Dynamic assessment of serum chromogranin A and treatment response with abiraterone acetate in metastatic castration-resistant prostate cancer.

OBJECTIVE: Elevated serum chromogranin A (CGA) is associated with intrinsic or treatment-related neuroendocrine differentiation (NED) in men with metastatic castration-resistant prostate cancer (mCRPC). Fluctuations in serum CGA during treatment of mCRPC have had conflicting results. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with abiraterone acetate (AA) therapy. METHODS: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial with uniform serum CGA processing performed before initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded), therefore 71 patients were analyzed. All patients underwent a composite response assessment at 12-weeks. Kaplan-Meier estimates and Cox Regression models were used to calculate the association with time-to-treatment failure analyses and overall survival. RESULTS: An increase in chromogranin was associated with a lower risk of treatment failure (hazard ratio [HR]: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6-16.0) and an elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). An increase in CGA was not found to be associated with OS (HR: 0.71, 95% CI: 0.42-1.21, p = 0.207). An elevated baseline CGA/PSA ratio was not associated with OS (HR: 0.62, 95% CI: 0.37-1.03, p = 0.062). An increase in PSA after 12 weeks of treatment was associated with an increased risk of treatment failure (HR: 4.14, CI: 2.21-7.73, p = < 0.0001) and worse OS (HR: 2.93, CI: 1.57-4.45, p = < 0.0001). CONCLUSIONS: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in patients with mCRPC were associated with a favorable response to AA/P with no changes in survival. There may be limited clinical utility in serum CGA testing to evaluate for lethal NED as AA/P did not induce lethal NED in this cohort. This highlights that not all patients with an increasing CGA have a worse OS.

The Impact of Metastasis Histopathology on Oncologic Outcomes for Patients With Surgically Resected Metastatic Renal Cell Carcinoma.

PURPOSE: Multiple prognostic models exist to assess survival among patients with metastatic clear cell renal cell carcinoma. However, the relative contribution of histopathological features of the metastasis has not been extensively studied. Herein, we compared models using clinical, primary tumor, and metastatic features to predict cancer-specific survival for patients with surgically resected metastatic clear cell renal cell carcinoma. MATERIALS AND METHODS: We studied 266 patients who had undergone nephrectomy between 1970 and 2019, and who had a single site of metastasis completely resected. Two versions of the metastatic clear cell renal cell carcinoma score published by Leibovich et al were calculated, using grade and necrosis from the primary tumor and using grade and necrosis from the metastasis. Predictive abilities of these 2 versions and a third model that included metastatic features only were compared using c-indexes from Cox proportional hazards models. RESULTS: A total of 197 patients died from renal cell carcinoma at a median of 2.3 years (IQR 1.1-4.5); median follow-up among survivors was 13.2 years (IQR 10.0-14.5). The Leibovich score using grade and necrosis from the metastasis (c=0.679) had similar predictive ability compared to the original Leibovich score using grade and necrosis from the primary tumor (c=0.675). A third model (c=0.707) demonstrated that metastasectomy within 2 years after nephrectomy, presence of bone metastasis, high grade, and sarcomatoid differentiation in the metastasis were significantly associated with cancer-specific survival. CONCLUSIONS: Scoring algorithms calculated using histopathological features of the metastasis can be used to predict cancer-specific survival for patients with surgically resected metastatic clear cell renal cell carcinoma. These findings are of particular importance for instances when primary tumor histopathology is not readily available.

The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.

BACKGROUND: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP-ribose polymerase inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. METHODS: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. RESULTS: One hundred and twenty-seven mCRPC patients treated with Ra-223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra-223 treatment was 61.0 and 68.6 years, respectively. Seventy-nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2-ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2-ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0-NR) versus 26.8 months (95% CI 20.9-35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28-NR) versus 9.0 months (95% CI 7.3-11.1) and a lower OS 13.9 months (95% CI 5.2-NR) versus 26.5 months (95% CI 19.8-33.8). CONCLUSIONS: Among mCRPC patients treated with Ra-223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2-ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra-223.

