Immune-inflammatory biomarkers as prognostic factors for immunotherapy in pretreated advanced urinary tract cancer patients: an analysis of the Italian SAUL cohort.

BACKGROUND: Reliable and affordable prognostic and predictive biomarkers for urothelial carcinoma treated with immunotherapy may allow patients' outcome stratification and drive therapeutic options. The SAUL trial investigated the safety and efficacy of atezolizumab in a real-world setting on 1004 patients with locally advanced or metastatic urothelial carcinoma who progressed to one to three prior systemic therapies. PATIENTS AND METHODS: Using the SAUL Italian cohort of 267 patients, we investigated the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) and the best performing one of these in combination with programmed death-ligand 1 (PD-L1) with or without lactate dehydrogenase (LDH). Previously reported cut-offs (NLR >3 and NLR >5; SII >1375) in addition to study-defined ones derived from receiver operating characteristic (ROC) analysis were used. RESULTS: The cut-off values for NLR and SII by the ROC analysis were 3.65 (sensitivity 60.4; specificity 63.0) and 884 (sensitivity 64.4; specificity 67.5), respectively. The median overall survival (OS) was 14.7 months for NLR <3.65 [95% confidence interval (CI) 9.9-not reached (NR)] versus 6.0 months for NLR ≥3.65 (95% CI 3.9-9.4); 14.7 months for SII <884 (95% CI 10.6-NR) versus 6.0 months for SII ≥884 (95% CI 3.7-8.6). The combination of SII, PD-L1, and LDH stratified OS better than SII plus PD-L1 through better identification of patients with intermediate prognosis (77% versus 48%, respectively). Multivariate analyses confirmed significant correlations with OS and progression-free survival for both the SII + PD-L1 + LDH and SII + PD-L1 combinations. CONCLUSION: The combination of immune-inflammatory biomarkers based on SII, PD-L1, with or without LDH is a potentially useful and easy-to-assess prognostic tool deserving validation to identify patients who may benefit from immunotherapy alone or alternative therapies.

Serum very long-chain fatty acid-containing lipids predict response to immune checkpoint inhibitors in urological cancers.

Checkpoint inhibitors (CPI) have significantly changed the therapeutic landscape of oncology. We adopted a non-invasive metabolomic approach to understand immunotherapy response and failure in 28 urological cancer patients. In total, 134 metabolites were quantified in patient sera before the first, second, and third CPI doses. Modeling the association between metabolites and CPI response and patient characteristics revealed that one predictive metabolite class  (n = 9/10) were very long-chain fatty acid-containing lipids (VLCFA-containing lipids). The best predictive performance was achieved through a multivariate model, including age and a centroid of VLCFA-containing lipids prior to first immunotherapy (sensitivity: 0.850, specificity: 0.825, ROC: 0.935). We hypothesize that the association of VLCFA-containing lipids with CPI response is based on enhanced peroxisome signaling in T cells, which results in a switch to fatty acid catabolism. Beyond use as a novel predictive non-invasive biomarker, we envision that nutritional supplementation with VLCFA-containing lipids might serve as an immuno sensitizer.

Development and validation of a nomogram for urothelial cancer in patients with chronic kidney disease.

Urothelial cancer (UC) is a common kidney cancer in Taiwan and patients with chronic kidney disease (CKD) are more at risk for UC than the general population. The diagnostic value of urine analysis and urine cytology is limited, especially in CKD patients. The aim of the study is to develop a nomogram to predict the risk of UC in CKD patients. We enrolled 169 UC patients and 1383 CKD patients from 9 hospitals in Taiwan between 2012 and 2015. CA125, HE4, clinical characteristics, and medical history were analyzed using multivariable logistic regression for its association with UC. A nomogram was developed to predict the risk of UC and was validated using Bootstrap. CA125 was associated with UC in CKD patients (OR: 5.91, 95% CI: 3.24-10.77) but HE4 was not (OR: 1.29, 95% CI: 0.67-2.35). A nomogram based on patients' age, estimated glomerular filtration rate, CA125 (log transformed), smoking, exposure of environmental toxin, use of nonsteroid anti-inflammatory drugs, and use of traditional Chinese medicine was conducted. The AUC of the nomogram was 0.90 (95% CI: 0.86-0.92, p < 0.01). Serum CA125 may identify UC patients from CKD patients but has limited diagnostic value due to low sensitivity. The diagnostic value of serum CA125 level can be improved by the combination with clinical characteristics including age, renal function, and medical history.

