Introduction: Urothelial carcinoma of the bladder (UCB) is the second most common genitourinary malignancy and is associated with a heterogeneous clinical outcome. Radical cystectomy (RC) with bilateral pelvic lymph node dissection (PLND) is currently the gold standard treatment for muscle-invasive UCB. Despite that, a significant proportion of patients develop disease recurrence. Several studies have evaluated the risk factors for survival after cystectomy. The implication of such factors will help in modification of treatment strategies to improve the prognosis of bladder cancer patients.

Objective/ Materials and Methods:  Our aim is to evaluate the influence of clinical and histopathological parameters on outcomes of patients with urothelial carcinoma of the bladder (UCB). A retrospective analysis was performed through the electronic process of all patients undergoing radical cystectomy between January 2014 and January 2020 (6 years). Demographic and clinical data were collected and the information was cross-checked with that of the anatomopathological and pharmaceutical services. Significance (p) of less than 0.05 was considered statistically significant. Statistical analysis was performed in Stata.

Results: 93 patients with a mean age of 72 years were analyzed. About 92% of the patients were male. The following factors were evaluated: age, gender, smoking habits, comorbidities (Charlson Index), tumor stage, tumor differentiation, histological variant, necrosis, lymphovascular/perineural invasion (LVI/PNI), concomitant carcinoma in situ (CIS), presence of lymph node metastasis, disease recurrence and performance of neoadjuvant chemotherapy. Of all the factors evaluated, a statistically significant relationship was observed between OS and tumor stage, presence of lymph node metastasis and disease recurrence. 

Conclusions: Invasive muscle tumors of the bladder and cystectomy are associated with high morbidity and mortality, and it is important to identify risk factors for a better treatment of this population. In this series of patients only presence of lymph node metastasis, disease recurrence and tumor stage were associated with higher mortality. The small sample size may justify the non-association of other risk factors as predictive of survival.

Muscle invasive bladder cancer - are there any survival prognostic predictors?

Introduction
Imunnotherapy has gained a high value in the oncology environment, with benefits for the patients (pts) that are eligible for it. However, these drugs are not completely harmless, and immune related adverse events (IRae) have been reported. There have been reports showing clinical benefit in patients that report IRae. Our mains goal is to show if our study matches the recent literature.

Material/ methods
In our study, we did a retrospective analyses in pts who were treated with checkpoint inhibitors for urotelial cancer in our center, between January 2015 and December 2019. Every patient must have had ECOG performance status of 0-2 and were treated with anti PD-1 or anti PD-L1. for advanced muscle invasive urothelial cancer. Progression free survival (PFS) and overall survival (OS) were evaluated starting from the time of the begining of imunnotherapy. Disease control rate was evaluated [Stable disease (SD) + Partial response (PR) + Complete response (CR)]. Results were compared with pts that developed IRae. Demographic and clinical data were collected and the information was cross-checked with that of the pharmaceutical services. A multivariate logistic regression was used to evaluated significance. Significance (p) of less than 0.05 was considered statistically significant. Statistical analysis was performed in stata.

Results:
A total of 30 pts were included in this study. The median age was 69 (63-88). 22 (74%) were male and 8 (26%) were female. 17 (57%) pts were treated with pembrolizumab, 7 (23%) nivolumab and 6 (20%) atezolizumab. 6 pts had 1st line treatment, 20 pts 2nd line and 4 had 3rd line treatment. 18 (61%) had cisplatin based treatment. 25 (83%) had ECOG PS 0-1. 7pts developed IRae. Every IRae were grade 2 or lower. The most common IRae was hypothyroidism (6pts). 1 pt had pneumonitis and 1 had skin related IRae. Median follow up time was 15 months ( 3.27 - 24.40). Median PFS was 6.3 months (2.1-19.5). Median OS was 13.6 months (7.6- not reached). Disease control rate was higher in the group that developed IRae, 85%(n=7) vs 56% (n=23). However, there was no statistical significance (p=0.19). Median PFS were higher in the IRae group (9.4m vs 5.6m) (p=0.13). Median OS was higher in the IRae group (17.6m vs 12.1m) (p=0.2)

Conclusions:
There seems to be a trend towards clinical benefit in patients that develop IRae with imunne checkpoint inhibition in advanced urothelial cancer. However, due to limitation of the low sample of patients no statistical significance could be established. Prospective trials with higher samples could be evaluated to adress this hipo

Can checkpoint inhibitor immune-related adverse events be a prognosis factor in urothelial cancer?

