bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous cone beam CT scanning during prostate radiotherapy to produce clinically useful images.
Authors: Choudhury Ananya , Dickinson Peter , Stratford Julia , Ryder David , Walshaw Richard C. , Mayes Sam , Logue John P. , Wylie James , Coyle Catherine , Livsey Jacqueline E. , Tran Anna , Alam Nooreen Sarah , Elliot Tony , Rowbottom Carl , Faivre-Finn Corinne , Boylan Christopher 
Published: February 2017

220 Background: Cone beam CT (CBCT) images can be acquired during delivery of rotational radiotherapy. We assessed the quality of simultaneous CBCTs captured during prostate radiotherapy and studied the effects of arc delivery time on image quality. Methods: Fifty patients with localised prostate cancer were treated with radical rotational radiotherapy. Treatment was delivered using a single eight or 10 MV arc on an Elekta Synergy linear accelerator. Standard (stCBCT) and simultaneous CBCTs (siCBCT) were captured on fractions 1, 6, 11, and 16. The siCBCT image was reconstructed and optimised using in-house software. The image quality was assessed by four observers using a validated scoring tool. The scoring clinician was blinded to whether the scan was stCBCT or siCBCT. Results: Seventy-four siCBCT scans were performed with a mean arc delivery time of 120 seconds during which 688 CBCT frames were acquired. Following a software upgrade the subsequent 122 siCBCTs were obtained with a mean arc delivery time of 83 seconds during which 502 CBCT frames were acquired. There was moderate agreement between the four observers regarding the quality of the CBCTs (Fleiss’ kappa statistic 0.51). StCBCTs were of good quality and the four observers agreed that 98 to 100% of these scans were of sufficient quality to be used to make a clinical decision. The four observers assessed that 35 to 79% of siCBCTs were of sufficient quality to be used to make clinical decisions. Before the software upgrade 65 to 93% of siCBCTs were judged to be of sufficient quality to make a clinical decision ("slow" simultaneous CBCT). Following the software upgrade this proportion fell to 16 to 69% ("fast" simultaneous CBCT). Conclusions: SiCBCT can produce images which are clinically useful. Image quality is affected by bowel gas, patient habitus and scatter from the MV beam. Reducing arc delivery time and the number of CBCT frames acquired by approximately one-third reduces the quality of siCBCTs. Further development and refinement of siCBCT scanning is warranted. Future reductions in arc delivery times may have to be limited if the use of siCBCT scanning becomes standard practice.
Correlation between recurrent chromosomal deletions status obtained on tissue cores and local invasive and systemic prostate cancer growth.
Authors: Adam Meike , Wenzel Philipp , Lanwehr Dominik , Tennstedt Pierre , Kluth Martina , Burkhardt Lia , Krohn Antje , Fisch Margit , Graefen Markus , Minner Sarah , Sauter Guido , Simon Ronald , Schlomm Thorsten 
Published: February 2017

24 Background: A variety of chromosomal deletions are known to occur frequently in prostate cancer, but the clinical significance of most of these deletions is unknown. To learn more about epidemiology, associations with other molecular features, and relevance for key clinical endpoints, several recurrent deletions were analyzed on a large-scale tissue microarray platform. Methods: A tissue microarray containing 11,156 prostate cancers was analyzed by fluorescence in situ hybridization (FISH) with dual-labeling probes including PTEN (10q23), TP53 (17p13.1), CHD1 (5q21), and MAP3K7 (6q15) together with their respective centromere probes. Patients were stratified into three major biological groups (organ confined, locally advanced, and systemic tumor growth) according to their multidimensional long-term follow up data. In addition, ERG fusion status and tumor cell proliferation (Ki67 labeling index) of all cancers were determined by immunohistochemistry. Results: Deletions were seen for PTEN in 17.9% of 6,122, TP53 in 14.7% of 7,604, CHD1 in 9.9% of 7,026, and for MAP3K7 in 18.7% of 3,528 interpretable cases. All deletions were strongly linked to a positive (PTEN, TP53) or negative ERG status (CHD1, MAP3K7, p<0.0001 each) and early prostate-specific antigen recurrence. The combination of deletion information provided even better prognostic information, showing a dose dependent relationship between the number of deletions and the growth pattern (organ confined, local invasive, or systemic) of the tumor. Patients with no deletion had a 16.8% risk for local invasive and only 8.9% risk for systemic tumor growth, whereas the respective figures were 17.9% and 44.6% in patients with more than or equal to three deletions (p<0.001). The chance of having an organ confined tumor was 68.0% for patients with no deletion and 23.1% for patients with more than or equal to three deletions (p<0.001), respectively. Conclusions: Our data show, that these analyzed chromosomal deletions are tightly linked with ERG status in prostate cancer and that the deletion status obtained on small tissue cores correlates with key biological tumor features. Combinatorial analysis of genomic alterations in prostate biopsies might provide clinically relevant information.
Enzalutamide after abiraterone in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Sandhu Gurprataap Singh , Parikh Rahul Atul , Appleman Leonard Joseph , Friedland David 
Published: February 2017

