Circulating tumor cells as Trojan Horse for understanding, preventing, and treating cancer: a critical appraisal.

Circulating tumor cells (CTCs) are regarded as harbingers of metastases. Their ability to predict response to therapy, relapse, and resistance to treatment has proposed their value as putative diagnostic and prognostic indicators. CTCs represent one of the zeniths of cancer evolution in terms of cell survival; however, the triggers of CTC generation, the identification of potentially metastatic CTCs, and the mechanisms contributing to their heterogeneity and aggressiveness represent issues not yet fully deciphered. Thus, prior to enabling liquid biopsy applications to reach clinical prime time, understanding how the above mechanistic information can be applied to improve treatment decisions is a key challenge. Here, we provide our perspective on how CTCs can provide mechanistic insights into tumor pathogenesis, as well as on CTC clinical value. In doing so, we aim to (a) describe how CTCs disseminate from the primary tumor, and their link to epithelial-mesenchymal transition (EMT); (b) trace the route of CTCs through the circulation, focusing on tumor self-seeding and the possibility of tertiary metastasis; (c) describe possible mechanisms underlying the enhanced metastatic potential of CTCs; (d) discuss how CTC could provide further information on the tissue of origin, especially in cancer of unknown primary origin. We also provide a comprehensive review of meta-analyses assessing the prognostic significance of CTCs, to highlight the emerging role of CTCs in clinical oncology. We also explore how cell-free circulating tumor DNA (ctDNA) analysis, using a combination of genomic and phylogenetic analysis, can offer insights into CTC biology, including our understanding of CTC heterogeneity and tumor evolution. Last, we discuss emerging technologies, such as high-throughput quantitative imaging, radiogenomics, machine learning approaches, and the emerging breath biopsy. These technologies could compliment CTC and ctDNA analyses, and they collectively represent major future steps in cancer detection, monitoring, and management.

Recommendations for follow-up of muscle-invasive bladder cancer patients: A consensus by the international bladder cancer network.

RATIONALE: Several guidelines exist that address treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC). However, most only briefly mention follow-up strategies for patients and hence the treating physician is often left to infer on what the preferred follow-up schema would be for an individual patient. Herein, we aim to synthesize recommendations for follow-up of patients with MIBC for easy reference. METHODS: A multidisciplinary MIBC expert panel from the International Bladder Cancer Network was assembled to critically assess currently available major guidelines on surveillance of MIBC patients. Recommendations for follow-up were extracted and critically evaluated. Important considerations for guideline assessment included both aspects of oncological and functional follow-up-frequency of visits, the use of different imaging modalities, the role of cytology and molecular markers, and the duration of follow-up. OUTCOME: An International Bladder Cancer Network expert consensus recommendation was constructed for the follow-up of patients with MIBC based on the currently available evidence-based data.

Low-Cost Intervention to Increase Influenza Vaccination Rate at a Comprehensive Cancer Center.

Influenza morbidity and mortality can be severe and costly. Vaccination rates remain suboptimal in cancer patients due to provider- and patient-related factors. The objective of this study was to evaluate whether low-cost provider- and patient-focused interventions would increase influenza vaccination rates at the University of Michigan Comprehensive Cancer Center (UMCCC). This quality improvement project included all patients without documentation of influenza vaccination prior to their first outpatient appointment during the 2011-2012 and 2012-2013 influenza seasons. The multi-stepped intervention included provider and patient reminders. Influenza vaccination rates were compiled using CPT-4 codes. Same-day (with appointment) vaccination rates during the intervention seasons were compared to historical (2005-2011 seasons) controls; vaccination rates were also compared to contemporary control population at the University of Michigan Health System (UMHS). Reasons for non-adherence with vaccination were explored. The cumulative same-day vaccination rate in eligible adults was 10.1 % (2011-2012) and 9.4 % (2012-2013) compared to an average 6.9 % during influenza seasons 2005-2011. Based on logistic regression analysis, there was a 37.6 % (95 % CI 35-40.3 %) and 56.1 % (95 % CI 40.9-73 %) relative increase in the adult vaccination rate associated with the intervention, with 399 and 697 additional vaccinations, respectively, for each season. During the 2012-2013 season, the UMCCC adult vaccination rate was higher compared to the remainder of that of the UMHS. The intervention was well accepted by providers. Reasons for no vaccination were provider- and patient-related. Increasing provider and patient awareness with a simple, inexpensive intervention was associated with higher influenza vaccination rates at a large academic cancer center. The intervention is permanently implemented during influenza seasons.