Introduction Inflammatory myofibroblastic tumor (IMT) is an unusual intermediate soft tissue tumor, rarely occurring in the urinary bladder. IMT has a relatively good prognosis and is considered to be a tumor with intermediate biologic potential because of its low risk of distant metastases. Clinical findings A 42-year old man with factor VII deficiency, non smoker, was evaluated by Internal Medicine because of microhematuria, severe anemia, frequency–dysuria syndrome and bladder outlet obstruction. Diagnosis and treatment The patient was referred to urological evaluation for the finding of a large bladder mass of 8 centimeters, without distant metastases on CT-scan. Abdominal MRI scan was performed, finding no evidence of extravesical mass and a tumor bed on left lateral bladder wall about 3 centimeters (Figure 1). Figure 1. Abdominal MRI scan showed a single giant bladder mass, with no signs of extravesical mass. Patient underwent to transurethral resection, that was incompletely performed, requiring the use of NovoSeven®, a recombinant human coagulation Factor VIIa (rFVIIa) and several units of red blood cells. Three weeks later, an additional “second – look” was performed, likewise incomplete. Pathology report revealed an inflammatory myofibroblastic tumor. Histological examination (hematoxylin-eosin staining) showed spindle cell proliferation with inflammatory cells on a myxoid stroma. The results of immunohistochemistry examination showed: Vimentin (+), CD68 (+), Desmin (+), Caldesmon (+) and ALK (+), AE1/AE3 (-), CK34β12 (-), actin (-), Myogenin (-), p53 (-), S-100 (-), EMA (-), BCL2 (-), DOG1 (-) and CD117 (-). After discussing the treatment plan with the patient and his family, a decision to do a conservative management with a partial laparoscopic cystectomy was made. Final pathology report was an inflammatory myofibroblastic bladder tumor with muscle layer infiltration (pT2b). Conclusions Also called inflammatory pseudotumor, first case report of an inflammatory myofibroblastic tumor of the urinary bladder was made in 1980. Most patients are young (mean age of 38.9). Hematuria is the commonest clinical manifestation. It is characterized by atypical spindle cell proliferation and inflammatory cell infiltrates primarily involving lymphocytes and plasma cells. Most frequently found on lung. IMT in the urinary bladder is unusual. Recent reports have indicated that ALK (anaplastic lymphoma kinase) was overexpressed in a substantial proportion of IMT. A positive finding of ALK in up to 87.5% of IMT can be useful for the differentiation of IMT from other spindle cell tumors. Surgical resection is the treatment of choice. Most patients goes to TURB, but partial and radical cystectomy can be considered. IMT of the bladder have a local tumor recurrence rate after surgery of 4%. Complete surgical resection is the most important factor to avoid local recurrence. IMT tumors are classified as intermediate (rarely metastasizing) tumors according to th

GIANT INFLAMMATORY MYOFIBROBLASTIC TUMOR OF URINARY BLADDER

Introduction Carcinoma arising in a bladder diverticulum is uncommon, and data on treatment and outcome are sparse. Our objective is to analyze clinicopathological features of diverticulum bladder cancer and difficulties on diagnosis. Clinical findings A 61-year old man healthy, never smoked, presented with frank hematuria and relapsing urinary lower tract infections with positive urine cultures to E. Coli. The clinic started a few months ago. Diagnosis and treatment Uroflowmetry was obstructive and urinary ultrasound revealed a small prostate with a large bladder diverticulum and a single stone within the diverticulum. Patient underwent cystoscopy under anesthesia. A large diverticulum on the right lateral wall was identified, without a real lithiasis, but a single calcified bladder tumour inside diverticulum. Neoplasm transurethral resection was incompletely performed because of obturator kicking and an elevated uncontrolled bleeding risk due to highly vascularized tumour bed. Pathology report revealed a high grade papillary urothelial carcinoma with extensively squamous differentiation with no muscularis propria or muscle staged as cT1R2. Random bladder biopsies and prostatic urethral biopsy were both negative. A multiphasic computed tomography scan showed a large diverticulum with narrow diverticular neck and residual tumour (2*3 cm) with doubt of perivesical tissues infiltration or inflammation post resection. No enlarged lymph nodes or other metastasis were detected (Fig. 1). Figure 1. Large diverticulum with residual tumour on CT scan. After discussing the treatment plan with the patient and his family and, with the difficulty to reliably predict tumour stage, a decision to do a laparoscopic radical cystectomy with standard lymph node dissection and orthotopic neobladder substitution was made. The pathology revealed a high-grade urothelial carcinoma with squamous differentiation with microscopically perivesical tissue infiltration and negative lymph nodes (on 29/29 identified lymph nodes) staged as pT3aN0. After 6 months, patient was free of tumour recurrence and recovered completely daytime continence in 3 months. Conclusions Neoplasms of urinary bladder diverticulum are uncommon, but not rare. Most malignant tumours in bladder diverticulum are transitional type, followed by squamous cell carcinoma. Bladder tumours arising in a diverticulum are difficult to diagnose because filling defects are not always visualized or they can be confused with stones due to calcified tumours. Bladder diverticulum neoplasms are characterized by early transmural invasion due to lack of muscular fibers thus, prompt diagnosis and treatment are crucial. Complete transurethral resection of diverticulum bladder tumours is often difficult considering the risk of bladder bleeding or perforation. Preoperative local staging remains a diagnostic challenge.

BLADDER DIVERTICULUM CANCER

COVID-19 lockdown reduces screening and follow-up in urinary cytology

Introduction: The national lockdown due to coronavirus disease 2019 (COVID-19) wholly altered our cytology lab's daily practice. We wanted to know how COVID-19 changed the number and composition of urinary specimens as a classic example of a cytological screening and follow-up procedure. 

Methods: The overall numbers and percentages of urinary cytology (voided urine, bladder washings, washings from the upper urinary tract) were processed at the University Medical Center Hamburg-Eppendorf during the first four weeks of Germany's national lockdown were compared with those of the equivalent period in 2019. All urinary specimens were classified according to the Paris System for Reporting Urinary Cytopathology.

Results: During the lockdown, the proportion of urinary specimens significantly dropped from 460 (34,7%) of 1323 total specimen in 2019 to 221 (23,8%) of 928 total specimens 
(X2-test, p<0.001). The numbers were checked for sample bias of sample senders dynamics. In 2019 of all 460 samples, 385 (83,7%) were voided urine, 56 (12,1%) were bladder washings, and 19 (4,1%) samples were from the upper urinary tract. In 2020 of all 221 samples, 198 (89,6%) were voided urine, 13 (5,9%) were bladder washings, and 10 (4,5%) were washings from the upper urinary tract. The malignancy rate significantly lowered from 14 (3%) of 460 total samples in 2019 to 1 (0,0045%) of 221 whole urine samples in 2020 (Fisher’s exact test p=0.0463). 

Conclusions: The COVID-19 lockdown reduced the overall case numbers in urinary cytology. The proportions of urine specimens and the urinary cytology's malignancy rates decreased significantly, indicating that bladder cancer screening and follow-up were reduced in the COVID-19 lockdown.

