Muscle-invasive Transitional Cell Carcinoma Research Articles

Systemic Inflammatory Index: A Promising Non-Invasive Marker for the Prediction of Response to Neoadjuvant Chemotherapy prior to Cystectomy

Introduction: The main challenge to the optimal use of neoadjuvant chemotherapy (NAC) is the difficulty in selecting patients who may or may not benefit from NAC. Our aim in this study was to investigate whether the Systemic Inflammatory Index (SII) predicts response to chemotherapy in patients who receive NAC prior to cystectomy. Methods: We retrospectively analysed the data of patients who underwent NAC followed by cystectomy at our institution between January 2010 and September 2015 and whose 5-year follow-up was completed. All patients who underwent diagnostic biopsy with complete transurethral resection of bladder tumour at our hospital and whose pathology result was muscle-invasive transitional cell carcinoma were included in the study. At least 3 courses of gemcitabine/cisplatin NAC were given to all patients. A pathological response was defined as a reduction in cystectomy to a lower pathological stage after NAC. Results: The SII was 320.8 ± 51 in the responders and 388.28 ± 50 in the non-responders. SII optimal cut-off of 350 was determined. The sensitivity and specificity of SII in predicting response were found to be 80% and 83%, respectively. Low SII (Conclusion: SII, together with known clinicopathological factors and newer genetic and molecular markers, can be used to select patients for NAC.

The Bristol Bladder Trial: Five year outcomes in patients treated with neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle invasive transitional cell carcinoma of the urinary bladder.

493 Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy of cabazitaxel with cisplatin in this patient group. These patients have now been followed for survival status for 5 years post NAC and radical cystectomy. Methods: This was a single arm (Simon 2 stage), phase 2 study. Patients with MIBC were included if fit to receive NAC and to undergo radical cystectomy. 26 evaluable patients were required to detect an objective response rate (ORR) of >35% with 80% power. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging, ≥T2 at diagnosis to ≤T1 at cystectomy). Treatment was with cisplatin 70mg/m2 and cabazitaxel 15mg/m2 on day 1 of a 21-day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. QoL data was assessed during and after chemotherapy using EQ-5D-5L and EORTC-QLQ-C30, BLM30 questionnaires. Patients were followed for 5 years post cystectomy for progression free survival (PFS) and overall survival (OS). Results: ORR was seen in 15 out of 26 evaluable patients, 57.7%, with 24.6% achieving pCR. 1 out of 15 patients who achieved ORR died due to disease progression in the 5 year follow up period. The median PFS and OS were not reached by the 5 year follow up time point with a 5 year survival rate of 65.4% being seen in this patient cohort. Median OS in non-responders (11 patients) was 20.5 months and 5 year survival rate for the non-responders was 36.4% compared to 93.3% for responders. Conclusions: Neoadjuvant cabazitaxel with cisplatin chemotherapy is an effective regimen with 65.4% patients alive and progression-free at 5 years. It also indicates that ORR (and not just pCR), is a good predictor of patient survival at 5 years post radical cystectomy with only 1 out of 15 patients who achieved ORR progressing and dying in this period. However, in current clinical practice, there are no validated predictive biomarkers regarding potential response to NAC. Taken together with our previously published data, cabazitaxel with cisplatin as neoadjuvant chemotherapy is a safe, well-tolerated and effective regimen and should be compared to the regimens e.g. cisplatin/gemcitabine considered as standard in this setting. Clinical trial information: NCT01616875 .