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.

Clinical and therapeutic factors associated with adverse pathological outcomes in clinically node-negative patients treated with neoadjuvant cisplatin-based chemotherapy and radical cystectomy.

PURPOSE: Several disease characteristics have been identified as potential predictors for pathological node involvement (pN+) following radical cystectomy (RC). However, these have not been assessed in patients treated with neoadjuvant chemotherapy (NAC). We endeavored to assess factors predicting adverse pathology in clinically node-negative patients treated with NAC and RC. METHODS: Patients from four North American institutions with cT2-4aN0M0 UC who received three or four cycles of NAC followed by RC were selected. Logistic regression was used to predict pN+,

Contemporary Systemic Therapy for Urologic Malignancies in Geriatric Patients.

Current data on systemic therapy in geriatric populations with genitourinary malignancies are largely derived from retrospective analyses of prospectively conducted trials or retrospective reviews. Although extrapolation of these data to real-world patients should be cautious, patients aged 65 years or older with good functional status and minimal comorbidities seem to enjoy similar survival benefit from therapy as their younger counterparts. Chronologic age alone should generally not be used to guide management decisions. Comprehensive geriatric assessment tools and prospective studies in older adults integrating comprehensive geriatric assessment can shed light on the optimal management of urologic malignancies in this population.

The biological complexity of urothelial carcinoma: Insights into carcinogenesis, targets and biomarkers of response to therapeutic approaches.

Bladder cancer is a major cause of morbidity, mortality and health-related costs. Urothelial carcinoma is by far the most common histologic type of bladder cancer and may also arise from the upper urinary tract, e.g. renal pelvis and ureter, as well as from the proximal urethra. There have been no major advances in the development of new systemic therapies for urothelial carcinoma for over two decades, which may be related to prior lack of profound comprehension of biological pathogenetic mechanisms. However, in the last few years there has been a major shift in the development of new promising therapies that stem from improved molecular profiling of this malignancy. Developments in molecular biology, genomics, bioinformatics and immunology provide a solid foundation for therapeutic advances. A plethora of novel treatment targets and biomarkers are being evaluated, but there has been no molecular biomarker with established clinical utility so far. Genomic characterization of each patient's tumor has not been implemented due to the high cost, lack of validated standardized techniques that could be available in different laboratories, as well as absence of validated biomarkers and available therapeutic agents with clinically proven benefit. However, genomic characterization before treatment has now started to be implemented in novel clinical trial designs in order to contribute to proper patient selection based on biomarker-based enrichment strategies. Several "umbrella" or "basket" type, molecular biomarkers-based trials, in which patient eligibility and/or stratification is based on the presence of specific genetic alterations regardless of tissue of origin and/or histology, are being launched. Mathematical models and bioinformatics platforms that perform high level computational integrated pathway analysis may reveal clinical relevant signaling pathways amenable for targeting in individual patient tumors. Moreover, the high mutational burden of urothelial carcinoma may create numerous neo-antigens that may explain the very promising results with immune checkpoint inhibitors in early phase clinical trials. A combination of several, e.g. DNA, mRNA, miRNA, protein, and other molecular biomarkers merit further investigation, but this process has to be based on stringent criteria that test and prove clinical utility.

A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma.

BACKGROUND: Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated. METHODS: Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m(2) ) on day 1 plus gemcitabine (1000 mg/m(2) ) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m(2) ) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints. RESULTS: Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%-76%) and 61.4% for arm B (95% CI = 48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7-10.4 months) and 7.6 months for arm B (95% CI = 6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death. CONCLUSIONS: GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes.

Double-blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma.