FM2 Path Planner for UAV Applications with Curvature Constraints: A Comparative Analysis with Other Planning Approaches.

This paper studies the Fast Marching Square (FM2) method as a competitive path planner for UAV applications. The approach fulfills trajectory curvature constraints together with a significantly reduced computation time, which makes it overperform with respect to other planning methods of the literature based on optimization. A comparative analysis is presented to demonstrate how the FM2 approach can easily adapt its performance thanks to the introduction of two parameters, saturation α and exponent ß, that allow a flexible configuration of the paths in terms of curvature restrictions, among others. The main contributions of the method are twofold: first, a feasible path is directly obtained without the need of a later optimization process to accomplish curvature restrictions; second, the computation speed is significantly increased, up to 220 times faster than other optimization-based methods such as, for instance, Dubins, Euler-Mumford Elastica and Reeds-Shepp. Simulation results are given to demonstrate the superiority of the method when used for UAV applications in comparison with the three previously mentioned methods.

Multi UAV Coverage Path Planning in Urban Environments.

Coverage path planning (CPP) is a field of study which objective is to find a path that covers every point of a certain area of interest. Recently, the use of Unmanned Aerial Vehicles (UAVs) has become more proficient in various applications such as surveillance, terrain coverage, mapping, natural disaster tracking, transport, and others. The aim of this paper is to design efficient coverage path planning collision-avoidance capable algorithms for single or multi UAV systems in cluttered urban environments. Two algorithms are developed and explored: one of them plans paths to cover a target zone delimited by a given perimeter with predefined coverage height and bandwidth, using a boustrophedon flight pattern, while the other proposed algorithm follows a set of predefined viewpoints, calculating a smooth path that ensures that the UAVs pass over the objectives. Both algorithms have been developed for a scalable number of UAVs, which fly in a triangular deformable leader-follower formation with the leader at its front. In the case of an even number of UAVs, there is no leader at the front of the formation and a virtual leader is used to plan the paths of the followers. The presented algorithms also have collision avoidance capabilities, powered by the Fast Marching Square algorithm. These algorithms are tested in various simulated urban and cluttered environments, and they prove capable of providing safe and smooth paths for the UAV formation in urban environments.

Path Planning and Collision Risk Management Strategy for Multi-UAV Systems in 3D Environments.

Multi-UAV systems are attracting, especially in the last decade, the attention of researchers and companies of very different fields due to the great interest in developing systems capable of operating in a coordinated manner in complex scenarios and to cover and speed up applications that can be dangerous or tedious for people: search and rescue tasks, inspection of facilities, delivery of goods, surveillance, etc. Inspired by these needs, this work aims to design, implement and analyze a trajectory planning and collision avoidance strategy for multi-UAV systems in 3D environments. For this purpose, a study of the existing techniques for both problems is carried out and an innovative strategy based on Fast Marching Square-for the planning phase-and a simple priority-based speed control-as the method for conflict resolution-is proposed, together with prevention measures designed to try to limit and reduce the greatest number of conflicting situations that may occur between vehicles while they carry out their missions in a simulated 3D urban environment. The performance of the algorithm is evaluated successfully on the basis of certain conveniently chosen statistical measures that are collected throughout the simulation runs.

Cigarette smoking is associated with adverse pathological response and increased disease recurrence amongst patients with muscle-invasive bladder cancer treated with cisplatin-based neoadjuvant chemotherapy and radical cystectomy: a single-centre experience.