Unusual Presentation of Bladder Tumour: Haematuria only after Administration of Anti-Platelet Drugs

Anti-thrombotic agents are used for the treatment and prevention of cardiovascular diseases. Bleeding is the most important side-effect of these agents. The common causes of haematuria after anti-thrombotic administration are benign prostatic hyperplasia, haemorrhagic cystitis, renal calculi, renal infarction, infection, and adult polycystic kidney disease. Haematuria only after anti-thrombotic administration can be the presentation of a bladder tumour. Here, 71 years old male patient, with a bladder tumour was reported, who presented with haematuria only after he took dual anti-platelet drugs (tablet Ecosprin and tablet Clopidogrel). He took these drugs after he underwent the insertion of cardiac stents. He never had any previous history of haematuria. After the complaint, ultrasonography was performed and it reported a normal urinary system. So, the anti-platelet drugs were suspected to be the cause of haematuria. Tablet Clopidogrel was stopped and patient was sent home on Tablet Ecosprin. However, one month later, he again developed haematuria. Repeat imaging studies (ultrasonography and computed tomography) detected a urinary bladder mass. Transurethral resection of the mass was performed and a biopsy reported high-grade, muscle-invasive transitional cell carcinoma. This case highlights the fact that all cases of haematuria, irrespective of anti-thrombotic agents’ administration, should be suspected to be due to urological malignancy and the patients should undergo complete urological investigations, including cystoscopy.

Characterizing the molecular and immune landscape of canine bladder cancer.

Transitional cell carcinoma (TCC), also known as urothelial carcinoma, is the most common bladder cancer in humans and dogs. Approximately one-quarter of human TCCs are muscle-invasive and associated with a high risk of death from metastasis. Canine TCC (cTCC) tumours are typically high-grade and muscle-invasive. Shared similarities in risk factors, histopathology, and clinical presentation suggest that cTCC may serve as a model for the assessment of novel therapeutics that may inform therapies for human muscle-invasive TCC. The goal of this study was to characterize cTCC at the molecular level to identify drivers of oncogenesis and druggable targets. We performed whole exome sequencing (WES) of 11 cTCC tumours and three matched normal samples, identifying 583 variants in protein-coding genes. The most common variant was a V-to-E missense mutation in BRAF, identified in 4 out of 11 samples (36%) via WES. Sanger sequencing identified BRAF variants in 8 out of the same 11 cTCC samples, as well as in 22 out of 32 formalin-fixed paraffin embedded (FFPE) cTCC samples, suggesting an overall prevalence of 70%. RNA-Seq was performed to compare the gene expression profiles of cTCC tumours to normal bladder tissue. cTCC tumours exhibited up-regulation of genes involved in the cell cycle, DNA repair, and antiviral immunity. We also analysed the immune landscape of cTCC using immune gene signatures and immunohistochemical analysis. A subset of tumours had characteristics of a hot tumour microenvironment and exhibited high expression of signatures associated with complete response to PD-1/PD-L1 blockade in human bladder cancer.

Treatment Modalities of Muscle Invasive Transitional Cell Carcinoma of Bladder

The treatment of muscle invasive bladder cancer (MIBC) is complex. This review describes the available therapies for invasive urothelial carcinoma. Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) and lymph node dissection has been considered the slandered treatment for MIBC. Many patients those are unfit for surgery or cisplatin ineligible, bladder sparing strategies are considered in highly selected patients. Even though there are no level I data, the treatment outcomes for highly select patients given bladder sparing therapy appear promising, with many patients retaining a functional bladder. So it can be concluded that treatment of MIBC is a multidisciplinary collaborative program of surgery, radiation and medical oncology.
 Bangladesh Journal of Urology, Vol. 23, No. 2, July 2020 p.205-209

Intravesical Gemcitabine and Mitomycin C Chemotherapy in the Treatment of Non Muscle Invasive Transitional Cell Carcinoma of Urinary Bladder - a Randommized Clinical Trial

