetylcholine receptors (nAChRs) localized on presynaptic striatal catecholaminergic neurons. alpha-Conotoxin MII (alpha-CTx MII) is a highly useful ligand to probe alpha(6)beta(2) nAChRs structure and function, but it does not discriminate among closely related alpha(6) * nAChR subtypes. Modification of the alpha-CTx MII primary sequence led to the identification of alpha-CTx MII[E11A], an analog with 500-5300-fold discrimination between alpha(6) * subtypes found in both human and non-human primates. alpha-CTx MII[E11A] binds most strongly (femtomolar dissociation constant) to the high affinity alpha(6) nAChR, a subtype that is selectively lost in Parkinson's disease. Here, we present the three-dimensional solution structure for alpha-CTx MII[E11A] as determined by two-dimensional (1)H NMR spectroscopy to 0.13+/-0.09A backbone and 0.45+/-0.08A heavy atom root-mean-square deviation from mean structure. Structural comparisons suggest that the increased hydrophobic area of alpha-CTx MII[E11A] relative to other members of the alpha-CTx family may be responsible for its exceptionally high affinity for alpha6alpha4beta2 * nAChR as well as discrimination between alpha(6)beta(2) and alpha(3)beta(2) containing nAChRs. This finding may enable the rational design of novel peptide analogs that demonstrate enhanced specificity for alpha(6) * nAChR subunit interfaces and provide a means to better understand nAChR structural determinants that modulate brain dopamine levels and the pathophysiology of Parkinson's disease.