Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients

Background: Immune therapy has gained significant importance in managing urothelial cancer. The value of PD-L1 remains a matter of controversy, thus requiring an in-depth analysis of its biological and clinical relevance. Methods: A total of 193 tumors of muscle-invasive bladder cancer patients (MIBC) were assessed with four PD-L1 assays. PD-L1 scoring results were correlated with data from a comprehensive digital-spatial immune-profiling panel using descriptive statistics, hierarchical clustering and uni-/multivariable survival analyses. Results: PD-L1 scoring algorithms are heterogeneous (agreements from 63.1% to 87.7%), and stems from different constellations of immune and tumor cells (IC/TC). While Ventana IC5% algorithm identifies tumors with high inflammation and favorable baseline prognosis, CPS10 and the TCarea25%/ICarea25% algorithm identify tumors with TC and IC expression. Spatially organized immune phenotypes, which correlate either with high PD-L1 IC expression and favorable prognosis or constitutive PD-L1 TC expression and poor baseline prognosis, cannot be resolved properly by PD-L1 algorithms. PD-L1 negative tumors with relevant immune infiltration can be detected by sTILs scoring on HE slides and digital CD8+ scoring. Conclusions: Contemporary PD-L1 scoring algorithms are not sufficient to resolve spatially distributed MIBC immune phenotypes and their clinical implications. A more comprehensive view of immune phenotypes along with the integration of spatial PD-L1 expression on IC and TC is necessary in order to stratify patients for ICI.

Download Full-text

Effect of variant histology presence and squamous differentiation on oncological results and patient’s survival after radical cystectomy

Archivio Italiano di Urologia e Andrologia ◽

10.4081/aiua.2018.3.172 ◽

2018 ◽

Vol 90 (3) ◽

pp. 172-175 ◽

Cited By ~ 2

Author(s):

Ertugrul Sefik ◽

Serdar Celik ◽

Ismail Basmaci ◽

Serkan Yarımoglu ◽

Ibrahim Halil Bozkurt ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Cancer Patients ◽

Radical Cystectomy ◽

Urothelial Cancer ◽

Squamous Differentiation ◽

Cancer Specific Survival ◽

T Stage ◽

Significant Difference ◽

Variant Histology ◽

Muscle Invasive

Objective: To evaluate the effect of variant histology on pathological and survival findings in patients undergoing radical cystectomy due to muscle invasive bladder cancer. Materials and methods: Data from 146 patients with radical cystectomy performed due to muscle-invasive urothelial carcinoma between January 2006 to November 2016 at our clinic were investigated. The preoperative and postoperative data of patients with variant histology were compared with nonvariant urothelial carcinoma patients. Then of patients with variant histology only those with squamous differentiation (SqD) were compared with nonvariant urothelial carcinoma patients in terms of preoperative, postoperative and survival data. Results: Of the 146 patients, 23 had carcinoma with variant histology. Of these, 17 had SqD, 4 had glandular differentiation, 1 patient had plasmocytoid variant and 1 patient had sarcomatoid variant. In patients with variant histology, postoperative T stage and upstaging was higher, with no difference observed in terms of overall and cancer-specific survival compared with nonvariant urothelial cancer patients. SqD patients were observed to have higher postoperative T stage compared to nonvariant urothelial cancer patients, with no significant difference observed in terms of survival. Conclusions: In cystectomy pathologies, patients with variant histology (especially SqD patients) were observed to have proportionally higher T stage compared to nonvariant urothelial carcinoma; however there were no significant differences for overall survival and cancer-specific survival.

Download Full-text

Augmenting TNM staging with machine learning-based immune profiling for improved prognosis prediction in muscle-invasive bladder cancer patients

Annals of Oncology ◽

10.1093/annonc/mdy269.091 ◽

2018 ◽

Vol 29 ◽

pp. viii28-viii29 ◽

Cited By ~ 3

Author(s):

N. Brieu ◽

C.G. Gavriel ◽

D.J. Harrison ◽

G. Schmidt ◽

P.D. Caie

Keyword(s):

Machine Learning ◽

Bladder Cancer ◽

Cancer Patients ◽

Tnm Staging ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Prognosis Prediction ◽

Muscle Invasive ◽

Immune Profiling

Download Full-text

FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients

Case Medical Research ◽

10.31525/fda1-ucm612484.htm ◽

2018 ◽

Author(s):

Keyword(s):

Cancer Patients ◽

Urothelial Cancer

Download Full-text

High Apelin Level Indicates a Poor Prognostic Factor in Muscle-Invasive Bladder Cancer

Disease Markers ◽

10.1155/2019/4586405 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Long Yang ◽

Yan-Lei Li ◽

Xiao-Qing Li ◽

Zheng Zhang

Keyword(s):