Objective:To compare the efficacy of Gemcitabine and Mitomycin C in the treatment of non muscle invasive transitional cell carcinoma of urinary bladder.
 Methods: This study was a randomized clinical trial conducted between the periods of November’2013 to October’2014 in the Department of Urology, Bangabandhu Sheikh Mujib Medical University (BSMMU) The patients with histopathologicaly diagnosed as non muscle invasive transitional cell carcinoma of urinary bladder after complete TURBT were included in the study. Total 54 patients were included in this study ( 27 patients in each group). Those treated with intravesical Gemcitabine were considered as experimental group and those treated with intravesical Mitomycin C (MMC) considered as control group. Intravesical Inj. Gemcitabine and Mitomycin C mg dissolved in 50 ml of normal saline and instilled into the urinary bladder through Foley urethral catheter in the considered group and kept for two hour after getting the histopathology report. Same schedule was maintained weekly for 6 weeks. All patients were followed up at 6 weeks after 1st cycle of intravesical instillation then 3 monthly for 1 year.
 Result : Presence of recurrence of tumour was found non-significant in Gemcitabine and Mitomycin C group (18.5% vs. 40.7%, p= 0.074). Recurrence free survival was found 81.5% patients in Gemcitabine group and that of 59.3% patients in Mitomycin group. Though there was more recurrence free survival in gemcitabine group than mitomycin group, there was no statistically significant difference. Tumour grade progression was found in 20% and 27.3% cases in Gemcitabine and Mitomycin C group respectively. On the other hand, tumour stage progression was found 40.0% and 27.3% patients in Gemcitabine and Mitomycin C group respectively. No statistically significant difference was observed between Groups (P>0.05). Haematuria, dysuria, urinary frequency, urgency and contact dermatitis were found non-statistically significant in both groups.
 Conclusion : Gemcitabine and Mitomycin C both drugs are effective as intravesical chemotherapy in the treatment of non muscle invasive transitional cell carcinoma of urinary bladder and have a better recurrence free survival. But, accounting statistical significance on chemopreventive activity, neither Gemcitabine nor Mitomycin C therapy showed superiority over each other.
 Bangladesh Journal of Urology, Vol. 22, No. 1, January 2019 p.25-29

Pathological response rates and quality of life outcomes of neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle-invasive transitional cell carcinoma of the urinary bladder.

5030 Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy, safety and tolerability of cisplatin cabazitaxel combination in this patient group. Methods: A phase 2 single arm trial (Simon 2 stage), to recruit at least 26 evaluable patients was designed with 80% power to detect the primary endpoint, objective response rate (ORR) of > 35%. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging), measured by pathologic staging (T2 or greater at diagnosis, to T1 or less at radical cystectomy). Treatment was with Cisplatin 70mg/m2 and Cabazitaxel 15mg/m2 on day 1 of a 21 day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. Quality of Life (QoL) data were collected at baseline, prior to each cycle of chemotherapy and at 3-5 weeks after 4th cycle of chemotherapy using EQ-5D and EORTC QLQ-C30, BLM30 questionnaires. Results: Objective response was seen in 15 out of 26 evaluable patients, 57.7% and over a third of patients achieved pCR (9/26; 34.6%). 78% (21/27) of patients completed all cycles of treatment, with only 6.7% of the reported adverse events (AEs) being graded 3 or 4. There were 6 treatment related SAEs reported but no SUSARs. In patients who achieved objective response the median progression free (PFS) and overall survival (OS) were not reached (median follow up: 41.5m). In contrast, median PFS (7.2m) and OS (16.9m) were significantly worse (p = 0.001) in patients who did not respond. Response rates for EORTC QLQ-C30, BLM 30 and EQ5D questionnaires was 70.4, 70.4 & 63% respectively, at end of treatment. There was no significant difference in EORTC QLQ C30 summary, global health scores and EQ5D score with treatment. There was a significant decline in mean QLQ C30 domain scores after 1st cycle compared to baseline, but no further deterioration with subsequent cycles of chemotherapy. Conclusions: Cabazitaxel with cisplatin as NAC of MIBC can be considered a safe, well-tolerated and effective regimen with higher pCR rate of 34.6%. This compares favorably to that with Cisplatin/Gemcitabine (23-26%). Minimal changes in Global Health & EQ5D observed during NAC further demonstrates the excellent tolerability of this regimen and to our knowledge are the first data regarding QoL in NAC in MIBC. These results warrant further evaluation in a larger phase 3 study. Clinical trial information: 2011 004090 82 .