Immunotherapy Combinations and Sequences in Urothelial Cancer: Facts and Hopes.

Immune checkpoint inhibitors (ICI) have emerged as a novel therapeutic strategy that achieves significant clinical benefit in several tumor types, including urothelial cancer. Overall, these agents have shown objective response rates of around 20% to 23%, which indicates that a significant proportion of patients do not benefit from immunotherapy when given as monotherapy. Moreover, despite an initial response to therapy and an improvement in the median duration of response compared with chemotherapy, still only half of the patients develop long-term maintained remissions. Active research is ongoing in several fields, aiming to increase the number of patients that benefit from ICI, and this research is largely based on the development of biomarkers for personalized immunotherapy and novel combinations of ICI with other agents. This article will review ongoing efforts to develop combinations of ICI with other therapeutic strategies in patients with urothelial cancer, including chemotherapy, targeted agents, other immunotherapy strategies, and radiotherapy.

Relationships among DNA hypomethylation, Cd, and Pb exposure and risk of cigarette smoking-related urothelial carcinoma.

Cigarette smoking and environmental exposure to heavy metals are important global health issues, especially for urothelial carcinoma (UC). However, the effects of cadmium and lead exposure, as well as the levels of DNA hypomethylation, on UC risk are limited. We evaluated the possible exposure sources of Cd and Pb and the relationship among DNA hypomethylation, urinary Cd and Pb levels, and UC risk. We recruited 209 patients with UC and 417 control patients for a hospital-based case-control study between June 2011 and August 2014. We collected environmental exposure-related information with questionnaires. Blood and urine samples were analyzed to measure the Cd and Pb exposure and 5-methyl-2'-deoxycytidine levels as a proxy for DNA methylation. Multivariate logistic regression and 95% confidence intervals were applied to estimate the risk for UC. Study participants with high Cd and Pb exposure in blood or urine had significantly increased risk of UC, especially among the smokers. After adjusting for age and gender, the possible connections of individual cumulative cigarette smoking or herb medicine exposure with the increased levels of Cd and Pb were observed in the controls. Participants with 8.66%-12.39% of DNA hypomethylation had significantly increased risk of UC compared with those with ≥12.39% of DNA hypomethylation. Environmental factors including cigarette smoking and herb medicine may contribute to the internal dose of heavy metals levels. Repeat measurements of heavy metals with different study design, detailed dietary information, and types of herb medicine should be recommended for exploring UC carcinogenesis in future studies.

Mutational signature of aristolochic acid: Clue to the recognition of a global disease.

Mutational signatures associated with specific forms of DNA damage have been identified in several forms of human cancer. Such signatures provide information regarding mechanisms of tumor induction which, in turn, can reduce exposure to carcinogens by shaping public health policy. Using a molecular epidemiologic approach that takes advantage of recent advances in genome sequencing while applying sensitive and specific analytical methods to characterize DNA damage, it has become increasingly possible to establish causative linkages between certain environmental mutagens and disease risk. In this perspective, we use aristolochic acid, a human carcinogen and nephrotoxin found in Aristolochia herbs, to illustrate the power and effectiveness of this multidisciplinary approach. The genome-wide mutational signature for this toxin, detected initially in cancers of the upper urinary tract, has subsequently been associated with cancers of the liver and kidney. These findings have significant implications for global public health, especially in China, where millions of individuals have used Aristolochia herbal remedies as part of traditional Chinese medicine and, thus, are at risk of developing aristolochic acid nephropathy and/or upper urinary tract carcinomas. The studies reported here set the stage for research into prevention and early detection, both of which will be required to manage a potentially devastating global disease.

