Urinary Carcinoma Research Articles

Abstract 5434: Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract

Abstract Introduction Clinical guidelines including the American Urological Association (AUA) state that neoadjuvant chemotherapy should be administered prior to surgery in cases of muscle invasive urinary bladder small cell neuroendocrine carcinoma. Although the recently described marker insulinoma-associated protein 1 (INSM1) has been reported to be sensitive and specific for neuroendocrine differentiation in neuroendocrine tumors at several sites, its efficacy as a marker in urinary bladder small cell carcinoma has not been well established. This study aims to examine the immunohistochemical expression pattern of INSM1 on whole tissue sections of urinary bladder small cell neuroendocrine carcinoma and compare INSM1 expression to those of established markers of neuroendocrine differentiation. Methods Archived tissue from 32 cases of urinary bladder small cell neuroendocrine carcinoma were obtained from Rhode Island Hospital and The Miriam Hospital. Immunohistochemical stains for CD56, INSM1, synaptophysin, and chromogranin were performed. Staining was scored for intensity (0: no staining; 1: weak; 2: moderate; 3: strong) and proportion of cells stained (0: 0%; 1: >0 to 25%; 2: >25 to 50%; 3: >50 to 75%; 4: >75 to 100%). Results INSM1 was positive (intensity 1-3 or proportion 1-4) in 87% (28/32) of small cell neuroendocrine carcinoma cases (20 with intensity 2-3, 17 with proportion 3-4). CD56, synaptophysin, and chromogranin were positive in 75% (24/32), 60% (19/32), and 44% (14/32) of cases, respectively. While the rate of positivity was high, INSM1 was negative (n=4) or only showed weak intensity staining (n=7) in 34% (11/32) of cases. Conclusion INSM1 is a sensitive marker of small cell neuroendocrine differentiation of the urinary bladder. However, the findings in this study suggest that optimal utilization of INSM1 would be in a limited panel of stains rather than as a stand-alone screening marker given that it is negative or only shows weak intensity staining in a significant proportion of cases. StainNegative [n (%)]Positive [n (%)]INSM14 (13)28 (87)CD568 (25)24 (75)Synaptophysin13 (40)19 (60)Chromogranin18 (56)14 (44) Citation Format: Isaac E. Kim, Ali Amin, Li Juan Wang, Liang Cheng, Carmen M. Perrino. Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5434.

Abstract 2293: A urine-based liquid biopsy method for detection of upper tract urinary carcinoma

Abstract Background: Upper tract urinary carcinoma (UTUC) includes renal pelvic cancer and ureteral cancer. For its diagnosis, ureteroscopy is the only method to obtain pathological result before surgery. However, there are also some problems with ureteroscopy. In addition to the trauma and infection risks, the possibility of exudation and adhesion of surrounding tissues after ureteroscopy is significantly increased, hypertension in the cavity may cause tumor spread, and the use of ureteroscopy and biopsy may cause recurrence of bladder tumors after surgery. These unfavorable factors make clinically urgent need for a sensitive and non-invasive method for the diagnosis of UTUC. Materials and Methods: In this study, 150 hematuria patients with upper tract urinary disease and 100 healthy people were enrolled. Among the patients, 75 were pathologically confirmed with upper tract urinary carcinoma while 75 with benign urinary diseases. A Genetron Urinary Assay was designed to maximize the number of unique driver gene variants of UTUC by a limited number of amplicons. Next-generation sequencing libraries were constructed using multiplex PCR methods. We also detected CpG-sites on ONECUT2 gene by performing bisulfite-specific real-time PCR for bisulfite converted DNA. Furthermore, we developed a prediction model based on several significant features to evaluate the risk of UTUC. Results: 234 samples were available for analysis. Our liquid biopsy assay demonstrated a sensitivity of 94%, a specificity of 96%, a positive predication value (PPV) of 92% and a negative predication value(NPV) of 98% in this study. By using a decision tree model, we found age, gene mutations of HRAS, TERT and TP53 and methylation of ONECUT2 did place at some key nodes to classify the risk of patients of UTUC, and age around 48.5, the frequencies of mutated genes above certain value and ΔCt value of ONECUT2 about 7.6 would be good cutoffs. This model was able to stratify patients into a low or high-risk group with an accuracy score at 94%. After further analysis, we found that ONECUT2 methylation and TP53 mutations were more common in high grade UTUC (p<0.01), while AKT1 and FGFR3 (trend, but no statistical significance) mutations were more often shown in low grade group. No significant difference of gene mutations frequency was found between non muscle invasive and muscle invasive group, but FGFR3 as well as TERT and PIK3CA gene showed a trend of higher occurrence. Conclusion: In this study, Genetron Urinary Assay has a good performance in the diagnostic of UTUC. Its high sensitivity, high specificity, and non-invasiveness make it a potential clinical alternative to ureteroscopy. Further validation in a large prospective cohort of wide population is necessary to prove the true clinical value of this newly developed method. Citation Format: Xin Ma, Yansheng Xu, Hongzhao Li, Xing Ai, Jiangping Gao, Yiming Liang, Qiaosong Zheng, Kaisheng Mao, Tonghui Ma, Xu Zhang. A urine-based liquid biopsy method for detection of upper tract urinary carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2293.