Total intracorporeal robot-assisted laparoscopic Mainz II rectosigmoid pouch

Objective To report the surgical techniques and results of robot-assisted laparoscopic radical cystectomy (RRC) with bilateral pelvic lymphadenectomy and the Sigma rectum pouch (Mainz II) performed with an intracorporeal robotic technique at our center. Methods There was 1 female 63 years old with organ confined, muscle invasive transitional cell carcinoma of the bladder who underwent completely robot assisted surgery. The procedure included pelvic lymph node dissection, radical cystectomy with uterus and tubal structures, creation of the rectal sigmoid pouch and bilateral stented antireflux implantation of the ureters into the pouch. A 20 cm segment of the sigmoid was isolated. The posterior wall of the pouch were anastomosed side-to-side. And a nipple was formed by suturing the mucosa over the ureters to accomplish an antireflux mechanism. The F8 mono-pigtail ureteral stents were led out through the rectum, and a F26 Foley catheter was placed transanally for pouch drainage. Finally the anterior wall of the pouch was closed two layers. Results Operating time was 470 min and blood loss was 600 ml. The rectal tube was removal on the 9d postoperative day and the ureteral stents were removed 11 d and 12 d postoperatively. No intraoperative or postoperative complications were observed. The patients were followed up for 2 years, urinating 4-5 times per day and 1-2 times at night, CO2CP is 17.8mmol/L. The patient showed no upper urinary occlusion, reflux or urine incontinence. Conclusion To our knowledge, this is the first robotic radical cystectomy with intracorporeal continent urinary diversion (Mainz Ⅱ), RRC with the Mainz Pouch Ⅱ may become a simple and effective alternative surgical method for treating select patients with localized muscle invasive bladder cancer. Key words: Bladder cancer; Robot-assisted laparoscopic surgery; Radical cystectomy; Controlled urinary diversion

Effect of age and gender on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive transitional cell carcinoma of the bladder: A retrospective study of 50 patients treated with radical cystectomy.

65 Background: Older age and female gender have been associated with worse outcomes in patients with muscle invasive bladder cancer undergoing radical cystectomy. Reduced immune response has been implicated in disease metastasis and worse survival. The objective of our study was to determine the expression patterns of various cellular proteins active in immune pathways in bladder cancer patients, and assess the correlation between age, gender, and expression of these immune markers. Methods: Tissue samples were obtained from equally distributed male/female patients with/without lymph node metastasis on final pathology after undergoing radical cystectomy for transitional cell carcinoma (TCC) of the bladder from 2009-2011 (n = 50). Immunohistochemistry (IHC) for CD3, CD4, CD8, LAG3, CD56, TIM3, PD-1 and PD-L1 were performed and scored by a single pathologist (scoring was on 0 to 100% scale). Statistical analyses investigated association between age, gender, lymph node metastasis, and IHC results. Results: Mean age at surgery was 67 yrs (range 50 to 78 yrs); all patients were Caucasians. Statistical analyses showed no association between patients' age, gender, and the expression of any of the immune markers (p > 0.05). Similarly, the staining scores for the immune markers were not noted to be correlated with LN metastasis. Correlation between stains showed a negative correlation between CD56 and PD-L1 (-0.286, p = 0.047) and between PD-1 and PD-L1 (-0.381, p = 0.007). Conclusions: Although age and female gender have been associated with worse outcomes in bladder cancer, this association may be independent of the immune pathways active in the disease. Increased expression of PD-L1 is associated significantly with suppression of anti-tumor natural killer cells in the transitional cell carcinoma of the bladder.