COVID-19 lockdown reduces screening and follow-up in urinary cytology

Objective

NICE bladder cancer guidelines currently recommend that patients with a pathological grading of G2ta bladder Transitional Cell Carcinoma (TCC) at first diagnosis Trans-Urethral Resection of Bladder Tumour (TURBT) without muscle in the specimen, should undergo a restaging TURBT within 6 weeks. We investigated our population of G2ta bladder TCC patients, to compare outcomes in patients with and without detrusor muscle in the initial specimen. The study aimed to ascertain whether a restaging TURBT was necessary in this group. 

Methods

Patients with a diagnosis of G2ta bladder TCC were identified from a bladder cancer database (diagnosed 2012 -2019). Retrospective data was collected from the Somerset Cancer Registry.

Results

A total of 143 patients were identified for inclusion, based on a first diagnosis of G2ta bladder TCC from 2012 – 2019. N=98 (69%) patients had muscle in their first specimen, n=45 (31%) patients did not have muscle in the initial diagnostic specimen. Of these patients with no muscle in their specimen, an MDT decision was made to perform a restaging TURBT in 13 patients (29%). Of these 13 patients, only one patient was upgraded to G3T1 TCC.
Of the 45 patients who did not have muscle present in their initial specimen, the recurrence rate at 1 year was 35% (n=16). In the 98 patients who had muscle present in their initial specimen, the recurrence rate at 1 year was 31% (n=31). No significant difference was detected between the recurrence rates in each group (p=0.7, Fisher’s exact test). The number of patients upgraded within the year was 8% (n=4/45) and 6% (n=6/98), in the groups with no muscle present and muscle present, respectively. No significant difference was detected in high-grade recurrence between the groups (p=0.7, Fisher’s exact test).

Conclusion

Our data shows that there is no difference in the recurrence or upgrade rate at 1 year in patients with initial G2ta bladder TCC, whether muscle is present in the specimen or not. This suggests that it is unnecessary to perform a restaging TURBT at 6 weeks in these patients, even if there is no detrusor muscle present in the initial resection specimen.

G2ta bladder cancer without detrusor, do we need to restage at 6 weeks?

Introduction & Objectives:
The WW Domain Containing Oxidoreductase (WWOX) tumor suppressor gene is located in direct proximity to chromosomal locus 16q24 that is related to tumor progression of 20-45% bladder cancers. It encodes protein containing two WW domains, the first of which recognizes proline-rich motifs of proteins such as Activating Enhancer-Binding Protein 2 Alpha (AP-2α) transcription factor (encoded by TFAP2A gene). The literature data indicate that WWOX sequestrates AP-2α outside nucleus, which suppresses its transcriptional transactivation functions.
The purpose of this research was to examine diverse properties of bladder cancer with various WWOX and TFAP2A expression levels in CAL-29 cell line (grade IV) and determine their effect on useful clinical features in patients.

Materials & Methods:
Using two lentiviral systems we created in vitro models with various WWOX and TFAP2A expression on which the cell viability, adhesion, proliferation and 3D culture growth assays were performed. 
Bioinformatic analyzes were conducted on bladder cancer data acquired from The Cancer Genome Atlas (TCGA) using Weighted Gene Correlation Network Analysis (WGCNA) and NETwork-based Gene Enrichment (NET-GE) tool with Molecular Signatures Database (MSigDB) used to assign the role of a particular gene to the biological process.

Results:
In variant with ↑WWOX/↑TFAP2A expression we observed reduced mitochondrial redox potential, decrease in the number and size of spatial colonies and lowered adhesion to fibronectin, collagen I and collagen IV in comparison to cells with ↑WWOX expression and native TFAP2A expression. Similar tendencies were noticed in variant with ↑TFAP2A overexpression and native WWOX expression compared to control cells although with additional demonstration of lower proliferative potential. Decreased size of 3D colonies was also observed in cells with ↑WWOX expression and native TFAP2A, compared to its control. 
To further investigate WWOX role, in silico analyzes (WGCNA, NET-GE) have been conducted on TCGA data of patients having ↑TFAP2A but various WWOX expression. Using WGCNA, we extracted cluster of 530 genes that noticeably differentiated samples in terms of bladder cancer papillary and non-papillary subtypes. Subsequently, ontological analysis of these genes indicated that these genes are primarily implicated in adhesion and proliferation but also in apoptosis, cell cycle or several signaling pathways (e.g. JAK-STAT, MAPK, Wnt, NFkB).

Conclusions:
Taken together, our study indicates that WWOX interplays with AP-2α in regulation of bladder cancer spatial colonies growth. However, the effect on tumor cell viability, proliferation and adhesion appears to be dependent on the AP-2α level. Thus, subsequent in silico analyzes were focused on characterizing the dissimilarities of groups differing in WWOX gene expression level. Ultimately, these tools revealed valuable data concerning correlation of clinical traits with expr

WWOX–AP-2α interaction affects biology of bladder cancer and demonstrates usefulness in its clinical features’ discrimination.

Introduction & objectives: Non-muscle invasive bladder cancer (NMIBC) is one of the most prevalent cancers, associated with a high recurrence-, but low mortality rate. Numerous surgical procedures through the life-time of those affected makes NMIBC an expensive cancer to treat, with significant impact on quality of life. Rigid Blue light cystoscopy (BLC) is routinely used in the operating room to allow improved detection of malignant tumors, leading to more complete tumor resection and reduced recurrence rates. Flexible BLC in the out-patient (OP) setting can assist diagnosis and treatment of NMIBC and could improve patient care by reducing therapeutic burden in addition to saving time and cost. The aim of the current study is to evaluate how OP BLC can improve patient management. 