240 Background: Abiraterone is a 17a hydroxylase and C17,20-lyase inhibitor that blocks androgen biosynthesis and is approved for treatment in patients with mCRPC. Enzalutamide, a second-generation androgen receptor signaling inhibitor was recently approved for use in patients with mCRPC post-docetaxel. There is paucity of information regarding sequential use of enzalutamide after abiraterone. Methods: This is a single-center, retrospective analysis of 23 patients with mCRPC who received enzalutamide after progression on abiraterone. Post-treatment prostate specific antigen(PSA) response and time to PSA progression were used to determine enzalutamide efficacy. Patients were followed for 6 months post initiation of enzalutamide. Results: At the time of enzalutamide initiation, median age was 70 years, with average Gleason score of 7 at the time of diagnosis. All patients were on ongoing androgen deprivation therapy, and 15 patients had received prior docetaxel chemotherapy. Median duration of abiraterone and enzalutamide treatment was 7 and 4.5 months respectively. 12 patients had at least one declining PSA value post enzalutamide treatment, with 5 patients showing >25% decline in PSA and 4 patients > 50%. Median time to PSA progression in patients receiving enzalutamide following abiraterone was 2.3 months. Conclusions: Sequential enzalutamide in patients with CRPC post-abiraterone showed only modest activity, indicating that the clinical benefit of sequential use of highly potent androgen pathway inhibitors cannot be assumed, and should be measured in prospective studies.
Association of alkaline phosphatase (ALP) with clinical outcomes in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302.
Authors: Yu Evan Y. , Saad Fred , Londhe Anil , Shore Neal D. , Van Poppel Hendrik , Rathkopf Dana E. , Smith Matthew R. , Logothetis Christopher , De Souza Paul L. , Fizazi Karim , Mulders Peter F.A. , Mainwaring Paul N. , Hainsworth John D. , Beer Tomasz M. , North Scott A. , Small Eric Jay , Scher Howard I. , Griffin Thomas W. , Yu Margaret K. , Ryan Charles J. 
Published: February 2017

27 Background: Prognostic models have been developed for men with mCRPC. In this analysis we undertook a pragmatic approach to focus on commonly obtained markers. Baseline ALP and normalization of elevated ALP post-docetaxel have prognostic value for overall survival (OS). We examined the association between ALP and prostate-specific antigen (PSA) elevation at baseline and after 4 cycles of therapy (C5D1), when both markers were assessed, with long-term clinical outcomes in COU-AA-302, a randomized phase 3 study of abiraterone acetate (AA) in chemotherapy-naive mCRPC pts. Methods: 1,088 pts were randomized 1:1 to AA (1 g) + prednisone (P) (5 mg BID) or placebo + P. Radiographic progression-free survival (rPFS) and OS were co-primary end points. The study design, as well as primary and secondary end point results obtained at the time of a prespecified interim analysis at 55% OS events, have been described in detail previously. The effect of elevated ALP (above upper limit of normal) and PSA (above 106.2 µg/mL, baseline third quartile) status on rPFS and OS was assessed retrospectively using a stratified Cox regression model that included treatment and baseline factors log (lactate dehydrogenase), hemoglobin, whether patient had only bone metastasis, and age. Results: Elevated status of ALP and PSA were independent significant predictors of increased risk for outcomes at baseline as well as after 4 cycles of therapy (Table). Conclusions: These post hoc analyses of data from COU-AA-302 suggest that elevated ALP and PSA at baseline and during treatment confers individual and additive risk for adverse clinical outcomes in chemotherapy-naive mCRPC. Clinical trial information: NCT00887198. [Table: see text]
Duration of response to androgen-deprivation therapy (ADT) and efficacy of secondary hormone therapy, docetaxel (D), and cabazitaxel (C) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Angelergues Antoine , Maillet Denis , Flechon Aude , Ozguroglu Mustafa , Mercier Florence , Guillot Aline , Le Moulec Sylvestre , Gravis Gwenaelle , Beuzeboc Philippe , Massard Christophe , De La Motte Rouge Thibault , Delanoy Nicolas , Elaidi Reza-Thierry , Oudard Stephane 
Published: February 2017

