Page 8 - BladderCancerAbstracts

Bladder Cancer Forum 2023 abstracts

Classification of micropapillary and urothelial carcinoma using Results: Our results indicate that, in the absence of a tumor, intravesi-
artificial intelligence-based histopathology image analysis cal BCG treatment leads to increased proportion of neutrophils in the
Graham Archibald , Maryam Asadi , Alberto Contreras-Sanz , bladder, which have been associated with a tumor-permissive niche.
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Hossein Farahani , Walid Eshumani , Peter C. Black , Gang Wang 2,3,4 , Systemic administration of BCG also led to antitumor tumor-draining
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Ali Bashashati 1,2 lymph node and bone marrow microenvironments. The ability of BCG to
1 School of Biomedical Engineering, University of British Columbia, induce trained immunity (TI), a heterologous form of memory acquired by
Vancouver, BC, Canada; Department of Pathology and Laboratory innate immune cells, has recently been characterized. To investigate the
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Medicine, University of British Columbia, Vancouver, BC, Canada; potential contribution of TI to these effects, trained or untrained macro-
3 Vancouver Prostate Centre, Department of Urologic Sciences, Vancouver, phages were co-instilled with MB49-OVA tumor cells into the bladders of
Canada; Department of Pathology and Laboratory Medicine, BC Cancer, mice. The presence of trained macrophages augmented adaptive immune
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Vancouver, BC, Canada responses, as a greater proportion of tumor-specific CD8 T cells were
Introduction: Micropapillary urothelial carcinoma (MPC) is a rare, aggres- present in the bladders of these mice, compared with those instilled with
sive histological subtype that frequently co-occurs with conventional uro- untrained macrophages. Furthermore, BCG-trained dendritic cells exhib-
thelial carcinoma (UC) and comprises 2–5% of all bladder cancers. Proper ited enhanced antigen uptake, presentation, and were able to promote
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identification and reporting of the proportion of MPC subtype are crucial proliferation of CD8 T cells.
for optimal risk stratification and treatment selection. Given the complex Conclusions: Understanding the link between systemic immunity, TI,
histological features of MPC and moderate (κ:0.54) interobserver agree- and the TiME following BCG therapy may facilitate the development of
ment among genitourinary (GU) pathologists, an artificial intelligence new approaches to improve outcomes and reduce recurrence rates in
(AI) tool that can not only reliably identify this subtype but also report patients with NMIBC.
the proportion of it within a sample would be a valuable resource for
pathologists and clinicians. The role of the urinary microbiome in determining response to
Methods: For the training dataset, we identified 29 MPC patients (with intravesical bacillus Calmette-Guérin in high-risk non-muscle-
128 whole slide images, [WSIs]) and 57 UC patients (with 134 WSIs). invasive bladder cancer
For the validation dataset, we obtained 88 MPC cases (with 88 WSIs) and Dalia Othman , Tuomas Jalanko , Moritz Reike , Igor Moskalev ,
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72 UC (with 72 WSIs) from across British Columbia. One GU patholo- Breanna Nelson , Ali Hussein , Carin Tin , Mathieu Roumigué ,
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gist annotated the MPC and UC-containing regions in all WSIs. Due to Demian Ferreira 1,2, Alberto Contreras-Sanz , Moritz Maas , Aaron Miller ,
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differences in scanners and staining conditions, the validation dataset Peter C. Black , Dirk Lange 1,2
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occupies a slightly different color space than the original dataset. We fed 1 The Stone Centre, Department of Urologic Sciences, University of
the data into a ResNet18 model using three-fold cross-validation, which British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre,
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trained to classify these subtypes based on slide-level labels, with each Department of Urologic Sciences, University of British Columbia,
WSI labelled as either MPC or UC. To improve model generalization to Vancouver, BC, Canada; Lerner Research Institute, Department of
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the validation dataset, we normalized the external color space based on Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland,
reference images from the training dataset. OH, United States
Results: Our classification of UC vs. MPC cases using AI attained 91.0% Introduction: Intravesical bacillus Calmette-Guérin (BCG) remains the
slide-level accuracy on the training dataset and 85.6% (p<0.032) slide- first-line treatment for high- and intermediate-risk non-muscle-invasive
level accuracy on our validation dataset. bladder cancer (NMIBC); however, up to 40% of patients recur despite
Conclusions: Using an AI-based approach for histopathology image clas- optimal BCG therapy. Given pre-existing evidence that commensal micro-
sification, we have successfully classified MPC and UC without the use biomes can affect inflammatory and immune responses, we hypothesized
of manual pathologist annotations for identifying tumor regions. These that the urinary microbiome of the bladder may affect the BCG-induced
findings demonstrate AI as a promising tool for the diagnosis of this rare antitumor immune response. The objective of this study was to determine
and aggressive subtype of urothelial carcinoma. Future work will seek whether the urinary microbiome composition impacts BCG responsive-
improvement of our AI algorithm to attain higher accuracy, and further ness in patients and to understand its impact on the BCG-induced immune
validation in an external dataset. Furthermore, we will include additional response using an in vivo mouse model.