[Urology in the concept of comprehensive cancer centers]. / Die Urologie im Konzept der "Comprehensive Cancer Center".

BACKGROUND: Urologic cancers comprise one quarter of all newly diagnosed cancers per year in Germany. In addition to the increasing incidence treatment of solid and hematological tumors has become more differentiated, complex and potentially more effective as well as more expensive. Following the example of the USA multidisciplinary translational comprehensive cancer centers (CCCs) have been established in Germany. The financial support from the government and nonprofit organizations, such as the German Cancer Aid aims to ensure and to optimize treatment of tumor patients now and in the future. Coupled with this development new funding opportunities for translational research are opening up for the participating clinical and scientific partners. DISCUSSION: Just as attractive and coherent integration of urology into the structures of a CCC where available appears to be, just as controversial is the professional modus operandi. Using the example of the National Center for Tumor Diseases in Heidelberg (NCT), the current manuscript discusses the risks and opportunities of this new centralized form of oncological care in urology. Detailed knowledge of organizational structures, clinical operations and funding is a prerequisite for any partner of a CCC to succeed in such a highly demanding environment as a specialty instead of becoming mere surgical proceduralists.

Distinguishing characteristics of urothelial carcinoma in kidney transplant recipients between China and Western countries.

OBJECTIVE: To identify significant distinctive characteristics of urothelial carcinoma (UC) in kidney transplant recipients between China and Western countries and investigate probable tumor screening and treatment factors contributing to these differences. METHODS: Renal transplant recipients from 1998 to 2011 in our institution diagnosed with UC were included in this study. Our data on tumor incidence, clinical characteristics, and outcomes were compared with literature reports. RESULTS: Among 2572 renal transplant recipients identified, 24 (0.93%) experienced UC, including 10 men and 14 women of overall mean age of 49.3 ± 11.6 years at transplantation and 53.5 ± 9.5 years at tumor detection. The Chinese traditional herbal intake mainly focused on 2 preparations: Aristolochic acid and rhubarb (the latter was mainly used in patients with chronic renal impairment) in 20 people. There were 21 (87.5%) cases of upper (UTUC) 5 cases of bilateral, and 13 cases of multifocal urinary tract urothelial carcinoma. Four subjects died owing to tumor progression at 4-63 months postoperatively. CONCLUSIONS: UC in renal transplant recipients shared notable characteristics in China with widespread herb intake: UTUC predominance; multifocal and bilateral organ involvement; high rates of recurrence, progression, and dissemination, in contrast with bladder tumor dominance in Western countries. As a consequence, we suggest that bilateral nephroureterectomy should be performed prophylactically in high-risk patients, especially those with a long history of Chinese herb intake. The relationship of rhubarb consumption to UC in renal transplant recipients should be noted and evaluated.

The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review.

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.

Transitional cell carcinoma in renal transplant recipients: a single center experience.

OBJECTIVE: To present a single center experience in managing transitional cell carcinoma (TCC) in Chinese renal transplant (RTx) recipients. METHODS: In a cohort of 1429 patients who received RTx operation, 27 patients (six males and 21 females) were pathologically diagnosed with TCC in their native urologic system. The data were analyzed retrospectively. RESULTS: The incidence of TCC was 1.89% and accounted for 41.5% of the patients with post-transplant de novo malignancies among 1429 recipients. Among the 27 recipients with TCC, 77.8% were female, 59.3% had taken a Chinese herb that contains aristolochic acid for at least 2 months before RTx, 51.9% had painless gross hematuria, while 40.7% had microscopic hematuria and/or repeated urologic infection. Two patients were found to have asymptomatic hydronephrosis during a routine check-up. The patients with upper tract carcinoma underwent simultaneous bilateral nephroureterectomy or unilateral nephroureterectomy and bladder cuff resection. Transurethral resection of the bladder tumor was carried out in patients with concomitant or solitary superficial bladder lesions. Intravesical chemotherapy was started and immunosuppressants were adjusted in all patients immediately after the surgery. Tumor recurrence in the bladder was noted in five patients. In one patient, residual and/or recurrent carcinoma in the contralateral pelvis was detected. CONCLUSIONS: Transitional cell carcinoma is the predominant malignancy in Chinese RTx recipients. Female sex, the Chinese herb containing aristolochic acid and immunosuppression are markedly associated with the development of TCC. Risk-adapted screening, strict follow up, standard surgical intervention and dose reduction of immunosuppressants are very important for early diagnosis and treatment of TCC.