Bladder Cancer ◽

Cancer Patients ◽

Vascular Invasion ◽

Tumor Stage ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Kaplan Meier ◽

Tumor Tissues ◽

High Tumor Stage ◽

Muscle Invasive

Purpose. To compare the expression level of apelin in muscle-invasive bladder cancer and matched paracarcinoma tissues and investigate the relationship between apelin and clinical prognosis in the patients. Methods. To assess apelin expression by using immunohistochemical method compared with bladder tumors and matched paracarcinoma tissues. Subsequently, the correlation of apelin expression with the clinicopathological features of bladder cancer patients was analyzed. Kaplan-Meier survival curves method was used to analyze apelin prognostic significance for muscle-invasive bladder cancer patients (including 404 muscle-invasive bladder cancer patients and 28 normal bladder tissues, in TCGA dataset). Results. Apelin protein level was overexpressed in bladder tumor tissues compared with paracarcinoma tissues. Furthermore, high apelin expression was associated with high tumor stage (P<0.05), distant metastasis (P<0.05), and vascular invasion (P<0.05). Kaplan-Meier curve analyses showed that the overexpression of apelin was a potential predictor of overall survival and disease-free survival. Conclusion. Apelin was upregulated in bladder tumor tissues compared with matched adjacent noncancer tissues, especially in the high tumor stage, distant metastasis, and vascular invasion. What is more, high expression of apelin in muscle-invasive bladder cancer indicates the poor prognosis. These data suggested that apelin might be a therapeutic potential biomarker in muscle-invasive bladder cancer patients.

Download Full-text

A qualitative evaluation of a nurse-led pre-operative stoma education program for bladder cancer patients

Supportive Care in Cancer ◽

10.1007/s00520-021-06093-0 ◽

2021 ◽

Author(s):

Elizabeth Marie Wulff-Burchfield ◽

Maryellen Potts ◽

Katherine Glavin ◽

Moben Mirza

Keyword(s):

Bladder Cancer ◽

Cancer Patients ◽

Education Program ◽

Management Practices ◽

Self Management ◽

Invasive Bladder Cancer ◽

Educational Approach ◽

Muscle Invasive Bladder Cancer ◽

Patient Advocate ◽

Muscle Invasive

Abstract Introduction Radical cystectomy remains the standard of care for muscle-invasive bladder cancer and high-risk non-muscle-invasive bladder cancer. Postoperative ostomy education is common, but patients struggle to maintain self-management practices. A preoperative ostomy education program was developed to meet this need, and we conducted a qualitative study with participating patient-caregiver dyads to evaluate the educational and psychosocial impacts of the program and examine alignment with program objectives. Materials and methods A qualitative descriptive study was conducted utilizing a thematic analysis approach. Sixteen patients, eighteen caregivers, and three program educators completed semi-structured interviews from 3 to 18 months post the program. Interviews were audio-recorded and transcribed. Thirteen end-of-course surveys from the initial educational program cohort were transcribed, coded, analyzed; this data was triangulated with patient, caregiver, and educator interviews. Results Analysis uncovered three themes: (1) Patient and caregiver motivation to attend the program, (2) attitudes toward this life-changing event, and (3) education. For theme 1, patients and caregivers cited lack of knowledge, fear, and concern about ostomy surgery and care as motivation. For theme 2, there were a variety of attitudes toward the ostomy, ranging from avoidance to acceptance, and a similar breadth of attitudes toward caregiving, with some patients and caregivers describing ongoing dependence and other patients seeking complete independence. For theme 3, the interactive curriculum was determined to be effective, and the patient advocate was cited as the most memorable program component. Conclusions A formal preoperative ostomy education program employing an interactive educational approach and featuring a patient advocate can prepare bladder cancer patients and caregivers for ostomy self-management and post-ostomy life.

Download Full-text

Characterizing the Tumor Immune Microenvironment with Tyramide-Based Multiplex Immunofluorescence

Journal of Mammary Gland Biology and Neoplasia ◽

10.1007/s10911-021-09479-2 ◽

2020 ◽

Vol 25 (4) ◽

pp. 417-432

Author(s):

Hidetoshi Mori ◽

Jennifer Bolen ◽

Louis Schuetter ◽

Pierre Massion ◽

Clifford C. Hoyt ◽

...

Keyword(s):

Tumor Microenvironment ◽

Multispectral Imaging ◽

Imaging System ◽

Predictive Biomarkers ◽

Cell Types ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Manual Processing ◽

Cell Densities ◽

Immune Profiling

AbstractMultiplex immunofluorescence (mIF) allows simultaneous antibody-based detection of multiple markers with a nuclear counterstain on a single tissue section. Recent studies have demonstrated that mIF is becoming an important tool for immune profiling the tumor microenvironment, further advancing our understanding of the interplay between cancer and the immune system, and identifying predictive biomarkers of response to immunotherapy. Expediting mIF discoveries is leading to improved diagnostic panels, whereas it is important that mIF protocols be standardized to facilitate their transition into clinical use. Manual processing of sections for mIF is time consuming and a potential source of variability across numerous samples. To increase reproducibility and throughput we demonstrate the use of an automated slide stainer for mIF incorporating tyramide signal amplification (TSA). We describe two panels aimed at characterizing the tumor immune microenvironment. Panel 1 included CD3, CD20, CD117, FOXP3, Ki67, pancytokeratins (CK), and DAPI, and Panel 2 included CD3, CD8, CD68, PD-1, PD-L1, CK, and DAPI. Primary antibodies were first tested by standard immunohistochemistry and single-plex IF, then multiplex panels were developed and images were obtained using a Vectra 3.0 multispectral imaging system. Various methods for image analysis (identifying cell types, determining cell densities, characterizing cell-cell associations) are outlined. These mIF protocols will be invaluable tools for immune profiling the tumor microenvironment.