282 Background: Early CRPC (<12 months, m) with 1st hormonal therapy (HT) was found to predict poor efficacy of 2nd HT, but did not seem to impair the benefit of D-based chemotherapy. We evaluated the impact of this variable in our cohort of patients (pts) treated also with second-line chemotherapy C. Methods: Records of 132 consecutive mCRPC pts were retrospectively collected in 9 centers. PSA response ≥ 30% and time to biochemical progression (TTBP) with 1st- and 2nd-HT, D and C were evaluated according to time to progression to CRPC (<12 m and ≥12 m). PSA-response, TTBP and Overall Survival (OS) were compared using exact, Wilcoxon and log-rank tests, respectively. Results: All patients received first HT, D and C, and 94 of them received second HT. Time to CRPC <12 m was associated with a reduced OS and poor PSA-response and TTBP with second HT. Taxanes showed a similar PSA response whatever the time to CRPC but TTBP was slightly shorter in men with time to CRPC <12m. Conclusions: This retrospective analysis of 132 pts with mCRPC suggests that rapid progression to CRPC (<12 m) is associated with a poor prognosis and a low response to second-HT. PSA response to taxanes does not seem to be affected by time to CRPC, but TTBP is shorter in men with early CRPC. Prospective randomized trials are needed to confirm these results. [Table: see text]
Evaluation of outcomes following centralization of cystectomy services in the United Kingdom.
Authors: Patel Prashant , Evison Felicity , Goodfellow Henry , Bryan Richard , James Nicholas David 
Published: February 2017

286 Background: NICE-Improving Outcomes in Urological cancers (2002) recommended that providers in UK carry out a cumulative total of at least 50 radical cystectomies or prostatectomies per year. Surgeons should perform ≥5 cystectomies per year and 30-day mortality rates of 3.5% or less must be achieved. We evaluated this effect of centralisation on cystectomy outcomes over the past decade. Methods: The Health Episode Statistic (HES) database for cystectomies in England over a period of 2001 to 2012 for patients with bladder cancer was interrogated. Banded provider volumes (<10, ≥10 to < 16, ≥16) and surgeon volumes (<5, ≥5 to <8, ≥8) with respect to age, sex, Charlsons’ comorbidity index, deprivation index are presented with outcomes related to 30, 60, 90 day mortality; length of stay (LOS); re-admission; complications; operation specific re-intervention; and overall survival related outcome data is analysed. Results: 14,693 cystectomies for bladder cancer were performed over the study period. 85.5% providers (35% of all cystectomies) and 70.9% Surgeons (40% of all cystectomies) were performing less than the recommend standard prior to the NICE 2002 recommendations. A decade later 50% providers (3.5% of all cystectomies) and 42% surgeons continue to perform less than the recommended standard but only 12.5% of all cystectomes were carried in non-compliant centres/surgeons. The 30-day mortality rate fell from 3.7% to 2.4%. There was no difference in age, sex or deprivation scores amongst the bands for providers/surgeons. However, high volume providers and surgeons operated on patients with higher comorbidity scores but achieved shorter LOS. No difference in complications was seen amongst the bands, but re-intervention rates were higher amongst low volume surgeons. Mortality (early and overall) was lower in high volume provider and surgeons when compared to low bands. Conclusions: The UK data suggests 87.5% cystectomies are carried out in a compliant centre indicative of centralisation. The 30-day mortality rates have fallen. Overall mortality is lower in high volume providers and surgeons despite these groups with higher co-morbidity scores reflective of improved service provision through centralisation.
Branched evolution and intratumor heterogeneity of urothelial carcinoma of the bladder.
Authors: Cha Eugene K. , Sfakianos John P. , Al-Ahmadie Hikmat , Scott Sasinya N. , Kim Philip H. , Iyer Gopa , Bajorin Dean F. , Rosenberg Jonathan E. , Berger Michael F. , Bochner Bernard H. , Solit David B. 
Published: February 2017