Papiloma invertido. Aportación de dos casos y revisión de la literatura / Inverted papilloma. Report of two cases and bibliographic review

Objetivo: El papiloma invertido es una rara lesión polipoidea del urotelio, conocida como entidad diferente desde 1963, desde cuando escasamente se han publicado más de 100 casos en la literatura. Aunque su potencial maligno es todavía desconocido, existen varias publicaciones científicas en las que se denota. Métodos: Presentamos dos casos de papiloma invertido y hacemos una detallada revisión de la literatura científica al respecto. Resultados: Ambos pacientes fueron diagnosticados por el servicio de Anatomía Patológica de papiloma invertido, siguiendo controles periódicos posteriores y no apareciendo recidivas en ninguno de los dos casos, a los 24 y 18 meses de seguimiento respectivamente. Conclusiones: La posibilidad de que el papiloma invertido sea una lesión con potencial maligno debe ser en todo caso considerada y sugerimos que los pacientes con este diagnóstico sean sometidos a los exámenes urológicos de seguimiento en cualquier neoplasia vesical (AU)

Objective: Inverted papilloma is a rare polypoid lesion of the urothelium, known as a different entity since 1963. Not many more than 100 cases have been published. Although its malignant potential is still unknown, several scientific publications have noted it. Methods: We report to cases of inverted papilloma and perform a detailed bibliographic review. Results: Both patients were diagnosed by the Pathology Department and entered periodic follow-up visits, being free of recurrence at 24 and 18 months respectively. Conclusions: The possibility that inverted papilloma is a lesion with malignant potential should be considered in every case, and we suggest that patients with this diagnosis should enter a follow-up protocol like any bladder neoplasia (AU)

Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract: an alternative therapy.

BACKGROUND: Cisplatin-based combinations are considered to be the standard treatment for advanced transitional cell carcinoma (TCC) of the urothelium. Many of the patients are elderly with concomitant diseases or impaired renal function. We studied the tolerance and activity of the gemcitabine/carboplatin combination as a therapeutic alternative. METHODS: Patients with locally advanced or metastatic TCC of the urothelium were treated with gemcitabine 1000 mg/m(2) on Days 1 and 8 and carboplatin area under the concentration-time curve 5 on Day 1 every 21 days. Patients with creatinine clearance of 30 mL/min or above and Karnofsky performance status (KPS) scores 60 or above were enrolled. RESULTS: A total of 227 cycles were administered to 41 patients, with an average of 5.5 cycles per patient (range, 1-8 cycles). Creatinine clearance was below 60 mL/min in 54% of patients, KPS was 70 or below in 37% of patients, and 37% of patients were 70 years old or older. Hematologic toxicity was mainly Grade 3/4 neutropenia in 63%, Grade 3/4 thrombocytopenia in 32%, and Grade 3/4 anemia in 54% of patients. There were only three episodes of febrile neutropenia and one death from neutropenic sepsis. Nonhematologic toxicity was mild, with asthenia as the most frequently reported event. We obtained 6 complete and 17 partial responses, for an overall response rate of 56.1% (95% confidence interval [CI], 40.6-71.6%). Progression-free survival was 7.2 months (95% CI, 5.7-8.5) and median survival was 10.1 months (95% CI, 8.8-12.2). CONCLUSIONS: The combination of gemcitabine plus carboplatin achieves a similar result to doublets using cisplatin. It has an acceptable toxicity profile and enables patients with impaired renal function and/or poor performance status and elderly patients to be treated.