BACKGROUND: Angiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC. METHODS: Patients with locally recurrent/metastatic UC and adequate organ function who achieved stable disease or a partial or complete response after 4 to 6 chemotherapy cycles were randomized to sunitinib at a dose of 50 mg/day (28 days on and 14 days off) or placebo. The primary endpoint was the 6-month progression rate. Secondary endpoints were safety, survival, change in serum vascular endothelial growth factor (VEGF)/soluble VEGF receptor-2 (sVEGFR2), and the activity of sunitinib in patients who developed disease progression while receiving placebo. A total of 38 eligible patients per treatment arm were required to select better therapy with 90% probability (α = .05). RESULTS: A total of 54 eligible patients were randomized to either the sunitinib arm (26 patients) or the placebo arm (28 patients). The median number of cycles received was 2 cycles per treatment arm. The most common grade 3 to 4 adverse events (graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) among patients receiving sunitinib were thrombocytopenia, diarrhea, mucositis, fatigue, and hypertension. There were no grade 3 or 4 adverse events noted among > 5% of patients receiving placebo. The 6-month progression rate was 72% versus 64%. The median progression-free survival (PFS) was 2.9 months (range, 0.5 months-32.5 months) versus 2.7 months (range, 0.8 months -65 months) for the sunitinib versus placebo arms, respectively. Patients receiving placebo were found to have no changes in their serum VEGF/sVEGFR2 levels over time. Patients treated with sunitinib had no significant change in their VEGF level, but the sVEGFR2 level significantly decreased after cycles 1 and 2 (P < .0001) and at the time of disease progression (P = .0002). A baseline VEGF level that was at or greater than the median was found to be correlated with a longer PFS. Sixteen patients who were receiving placebo received sunitinib at the time of disease progression, with the best responses being 1 partial response (6.3%), 6 cases of stable disease (37.5%), and 5 cases of progressive disease (31.3%); 4 patients were not evaluable for response. The median PFS was 3.7 months (range, 0.1 months-22 months). CONCLUSIONS: The current multicenter study was limited by premature closure and a small sample size. Maintenance sunitinib did not appear to improve the 6-month progression rate. Open-label sunitinib was found to have only modest activity. The sVEGFR2 level decreased among patients receiving sunitinib.

Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer.

Members of the human epidermal growth factor receptor (HER) family play a significant role in bladder cancer progression and may underlie the development of chemotherapy resistance. Dacomitinib is an irreversible tyrosine kinase inhibitor with structural specificity for the catalytic domains of epidermal growth factor receptor (EGFR), HER2 and HER4 that has exhibited vigorous efficacy against other solid tumors. We evaluated the antitumor activity of dacomitinib in human bladder cancer cell lines expressing varying levels of HER family receptors. These cell lines also were established as bladder cancer xenografts in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice to assess dacomitinib activity in vivo. Significant cytotoxic and cytostatic effects were noted in cells expressing elevated levels of the dacomitinib target receptors with apoptosis and cell cycle arrest being the predominant mechanisms of antitumor activity. Cells expressing lower levels of HER receptors were much less sensitive to dacomitinib. Interestingly, dacomitinib was more active than either trastuzumab or cetuximab in vitro, and exhibited increased growth inhibition of bladder tumor xenografts compared with lapatinib. Pharmacodynamic effects of dacomitinib included decreased E-cadherin (E-cad) expression, reduction of EGFR and extracellular signal-regulated kinase (ERK) phosphorylation and reduced mitotic count. Dacomitinib also inhibited tumor growth in a chemotherapy-resistant xenograft and, when combined with chemotherapy in a sensitive xenograft, exhibited superior antitumor effects compared with individual treatments. Evaluation in xenograft-bearing mice revealed that this combination was broadly feasible and well tolerated. In conclusion, dacomitinib exhibited pronounced activity both as a single agent and when combined with chemotherapy in human bladder cancer models. Further investigation of dacomitinib in the preclinical and clinical trial settings is being pursued.

A phase II trial of neoadjuvant nab-paclitaxel, carboplatin, and gemcitabine (ACaG) in patients with locally advanced carcinoma of the bladder.