The British Association of Urological Surgeons radical cystectomy audit 2014/2015: An update on current practice, and an analysis of the effect of centre and surgeon case volume

Objective: The Consultant Outcomes Publication has made it mandatory to submit surgeon-level data on radical cystectomy (RC) practice in England. The current analysis describes contemporary surgical practice and compares this by surgeon and centre case volume. Materials and methods: Between 1 January 2014 and 31 December 2015, data on 3742 RCs performed by 161 surgeons over 84 centres were recorded on the British Association of Urological Surgeons audit and data platform. Centre case volumes were grouped as high (> 60), medium (30–60) and low (< 30), while surgeon case volumes were grouped as high (> 30), medium (8–30) and low (< 8). All data averages were for the combined 2-year period. Results: The median number of RCs performed was 16/surgeon and 31/centre; 45.4% of cases were performed for muscle-invasive transitional cell carcinoma (TCC). The commonest performed urinary diversion was ileal conduit (85.2%), followed by orthotopic bladder substitution (5.7%). Open radical cystectomy (ORC) was performed in 67.8%, robotically-assisted cystectomy (RARC) in 20.6% and laparoscopic cystectomy (LRC) in 9.1% of cases. RARC was more likely to be performed by high-volume surgeons and centres. The majority of patients underwent a lymph node dissection (LND), with rates varying from 79.5% to 90.3%. Reported rates of high-grade complication were generally low across all groups, suggesting under-reporting. There was a trend towards higher reported transfusion rates as centre volumes decreased. The median length of stay (LOS) was 7–9 days for minimally invasive approaches compared to open surgery, which was 11–12 days. Mortality rates were low across all groups. Conclusions: Compliance with the data registry is high. ORC remains the most common approach. High-case volume surgeons and centres more commonly offer RARC. The majority of patients undergo LND. There is a trend towards higher reported rates of transfusion as centre volume decreases. LOS is shorter in RARC and LRC in comparison to ORC, but is otherwise similar across centres and surgeons. Level of evidence: 2b

Analytical study of bladder tumor

Background: Treatment of bladder tumor still provides the romance in Urology. The purpose of this study is to study the prevalence of various types of bladder tumors, to compare various treatment modalities for bladder tumors, to study different presentations of patients with bladder tumor.Methods: The present study was a prospective analytical study of 30 patients of bladder tumor conducted at Dhiraj General Hospital attached to S.B.K.S Medical College from October 2011 to July 2013. All the details of patients in term of demography, risk factors, symptoms and sign, radiological, endoscopic, histopathological features, various treatment modalities offered, and follow-up of patients were studied and analysed using descriptive statistics.Results: Maximum number of patients was presented in sixth decade of life. Youngest patient was 30 years old and oldest patient was 77 years old. 80% patients were male, and 20% patients were female. History of smoking was present in 22 patients, history of exposure to occupational hazards was present in 4 patients and only 2 patients had positive family history. Majority 93.3% patients were presented with haematuria and 16 patients had anaemia. 15 patients had high grade muscle invasive TCC, followed by 10 patients with low grade non-muscle invasive TCC. 3 patients were having low grade non-muscle invasive SCC, 1 patient was having high grade muscle invasive SCC and 1 patient was having high grade non-muscle invasive TCC.Conclusions: The findings of the study conclude that TURBT followed by intravesical instillation of BCG gave good results in patients with low grade and high grade non-muscle invasive tumor. For muscle invasive tumor radical cystectomy with urinary diversion is the ideal treatment but TURBT followed by radiotherapy has also given good results with fewer side effects.

A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS).