Risk stratification for upper tract urinary carcinoma.

Upper tract urinary carcinoma (UTUC) is a heterogeneous group of rare tumors. The aim of this article is to critically review current therapeutic strategies and to propose a change in the risk-stratification of the disease. A non-systematic review of the literature was performed using the Medline database with the search terms: “upper tract urothelial carcinoma” together with “prognostic factor”, “risk stratification”, “risk factor”, “recurrence”, “predictive tool”, “nomograms” and “treatment”. Preoperative risk factors can be viewed as patient-related risk factors (gender, age, ethnicity, body mass index, smoking status, or genetic factors), or tumor-related risk factors (stage, grade, size, architecture, multifocality, ureteric obstruction). Several biomarkers, available either in blood, urine, or the tumor itself have also been proposed. However, many of these prognostic factors lack accuracy and validation in predicting oncological outcomes, despite their use in predictive tools. After risk stratification, kidney-sparing strategies should be considered (endoscopic management and segmental ureterectomy) and could benefit from new diagnostic tools and technical improvements in in situ adjuvant endocavitary instillations. Radical nephroureterectomy remains the first choice therapy for high-grade disease and will probably be associated with other treatments in the future (lymphadenectomy, perioperative chemotherapy, or immunotherapy). In view of the major recent improvements in UTUC treatment strategies, a new classification should be proposed, including low-, intermediate-, high- and very high-risk disease. Subgroup analysis of good quality trials and better understanding of UTUC risk factors will help validate this new approach toward more personalized medicine.

V050 - Dual thulium-holmium laser ablation by percutaneous approach of upper tract urinary carcinoma in a solitary kidney: An imperative case

V050 - Dual thulium-holmium laser ablation by percutaneous approach of upper tract urinary carcinoma in a solitary kidney: An imperative case

A case report of primary upper urinary tract signet-ring cell carcinoma and literature review

BackgroundUpper tract urothelial carcinoma with pure non-urothelial histology is an exception but variants are present in ~ 25% of cases. Primary upper urinary tract signet -ring cell carcinoma is extremely rare.Case presentationWe report the case of a 65-year-old male diagnosed primary upper urinary tract signet-ring cell carcinoma while underwent percutaneous nephrolithotomy. Radical nephroureterectomy and adjuvant chemotherapy were performed sequentially. The patient is now recovering well with a regular follow-up for more than 1 year.ConclusionsThe upper urinary tract malignancy often appears as a high grade, high stage tumor and has a uniformly poor prognosis, but a timely multimodal management can bring a good outcome.

The Diagnostic Dilemma of GATA3 Immunohistochemistry in Pheochromocytoma and Paraganglioma.