OBJECTIVE: To assess the activity of neoadjuvant nab-paclitaxel, carboplatin, gemcitabine (ACaG) followed by cystectomy in patients with muscle-invasive urothelial carcinoma of the bladder. METHODS: Patients who were candidates for cystectomy received nab-paclitaxel 260 mg/m(2) on day 1, carboplatin area under the curve 5 on day 1, and gemcitabine 800 mg/m(2) on days 1 and 8, every 21 days for 3 cycles. The first 3 patients received nab-paclitaxel 100 mg/m(2) weekly and were not included in the efficacy analysis of evaluable patients. Efficacy was assessed by the percentage of patients with pathologic complete response (pT0) at cystectomy. Progression-free and overall survival was estimated using the Kaplan-Meier methods. RESULTS: Of 29 patients enrolled, 26 received the planned 3 cycles with 82 cycles overall; doses were reduced in 16 patients. Of 29 patients, nearly all patients experienced grade 3-4 neutropenia; 17 patients (58.6%) required growth factor, and 16 patients (55.2%) experienced grade 3-4 thrombocytopenia; there was 1 toxicity-related death. Nonhematological toxicity was generally tolerable. Twenty-two of 26 patients were evaluable for the primary endpoint: 6 patients (27.3%, 95% confidence interval [CI] 10.7-50.2) had pT0, 6 pTis, 1 pT1, 54.5% of patients had no residual muscle-invasive disease (

Predicting response to hormonal therapy and survival in men with hormone sensitive metastatic prostate cancer.

Androgen deprivation is the cornerstone of the management of metastatic prostate cancer. Despite several decades of clinical experience with this therapy there are no standard predictive biomarkers for response. Although several candidate genetic, hormonal, inflammatory, biochemical, metabolic biomarkers have been suggested as potential predictors of response and outcome, none has been prospectively validated nor has proven clinical utility to date. There is significant heterogeneity in the depth and duration of hormonal response and in the natural history of advanced disease; therefore to better optimize/individualize therapy and for future development, identification of biomarkers is critical. This review summarizes the current data on the role of several candidate biomarkers that have been evaluated in the advanced/metastatic disease setting.

Transcriptional corepressors in cancer: emerging targets for therapeutic intervention.

The normal cell transcriptional process entails a high degree of combinatorial effects and time-dependent "flexibility" to translate cellular signaling into differential gene expression levels. Transcriptional corepressors can function as histone-modifying enzymes to regulate epigenetic events, modulate chromatin structure, and hence control transcriptional activity. Various corepressor complexes have been described; qualitative and quantitative alterations of corepressors can crucially influence the transcriptional output of both normal and malignant cells. Because these molecules can exert epigenetic control of tumorigenic signaling pathways, they can be considered potential regulators of cancer cell-related phenomena. Alterations of the expression level and/or function of transcriptional corepressors have been reported in a wide range of human cancers; thus, corepressors may present rational therapeutic targets as well as potential biomarkers of response to selective therapeutic interventions. Deeper insights into the context-specific and time-specific physical connections among transcription factors, coregulators, and gene regulatory elements, as well as epigenetic modifications, and their interactions, can enhance the capacity to interfere with small molecules that may restore the normal transcriptome/interactome in a cancer cell. There are several conceivable mechanisms of corepressor targeting in cancer that create enthusiasm. However, design, discovery, and testing of such innovative treatment approaches require extensive elaboration before they can achieve practical implementation in the clinic.

Urethral cancer.

Urethral carcinoma is a rare tumor with predominantly poor survival. Both the disease and its treatment can affect both sexual and urinary function. The natural history of urethral carcinoma varies, therefore the appropriate application of surgery, radiation, and chemotherapy remain unknown. Management of this disease remains driven by individual clinician experience and data derived from small case series. This article discusses the histology and anatomy of the male and female urethra, as well as their natural history. In addition, the epidemiology, clinical presentation, diagnosis, staging, treatment, and future directions of management of cancer arising in the urethra are addressed.