Materials & methods: The Nordic Flexible BLC registry is an ongoing prospective multicenter study initiated to observe the clinical use and explore possible benefits of OP BLC. Data recorded include NMIBC history, cystoscopy findings, treatment performed and further management. The role of OP BLC in follow-up of NMIBC with focus on number of cases that required no further work-up is presented.

Results: To date, a total of 354 patients in follow-up of NMIBC have been included in the study from five participating sites. Patients are predominantly of high (67%) and intermediate (29%) risk categories, according to the EAU risk classification. In these patients, 462 procedures were performed during follow-up, 370 cases showing suspicious lesions. 
A total of 737 lesions were observed, of which 409 (55%) were fulgurated on-site by laser (42%) or diathermia (57%). Biopsies of 319 suspicious lesions confirmed malignancy in 166 lesions, of which 24% were only visible with BLC. In 88% of cases with suspicious lesions, the patient could be spared from a TURBT, of which 32% received intravesical therapy. 

Conclusions: In follow-up of high and intermediate-risk patients, flexible OP BLC helped resolve a substantial amount of cases by complete fulguration on-site or direct referral to intravesical instillation treatment, providing increased efficacy to manage NMIBC and a reduction in surgical burden.

Flexible blue light cystoscopy provides increased efficacy to manage non-muscle invasive bladder cancer in the outpatient clinic

INTRODUCTION AND OBJECTIVES: EAU guidelines recommend a single, post-operative instillation (SPI) of intravesical chemotherapy within 24 hours after transurethral resection of a bladder tumor (TURBT) in patients with a low- to intermediate risk non-muscle invasive bladder cancer (NMIBC). However, remarkable variation exists in the use of SPI. Fear for severe and potential deadly complications is likely to contribute to this variation but evidence is limited. Therefore we investigated the risk of severe complications and mortality after SPI in patients with low- and intermediate risk NMIBC. 

MATERIALS AND METHODS: Patients diagnosed with TaG1G2 urothelial bladder carcinoma between 2009 and 2018 who underwent TURBT were identified in the Netherlands Cancer Registry. Data were supplemented with information on cause of death and severe complications after cancer treatment by re-examining the electronic health records. Severe complications were defined as complications possibly related to SPI which required a prolonged hospital stay of at least 3 days after SPI or readmission within 14 days. Based on these data the 14-day complication risk and the 30-day mortality risk were evaluated. To assess the reasons for not administering SPI, a telephone survey was performed among a subset of Dutch urologists (n=10). 

RESULTS: In the Netherlands, large variation in the use of SPI is observed. In recent years, the proportion of patients with SPI ranged from 0% to over 80% between hospitals, with a median of 53%. Of the 14,177 patients who received SPI, 18 patients died within 30 days. Three deaths could possibly be attributed to the SPI, resulting in a 30-day mortality risk of 0.02% (3 of 14,177 patients). Of 2,634 patients who had SPI in 2017 and 2018, 47 patients experienced complications which might be linked to SPI, resulting in a 14-day complication risk of 1.78% (47 of 2,634 patients). Complications possibly related to SPI included voiding dysfunction (n=22, 0.84%), pain (n=18, 0.68%) and irritative complaints (n=2, 0.08%). The telephone survey revealed that the most important reasons not to administer SPI include both the fear of severe complications and non-belief in the efficacy of SPI. 

CONCLUSIONS: In the worst case scenario, the risk of possibly SPI related mortality (0.02%) and severe complications (1.78%) is very low after a TURBT in TaG1G2 bladder tumours followed by SPI of intravesical chemotherapy. Given these data, SPI can be considered a safe treatment in patients with low- or intermediate risk NMIBC who underwent TURBT without (suspected) perforation. As fear of complications and non-belief in the effect of SPI is still present in current practice and considering the substantial variation in use of SPI, our findings suggest that at least a part of patients is wrongly withheld an effective treatment.

Very low risk of severe complications after a single, post-operative instillation of intravesical chemotherapy in patients with low- or intermediate risk urothelial carcinoma of the bladder

Introduction and objectives: Radical cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC). Multimodal bladder preserving treatment (MMT), which combines transurethral resection of the bladder (TURB), chemotherapy and radiotherapy (RT), may be an option for well-informed patients who refuse radical surgery or for those unfit for cystectomy. The aim of our study is to evaluate the oncological outcomes of patients treated with MMT in our institution.

Material and Methods: Retrospective evaluation of the electronic medical records (EMR) of all pts diagnosed with MIBC who underwent MMT in Hospital Beatriz Ângelo, from 2012 to 2019. Statistical analysis was performed with the use of SPSS version 24.

Results: A total of 16 patients (pts) were included, with a median age of 76 [59;85] years-old (yo), 94% being males. Fourteen pts were initially diagnosed with MIBC and two progressed from non-muscle invasive disease. Six patients were unfit for platinum-based chemotherapy regimens, and were treated with 5-fluorouracil plus mitomycin. Four patients discontinued chemotherapy due to hematological toxicity. After a median follow-up of 36,7 months [10,2;82], there were 8 deaths, 4 of which disease-related. Two pts developed metastatic disease. The median overall survival (OS) was 68,3 months [95%CI: 10,7 – 125,9].

Conclusion: As tends to occur in most centers, all our patients selected for MMT were unfit for radical surgery. In spite of being a small cohort of patients, we found encouraging results, with only four disease related deaths over a median period of  36,7 months. Evaluating real-life outcomes may contribute to a better selection of patients for bladder sparing treatments, eventually allowing us to expand its indications for frail patients with a small burden of disease.

Real-life experience in multimodal bladder preserving treatment for muscle-invasive bladder cancer

Metastasis to the penis from a bladder carcinoma invading only the lamina propria: case report. Review of the literature and description of the metastatic pathways.

