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Summary Multiplex immunofluorescence (mIF) staining combined with quantitative digital image analysis is a novel and increasingly used technique that allows for the characterization of the tumor immune microenvironment (TIME). Generally, mIF data is used to examine the abundance of immune cells in the TIME; however, this does not capture spatial patterns of immune cells throughout the TIME, a metric increasingly recognized as important for prognosis. To address this gap, we developed an R package spatialTIME that enables spatial analysis of mIF data, as well as the iTIME web application that provides a robust but simplified user interface for describing both abundance and spatial architecture of the TIME. The spatialTIME package calculates univariate and bivariate spatial statistics (e.g. Ripley’s K, Besag’s L, Macron’s M and G or nearest neighbor distance) and creates publication quality plots for spatial organization of the cells in each tissue sample. The iTIME web application allows users to statistically compare the abundance measures with patient clinical features along with visualization of the TIME for one tissue sample at a time. Availability and implementation spatialTIME is implemented in R and can be downloaded from GitHub (https://github.com/FridleyLab/spatialTIME) or CRAN. An extensive vignette for using spatialTIME can also be found at https://cran.r-project.org/web/packages/spatialTIME/index.html. iTIME is implemented within a R Shiny application and can be accessed online (http://itime.moffitt.org/), with code available on GitHub (https://github.com/FridleyLab/iTIME). Supplementary information Supplementary data are available at Bioinformatics online.

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Key Points Question What is the comparative effectiveness of first-line targeted therapy, immunotherapy, and combination therapy in a real-world cohort of patients with metastatic clear cell renal cell carcinoma? Findings In this propensity-matched cohort study of 5872 patients treated in real-world clinical practice, first-line immunotherapy and combination therapy were associated with improved overall survival compared with first-line targeted therapy. Meaning This study suggests that clinical trial findings demonstrating an overall survival benefit associated with first-line immunotherapy-based regimens compared with targeted therapy are generalizable to a broader population of patients.

IMPORTANCELevel I evidence has failed to demonstrate an overall survival (OS) advantage for cytoreductive nephrectomy in patients with metastatic clear cell renal cell carcinoma (ccRCC) in the modern era, which is at odds with observational studies reporting a marked OS benefit associated with these operations. These observational studies were not designed to adjust for unmeasured confounding.OBJECTIVE To assess whether cytoreductive nephrectomy is associated with improved OS in patients with metastatic ccRCC.

Purpose: Patients with muscle invasive bladder cancer (MIBC) of variant histology have a poor prognosis. It is unclear if neoadjuvant chemotherapy prior to radical cystectomy is associated with pathological downstaging or improved overall survival (OS) for patients with variant histology. Our objective was to assess for associations between receipt of neoadjuvant chemotherapy, pathological downstaging and OS for patients with variant histology MIBC. Materials and Methods: Patients were identified in the National Cancer Database from 2004 to 2017 with MIBC, without metastases, who underwent radical cystectomy. Patients were stratified by histological subgroup, and receipt or nonreceipt of neoadjuvant chemotherapy. Pathological downstaging was defined as pT0N0 or pT 1N0, and OS from the time of diagnosis to date of death or censoring at last followup. Multivariable logistic regression analysis determined associations between neoadjuvant chemotherapy and pathological downstaging. Multivariable Cox regression analysis determined associations between neoadjuvant chemotherapy and OS. Results: A total of 31,218 patients were included in the final study population (urothelial carcinoma [UC]: 27,779; sarcomatoid UC: 501; micropapillary UC: 418; squamous cell carcinoma: 1,141; neuroendocrine carcinoma: 629; adenocarcinoma: 750). Neoadjuvant chemotherapy was associated with pathological downstaging to pT0N0 in all histological subgroups (UC: OR 5. 1 [4.6e5.6]; sarcomatoid UC: OR 13.8 [5.5e39.0]; micropapillary UC: OR 9.7 [2.8e46.8]; squamous cell carcinoma: OR 7.4 [2.1e24.5]; neuroendocrine: OR 4.7 [2.6e9.2]; adenocarcinoma: OR 23.3 [8.0e74.2]). Neoadjuvant chemotherapy was associated with improved OS for UC (HR 0.8 [0.77e0.84]), sarcomatoid UC (HR 0.64 [0.44-0.91]) and neuroendocrine carcinoma (HR 0.55 [0.43e0.70]). Conclusions: Neoadjuvant chemotherapy was associated with pathological downstaging for all MIBC histological variants, with improved OS for patients with UC, sarcomatoid variant UC and neuroendocrine carcinoma.

Purpose:Our primary objective is to detail the incidence, site, and timing of penile squamous cell carcinoma (pSCC) recurrence after inguinal lymph node dissection (ILND).Materials and Methods:We performed a retrospective analysis of 551 patients who underwent ILND for pSCC from 2000 to 2017. The primary outcome was pSCC recurrence after ILND. Recurrences were identified and stratified by site. Timing of recurrence was determined. Multivariable logistic regression analysis determined associations with recurrence. Multivariable Cox regression analysis determined associations with overall survival (OS). Sub-group analysis of the distant recurrences analyzed timing and OS by site of distant recurrence.Results:After ILND pSCC recurred in 176 (31.9%) patients. Median time to recurrence was 10 months for distant recurrences, 12 for inguinal, 10.5 for pelvic, and 44.5 for local. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months of ILND, versus 127 months for local recurrences. Post-ILND recurrence was associated with pN2 (OR 1.99, 95% CI 1.0–4.1), and pN3 (OR 7.2, 95% CI 4.0–13.7). Patients who had local recurrence had similar OS to those without (HR 1.5, 95% CI 0.6–3.8), and worse OS was identified in patients with inguinal (HR 4.5, 95% CI 2.8–7.1), pelvic (HR 2.6, 95% CI 1.5–4.5), or distant (HR 4.0, 95% CI 2.7–5.8) recurrences. Patients with lung recurrences had worse OS than other sites (HR 2.2, 95% CI 1.1–4.3).Conclusions:Of the patients 31.9% had post-ILND recurrence associated with high pN staging. Greater than 95% of distant, inguinal, and pelvic recurrences occurred within 48 months, suggesting surveillance beyond this is low yield. Local recurrences occurred over a longer timeline, emphasizing necessity of long-term surveillance of the primary site.