Although GATA3 has been recognized as a useful marker for mammary and urothelial carcinomas, there is large variation in GATA3 expression detected in pheochromocytoma (PC) and paraganglioma (PGL), from 90% to less than 5%. For GATA3 to be a useful diagnostic marker for PCCs/PGLs, the reasons for such discrepancy must be elucidated. Thus, we compared different immunohistochemistry protocols. Three protocols for GATA3 immunohistochemistry, including the use of an automated slide stainer or manual staining with an autoclave and EDTA buffer vs citric acid buffer, were compared. Whole sections of paraffin-embedded tumors, including 30 PCCs, 37 PGLs including 15 head and neck PGLs, 5 retroperitoneal PGLs, 17 urinary bladder PGLs, and 14 neuroblastoma group tumors, were examined and compared with mammary and urothelial carcinoma sections as positive controls. Using the automated slide stainer (Benchmark ULTRA; Ventana Medical Systems) with both buffers, mammary and urothelial carcinomas demonstrated strong GATA3 positivity; however, PCCs/PGLs showed negative or weak heterogeneous staining. Manual staining with an autoclave for antigen retrieval resulted in increased GATA3 immunoreactivity in all head and neck PGLs, all retroperitoneal PGLs, 88% of urinary PGLs, 17% of PCCs, and all neuroblastomas, except for ganglion cells. The normal adrenal medulla stained weakly and heterogeneously. In conclusions, immunohistochemistry for GATA3 in PCCs/PGLs requires stronger antigen retrieval than that in mammary and urinary carcinomas. This finding is especially important to consider if GATA3 is applied for the differential diagnosis of PGLs in unusual sites as supplemental data to the expression of catecholamine-synthesizing enzymes.

A Study of Postoperative Adjuvant Chemotherapy for Upper Urinary Urothelial Carcinoma With Lymphatic Invasion

A Study of Postoperative Adjuvant Chemotherapy for Upper Urinary Urothelial Carcinoma With Lymphatic Invasion

The prognostic value of concomitant carcinoma in situ in patients with upper tract urinary carcinoma after radical nephroureterectomy: an systematic review and Meta-analysis

Objective The aim of this study was to evaluate the influence of in (CCIS) on tumor survival for the tract urinary (UTUC) through systematic review and meta-analysis. Methods In the light of Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, a systematic search of Web of Science, PubMed and EMBASE China National Knowledge Infrastructure (CNKI) and Wanfang database by key words upper urinary tract urothelial carcinoma renal sputum cancer concomitant in situ , and ureterectomy were performed for all reports that included detailed results on the predictors of CCIS. The search deadline is June 2019, and the search terms are English and Chinese. Methodological quality evaluation was performed using the QUIPS tool, and statistical analysis of the relevant data was performed using Stata 12.0 and RevMan 5.3 software. Results Sixteen articles were included in this study and all published between 2012 and 2019. A total of 11 131 patients with UTUC, including 1 774 (15.9%) patients with CCIS. According to our final results, there was a significant correlation of CCIS with worse cancer-specific survival (CSS) (HR=1.10, 95%CI 1.05-1.16, P<0.001), recurrence-free survival (RFS) (HR=1.15, 95%CI 1.09-1.21, P<0.001) and overall survival (OS) (HR=1.10, 95%CI 1.03-1.17, P=0.003). Begg′s bias analysis showed no significant publication bias in CSS (P=0.822), RFS (P=0.348), and OS (P=0.452). Conclusions This study demonstrated that CCIS was associated with poor oncological outcome and could serve as a independent prognostic factor for patient with UTUC after radical nephroureterectomy. Key words: Urologic diseases; Upper tract urinary carcinoma; Radical nephroureterectomy; Concomitant in situ; Prognosis; Meta-analysis

Prevalence, clinicopathological features, and prognosis in upper tract urinary carcinoma patients with severe preoperative chronic kidney disease.