OBJECTIVE: To investigate the association between smoking status and pathological response to cisplatin-based neoadjuvant chemotherapy (NAC) and survival outcomes in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy (RC). PATIENTS AND METHODS: We reviewed 201 patients treated with NAC and RC for cT2-cT4N0M0 BC between 01/1999 and 01/2015. Smoking status was categorised as: 'never', 'former', and 'current' smoker. Pathological response to NAC was defined as: complete (ypT0N0), partial (ypTis/Ta/T1, N0), and no response (ypT2-4 or ypN+). Clinicopathological characteristics were analysed according to smoking status. Logistic regression analyses tested the association between smoking status and pathological response to NAC. Cox regression analyses tested risk factors associated with recurrence, overall (OM) and cancer-specific mortality (CSM). RESULTS: Overall, there were 58 (28.9%) never smokers, 87 (43.3%) former smokers, and 56 (27.9%) current smokers. No response to NAC was more frequently noted in current smokers (73.2%; P = 0.007). Former smoker (odds ratio [OR] 2.28; P = 0.024) and current smoker statuses (OR 4.52; P < 0.001) were significantly associated with no response to NAC, after adjusting for age, gender, Charlson Comorbidity Index, and clinical stage. Similarly, current smoking status (hazard ratio [HR] 2.14; P = 0.03) and extravesical pathological tumour stage (HR 3.31; P < 0.001) were independently associated with an increased risk of recurrence after RC. CONCLUSION: Cigarette smoking was significantly associated with adverse pathological response to cisplatin-based NAC in patients with MIBC treated with RC. Current smokers were at significantly higher risk of disease recurrence as compared to former and never smokers.

Use of Imaging During Staging and Surveillance of Localized Colon Cancer in a Large Insured Population.

BACKGROUND: Adherence to surveillance guidelines in resected colon cancer has significant implications for patient morbidity, cost of care, and healthcare utilization. This study measured the underuse and overuse of imaging for staging and surveillance in stage I-II colon cancer. METHODS: The OptumLabs database was queried for administrative claims data on adult patients with stage I-II colon cancer who underwent surgery alone in 2008 through 2016. Use of PET and CT imaging was evaluated during both initial staging (n=6,921) and surveillance for patients with at least 1 year of follow-up (n=5,466). "High use" was defined as >2 CT abdominal/pelvic (CT A/P) or PET scans per year during surveillance. RESULTS: Overall, 27% of patients with stage I-II colon cancer did not have a staging CT A/P or PET scan and 95% did not have a CT chest scan. However, rates of staging CT A/P and CT chest scans increased from 62.0% (2008) to 74.8% (2016) and from 2.3% (2008) to 7.1% (2016), respectively. Staging PET use was overall very low (5.2%). During surveillance, approximately 30% of patients received a CT A/P or PET and 5% received a CT chest scan within the first year after surgery. Of patients who had surveillance CT A/P or PET scans, the proportion receiving >2 scans within the first year (high use) declined from 32.4% (2008) to 9.6% (2016) (P = .01). CONCLUSIONS: Although PET use remains appropriately low, many patients with stage I-II colon cancer do not receive appropriate staging and surveillance CT chest scans. Among those who do receive these scans during surveillance, high use has declined significantly over time.

Clinical predictors and survival outcome of patients receiving suboptimal neoadjuvant chemotherapy and radical cystectomy for muscle-invasive bladder cancer: a single-center experience.