Authors: 
Marius Stanimir,
Marcelo Di Gregorio,
Francis Lorge,
Marie-Cécile Nollevaux,
Lionel D'Hondt
Keywords: Penile metastasis, Cystoprostatectomy, Total penectomy, Immunotherapy

Topic

Case report
Abstract / Case report

Introduction: Penile cancer is uncommon in industrialized countries with a low incidence of the disease of about 1/100.000 men in Europe and USA. Despite its rich venous and lymphatic vascularization, secondary metastasis to the penis are rare. Case presentation: We present the case of a 70 years old male, who was initially referred for gross hematuria in May 2018. After meticulous anamnesis, a cystoscopy was performed under local anesthesia, which detected a bladder lesion situated at the dome of the bladder that seemed to be muscular invasive bladder tumor. The histological exam after a transurethral resection of the tumor, revealed an invasive high-grade papillary transitional carcinoma of the bladder with lamina propria invasion (pT1 HG). The second-look transurethral resection was performed at the site of the anterior resection and the histological examination of the tissue revealed the same high-grade papillary transitional carcinoma of the bladder with lamina propria invasion but no muscular invasion (pT1 HG). During the follow-up, a thoraco-abdominal CT scan was performed and a nodule in the upper right lobe of the lung was discovered which was resected (lung acinar adenocarcinoma - pT1cN0). At 7 months from the diagnosis, an abdominal CT scan was performed finding a tumor at the anterior bladder wall measured at about 78x77x78 mm and staging of cT4. Following these findings, a MVAC chemotherapy (Methotrexate, Vinblastine, Doxorubicin and Cisplatin) was admistrated and a cystoprostatectomy was performed with an histological result of fibrosis and ypT0pN0 classification. About eight months after the cystoprostatectomy, the patient complained of having pain and swelling of the right side cavernous body. An MRI of the pelvis was performed and a lesion of about 30x20x20 mm was observed at the base of the penis. A total penectomy with perineal urethrostomy was performed and the result of the histological examination of the tumor revealed a transitional carcinoma suggesting a metastasis of the urothelial carcinoma of the bladder, pM1bR2. A PET/CT had been performed 3 months after the penectomy and it showed multiple retroperitoneal, right external iliac and bilateral inguinal positives lymph nodes. Metastasis of the obturator foramen and of the right peritoneal flank were also observed. Giving the mentioned results of the PET/CT, we started a treatment based on Pembrolizumab. At the time of publishing, the patient is following the immunotherapy treatment and he has no progression of the disease. Conclusion: Although the metastasis to the penis is a rare condit

Metastasis to the penis from a bladder carcinoma invading only the lamina propria: case report. Review of the literature and description of the metastatic pathways.

INTRODUCTION
Pheochromocytomas are tumors of chromaffin cells, derived from the embryonic neural crest, usually originate from the adrenal medulla. 10% of these tumors occur at extra-adrenal sites and are known as paragangliomas. Paraganglioma is rare account for <0.06% of all urinary bladder tumors and 6% of all extra-adrenal pheochromocytomas. It arises from chromaffin tissue of the sympathetic nervous system within the layers of the bladder wall. Most common site is the dome or the trigone of the bladder. Bladder paraganglioma is an extremely rare tumor with a high recurrence rate.
CASE REPORT
A 20 year old female patient presented with complaints of burning sensation during micturation and intermittent hematuria since 1 month. she had a history of similar complaint in the past and found to have bladder growth, for which she underwent TURBT 6 months back. The histopathology report was suggestive of bladder Paraganglioma. 
On examination general condition and vitals were stables; abdomen was soft, nontender and no lump palpable. Serum Chromogranin A level was 184 ng/ml (<108) with raised 24 hour Urine Metanephrine - 1760 (600-1600). Ultrasonography of abdomen & pelvis showed a 4.4.x 1.9 cm lesion in region of trigone on left side of bladder with increased vascularity. CECT abdomen & pelvis showed a pedunculated heterogenously enhancing lesion arising from posterolateral wall of Urinary bladder on left side of size 2.5 x 2.5 x 1.3 cm without extravesical spread. 
DIAGNOSIS & TREATMENT
Based on past history, laboratory and imaging investigation recurrent paraganglioma was diagnosed and the patient underwent partial cystectomy. Histopathological findings were compatible with the diagnosis, on gross examination the tumor showed 2.2x2x1.3 cm submucosal lesion. On microscopy the specimen showed presence of round to polygonal cells arranged in small nests or “zellballen” pattern, separated by highly vascularized fibrous septa; on immunohistochemistry staining was strongly positve for synaptophysin and chromogranin. S-100 staining shows diffuse positivity. 
DISCUSSION  	
Paraganglioma of bladder are generally solitary and submucosal in nature. Most commonly seen in women of 2 to 3 decade of life. 15-20% of these tumour are malignant, 80-85 % of it are hormonally active. Both CT scanning and MRI are useful in the localisation of both the primary tumour and any metastases however Scanning with 131 Iodine metaiodinebenzylguinidine (MIBG) has been shown to have a very high sensitivity and specificity for phaeochromocytoma detection. 
CONCLUSION 
Paraganglioma of urinary bladder have a characteristic histological and immunochemistry feature and it’s a cornerstone for diagnosis, it is found that metastatic dissemination is the only real proof of malignancy. Surgery is the mainstay of the treatment that requires total excision. Bladder paragangliomas tends to recur and metastasis, so lifelong follow-up is required.