Studies regarding the prevalence and factors associated with severe pre-operative chronic kidney disease (CKD) in upper tract urinary carcinoma (UTUC) patients were rare due to the low prevalence of UTUC. We conducted the present study to investigate the prevalence, clinicopathological features, and prognosis in UTUC patients with severe preoperative CKD. The study included 731 patients with UTUC treated with radical nephroureterectomy (RNU) in a large Chinese center. Estimated glomerular filtration rate (eGFR) was calculated by re-expressed Modification of Diet in Renal Disease (MDRD) formulas for the Chinese population. Severe preoperative CKD was defined as CKD stage 4-5 (eGFR <30 mL/min). Relationships of CKD stage 4-5 with clinicopathological characteristics, overall survival (OS), cancer-specific survival (CSS), contralateral recurrence-free survival and intravesical recurrence (IVR)-free survival were analyzed. A total of 73 (10.0%) patients presented severe preoperative CKD in this cohort. Multivariate logistic analysis indicated that female gender (OR =1.791; 95% CI: 1.018-3.150; P=0.043), lower BMI (OR =0.452; 95% CI: 0.262-0.778; P=0.004), concomitant bladder tumor (OR =2.944; 95% CI: 1.360-6.373; P=0.006), lower pathological T stage (OR =0.578; 95% CI: 0.339-0.984; P=0.043), tumor necrosis (OR =2.764; 95% CI: 1.411-5.416; P=0.003), and exposure of aristolochic acid (AA) (OR =3.115; 95% CI: 1.536-6.316; P=0.002) were significantly related to severe CKD. Multivariate Cox's regression analysis showed that severe preoperative CKD was significantly associated with worse OS (HR =1.840; 95% CI: 1.150-2.944; P=0.011) and worse contralateral recurrence-free survival (HR =3.269; 95% CI: 1.607-6.650; P=0.001), while no statistical difference in terms of CSS or IVR-free survival were noticed. Female gender, lower BMI, concomitant bladder tumor, lower pathological T stage, exposure of AA, and tumor necrosis were independently associated with severe preoperative CKD in UTUC patients. UTUC patients with severe preoperative CKD possess worse OS and higher possibility of contralateral upper urinary tract recurrence.

Initial experience of flexible ureteroscopy combined with thulium laser for the treatment of upper urinary tract urothelial carcinoma

Objective To summarize the initial experience of flexible ureteroscopy combined with thulium laser for the treatment of high-risk upper urinary tract urothelial carcinoma (UTUC) in patients with solitary kidney or renal insufficiency. Methods A retrospective analysis was performed in 5 cases of UTUC with solitary kidney or renal insufficiency treated via flexible ureteroscopy combined with thulium laser from May 2016 to November 2018. Patients consisted of 4 cases of left side tumor, 1 case of right side tumor, with median age of 73 years old(ranging 53-87 years old). Among the 5 cases, 3 were solitary kidney with renal pelvis tumors, 2 cases were renal insufficiency accompanied with proximal ureter or renal pelvis tumor. All the patients had tumors large than 2 cm in diameter. The creatine in 3 cases with solitary kidney was 102, 128, 143μmol/L, respectively. The creatine in 2 cases with renal insufficiency was 281, 179μmol/L, respectively. Variable hydronephrosis was noticed in all paients. The cytological examination could reveal tumor cells in all cases. During the operation, part of tumor tissues were resected for pathological examination and the remaining visible tumor tissue was all ablated and vaporized. As there was no obvious residual tumor tissue, double J stent was retained. Patients were regularly reexamined after surgery. Results Of the 5 cases, 4 patients were successfully performed, while intraoperative bleeding occurred in 1 case. The operation was suspended after indwelling double J stent. Then, the renal artery interventional embolism was performed after ineffective conservative treatment, and the bleeding was well controlled. One month later, the patient was treated with thulium laser tumor ablation and vaporizaiton under flexible ureteroscopy again. The pathology of all cases was high-grade invasive urinary epithelial carcinoma. Patients were followed up with regular imaging and endoscopic examination. The median follow-up period was 19 (4-26) months, during which 4 cases had local recurrence, one patient died of non-tumor factors. No recurrence of urothelial carcinoma occurred in the bladder during follow-up, the overall recurrence rate was 80%, and the median recurrence time was 6 (1-24) months. Patients with recurrence was treated with thulium laser tumor ablation and vaporizaiton under flexible ureteroscopy again. Conclusions Flexible ureteroscopy combined with thulium laser is an alternative treatment for high-risk upper urinary tract urothelial carcinoma in patients with solitary kidney or renal insufficiency, while with high tumor recurrence rate. Therefore, a stringent imaging and endoscopic follow-up should carry out postoperatively. Key words: Ureteroscopy; Flexible ureteroscope; Thulium laser; Upper urinary tract urothelial carcinoma