PURPOSE: To investigate the prevalence of and factors' association with receiving suboptimal neoadjuvant chemotherapy (NAC) and its impact on survival outcomes in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy (RC). METHODS: We reviewed 1119 patients treated with NAC and/or RC for cT2-cT4N0M0 BC. Patients were segregated into three groups: (i) suboptimal NAC (received < 3 cycles of cisplatin-based NAC or non-cisplatin-based regimen), (ii) optimal NAC and (iii) no NAC. Clinical characteristics were compared among groups. Logistic regression analyses tested the association between clinical variables and the odds of receiving suboptimal NAC. To adjust for potential baseline confounders, propensity score matching was performed. Pathologic outcomes were compared between groups and Cox regression analyses tested the risk factors associated with recurrence, overall (OM) and cancer-specific mortality (CSM). RESULTS: Before matching, 84/315 (26.6%) patients received a suboptimal NAC regimen. Lower general health status and impaired renal functions were the most significant factors associated with the administration of a suboptimal NAC. After matching, the optimal NAC group achieved higher rates of complete pathological response as compared to the suboptimal group (p = 0.03). Suboptimal NAC (HR 1.77; p = 0.015) and no NAC (HR 1.52; p = 0.03) were both associated with higher risk of recurrence and OM (HR 1.71; p = 0.02 and HR 1.61; p = 0.02) as compared to optimal NAC. CONCLUSION: One out of four MIBC patients received a suboptimal NAC regimen before RC. Receiving a suboptimal NAC regimen was associated with worse disease recurrence and survival outcomes following surgery, as compared to an optimal NAC regimen.

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma.

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04-0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05-0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

Low hypoxia inducible factor-1α (HIF-1α) expression in testicular germ cell tumors - a major reason for enhanced chemosensitivity?

The molecular basis for enhanced chemosensitivity of testicular germ cell tumors (GCT) has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of GCT has been variously attributed to multiple factors - an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-1α (HIF-1α) expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.

[Clinical features of Guillain-Barré syndrome in 41 patients admitted to a public hospital]. / Características epidemiológicas del síndrome de Guillain-Barré en población chilena: estudio hospitalario en un período de 7 años.

BACKGROUND: Guillain-Barré syndrome (GBS) is the commonest cause of acute flaccid paralysis worldwide, with an incidence of 0.6-4 per 100.000 inhabitants per year. It affects all age groups and carries an incapacity burden of up to 20%. AIM: To describe the features of GBS in adult Chilean patients admitted to a tertiary care hospital. MATERIAL AND METHODS: Review of medical records of 41 patients aged 17 to 81 years (30 males) admitted to a public hospital with the diagnosis of GBS between 2003 and 2009. According to clinical and electrophysiological criteria, the patients were classified into different varieties of GBS. RESULTS: The incidence of GBS was higher in males (2.7:1) and the demyelinated GBS variety was found in 66% of cases. According to the Hughes’ disability score, patients treated with plasmapheresis, showed non-statistically significant better outcomes than those treated with intravenous immunoglobulin. CONCLUSIONS: In this group of patients the demyelinated variety of GBS was more common than the axonal type. Although not statistically significant, the better response to plasmapheresis is encouraging and should prompt a controlled study.

Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies.

BACKGROUND: Sorafenib (a VEGFR and multi-targeted kinase inhibitor) and Bortezomib (a proteasome inhibitor) have clinical antineoplastic activities as single agents, and combine synergistically in preclinical models. METHODS: This Phase I study was undertaken to define the toxicity and the maximum tolerated doses (MTD) of the combination in patients with advanced solid tumors. Patients with cytologic or histologic proof of unresectable solid tumors were treated with escalating doses of sorafenib (twice daily) and bortezomib (days 1, 4, 8 and 11 intravenously) with 21-day cycles. RESULTS: Fourteen patients (7 males, median age 65, range 24-74), with renal (3), lung (3), pancreas (2), and breast, adrenal gland, melanoma, spindle cell tumor, chronic lymphocytic leukemia and multiple myeloma (1 each) were enrolled. All patients are off treatment, 10 due to disease progression. DLT was seen in two patients (one grade 3 abdominal pain and grade 4 lipase elevation; one with grade 3 vomiting) at sorafenib 200 mg twice daily and bortezomib 1.3 mg/m(2), establishing the MTD. No grade 4 hematologic or grade 5 toxicities were seen. One patient with renal cell cancer had a partial response and 5 patients attained stable disease. CONCLUSIONS: The combination of sorafenib and bortezomib was tolerated well. The recommended phase 2 doses are sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m(2) on days 1, 4, 8, 11 (21 day cycles). The combination shows preliminary signs of efficacy, supporting phase 2 studies.