A rare case of recurrent paraganglioma of urinary bladder

INTRODUCTION
Bladder cancer is the most common cancer of the urinary tract with a peak incidence seen in 6th to 7th decade of life. The incidence is more common in males, nearly three-quarters of total bladder cancer occurs in men. Non muscle invasive bladder cancer (NMIBC) is the malignant urothelial tumor that is not involving the detrusor muscle. Approximately 70-80% of bladder tumors at presentation are NMIBC with 60-70% as Ta, 20-30% as T1 and 10% as CIS. Radical cystectomy is the gold standard treatment for muscle invasive bladder cancers, but should be considered in NMIBC with high risk for progression.
CASE REPORT
A 51 years old male patient, who is known case of bladder cancer (Low grade papillary urothelial carcinoma- pT1, N0) underwent radical cystectomy with orthotopic ileal neobladder  5 years ago on regular follow up, complained of right groin swelling for 2 weeks.  On examination there was multiple right inguinal lymph nodes of  largest of 2x2 cm size. In CECT abdomen and pelvis there was  few necrotic inguinal lymphnodes without any  significant abnormality in the neobladder or in rest of the abdominal organs .  Urine cytology showed features suspicious of malignancy and the patient underwent cystoscopy which showed a small papillary growth at urethral anastamotic site. USG guided right inguinal lymphnode biopsy showed metastatic urothelial carcinoma and the wholebody PET-CT scan revealed increased FDG uptake in right iliac and right inguinal lymphnodes. 
DIAGNOSIS & TREATMENT	
The patient was diagnosed as Anastamotic site recurrence with metastasis and planned for chemotherapy. 4 cycles of cisplatin and gemcitabine was given following which the whole body PET-CT showed metabolic and morphologic regression of the right iliac and right inguinal lymph nodes. He subsequently underwent excision of the orthotopic ileal neobladder with urethrectomy and conversion to ileal conduit. The enlarged iliac lymphnodes were removed with right inguinal lymphnode dissection. 
CONCLUSION
Recurrence and survival following radical cystectomy depends on the final pathological stage and lymphnode metastasis. The 5 year cancer specific survival following radical cystectomy is approximately 90 % for those with non-invasive disease on the final pathological examination. The risk of urethral recurrence following cystectomy range from 4-8% in men; risk factors are non-muscle invasive disease in the final pathology and prostatic urethral involvement.  Inguinal lymphnode metastasis is uncommon in bladder cancer. Systemic therapy alone is not curative and metastasectomy should be considered in selected patients. Long-term follow up is essential for timely diagnosis and management of late recurrences following radical cystectomy.

Late recurrence following radical cystectomy with orthotopic ileal neobladder in NMIBC: A case report

Introduction & Objectives: Standard of care for bladder-preserving treatment with MIBC is CRT. Pembrolizumab has clinical activity across many stages of bladder cancer, including metastatic bladder cancer, MIBC, and non–muscle-invasive bladder cancer (NMIBC). Two phase 2 studies (NCT02662062 and NCT02621151) to test pembrolizumab plus CRT for MIBC are ongoing, and initial data are promising. KEYNOTE-992 (NCT04241185) will further investigate the safety and efficacy of pembrolizumab plus CRT in patients with MIBC who opt for bladder preservation.
Materials & Methods: KEYNOTE-992 is an ongoing, multicenter, double-blind, placebo-controlled, randomized, phase 3 trial to evaluate the efficacy and safety of first-line pembrolizumab versus placebo—both added to CRT—in patients with MIBC. Adults with confirmed cT2-T4a, nonmetastatic (N0M0) MIBC who opt to undergo bladder-preserving therapy will be eligible for enrollment. Approximately 636 patients will be randomly assigned 1:1 to receive CRT plus either pembrolizumab 400 mg IV Q6W or placebo. The study drug—ie, pembrolizumab or placebo—will be discontinued after 9 doses. The investigator must choose 1 of the following radiotherapy (RT) plans before study begins: conventional RT consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated RT consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder). Investigators must likewise choose 1 of the following radiosensitizing chemotherapy regimens: cisplatin monotherapy (35 mg/m2 IV weekly), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) plus mitomycin C (12 mg/m2 on day 1), and gemcitabine monotherapy (27 mg/m2 IV twice weekly). Efficacy will be assessed by cystoscopy (± biopsy); imaging (CT or MRI) with blinded independent central review; and urine cytology at 10 weeks after CRT, then Q12W until the end of year 2, and every 24 weeks thereafter. Enrollment will be stratified by ECOG PS (PS 0 or 1 vs 2), PD-L1 combined positive score (<10 vs ≥10), T stage (T2 vs T3 or T4), and geographic region (US vs Europe vs rest of world). Primary end point is bladder-intact event-free survival, defined as the time from randomization to first occurrence of the following: residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause. Key secondary end point is overall survival. Other secondary end points include metastasis-free survival, time to any NMIBC, time to cystectomy, and safety. Adverse events (AEs) will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs).
Results: KEYNOTE-992 is enrolling at sites in Czech Republic, Denmark, Estonia, Guatemala, Italy, Israel, Republic of Korea, Latvia, Malaysia, Netherlands, Spain, Taiwan, Turkey, Ukraine, and the United States of America.
Conclusions: KEYNOTE-992 will provide further clarity on the efficacy of pembrolizumab plus CRT in previously untreated MIBC.

Phase 3 KEYNOTE-992 Study: Pembrolizumab Plus Chemoradiotherapy (CRT) Versus Placebo Plus CRT for Patients with Muscle-Invasive Bladder Cancer (MIBC)

Introduction & Objectives: Despite aggressive local and systemic therapy, MIBC outcomes remain dismal, with high recurrence rates and poor survival outcomes. Standard-of-care therapy of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy results in a modest 5-year survival benefit. A phase 2 trial of neoadjuvant chemotherapy plus pembrolizumab had promising antitumor activity in cisplatin-eligible patients with MIBC (HCRN GU14-188; NCT02365766). In this trial, the estimated 36-month overall survival (OS), relapse-free survival, and disease-specific survival rates were 82%, 63%, and 87%, respectively, and toxicity was manageable, thus warranting further study of perioperative pembrolizumab plus neoadjuvant chemotherapy in MIBC.