Urine Based Liquid Biopsy Assist Evaluating Upper Tract Urinary Carcinoma Risk of Patients with Hematuria

Background: In the large amount of hematuria patients, a considerable part of them originate in upper tract urinary carcinoma(UTUC). The most important in the evaluation of hematuria is to find accurate and economical method to discriminate between non-malignant and malignant causes. Liquid biopsy for urine samples can be helpful for UTUC diagnosis in patients with hematuria and rule out individuals with low-risk. Methods: In this study, we combined high-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites as a liquid biopsy panel. We developed a prediction model which contained several significant features to evaluate the risk of UTUC in hematuria patients. Findings: 94 healthy, 70 UTUC- and 70 UTUC+ cases’ samples are qualified for this study, our liquid biopsy panel resulting in a sensitivity of 94% (66/70), and a specificity of 96% (158/164), the positive predication value of 92% and a negative predication value of 98% in this study. With age as additional factor, our model was able to stratify patients into a low or high-risk group with an accuracy score at 94%. Further validation in a large prospective cohort will answer whether this early screening tool can also be used in monitoring postoperative patients who need serials of follow-ups. Interpretation: Urine based liquid biopsy can assist evaluating upper tract urinary carcinoma risk of patients with hematuria and outperformed FISH for accurately ruling out patients who do not have UTUC. Funding Statement: In this research, no funding or other financial supports was received. Declaration of Interests: The authors declared that they have no conflicts of interest to this study. Ethics Approval Statement: Informed written consent was obtained from patients at PLA General Hospital and the study was approved by the Committees on Clinical Research Ethics of the Chinese PLA General Hospital.

Altered Gene Expression of Cancer-Associated Fibroblasts is Related to Stiffness Properties between Different Tumor Architectures of Upper Tract Urinary Carcinoma

Recent publications have assessed the prognostic significance of tumor architecture in upper tract urinary carcinoma (UTUC), including sessile architecture (SA) type and papillary architecture (PA) type. However, there are still no reports of the mechanisms about the differences of biomechanical properties and gene expression between two types. After retrospectively reviewing the medical records of UTUC who had undergone surgery at multi-centers, we detected average elasticity value and structural changes of tumor-matrix between PA type UTUC and SA type UTUC. The gene expression profiles between two types were identified by mRNA expression profiling and quantitative real-time PCR (qRT-PCR). Moreover, the expression of cancer-associated fibroblasts and extracellular matrix were detected by immunohistochemical staining.The multi-center retrospective study of 241 patients showed that tumor architecture was found to be positively correlated with the tumor location and the histological grade. Kaplan-Meier curves showed that patients with SA type UTUC had significantly poor progression-free survival (PFS) and cancer specific survival (CSS). Then, we further reported that SA type has more elastic value (63.74±3.88 Kpa vs 32.46±1.68 Kpa) and higher tumor-stroma ratio (54.41±2.85 vs 29.87±1.41) than PA type. Microarray analysis of mRNA expression profiles and qRT-PCR showed that genes clustered of cancer-associated fibroblasts marker, composition of extracellular matrix (ECM) marker and epithelial mesenchymal transition (EMT) marker may be closely associated with progression and metastasis in patients with SA type UTUC.These studies may offer a useful marker for investigation tumor development, search therapeutic target and evaluation of disease prognosis for two types of UTUC. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No. 31800787,No. 31570953,No. 31470799 and No. 81372761) and the Natural Science Foundation of Liaoning Province (No. 5061116). the Doctoral Research Startup Foundation of Liaoning Province (No. 20180540020) and the Medical Scientific Research Project of Dalian City (No. 1812038) . Declaration of Interests: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Ethics Approval Statement: approval by the institution Ethics Committee (No.LCKY2015-08)

Bladder recurrence of primary upper tract urinary carcinoma following nephroureterectomy, and risk of upper urinary tract recurrence after ureteral stent positioning in patients with primary bladder cancer.