Radiation Therapy in Oligometastatic Prostate Cancer.

Prostate cancer ranges from localized, low risk to metastatic, morbid disease. Although radiation therapy (RT) is commonly incorporated in the treatment of early disease or for palliation of symptomatic lesions, its role in extending survival in metastatic disease is less well-established. Here, we review the available evidence surrounding localized RT in the presence of oligometastatic disease and metastasis-directed therapy in both hormone-sensitive and hormone-resistant prostate cancer. We further outline potential future incorporation of RT as an immune-sensitizing therapy and the importance of highly sensitive imaging modalities in considering RT in metastatic disease.

Predictors of Locoregional Recurrence and Delineation of Adjuvant Radiation Therapy Fields for Patients With Upper Tract Urothelial Carcinoma Receiving Nephroureterectomy.

PURPOSE: To identify factors predictive of locoregional recurrence (LRR) in upper tract urothelial carcinoma (UTUC) treated with nephroureterectomy and to propose adjuvant radiation therapy (ART) fields. METHODS AND MATERIALS: Clinical and pathologic variables for patients receiving nephroureterectomy for UTUC between 1995 and 2009 were analyzed for associations with outcomes. Sites of LRR from all patients with available imaging (39) were contoured on computed tomography image sets of patients with representative anatomy, and ART fields were proposed based on these distributions. RESULTS: A total of 279 patients with a median follow-up of 13.0 years were analyzed. The 5-year cumulative incidence of LRR was 16.7% (95% CI, 12.2-21). Pathologic risk factors (PRFs) associated with increased risk of LRR included tumor in both the renal pelvis and ureter, T stage ≥2, lymph node involvement, grade 3 histology, and positive surgical margins (P < .05). Patients with an increased number of PRFs had a significantly greater risk of LRR. The 5-year cumulative incidence estimates of LRR were 5.3% (95% CI, 1.8%-16.0%), 15.6% (95% CI, 9.5%-25.7%), and 43.9% (95% CI, 31.1%-62.1%) for those with 1, 2, and ≥3 PRFs, respectively. ART fields covering the renal fossa and retroperitoneal lymph nodes from the superior border of L1 through the aortic bifurcation would encompass all sites of LRR for 33 of 46 patients (72%). Non-LRR bladder and distant failure occurred in 101 (36.2%) and 73 (26.2%) of the patients, respectively. The 5-year cumulative incidence estimate of distant failure was 22.5% (95% CI, 17.4%-27.3%). CONCLUSIONS: In patients receiving nephroureterectomy for UTUC, LRR is significantly increased in patients with 2 or more PRFs. These data provide clinically valuable insight into the selection of candidates for ART and the design of ART fields.

Changes in Frequency of Surveillance Imaging of Survivors of Diffuse Large B-Cell Lymphoma After the American Society of Hematology Choosing Wisely Recommendations.

In 2013, the American Society of Hematology (ASH) published recommendations with Choosing Wisely to limit surveillance imaging in aggressive lymphoma. We studied surveillance imaging practice patterns for diffuse large B-cell lymphoma (DLBCL) before and after the ASH Choosing Wisely campaign. We used OptumLabs Data Warehouse, a national insurance claims database, to retrospectively study imaging frequency in survivors of DLBCL from 2008 to 2016. Three time periods were defined: Period 1 (2008 to 2010), Period 2 (2011 to 2013), and Period 3 (2014 to 2016). One thousand four hundred seventy-two patients were included. Median follow up was approximately 2 years. During the first and second years of surveillance, imaging remained stable between Period 1 (years 1 and 2: 199 [91%] and 137 [83%], respectively) and Period 2 (years 1 and 2: 257 [88%] and 172 [77%], respectively; P = .38), but decreased in Period 3 (years 1 and 2: 315 [78%] and 83 [61%], respectively; P < .01). In a multivariable logistic regression, year after 2012 was a significant predictor of decreased overuse (more than two scans per year in the first year of surveillance; [odds ratio, 0.49 for 2013 v 2008; P = .02]). Our study demonstrated the rate of surveillance scans-both computed tomography and positron emission tomography imaging-in DLBCL decreased after the ASH Choosing Wisely campaign. Multiple factors, such as changes in recommendations, reimbursement, and provider knowledge base, may have all contributed and should be studied further.