4506Background: Atezolizumab is a PD-L1 inhibitor which is licenced in metastatic urothelial cancer. This study investigates the efficacy and safety of neoadjuvant atezolizumab given prior to cystectomy in operable muscle invasive transitional cell carcinoma bladder cancer. Methods: This single arm phase 2 study investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint. Cross sectional imaging was performed at baseline and prior to cystectomy which occurred 4 - 8 weeks after starting atezolizumab. Radiological response was assessed. Adverse events (AEs) and surgical complications were assessed using CTCAE v4.03 and the Clavien-Dindo classification. The IDMC reviewed the first 69 patients (of 85) and supported this interim presentation. Results: The median age of the 69 patients was ...

The Bristol Bladder trial: A single-arm phase II trial of cisplatin and cabazitaxel for muscle invasive transitional cell carcinoma of the urinary bladder prior to radical cystectomy.

468 Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle invasive transitional cell carcinoma (MI-TCC). However response rates and survival remain suboptimal. We sought to evaluate the efficacy of cabazitaxel (CBZ) with cisplatin (CIS) in this setting. Methods: A single arm phase 2 study was designed with 80% power to detect an objective response rate (ORR) of >35%. Patients with MI-TCC were included if fit to receive neoadjuvant chemotherapy and to undergo radical cystectomy. Treatment was with CIS 70mg/m2 and CBZ 15mg/m2 on day 1 of a 21 day cycle, for 4 cycles prior to surgery. Primary prophylaxis was with pegylated GCSF. Toxicity was recorded using CTCAE v.4.03. Objective response was defined as a reduction in Tumour (T) stage from T2 or greater at diagnosis, to T1 or less at radical cystectomy. QoL data was assessed during and after chemotherapy using EQ-5D and EORTC-BLM30 questionnaires. Results: 28 patients were enrolled with median age 68.6 years (range 47-79). Response outcome (first 23 cases) and toxicity data (first 24 cases) are in this abstract; the remaining cases, currently scheduled for surgery, will be added to the final presentation. Pathological complete response (pCR) was observed in 7/23 patients (30.4%) and ORR was 56.5% (13/23). 18/24 (75%) completed 4 cycles; reasons for stopping were disease progression (2/24, 8.3%), adverse events (2/24, 8.3%) and patient choice (2/24, 8.3%). 7/24 patients (29%) experienced treatment related grade 3 and 4 adverse events. Conclusions: These results demonstrate that CIS and CBZ chemotherapy has an acceptable safety profile and is well tolerated in this setting. This combination shows promising efficacy (pCR 30.4%, ORR 56.5%) prior to definitive treatment for MI-TCC. Response outcomes for all patients and QoL data will be reported in the final presentation. Grade 3/4 adverse events. Clinical trial information: NCT01616875. [Table: see text]

CARCINOMA OF URINARY BLADDER;

Introduction: The most common presentation of carcinoma of urinarybladder is haematuria. Almost 80-90% of patients with carcinoma of bladder present eitherwith microscopic or gross haematuria and it is mostly intermittent rather than constant. Somepatients also complain of irritative voiding symptoms such as frequency, urgency and dysuria.Study Design: Descriptive, case series study. Setting: Department of Urology, DHQ Hospital,Gujranwala, Pakistan. Period: July 2015 to June 2016. Materials & Methods: Total 30 patientsirrespective of age and gender with diagnosis of bladder tumor based on clinical symptomsand supported by laboratory tools like Urine cytology, Ultrasound and IVU were included. Thealready diagnosed patients of bladder tumor that have been treated with different modalitieswere excluded. All the tumors were staged according to TNM classification after TURBT andgraded on the basis of histopathology. Results: Mean age was 53.17+16.07SD years. Maleswere 25(83.3%) and females were 5(16.7%). Male to female ratio is 5:1. Twenty eight (93.3%)patients out of 30 presented with painless haematuria. 23(73.33%) patients out of 30 patientswere smokers. 09 (30%) patients had Ta, in which G1 was found in 2 patients and G2 in 7patients. T1 was found in 10 (33.3%) patients, in which G2 was 5(17.3%) and G3 was 5(17.3%)cases. Muscle invasive T2a was diagnosed in 04 patients amongst them G2 and G3 wasdetected in 2(6.6%) patients each respectively. T2b was present in 3 patients, which had G1 in1(3.3%) and G3 in 2(10%) patients. T3b G2 was found 01 patient and T3b G3 was detected in1(3.3%) patient, T4M1 G3 was present in 2(6.6%) patients. Conclusion: This study concludedthat the bladder tumor is quite common with muscle invasive TCC is more common. Painlesshematuria is the commonest presentation and also smoking has a definite association with CAbladder.