Upper tract urinary carcinoma (UTUC) and bladder cancer (BCa) share similar biological, histological and pathological characteristics. These resemblances could explain the high rate of synchronous and metachronous tumors affecting both upper urinary tract and bladder. In patients affected by primary UTUC bladder recurrence is quite common and it represents one of the major concerns during the follow-up of patients who underwent radical nephroureterectomy. Conversely, UTUC recurrence after primary non-muscular invasive BCa is a relatively rare event. Moreover, there is no clear evidence on whether the use of Double-J stenting as drainage in patients affected by BCa increases the risk of UTUC recurrence. The aim of the current study was to summarize the most recent evidence regarding the bladder recurrence after UTUC surgical treatment, and the UTUC recurrence after stent positioning in patients affected by primary BCa.

Kaempferol Attenuates ROS-Induced Hemolysis and the Molecular Mechanism of Its Induction of Apoptosis on Bladder Cancer.

Bladder cancer has become the most common malignant urinary carcinoma. Studies have shown that significant antioxidant and bladder cancer-fighting properties of several plant-based diets like Psidium guajava, ginger and amomum, are associated with their high kaempferol content. In this paper, we evaluated the antioxidant and anticancer activities of kaempferol and its mechanism of induction to apoptosis on bladder cancer cells. Our findings demonstrated that kaempferol showed an obvious radical scavenging activity in erythrocytes damaged by oxygen. Kaempferol promoted antioxidant enzymes, inhibited ROS generation and lipid peroxidation and finally prevented the occurrence of hemolysis. Additionally, kaempferol exhibited a strong inhibitory effect on bladder cancer cells and high safety on normal bladder cells. At the molecular level, kaempferol suppressed EJ bladder cancer cell proliferation by inhibiting the function of phosphorylated AKT (p-AKT), CyclinD1, CDK4, Bid, Mcl-1 and Bcl-xL, and promoting p-BRCA1, p-ATM, p53, p21, p38, Bax and Bid expression, and finally triggering apoptosis and S phase arrest. We found that Kaempferol exhibited strong anti-oxidant activity on erythrocyte and inhibitory effects on the growth of cancerous bladder cells through inducing apoptosis and S phase arrest. These findings suggested that kaempferol might be regarded as a bioactive food ingredient to prevent oxidative damage and treat bladder cancer.

Application of ERAS in the treatment of partial resection of urinary tract for unilateral renal carcinoma

Objective To explore the clinical effect of enhanced recovery after surgery (ERAS) in treatment of partial resection of urinary tract unilateral renal carcinoma. Methods From March 2015 to September 2017 in our hospital 80 patients with unilateral renal carcinoma were treated by partial resection of urinary. According to the wishes of patients and their families, 47 cases were treated with ERAS regimen (treatment group), 33 patients with conventional treatment (control group) in perioperative period. The changes of the corresponding indexes and recovery were observed in two groups. Results After surgery the time of feeding, ventilation , postoperative hospital stay and ambulation time in treatment group were significantly shorter than in control group (P<0.05), while the incidence of postoperative complications in the treatment group was significantly lower than that in the control group (P<0.05). Compared with 24 h after treatment, level of TP, HB, Alb, CRP, blood glucose, insulin and insulin resistance in the two groups was significantly increased (P<0.05), and the treatment group was significantly higher than the control group (P<0.05). The average total cost of the treatment group was 25 700 yuan and the control group was 30 400 yuan, from the perioperative period to the hospital discharge. Conclusions ERAS can reduce the postoperative stress response of patients with renal carcinoma, the incidence of postoperative complications, and the cost of treatment, improve the nutritional status of patients after surgery, and accelerate the postoperative recovery of patient. Key words: Kidney Neoplasms; Rehabilitation

The evolving genomic landscape in urothelial cancer.