Phase I trial of a pathotropic retroviral vector expressing a cytocidal cyclin G1 construct (Rexin-G) in patients with advanced pancreatic cancer.

Rexin-G is a pathotropic retroviral vector displaying a von Willebrand factor-targeting motif and expressing a dominant negative cyclin G1 gene. We undertook a phase I trial of intravenous (i.v.) administration of Rexin-G in patients with gemcitabine refractory, metastatic pancreatic adenocarcinoma. Twelve patients were treated. Dose escalation was performed from a dose of 1 x 10(11) colony forming units (CFU) per cycle to 6 x 10(11) CFU per cycle. The treatment was well tolerated. One dose-limiting toxicity (DLT) at dose level 2 (1.5 x 10(11) CFU per cycle) was observed, consisting of grade 3 transaminitis. There was no detection of replication-competent virus in patients' peripheral blood mononuclear cells (PBMCs) or viral integration in DNA obtained from PBMCs, and no development of neutralizing antibodies. No evidence of antitumor activity was observed. The best objective response was progressive disease in 11 of the 12 study patients, while 1 patient showed radiographically stable disease with clinical deterioration and increase in the CA19.9 tumor marker. Median time to progression was 32 days. The median duration of survival of the study patients was 3.5 months from treatment initiation. Rexin-G is well tolerated in doses up to 6 x 10(11) CFU in patients with recurrent pancreatic cancer, but there was no evidence of clinical antitumor activity.

Delaying Radical Cystectomy After Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer is Associated with Adverse Survival Outcomes.

BACKGROUND: Delaying radical cystectomy (RC) after a diagnosis of muscle-invasive bladder cancer (MIBC) has been associated with adverse survival. However, data are lacking regarding the impact of RC delay in patients receiving neoadjuvant chemotherapy (NAC). OBJECTIVES: To assess whether the time from last cycle of NAC to RC (time to cystectomy, TTC) is associated with survival among MIBC patients. DESIGN, SETTING, AND PARTICIPANTS: The study cohort comprised 226 patients treated with NAC and RC between 1999 and 2015 for cT2-T4N0M0 bladder cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics were used to test the association between TTC and clinicopathologic variables. Overall mortality (OM) and cancer-specific mortality (CSM) were analyzed via Kaplan-Meier estimation according to TTC. We assessed factors associated with OM and CSM using multivariable Cox regression analyses. RESULTS AND LIMITATIONS: The median TTC was 7.57wk (interquartile range 5.2-10.8). Patients with a Charlson comorbidity index (CCI) ≥1 had a longer TTC than those with a score of <1 (p=0.027). The group with TTC >10wk had significantly lower OM-free (p=0.003) and CSM-free rates (p<0.001) than the group with TTC ≤10wk. TTC was independently associated with higher risk of OM (p=0.027) and CSM (p=0.004) after accounting for age, gender, pathologic extravesical disease, and nodal status. CONCLUSIONS: TTC of >10wk after NAC was associated with adverse survival among patients with MIBC. Patients with a higher CCI were more likely to have prolonged TTC. PATIENT SUMMARY: The impact of delaying radical cystectomy in patients who have received neoadjuvant chemotherapy (NAC) is unknown. In this study we assessed whether prolonged time to cystectomy (TTC) after NAC affects survival outcomes in patients with muscle-invasive bladder cancer. We found that TTC of >10wk was associated with adverse overall survival and cancer-specific survival, and attempts should be made to shorten TTC after preoperative chemotherapy.