Prognostic value of novel biomarkers in astrocytic brain tumors: nuclear receptor co-regulators AIB1, TIF2, and PELP1 are associated with high tumor grade and worse patient prognosis.

Estrogen receptors alpha (ERα) and beta (ERß) and their co-regulatory proteins are key components of complex signaling networks that specifically regulate the growth and development of various tissues and tumors. Still, their protein expression profiles and possible role in the pathogenesis of astrocytic tumors remain largely unknown. The purpose of the present study is to evaluate the differential protein expression of ΕRα, ERß, and their co-activators, AIB1, TIF2, and PELP1 in astrocytic tumors of World Health Organization (WHO) grade II-IV, using immunohistochemistry. Potential correlations with clinicopathological parameters and patient prognosis were also explored. ERα protein expression was undetectable while ERß levels were significantly decreased with progression of tumor grade (P < 0.001). High expression of ERß was an independent favorable prognostic factor on multivariate analysis (P = 0.003). Expression of AIB1, TIF2, and PELP1 was not correlated with ERß expression and followed an opposite trend, with increasing levels in high-grade relative to low-grade tumors (P < 0.001). Univariate survival analysis revealed that high AIB1, TIF2, and PELP1 expression was associated with worse prognosis (P = 0.049, P = 0.033, and P = 0.020, respectively). ERß and ER co-activators AIB1, TIF2, and PELP1 appear to play an important role in the pathogenesis and progression of astrocytic tumors and might have prognostic significance. The mechanisms underlying their involvement in astrocytic tumorigenesis, as well as their utility for prognostic and therapeutic purposes merit further investigation.

Urothelial carcinomas: a focus on human epidermal receptors signaling.

Bladder cancer is a common malignancy and a frequent cause of cancer-related death worldwide. The benefit from current chemotherapy has reached a relative plateau, thus identification of molecular targets for better therapy is a high priority. Human epidermal receptors constitute a family of receptor tyrosine kinases, which appear to be implicated in cellular transformation and can be over-expressed in a variety of solid tumors. There is preclinical and clinical data suggesting the role of EGFR and HER2 in urothelial carcinoma, thus prompting clinical investigation of anti-HER targeted therapies attempting to inhibit HER-induced tumor-promoting signaling. There is significant and dynamic cross-talk between HER and other signaling pathways and the identification of the structure and function of such cellular networks in the setting of urothelial cancer is a complex and difficult task. The development of prognostic and predictive biomarkers is needed in order to improve the personalized management of patients with urothelial cancer.

Immunotherapy of kidney cancer.

Renal cell carcinoma (RCC) accounts for 4% of all new cancer cases in males and 3% in females in the US. Compared to other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiation therapy. However, it appears to be an immune-responsive tumor and several immunotherapeutic strategies have been investigated in the management of RCC with variable degrees of success. Active immunotherapy refers mainly to the use of vaccines, while adoptive (passive) immunotherapy includes the use of autologous immune cells, allogeneic immune cells (stem cell transplantation, donor lymphocyte infusion), as well as antibody delivery. Cytokine delivery with IL-2 has resulted in long-term disease-free survival in a small proportion of patients with metastatic disease. The continuous understanding of the mechanisms that underlie the immune complex networks has led to the identification of key molecules that play a major role in the immune response process. A panel of immuno-modulatory compounds that target such molecules has been tested in the preclinical and clinical setting. At the post-genomic era, the development of novel biomarkers can contribute to more accurate patient selection, resulting in higher responses and less toxicity of immunotherapeutic approaches.

Post-transplantation lymphoproliferative disorder (PTLD) twenty years after heart transplantation: a case report and review of the literature.

We report a 62-year-old man who developed biopsy-proven post-transplantation lymphoproliferative disorder (PTLD) 20 years after receiving a heart transplant while being treated with immunosuppressive agents. The patient presented with large retroperitoneal and intestinal wall masses that caused partial gastrointestinal stenosis. Monoclonal antibody against CD20 in conjunction with chemotherapy and tapering of the immunosuppressive regimen was instituted, resulting in objective response of the disease bulk. To the best of our knowledge, this is the second reported case of PTLD 20 years after heart transplantation.