Recent advances in next-generation sequencing have allowed for detailed molecular analysis of urothelial carcinomas, with potentially significant clinical implications for personalized treatment. Our objective in this review is to highlight studies from the past year that have furthered the understanding of urothelial cancer genomics. Recent studies by The Cancer Genome Atlas consortium further characterized urothelial carcinomas via molecular subtyping, and a schema was proposed to match each subtype with potential therapeutic implications. Molecular subtyping was also utilized in a separate analysis to determine which tumours benefit from neoadjuvant chemotherapy. Tumour characteristics were also explored pre and postneoadjuvant chemotherapy and a mutational signature associated with postcisplatin treatment was described. We also review a comprehensive analysis of upper tract urinary carcinomas published this past year. Recent genomic analyses have revealed that the classification of urothelial carcinoma is much more complex than the traditional dichotomy of nonmuscle-invasive and muscle-invasive bladder cancers. Molecular subtyping has provided additional insights into prognoses and treatment options for these patients. Although molecular subtyping is not yet ready for implementation into clinical practice, these latest efforts offer an exciting opportunity to integrate such information into prospective clinical studies that may ultimately lead to improved treatment outcomes.

Prognostic value of circulating microRNAs in upper tract urinary carcinoma.

The identification of upper tract urinary carcinoma (UTUC) prognostic biomarkers is urgently needed to predict tumour progression. This study aimed to identify serum microRNAs (miRNAs) that may be useful as minimally invasive predictive biomarkers of tumour progression and survival in UTUC patients. To this end, 33 UTUC patients who underwent radical nephroureterectomy at the Hospital Clinic of Barcelona were prospectively included. Expression of 800 miRNAs was evaluated in serum samples from these patients using nCounter® miRNA Expression Assays. The study was divided into an initial discovery phase (n=12) and a validation phase (n=21). Cox regression analysis was used for survival analysis. The median follow-up (range) of the series was 42 months (9-100 months). In the discovery phase, 38 differentially expressed miRNAs were identified between progressing and non-progressing UTUC patients (p<0.05). Validation of these 38 miRNAs in an independent set of UTUC patients confirmed the differential expression in 18 of them (p<0.05). Cox Regression analysis showed miR-151b and pathological stage as significant prognostic factors for tumour progression (HR=0.33, p<0.001 and HR=2.62, p=0.006, respectively) and cancer specific survival (HR=0.25, p<0.001 and HR=3.98, p=0.003, respectively). Survival curves revealed that miR-151b is able to discriminate between two groups of UTUC patients with a highly significant different probability of tumour progression (p=0.006) and cancer specific survival (p=0.034). Although the data needs to be externally validated, miRNA analysis in serum appears to be a valuable prognostic tool in UTUC patients. Particularly, differential expression of miR-151b in serum may serve as a minimally invasive prognostic tool in UTUC.

A tumor growth rate/overall survival model for atezolizumab as an early predictor of OS in patients with first or second line metastatic urothelial carcinoma.

62 Background: Standard early endpoints are often poor predictors of overall survival (OS) for immunotherapies. There is a need for new intermediate endpoints to support upcoming combination studies with immune checkpoint inhibitors. We investigated the predictive performance of on-treatment tumor growth rate (TGR) estimates to predict OS in atezolizumab clinical trials in patients (pts) with metastatic urinary carcinoma (mUC). Methods: Atezolizumab showed durable response, prolonged OS and good tolerability supporting its therapeutic use in mUC (Rosenberg, Lancet 2016; Balar, lancet 2017; Powles, EACR-AACR-SIC 2017). A multivariate model linking baseline patient characteristics and TGR (estimated using time profile of sum of longest diameters (SLD) of target lesions, RECIST 1.1) to OS was developed using phase 2 data (IMvigor210) and validated to predict phase 3 trial (IMvigor211). Results: To estimate TGR, patients needed to have at least one post-baseline measurement: n = 365/429 (85%) in IMvigor210 (102 in cohort 1, 1L cisplatin-ineligible and 263 in cohort 2, prior platinum-treated 2L+) and n = 745/902 treated (83%) in IMvigor211 (prior platinum-treated 2/3L). A lognormal model with independent baseline prognostic factors (alkaline phosphatase, ECOG performance status and number of metastatic sites) and estimated TGR was developed. The model predicted OS distributions in the two IMvigor210 cohorts in all comers as well as by PD-L1 expression on tumor-infiltrating immune cells (IC). In IMvigor211, SLD profiles in atezolizumab and chemotherapy arms crossed at about 40 weeks with more initial shrinkage in chemotherapy-treated pts but slower overall TGR in atezolizumab-treated pts. The IMvigor210 OS model predicted OS hazard ratio (HR) in IMvigor211 in all comers with post-baseline tumor scans (model-predicted HR [prediction interval]: 0.80 [0.70-0.92] vs. 0.74 observed) as well as by IC status: 0.66 [0.50-0.87] vs. 0.70 observed in IC23. Conclusions: Model-based TGR is a promising exploratory endpoint and is being investigated to support early decisions in signal-seeking atezolizumab combination trials in mUC.

