Considerations for successful cancer immunotherapy in aged hosts.

Immunotherapy is now experiencing unprecedented successes in treating various cancers based on new understandings of cancer immunopathogenesis. Nonetheless, although ageing is the biggest risk factor for cancer, the majority of cancer immunotherapy preclinical studies are conducted in young hosts. This review will explore age-related changes in immunity as they relate to cancer immune surveillance, immunopathogenesis and responses to immunotherapy. Although it is recognized that declining T cell function with age poses a great challenge to developing effective age-related cancer immunotherapies, examples of successful approaches to overcome this hurdle have been developed. Further, it is now recognized that immune functions do not simply decline with age, but rather change in ways than can be detrimental. For example, with age, specific immune cell populations with detrimental functions can become predominant (such as cells producing proinflammatory cytokines), suppressive cells can become more numerous or more suppressive (such as myeloid-derived suppressor cells), drugs can affect aged immune cells distinctly and the aged microenvironment is becoming recognized as a significant barrier to address. Key developments in these and other areas will be surveyed as they relate to cancer immunotherapy in aged hosts, and areas in need of more study will be assessed with some speculations for the future. We propose the term 'age-related immune dysfunction' (ARID) as best representative of age-associated changes in immunity.

Perioperative outcomes and hospital reimbursement by type of radical prostatectomy: results from a privately insured patient population.

BACKGROUND: With the increasing use of robotic surgery in the United States, the comparative effectiveness and differences in reimbursement of minimally invasive radical prostatectomy (MIRP) and open prostatectomy (ORP) in privately insured patients are unknown. Therefore, we sought to assess the differences in perioperative outcomes and hospital reimbursement in a privately insured patient population who were surgically treated for prostate cancer. METHODS: Using a large private insurance database, we identified 17,610 prostate cancer patients who underwent either MIRP or ORP from 2003 to 2010. The primary outcomes were length of stay (LOS), perioperative complications, 90-day readmissions rates and hospital reimbursement. Multivariable regression analyses were used to evaluate for differences in primary outcomes across surgical approaches. RESULTS: Overall, 8981 (51.0%) and 8629 (49.0%) surgically treated prostate cancer patients underwent MIRP and ORP, respectively. The proportion of patients undergoing MIRP markedly rose from 11.9% in 2003 to 72.5% in 2010 (P<0.001 for trend). Relative to ORP, MIRP was associated with a shorter median LOS (1.0 day vs 3.0 days; P<0.001) and lower adjusted odds ratio of perioperative complications (OR: 0.82; P<0.001). However, the 90-day readmission rates of MIRP and ORP were similar (OR: 0.99; P=0.76). MIRP provided higher adjusted mean hospital reimbursement compared with ORP (US $19,292 vs. US $17,347; P<0.001). CONCLUSIONS: Among privately insured patients diagnosed with prostate cancer, robotic surgery rapidly disseminated with over 70% of patients undergoing MIRP by 2009-2010. Although MIRP was associated with shorter LOS and modestly better perioperative outcomes, hospitals received higher reimbursement for MIRP compared with ORP.

Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients. METHODS: We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models. RESULTS: With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high-risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients. CONCLUSION: The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design.

Risk stratification of pT1-3N0 patients after radical cystectomy for adjuvant chemotherapy counselling.

BACKGROUND: In pT1-T3N0 urothelial carcinoma of the bladder (UCB) patients, multi-modal therapy is inconsistently recommended. The aim of the study was to develop a prognostic tool to help decision-making regarding adjuvant therapy. METHODS: We included 2145 patients with pT1-3N0 UCB after radical cystectomy (RC), naive of neoadjuvant or adjuvant therapy. The cohort was randomly split into development cohort based on the US patients (n=1067) and validation cohort based on the Europe patients (n=1078). Predictive accuracy was quantified using the concordance index. RESULTS: With a median follow-up of 45 months, 5-year recurrence-free and cancer-specific survival estimates were 68% and 73%, respectively. pT-stage, ge, lymphovascular invasion, and positive margin were significantly associated with both disease recurrence and cancer-specific mortality (P-values ≤ 0.005). The accuracies of the multivariable models at 2, 5, and 7 years for predicting disease recurrence were 67.4%, 65%, and 64.4%, respectively. Accuracies at 2, 5, and 7 years for predicting cancer-specific mortality were 69.3%, 66.4%, and 65.5%, respectively. We developed competing-risk, conditional probability nomograms. External validation revealed minor overestimation. CONCLUSION: Despite RC, a significant number of patients with pT1-3N0 UCB experience disease recurrence and ultimately die of UCB. We developed and externally validated competing-risk, conditional probability post-RC nomograms for prediction of disease recurrence and cancer-specific mortality.

