Complete Response To Tislelizumab In A Muscle-Invasive Urothelial Carcinoma After Surgery Associated With Tumor Mutational Burden High: A Case Report

Muscle-invasive urothelial carcinoma (MIUC) is a highly aggressive urothelial carcinoma. Radical cystectomy (RC) is standard of treatment, but still more than 50% patients with cancer invading the muscularis propria or involving the regional lymph nodes will have metastatic recurrence. In CheckMate274 study, programmed cell death-1 (PD-1) inhibitor nivolumab as adjuvant treatment has shown effective for patients with MIUC. Tislelizumab is an anti-human PD-1 monoclonal IgG4 antibody which was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. But there is no report of tislelizumab as adjuvant treatment in MIUC currently. Here, we report a case of MIUC in a patient with PD-L1-negative, microsatellite stable (MSS), high tumor mutational burden (TMB-H) obtained complete response (CR) receiving tislelizumab therapy after surgery. Progression-free survival (PFS) exceeded 6 months since tislelizumab treatment. To our knowledge, this is the first reported case of MIUC patient with PD-L1-negative, MSS and TMB-H who responded well to tislelizumab as adjuvant treatment. However, we still need more studies to assess the efficacy of tislelizumab as adjuvant treatment in MIUC and to confirm that TMB is a predicted biomarker of tislelizumab for efficacy.

Upregulation of IFNɣ-mediated chemokines dominate the immune transcriptome of muscle-invasive urothelial carcinoma

Tumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune gene expression patterns, we performed transcriptomic profiling of 40 MIBC archival tumors using the NanoString nCounter Human v.1.1 PanCancer Panel. Findings were validated using the TCGA MIBC dataset. Unsupervised and supervised clustering identified a distinctive immune-related gene expression profile for inflammation, characterized by significant upregulation of 149 genes, particularly chemokines, a subset of which also had potential prognostic utility. Some of the most enriched biological processes were lymphocyte activation and proliferation, leukocyte adhesion and migration, antigen processing and presentation and cellular response to IFN-γ. Upregulation of numerous IFN-γ-inducible chemokines, class II MHC molecules and immune checkpoint genes was detected as part of the complex immune response to MIBC. Further, B-cell markers linked to tertiary lymphoid structures were upregulated, which in turn is predictive of tumor response to immunotherapy and favorable outcome. Our findings of both an overall activated immune profıle and immunosuppressive microenvironment provide novel insights into the complex immune milieu of MIBC with inflammation and supports its clinical significance for predicting prognosis and immunotherapeutic responsiveness, which warrants further investigation. This may open novel opportunities to identify mechanisms for developing new immunotherapeutic strategies.

Lapatinib as first-line treatment for muscle-invasive urothelial carcinoma in dogs

Epidermal growth factor receptors 1 and 2 (EGFR and HER2) are frequently overexpressed in various malignancies. Lapatinib is a dual tyrosine kinase inhibitor that inhibits both EGFR and HER2. Although a phase III trial failed to show the survival benefits of lapatinib treatment after first-line chemotherapy in patients with EGFR/HER2-positive metastatic urothelial carcinoma, the efficacy of lapatinib for untreated urothelial carcinoma is not well defined. Here, we describe the therapeutic efficacy of lapatinib as a first-line treatment in a canine model of muscle-invasive urothelial carcinoma. In this non-randomized clinical trial, we compared 44 dogs with naturally occurring urothelial carcinoma who received lapatinib and piroxicam, with 42 age-, sex-, and tumor stage-matched dogs that received piroxicam alone. Compared to the dogs treated with piroxicam alone, those administered the lapatinib/piroxicam treatment had a greater reduction in the size of the primary tumor and improved survival. Exploratory analyses showed that HER2 overexpression was associated with response and survival in dogs treated with lapatinib. Our study suggests that lapatinib showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use for untreated advanced urothelial carcinoma in dogs. The use of lapatinib as a first-line treatment may be investigated further in human patients with urothelial carcinoma.

Thromboembolic events during neoadjuvant chemotherapy in muscle invasive bladder cancer – any correlation to the central venous access? A clinical practice article

Patients with muscle invasive bladder cancer have a generally known 5-year overall survival of approximately 58% with neoadjuvant chemotherapy (NAC). During the last decades, addition of Cisplatinum-based NAC in fit patients prior to radical cystectomy (RC), has significantly improved OS, compared to RC only. However, some published studies following NAC addition, describe an intermediate risk increase of thromboembolic events (TEEs). Placement of central venous access (CVA) before NAC has also been suggested as being a potential risk factor for thrombosis. We present a combination of images and cases from the Northern Swedish health region where three patients developed venous TEE after CVA placement for NAC-administration and found that the time until curable RC was prolonged circa one month each, with an addition of one RC cancelled. These are serious events and to our knowledge, there are no current guidelines on prevention of TEE before RC. The aim with this report was to provide examples of these events and conclude that further prospective trials are warranted on prevention and future guidelines regarding venous anticoagulant treatment for TEE that occur pre-RC in NAC-patients.