Download Full-text

Longitudinal Follow‐up and Performance Validation of a mRNA‐based Urine Test (Xpert® Bladder Cancer Monitor) for surveillance in Non‐Muscle Invasive Bladder Cancer Patients

BJU International ◽

10.1111/bju.15418 ◽

2021 ◽

Author(s):

Barrett Cowan ◽

Eric Klein ◽

Ken Jansz ◽

Karl Westenfelder ◽

Timothy Bradford ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Patients ◽

Invasive Bladder Cancer ◽

Urine Test ◽

Muscle Invasive Bladder Cancer ◽

And Performance ◽

Muscle Invasive ◽

Performance Validation

Download Full-text

Long-Term Outcomes and Costs Among BCG-treated High-Risk Non-Muscle Invasive Bladder Cancer Patients in an Equal Access Setting

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2020.10.041 ◽

2020 ◽

Vol 38 (12) ◽

pp. 902

Author(s):

SB Williams ◽

LE Howard ◽

ML Foster ◽

Z Klaassen ◽

H Li ◽

...

Keyword(s):

Bladder Cancer ◽

High Risk ◽

Cancer Patients ◽

Equal Access ◽

Invasive Bladder Cancer ◽

Long Term Outcomes ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive

Download Full-text

186 Distinct immune signatures predicting clinical response to PD-1 blockade therapy in gynecological cancers revealed by high-dimensional immune profiling

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0186 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A200-A200

Author(s):

Yuki Muroyama ◽

Sasikanth Manne ◽

Alexandar Huang ◽

Divij Mathew ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Endometrial Cancer ◽

T Cell ◽

Clinical Response ◽

Cancer Patients ◽

T Cell Response ◽

High Dimensional ◽

Uterine Endometrial Cancer ◽

Immune Profiling

BackgroundAlthough immune checkpoint blockade revolutionized cancer therapy, response rates have been mixed in gynecological malignancies. While uterine endometrial cancer with high microsatellite instability (MSIHI) and high tumor mutational burden (TMB) respond robustly to checkpoint blockade, high-grade serous ovarian cancer (HGSOC) with low TMB respond modestly. Currently, there has been no known immune signature or T cell phenotype that predicts clinical response in gynecological tumors.MethodsTo dissect the immune landscape and T cell phenotypes in gynecological cancer patients receiving PD-1 blockade, we used high-dimensional cytometry (flow cytometry and mass cytometry (CyTOF)). We performed longitudinal deep immune profiling of PBMC from patients with recurrent uterine endometrial cancer receiving single-arm nivolumab, and HSGOC patients receiving neoadjuvant nivolumab plus platinum-based chemotherapy prior to debulking surgery.ResultsChemotherapy-resistant MSI-H uterine cancer patients treated with nivolumab had a proliferative T cell response 2–4 weeks post PD-1 blockade, consistent with responses seen in high TMB melanoma and lung cancer. The responding Ki67+ CD8 T cell population was largely CD45RAloCD27hi or CD45RAloCD27lo and highly expressed PD1, CTLA-4, and CD39, consistent with the phenotype of exhausted T cells (TEX). These exhausted-like cells are enriched in responders, whereas early expansion Tregs are enriched in non-responders. Unlike patients with uterine endometrial cancer, patients with TMBlo ovarian cancer did not have a clear proliferative CD8 T cell response after neoadjuvant nivolumab plus chemotherapy treatment, suggesting systemic immune suppression. At baseline, ovarian cancer without recurrence have more terminally differentiated effector-like CD8 T cells, and patients with recurrence have more naive-like cells. Thus, both high and low TMB gynecological tumors have distinct immune landscapes associated with clinical response. Additionally, in MSI-H uterine endometrial cancer patients, the length of time between the prior chemotherapy and the initiation of immunotherapy was negatively correlated with T cell reinvigoration post immunotherapy and clinical response. This suggests the importance of optimize therapeutic timing to maximize the therapeutic efficacy when combining immunotherapy and chemotherapy.ConclusionsCollectively, our immune profiling revealed the distinct immune signatures associated with clinical response to PD-1 blockade in gynecological cancers. Our results also suggest that TMBhi inflamed versus TMBlo cold tumor microenvironment, and timing of chemo/immunotherapy could impact differentiation and functions of T cells.Ethics ApprovalThe study was approved by MSKCC Ethics Board, approval number 17–180 and 17–182.

Download Full-text