Materials & Methods: The KEYNOTE-866 (NCT03924856) randomized, multinational, phase 3 study will assess efficacy and safety of perioperative pembrolizumab plus chemotherapy (gemcitabine plus cisplatin) versus perioperative placebo plus chemotherapy for patients with MIBC. Enrolled patients are adults with histologically confirmed MIBC (T2-T4aN0M0) with predominant (≥50%) urothelial histology confirmed by blinded independent central pathology and imaging review. Patients must also be previously untreated, be cisplatin-eligible, have Eastern Community Oncology Group (ECOG) performance status 0 or 1, and have tumor tissue for histology and PD-L1 analysis. Approximately 790 patients will be randomly assigned in a 1:1 ratio to 4 cycles of neoadjuvant pembrolizumab or placebo plus chemotherapy followed by 13 cycles of adjuvant pembrolizumab or placebo after radical cystectomy plus pelvic lymph node dissection. Neoadjuvant or adjuvant pembrolizumab 200 mg or placebo will be administered intravenously every 3 weeks (Q3W); neoadjuvant chemotherapy consists of 4 cycles of gemcitabine 1000 mg/m2 plus cisplatin 70 mg/m2 Q3W. Stratification factors will be PD-L1 status (combined positive score [CPS] ≥10 vs <10), disease stage (T2 vs T3/4), and region (United States vs Europe vs rest of world). Imaging (CT or MRI) will be performed 5 weeks or less prior to cystectomy and at 6 weeks postcystectomy. Imaging will then be performed Q12W up to week 96 postcystectomy and at discontinuation. Thereafter—year 3 and beyond—imaging will be Q24W. The dual primary end points are pathologic complete response (pCR) and event-free survival (EFS) evaluated in patients whose tumors express PD-L1 (CPS ≥10) and in all patients irrespective of CPS score. Secondary end points are OS, disease-free survival, and pathologic downstaging in patients with CPS≥10 and in all patients irrespective of CPS score, as well as safety, and patient-reported outcomes. Adverse events (AEs) graded per Common Terminology Criteria for Adverse Events, version 4.0, will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs).

Results: The KEYNOTE-866 study is underway in 22 countries across Asia, Australia, E

Perioperative Pembrolizumab or Placebo and Neoadjuvant Chemotherapy in Patients With Muscle-Invasive Bladder Cancer (MIBC) Who Are Eligible for Cisplatin (KEYNOTE-866 phase 3 study)

Atezolizumab-induced myasthenia gravis in a patient with metastatic urothelial carcinoma

Tocco B, Hijab A, Huddart R, Hafeez S
1 The Royal Marsden NHS Foundation Trust, London, UK 
2 The Institute of Cancer Research, London, UK

Acknowledgements
We acknowledge support from National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Competing interest 
BT and AH have no conflicts to disclose.  RH reports non-financial support from Janssen, grants and personal fees from MSD, personal fees from Bristol Myers Squibb, grants from Cancer Research UK, other from Nektar Therapeutics, personal fees and non-financial support from Roche  outside the submitted work; SH reports non-financial support from Elekta (Elekta AB, Stockholm, Sweden), non-financial support from Merck Sharp & Dohme (MSD), personal fees and non-financial support from Roche outside the submitted work. 

Author for correspondence 
Dr B Tocco
The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT. UK
Boris.Tocco@rmh.nhs.uk 
 
Abstract
Introduction
The increasing use of immune checkpoint blockade in metastatic cancer has resulted in greater prevalence of immune-related adverse events (irAEs). The anti-CTLA-4 and anti-PD-1 action resulting in T-cell mobilisation causes a surge in tumoural immune response but is also well documented to result in autoimmune toxicities [1]. 

The use of atezolizumab in cisplatin-ineligible metastatic bladder cancer was approved in the UK based on the IMvigor trial [2]. The toxicities arising from its use more commonly affect bowel, liver, lung and endocrine tissue[1]. The development of immunotherapy-induced myasthenia gravis has been reported with other checkpoint inhibitors [3] but rarely related to atezolizumab – this report describes a case of atezolizumab-induced myasthenia gravis in the context of metastatic bladder cancer.


Clinical history
A 77 year old gentleman, with a history of hypercholesterolemia, underwent a primary radical cystectomy and bilateral pelvic lymph node dissection for pT3bN2 transitional cell carcinoma of the bladder. He was ineligible for neoadjuvant cisplatin-based chemotherapy due to hearing loss and declined adjuvant treatment. Immunohistochemistry of operative tissue sample revealed a PD-L1 expression of 5-10%. He suffered a nodal relapse 4 months post-operatively.

He was surveyed with interval CT scans which found slowly-progressive disease and, 8 months later, started palliative systemic therapy with 3-weekly intravenous atezolizumab at 1200mg.

After his 2nd cycle of treatment, he presented with double vision and head drop. On examination, he was diplopic throughout all ocular movements with MRC grade 4/5 power of neck extension and proximal muscles groups. Neck flexion and 

Atezolizumab-induced myasthenia gravis in a patient with metastatic urothelial carcinoma

Introduction & Objectives: Patients with MIBC who are ineligible for neoadjuvant cisplatin-based chemotherapy receive the standard of care treatment of radical cystectomy (RC) and pelvic lymph node dissection (PLND). This therapy alone is associated with high rates of recurrence and relatively poor overall survival (OS); novel perioperative systemic therapy regimens are needed. The PURE-01 single-arm study (NCT02736266) found that the PD-1 inhibitor pembrolizumab as single-agent neoadjuvant therapy in patients with MIBC had antitumor activity. The study also found that high PD-L1 expression was associated with a higher pathologic complete response rate (pCR).