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

Background: Muscle-invasive bladder cancer is a common aggressive disease with unmet clinical needs. Recent work established a set of consensus bladder cancer transcriptomic subtypes that distinguishes the cell identity of bladder cancers for improved diagnosis and treatment. However, how these distinct subtypes are regulated remains unclear. Given the link between super-enhancers and the regulation of cell identity, we hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of the various bladder cancer subtypes. Results: Through integrated RNA sequencing and epigenomic profiling of histone marks (H3K27ac, H3K27me3, H3K9me3) in a diverse panel of 15 primary bladder tumours, seven bladder cancer cell lines, and two primary cultures from normal human urothelia, we established the first integrated epigenetic map of bladder cancer and demonstrate the link between bladder cancer subtype and epigenetic control. Through H3K27ac analysis, we identify the repertoire of activated super-enhancers in bladder cancer that distinguish molecular subtypes. Building on these findings, we reveal the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal bladder cancer subgroups. We find that FOXA1, a key pioneer factor in Luminal bladder cancers identified in our Luminal transcription factor network, binds subgroup-specific bladder super-enhancers and correlates with their activation. Furthermore, CRISPR-Cas9 inactivating mutation of FOXA1 triggers a shift from Luminal to Basal cell identity. This shift is accompanied by an overexpression of ZBED2, one of the newly identified transcriptional regulators in the Basal-specific transcription factor network. Finally, we show that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in bladder cancer cells through STAT2 inhibition and promote cancer cell survival. Conclusions: Overall, our study provides new data for understanding epigenetic regulation of muscle-invasive bladder cancer and identifies a coregulated network of super-enhancers and associated transcription factors as new potential targets for the treatment of this aggressive disease.

Concomitant Radical Cystectomy and Infrarenal Aortic Aneurysm Repair with Cryopreserved Aortic Allograft: A Case Report

In localized muscle invasive bladder cancer (MIBC), the gold standard treatment is radical cystectomy (RC) with bilateral pelvic lymph node dissection (PLND), associated with cisplatin-based neoadjuvant chemotherapy, whereas first-line treatment for metastatic patients is cisplatin-based chemotherapy. In men with an abdominal aortic aneurysm (AAA), elective repair is recommended when its diameter is >5.5 cm, while cryopreserved arterial allografts (CAA) offer resistance to infection. A patient with simultaneous metastatic MIBC, associated with left hydronephrosis, and infrarenal AAA of 49 mm diameter was evaluated in an interdisciplinary study. Concomitant surgery was opted for; first, the AAA repair with CAA implantation was practiced, followed by retroperitoneal and common iliac lymphadenectomy. Thereafter, RC and PLND were conducted, and a Wallace-1 ileal conduit and a stoma were constructed. Chest and abdomen contrast-enhanced CT at 2 months showed the onset of two osteolytic lesions on the left ilium. At oncological re-evaluation the patient was deemed cisplatin-fit.

Prognostic value of hepatocyte growth factor for muscle-invasive bladder cancer

Purpose The HGF/MET pathway is involved in cell motility, angiogenesis, proliferation, and cancer invasion. We assessed the clinical utility of plasma HGF level as a prognostic biomarker in patients with MIBC. Methods We retrospectively analyzed 565 patients with MIBC who underwent radical cystectomy. Logistic regression and Cox regression models were used, and predictive accuracies were estimated using the area under the curve and concordance index. To estimate the clinical utility of HGF, DCA and MCID were applied. Results Plasma HGF level was significantly higher in patients with advanced pathologic stage and LN metastasis (p = 0.01 and p < 0.001, respectively). Higher HGF levels were associated with an increased risk of harboring LN metastasis and non-organ-confined disease (OR1.21, 95%CI 1.12–1.32, p < 0.001, and OR1.35, 95%CI 1.23–1.48, p < 0.001, respectively) on multivariable analyses; the addition of HGF improved the predictive accuracies of a standard preoperative model (+ 7%, p < 0.001 and + 8%, p < 0.001, respectively). According to the DCA and MCID, half of the patients had a net benefit by including HGF, but the absolute magnitude remained limited. In pre- and postoperative predictive models, a higher HGF level was significant prognosticator of worse RFS, OS, and CSS; in the preoperative model, the addition of HGF improved accuracies by 6% and 5% for RFS and CSS, respectively. Conclusion Preoperative HGF identified MIBC patients who harbored features of clinically and biologically aggressive disease. Plasma HGF could serve, as part of a panel, as a biomarker to aid in preoperative treatment planning regarding intensity of treatment in patients with clinical MIBC.