Abstract 3934: Bladder cancer tumor heterogeneity: development of a system-level mutation assay

Abstract Survival rates for patients with muscle-invasive bladder cancer have not improved in the past 20 years, and new therapies are imperative. Intratumor heterogeneity can complicate molecular profiling attempts to optimize therapy for cancers harboring several actionable tumor subclones. To develop personalized treatment strategies, there is a need for assays to measure intratumor heterogeneity in bladder cancers. We conducted a pilot study of two muscle invasive high-grade transitional cell carcinoma cases. We used a comprehensive cancer panel (Thermo Fisher) covering >400 cancer genes to analyze distinct tumor loci and matched normal tissues. Based on the identified somatic mutations, we designed a bladder-specific panel to (1) validate our results with increased coverage, and (2) analyze liquid biopsy samples. Using the comprehensive cancer panel, we sequenced 6 tumor loci to an average sequencing depth of approximately 100x. We detected intratumor heterogeneity in both patients: By applying a combination of frequency-based (minor allele frequency >10%) and probabilistic (probability of difference between observed frequencies due to sampling) filters, we identified 44 credible somatic SNVs, including mutations that were not shared among all three loci. We used these SNVs to design a custom amplicon panel covering 42 SNVs across 38 genes that is suitable for highly fragmented DNA. The custom panel was used to validate the SNVs in the same tumor regions and in liquid biopsy samples from plasma and urine (approximate coverage 6,000x). In both cases, we identified private mutations reported in The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) data collection, reflecting tumor evolution. Liquid biopsy samples from urine revealed all trunk mutations but only 1 out of 5 private mutations. We conclude that tumor evolution can affect distinct loci within bladder tumors, which may not be fully represented in liquid biopsy samples. These results suggest the need for analyzing multiple tumor regions to identify all actionable driver mutations. In the future, we plan to apply our assay to additional foci and patients in order to identify optimal bladder tumor sampling strategies. Citation Format: Katherin Patsch, Naim Matasci, Anjana Soundararajan, John Nicoll, Jonathan Katz, Antonio Sanchez, Erika Feierstein, Christina Van Loy, Zhao Xu, David B. Agus, Mitchell E. Gross, Daniel Ruderman. Bladder cancer tumor heterogeneity: development of a system-level mutation assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3934. doi:10.1158/1538-7445.AM2017-3934

Безопасность спасительной цистэктомии после неудачи органосохраняющего лечения больных мышечно-инвазивным раком мочевого пузыря