Serum chromogranin-A-based prognosis in metastatic castration-resistant prostate cancer.

OBJECTIVE: To determine the prognostic value of serum chromogranin-A (CGA) in a two-cohort study of men with metastatic castrate resistant prostate cancer (mCRPC) and to compare with circulating tumor cells (CTCs)-based prognosis. PATIENTS AND METHODS: A two-cohort-based evaluation for serum CGA for prognostication in CRPC stage was performed using a screening cohort of 256 men with mCRPC and an independent validation cohort of 92 men with mCRPC. In both cohorts, men receiving proton pump inhibitors and those with non-castrate levels of testosterone (>50 ng/dl) were excluded. Serum CGA was measured in a homogeneous automated immunofluorescent assay using time-resolved amplified cryptate emission. In the validation cohort, CTC enumeration was also performed using the FDA-cleared CELLSEARCH® CTC test. Cox proportional hazard regression models were used for prognostic association of serum CGA and CTC counts with overall survival. RESULTS: In the screening cohort, 200 men were eligible for analysis. The median serum CGA was 100.3 ng/mL (interquartile range: 67-161.3) and 34/200 were above the reference range. In the subset of men with Gleason scores ≥ 8, elevated CGA was associated with shorter overall survival [hazard ratio (HR) 2.19, p = 0.017]. In the validation cohort for 71 men eligible for analysis, the median serum CGA was 90 ng/mL (interquartile range: 55-156) and 31/71 patients had an elevated CGA. 51% of patients had a Gleason score ≥ 8 and 66/71 patients had CTCs enumerated with 26/66 with a CTC count ≥ 5 per 7.5 ml blood sample (unfavorable). Both elevated serum CGA (HR: 1.91, p = 0.043) and unfavorable CTC counts (HR: 2.97, p = 0.0012) were adversely associated with overall survival and patients with ≥ 5 CTCs and elevated serum CGA had the shortest overall survival (HR: 3.76, p = 0.008). CONCLUSION: Elevated serum CGA was negatively associated with OS in men with mCRPC. Serum CGA represents a prognostic biomarker that may complement CTC enumeration.

Factors Associated With Survival Following Radium-223 Treatment for Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Radium-223 (223Ra) improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This retrospective analysis was performed to better understand its efficacy in routine clinical practice and identify factors associated with survival. MATERIALS AND METHODS: Sixty-four patients with mCRPC who received 223Ra between 2013 and 2015 were the basis of this retrospective study. Clinical outcomes and patient characteristics were obtained. Potential prognostic factors for survival were evaluated by univariate analysis using the log-rank test and multivariate analysis using the Cox proportional hazard method. RESULTS: The median survival was 12.9 months. Twenty-one patients (33%) developed a skeletal event, and the median time to the first skeletal event was 4.4 months. In univariate analysis, factors significantly associated with survival included: no prior chemotherapy, ≤ 5 bone metastases, baseline prostate-specific antigen (PSA) ≤ 36 ng/mL, baseline alkaline phosphatase (ALP) < 115 U/L, baseline hemoglobin > 12 g/dL, ALP response after 223Ra treatment, PSA decrease during 223Ra treatment, and absence of > 25% PSA increase during 223Ra treatment. In multivariate analysis, 4 factors remained significant: no prior chemotherapy, ≤ 5 bone metastases, baseline ALP < 115 U/L, and ALP response after 223Ra treatment. CONCLUSION: When 223Ra is administered in routine clinical practice, clinical outcomes can be more variable than those reported in the randomized study owing to patient heterogeneity. Four factors were identified to be significantly associated with survival after 223Ra treatment. These pretreatment factors may be used as stratification factors in future studies to investigate whether 223Ra would be more effective for patients with newly diagnosed metastatic disease that is sensitive to androgen deprivation therapy.