histological subtypes. Methods: Urine and stool samples were collected from patients with
high-risk NMIBC before and after first BCG treatment to identify the
Systemic BCG immunotherapy enhances antitumor immunity composition of the urinary and gut microbiomes through metagenomic
in a mouse model of bladder cancer: Novel role of trained sequencing. To assess the role of the urinary microbiome on the BCG-
immunity induced inflammatory response, mice underwent ultrasound-guided instil-
Richard Nauman , Aline Atallah , Arielle Grossman , Adam Khan , lation of BCG into the bladder lumen. The mice had either a healthy
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Jean-François Paré , D. Robert Siemens , Tiziana Cotechini , or a disrupted urinary microbiome. Disruption was achieved through
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Charles H. Graham 1 gentamicin instillation prior to BCG treatment. Whole bladder, spleen,
1 Department of Biomedical and Molecular Science, Queen’s University, and bladder-draining lymph node tissue was collected to assess changes
Kingston, ON, Canada; Department of Urology, Queen’s University, in immune cell populations through fluorescence-activated cell sorting
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Kingston, ON, Canada (FACS) and histology.
Introduction: Despite decades of intravesical bacillus Calmette-Guérin Results: 16s rRNA sequencing from 32 patients demonstrated a loss
(BCG) administration for the management of higher-risk non-muscle-inva- in alpha diversity of both urinary and gut microbiome after treatment.
sive bladder cancer (NMIBC), the mechanism of this immunotherapy is Furthermore, BCG resulted in a significant change of urinary microbiome
not fully understood. Mounting evidence indicates that systemic immune beta diversity. FACS analysis from in vivo studies observed a significant
activation is required for maximal immunotherapeutic benefit, and intra- shift in immune cell populations. Gentamicin instillation induced a pro-
vesical BCG alone may not result in sufficient systemic immune activation inflammatory environment through elevated M1 and reduced M2 macro-
and hence optimal antitumour responses. Here, we compared the effect phages, compared to control; however, subsequent BCG treatment shifted
of intravesical BCG vs. intravenous BCG (to maximize systemic immune the environment towards an anti-inflammatory response by increasing
activation) on antitumor immune responses. M2 and reducing M1 macrophages, which was also observed in mice
Methods: Using a syngeneic orthotopic mouse model of NMIBC, we with a healthy microbiome.
demonstrate a reduction in tumor volume and skew towards an antitumor Conclusions: In patients, BCG induces changes to the composition of the
microenvironment in mice that were treated intravenously with BCG urinary and gut microbiomes. Preliminary findings from in vivo studies
compared with those that received intravesical BCG. demonstrate that disruption of the urinary microbiome alters the immune
S6 CUAJ • MARCH 2023 • VOLUME 17, ISSUE 3(SUPPL1)