Purpose: To prove the safety of the salvage cystectomy after organ preserving treatment in patients with muscle invasive bladder cancer.
 Material and methods: In the research retrospective data of 130 patients with muscle invasive transitional cell carcinoma of the bladder were selected. In the main group 66 patients undergoing of the salvage cystectomy after radiotherapy were included, in the control group – 64 patients who underwent of radical cystectomy without prior treatment. The main and control groups were matched by age, gender, category with cN (p > 0.05 for all). In the main group tumors which were beyond the bladder wall, hydronephrosis were more frequently diagnosed; during the salvage operations pelvic lymph node dissection rarely performed (p = 0.03) and orthotopic bladder substitution was made (p = 0.027).
 Results: The median of duration of the salvage cystectomy was 310 min, which was not significantly different from 300 minutes in the control group (p = 0.711). The median of amount of bleeding of the patients undergoing surgery after irradiation, was not significantly lower than that the patients who had cystectomy which performed without prior radiation therapy (1329 and 1802 ml respectively, p = 0.118). The frequency of intraoperative complications of saving cystectomy was 10.6 %, which did not differ from 7.8 % in the control group (p = 0.300). Only one kind of complication of cystectomy after radiation therapy was difficult to control the bleeding in 6 cases (9.1 %). The frequency of postoperative complications – 42.7 % in the main and control group 42.2 % (p = 0.530). The perioperative mortality was equal to 6.1 %. The operating time, blood loss, frequency, structure and severity of complications i did not differ significantly n the main and control groups (p > 0.05 for all).
 Conclusion: The salvage cystectomy is indicated to a sick muscle-invasive bladder cancer with an incomplete effect, relapse or intolerable toxicity, organ-preserving treatment, including radiation therapy. Desmoplastic reactions of the irradiated tissue cause the technical complexity of the interference and worsen the conditions for reparation. The most common intraoperative complication of salvage cystectomy is bleeding, in the structure of postoperative complications infections, intestinal obstruction and complications of the urinary anastomoses dominate. The accumulation of surgical experience make the frequency and severity complications of the salvage radical cystectomy comparable, offsetting an increase of operational risk in previously irradiated patients.

Functional outcome and oncological safety of genital-sparing radical cystectomy in female patients with muscle invasive transitional cell carcinoma of the bladder

Background: To evaluate the functional and oncological outcome after genital-sparing radical cystectomy with orthotopic bladder substitution in female patients with bladder cancer.

Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder.

Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder.

Changes in autofluorescence based organoid model of muscle invasive urinary bladder cancer.

Muscle invasive urinary bladder cancer is one of the most lethal cancers and its detection at the time of transurethral resection remains limited and diagnostic methods are urgently needed. We have developed a muscle invasive transitional cell carcinoma (TCC) model of the bladder using porcine bladder scaffold and the human bladder cancer cell line 5637. The progression of implanted cancer cells to muscle invasion can be monitored by measuring changes in the spectrum of endogenous fluorophores such as reduced nicotinamide dinucleotide (NADH) and flavins. We believe this could act as a useful tool for the study of fluorescence dynamics of developing muscle invasive bladder cancer in patients.Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.

Outcome of radical cystectomy series in the management of muscle invasive bladder cancer: Liverpool experience.

396 Background: Cystectomy has become one of the standard forms of therapy for patients with muscle invasive bladder cancer with long term follow-up data supporting radical surgical management. Methods: Data are collected retrospectively on patients who underwent cystectomy at the Royal Liverpool University Hospital. The aim was to document the overall survival of patients undergoing cystectomy at this centre. Results: Data were collected on 147 patients between September 2007 and June 2013. Median patient age was 66 (IQR: 61, 72) with 33 (23%) females. 107 (73%) patients had muscle invasive TCC, 13 (9%) had recurrent non-muscle invasice disease, 9 (6%) had salvage surgery following radical radiotherapy and 6 (4%) had persistent carcinoma in situ. 28 patients (20%) had hydronephrosis. 34 (23%) patients underwent neo-adjuvant chemotherapy. 2 (1%) patients had Combined synchronous urethrectomy and 5 (3%) had Combined synchronous nephroureterectomy. Post operatively positive lymph nodes were observed in 22 (19%) of surgical specimens and 83 (72%) had persistent muscle invasive disease. Survival rates at 12 and 60 months are 0.92 (0.88, 0.97) and 0.52 (0.39, 0.71) respectively. Multivariate analysis show that post operative T (HR: 3.99 (1.05, 15.18)) and N (HR: 5.40 (2.17, 13.44)) status are both independent predictors of over all survival. Conclusions: Real life data from our centre showed that the patient population and overall survival estimates for patients with muscle invasive bladder cancer treated with radical cystectomy and lymph node dissection are consistent with previous published literature. .