Urine-based biomarkers for the early detection and surveillance of non-muscle invasive bladder cancer.

Bladder cancer has a very high frequency of recurrence and therefore requires lifelong surveillance, traditionally consisting of serial cystoscopy and cytology. These tests are both invasive and expensive, with considerable inter-user and inter-institutional variability. In addition, the sensitivity of cytology in detecting low-grade tumors is low. Therefore, there has been active investigation into urinary biomarkers that can either supplement or supplant these tests. At this point there are only six urine-based tests that are FDA-approved in bladder cancer surveillance, but a wide variety of other biomarkers are being studied. In this review, we examine the natural history of bladder cancer as well as the rationale and performance of an ideal urinary biomarker. The authors describe the FDA-approved biomarkers such as Bladder Tumor Antigen, ImmunoCyt, Nuclear Matrix Protein-22, and Fluorescent In Situ Hybridization, as well as the most promising investigational tests (i.e., Urinary bladder cancer test, BLCA-1, BLCA-4, hyaluronic acid, hyaluronidase, Lewis X antigen, microsatellite analysis, Quanticyt, soluble Fas, Survivin, and telomerase). The biological foundation, methodologies, and diagnostic performance of the biomarkers are discussed. The characteristics of the biomarkers are compared to urine cytology. At this time, urine biomarkers are utilized in a variety of clinical situations but their role is not well defined. The goal of identifying an optimal marker that will replace cystoscopy and/or cytology is still ongoing.

Screening for bladder cancer using urine-based tumor markers.

Bladder cancer screening differs from routine detection of bladder cancer in patients with symptoms, such as hematuria, or a history of bladder cancer. The ultimate goal of cancer screening is to decrease cancer-related mortality by detecting disease prior to the time that the disease would normally prompt evaluation from symptoms. There are several features of urothelial carcinoma of the bladder which make screening for this disease an attractive alternative to the current approach to this disease. The disease targets a defined population and survival for patients with this disease is strongly associated with disease stage at presentation. In addition, quick, easy, and painless screening tests are theoretically possible using tumor-related markers because of the direct exposure of cancer cells to urine. Indeed, recent insights into the biology of bladder cancer initiation and progression have resulted in the identification of several urine-based markers which have promise for detecting the presence of bladder cancer. Nevertheless, adoption of screening programs prior to establishing evidence of effectiveness and large-scale financial considerations has substantial damaging consequences. This article reviews the current literature regarding screening for bladder cancer using urine-based markers.

Intraluminal crystalloids are highly associated with prostatic adenocarcinoma on concurrent biopsy specimens.

Prostatic crystalloids are intraluminal eosinophilic structures with variable size and shape. Their presence has been described in conjunction with the occurrence of prostatic adenocarcinoma (pCA). We herein report the association of crystalloids and pCA in a prospective trial utilizing an extended multi-site transrectal ultrasound-guided (TRUS) prostate biopsy protocol. Three hundred and forty-four consecutive patients were prospectively enrolled at the Dallas Veterans Administration Hospital from November 2002 to September 2003. Indications for biopsy included a prostate-specific antigen (PSA) > or =4 ng/ml and/or abnormal digital rectal exam. A single pathologist evaluated all biopsy cores and documented the presence or absence of significant histopathologic features. Univariate and multivariate logistic regression analysis were applied to test the association of these features with the presence of pCA on concurrent biopsy. Median number of core biopsies per patient was 12 (range 3-36). Overall cancer detection rate was 42.7%. pCA was diagnosed in 66 (81.5%) of 81 patients with crystalloids, 70 (69.3%) of 101 patients with high-grade prostatic intraepithelial neoplasia (HGPIN), and 32 (84.2%) of 38 patients with both HGPIN and crystalloids on biopsy. Multivariate analysis identified crystalloids (RR 4.53, 95% CI 2.30-8.88) and HGPIN (RR 3.20, 95% CI 1.84-5.57) as independent predictors of the presence of cancer on concurrent biopsy (P<0.001). In this prospective analysis, crystalloids were significantly associated with pCA on concurrent biopsy and more predictive of the presence of pCA than HGPIN. These findings suggest that the presence of crystalloids alone or in combination with HGPIN in prostate biopsies may be a more compelling indication for repeat biopsy than HGPIN alone.