Materials & Methods: The KEYNOTE-905 (NCT03924895) randomized, multinational phase 3 study will assess efficacy and safety of perioperative pembrolizumab plus RC and perioperative EV with pembrolizumab plus RC vs RC alone for patients with MIBC. The patient population will comprise adults with histologically confirmed MIBC (T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, confirmed by blinded independent central review. These patients must also be previously untreated with systemic therapies for MIBC, be cisplatin-ineligible, have Eastern Cooperative Oncology Group performance status of 0-2, and have tumor tissue for histology and PD-L1 analysis. Approximately 836 patients will be randomized 1:1:1 to 3 cycles of neoadjuvant pembrolizumab followed by RC plus PLND and 14 cycles of adjuvant pembrolizumab or 3 cycles of neoadjuvant EV and pembrolizumab followed by RC plus PLND and 6 cycles of adjuvant EV and 14 cycles of adjuvant pembrolizumab or RC plus PLND alone. Neoadjuvant or adjuvant pembrolizumab 200 mg will be administered intravenously every 3 weeks (Q3W). Neoadjuvant or adjuvant EV 1.25 mg/kg will be administered on days 1 and 8 Q3W. Stratification factors will be PD-L1 status (combined positive score [CPS] ≥10 vs <10), disease stage (T2N0 vs T3/T4N0 vs T1-T4aN1), and region (United States vs European Union vs Most of the World). Imaging (CT or MRI) will be performed 5 weeks or fewer precystectomy and at 6 weeks postcystectomy. Scans will then be performed Q12W up to week 96 postcystectomy and at discontinuation. Thereafter (ie, year 3 and beyond) imaging will be Q24W. The coprimary endpoints are pCR and event-free survival (EFS) (expressing PD-L1 [CPS ≥10] and all patients regardless of CPS). Secondary endpoints are OS, disease-free survival, and pathologic downstaging in populations described for pCR and EFS safety, and patient-reported outcomes. Adverse events (AEs) graded according to Common Terminology Criteria for Adverse Events v4.0 will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs).

Results: KEYNOTE-905 study is ongoing or planned in 25 countries across Asia, Australia, Europe, and North America.

Conclusions: KEYNOTE-905 will provide further clarity on efficacy of perioperative pembrolizum

Perioperative Pembrolizumab or Pembrolizumab plus Enfortumab Vedotin (EV) and Cystectomy Compared to Cystectomy Alone in Patients With Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin-Ineligible (KEYNOTE-905/EV-303)

INTRODUCTION
The increased use of inmune checkpoint inhibitors has shown a new spectrum of toxicities1. Inmune-related adverse events (irAEs) are diverse. Neurologic toxicity is uncommon, representing 1-14% of all irAEs2. We report a case of immunotherapy-induced myasthenia gravis in a patient under treatment for urothelial cancer.

CASE – CLINICAL FINDINGS, DIAGNOSIS AND TREATMENT
A 67-year-old male diagnosed with stage IV upper tract urothelial cancer completed four cycles of cisplatin-gemcitabine along with anti-CTLA4 and anti-PDL1. Subsequently the patient continued with anti-PDL1 single-agent maintenance. Around the start of monotherapy, the patient referred progressive fatigue being ruled out metabolic and analytic causes. Following, muscle weakness and eyelid dropped appeared. Upon a myasthenic syndrome suspicion treatment was interrupted and patient referred to neurology where the diagnosis was confirmed [positive acetylcholine receptor antibodies] and treatment started accordingly requiring pyridostigmine, steroids and finally immunoglobulins to control. 

CONCLUSIONS
IrAE physiopathology is not fully understood and seems to follow a stochastic pattern3. Promoting a pro-inflammatory environment with T-cells and cytokines stimulates auto-antibodies production and/or auto-reactive T-cells3. Similarities among tissue-antigens and neo-antigens produced by the tumor could induce a crossed-reaction3. 
Clinical identification of “high risk” patients is still a challenge with no established predictive factors. The incidence of neurologic irAEs has been estimated in 3.8% with single agent anti-CTLA4, 6.1% with anti-PD1 and 12% with the combination4. Myasthenia gravis (MG) has been described both in association with monotherapy and combinations3. It can present as a new diagnosis (72.7%) or an exacerbation of a previous known MG (18.2%) or a subclinical MG(9.1%)5. Myasthenia gravis is usually associated with myositis3. Most frequent clinical presentation includes weakness of ocular, bulbar and respiratory muscles. Half of the patients developed fast crisis and required ventilator support3.  Abnormal results in neurophysiology studies were only observed in half of the patients, which could be related to the co-existence of myositis3. Acetylcholine receptor antibody resulted positive in 57-83% of cases, lower index than in conventional myasthenia3. 
Interrupting immunotherapy and corticosteroids (1-1.5 mg/Kg) is the main treatment2. Pyridostigmine, inmunoglobulins and plasmapheresis are  other measures to be considered according to severity and response to treatment3. 
In conclusion, neurologic IrAEs are infrequent but can be potentially severe. It is critical to be familiar with their presentation and management. A prompt identification might lead to an early intervention and increase treatment success.

BIBLIOGRAHPY
1. 	Magee DE, Hird AE, Klaassen Z, et al. Adverse event profile for immunotherapy agents compared with chemotherapy in s

UROTHELIAL CANCER. NEW THERAPIES, NEW TOXICITIES: MYASTHENIA GRAVIS

Targeting antisense mitochondrial noncoding RNAs induces bladder cancer cell death and inhibition of tumor growth through reduction of survival and invasion factors

Intracorporeal Versus Extracorporeal Urinary Diversion Following Robot-Assisted Radical Cystectomy: A Meta-Analysis, Cumulative Analysis and Systematic Review