The efficacy and safety of pemetrexed and nedaplatin in salvage chemotherapy of advanced urinary carcinoma

Objective To evaluate the efficacy and toxicity of pemetrexed and nedaplatin in the treatment of patients with locally advanced or metastatic urothelial cell carcinoma who failed a first-line GC regimen. Methods A total of 11 patients with locally advanced or metastatic urothelial carcinoma failed with first-line treatment of GC regimen were included in the present study. There were 6 males and 5 females, aged 56-80 years old, median age was 65 years old. Six patients′ primary tumors were in bladder, 4 in the renal pelvis, 1 ureter. There were 7 cases with ECOG score 0 point, 3 cases 1 point, 1 case 2 points. Patients received pemetrexed 500 mg/m2 intravenously on the 1st day, and nedaplatin 25mg/m2 from the 1st to 3th day every 21 days. The evaluation of efficacy and adverse reactions were carried out after 2 to 3 cycles. Results Eleven patients received 1 to 6 cycles (mean 3.3 cycles) treatments. There were 2 cases (18.2%) complete remission, 5 cases (45.5%) partial remission, 2 cases (18.2%) no change and 2 cases (18.2%) progressed. The total effective rate was 63.6%. The main adverse events were anemia (6 cases), leukopenia (5 cases), nausea and vomiting (6 cases) and rash (5 cases) , all of which were mild to moderate. No treatment-related death occurred. Conclusions Pemetrexed and nedaplatin regimen could be effective in the treatment of advanced urothelial carcinoma after first-line chemotherapy failed. The side effect is mild. Key words: Urothelial carcinoma; Pemetrex; Second-line therapy

First referral to an integrated onco-palliative care program: A retrospective analysis of its timing.

167 Background: Despite being recommended early in the course of advanced cancer, palliative care (PC) referral remains often late. Taking into account limited PC resources, disease-specific referral criteria and models of care need to be explored. In a previous work, we showed that a weekly onco-palliative meeting (OPM) allowed earlier introduction of the PC team (PCT) and decreased aggressiveness of end-of-life (EOL) care1. We describe patient’s profile when first referred to this Integrated Onco-Palliative Care program (IOPC), the timing of the referral relatively to the course of his/her disease and the impact on the trajectory of EOL care. Methods: The IOPC of our University Hospital combined a weekly OPM, dedicated to patients with incurable diseases for whom goals and organization of care need to be discussed, and/or clinical evaluation with possible follow-up by the PCT. We retrospectively analysed all patients reported for the first time at OPM between 2011 and 2013. We calculated an index of precocity, defined as the ratio of time from the first referral to death and the time from the diagnosis of incurability to death, with values ranging from 0 (late referral) to 1 (early referral). Results: Of the 416 patients included, 57% presented with lung cancer, urinary carcinoma and sarcoma. At first referral to IOPC program, 76% were receiving chemotherapy, 63% were outpatients, 56% had a PS ≤ 2 and 46% had a serum albumin level &gt; 35g/l. The median (1st-3rd quartile) index of precocity was 0.39 (0.16-0.72), ranging between 0.53 (0.20-0.79) (earliest, for lung cancer) to 0.16 (0.07-0.56) (latest, for prostate cancer). Among 367 decedents, 42 (13%) received chemotherapy within 14 days before death, 157 (43%) died in hospice care setting. Conclusions: Most patients first referred to IOPC were still under antitumoral treatment and had intermediate prognostic markers. However the time of referral between diagnosis of incurability and death is highly variable according to cancer type, and should probably be adapted while therapies progress.1 Colombet I, et al. Effect of integrated palliative care on the quality of end-of-life care: retrospective analysis of 521 cancer patients. BMJ Support Palliat Care. 2012;2(3):239–47