293 Background: Genomic characterization of urothelial carcinoma of the bladder (UCB) has begun to reveal significant intertumor heterogeneity when comparing samples from different subjects. As in other malignancies, intratumor heterogeneity, which may allow for tumor evolution and adaption, poses a significant challenge to personalized-medicine strategies. Methods: To examine UCB tumor evolution and heterogeneity, we performed next-generation targeted sequencing on multiple temporally and spatially separated bladder tumors obtained at time of transurethral resection (TUR) and radical cystectomy (RC). Specimens were analyzed using a next-generation, targeted sequencing assay designed to identify point mutations, indels, and copy number alterations in 300 cancer-associated genes. Results: Phylogenetic reconstruction revealed evidence of branched evolutionary growth. Evaluation of multiple tumors from individual subjects identified both shared and unique potential driver mutations. Evidence of convergent phenotypic evolution was detected through analysis of multiple distinct tumors from several subjects. For example, three separate tumors in one subject shared a common PIK3CA mutation (E453K) and had unique second mutations in PIK3CA (E542V, E545K, and E545Q, respectively). In another subject, distinct inactivating mutations of EP300 were identified in two temporally separated tumor samples. Macrodissection of single tumors into non-invasive and invasive components revealed significant intratumor heterogeneity; one case illustrates how analysis of a muscle-invasive TUR specimen could result in undersampling and thereby miss the tumor clone that persisted at time of RC. Conclusions: We demonstrate branched evolution of UCB through genomic analyses of multiple temporally and spatially distinct bladder tumors from individual subjects. Macrodissection of individual tumor samples identified significant intratumor heterogeneity. These concepts may present major challenges to personalized-medicine approaches that rely on sampling of a single tumor at a specific timepoint in the evolution of a patient’s UCB.
Phase II trial of pazopanib and weekly paclitaxel in metastatic urothelial cancer (UC).
Authors: Srinivas Sandy , Narayanan Sujata , Harshman Lauren Christine , Lam Anthony P. , Vaishampayan Ulka N. , Haas Denise , Poushnejad Shermeen , Pachynski Russell 
Published: February 2017

299 Background: Currently, there are no standard treatments for relapsed or refractory urothelial carcinoma (UC). Discouraging results have been achieved in trials evaluating drugs as single agents or in combination regimens. Paclitaxel has activity when used alone and in combination in urothelial cancer, and pazopanib is active in solid tumors secondary to its potent anti-angiogenic effect. We report the results of an ongoing multicenter phase II study evaluating the combination of paclitaxel with pazopanib in refractory UC. Methods: Patients (pts) eligible for the study have histologically confirmed UC, with relapse after receiving up to 2 chemotherapeutic regimens. Pazopanib (800 mg) is administered daily, with weekly paclitaxel (80mg/m2) for 3 weeks in a 28 day cycle. Treatment is continued until disease progression or unacceptable toxicity. Primary endpoint of the study is the response-rate (RR) based on RECIST criteria. Secondary endpoints include safety, and progression free-survival (PFS). For designing the study, Simon’s two-stage method was applied, and 9 pts were recruited in the first stage. After having ≥1 response in the first group, a full enrollment of 32 pts has been initiated. Results: 25 pts were enrolled from April 2010 to September 2013. Their median age was 67 years (47-89), with a median ECOG performance status of 1 (0-2). 10 pts (40%) had UC of the upper urinary tract and 15 had primary bladder/ureter tumors. All pts had multiple metastatic sites, including 11 (44%) with liver metastases. Median number of prior cytotoxic regimens was 2, and 50% were considered cisplatin responsive. Based on RECIST (v1.1) criteria,13 pts (52%) had partial response (PR), 5 (20%) had stable disease (SD), and 2 (8%) had complete response (CR) (80% clinical benefit). The side effects included grade 3 hypertension (n=2), grade 3 fatigue (n=4), grade 3 thrombosis (n=2) and grade 4 neutropenia (n=2). 14 pts required growth factor support. Conclusions: Our phase II study combining paclitaxel and pazopanib demonstratedsignificant anti-tumor activity of combining paclitaxel in relapsed/refractory UC. This combination is safe, and is worthy of evaluation in larger studies. Clinical trial information: 1108055.
Racial disparities in the morbidity of radical cystectomy in the United States.
Authors: Borza Tudor , Feng Chen Chen , Leow Jeffrey , Chung Benjamin I. , Chang Steven L. 
Published: February 2017

304 Background: Racial disparities in the management of bladder cancer have been previously reported. However, limited data exists on inequalities in the morbidity of radical cystectomy. We performed a contemporary population-based analysis to examine the association between race and surgical complications among patients undergoing radical cystectomy. Methods: We analyzed the Prospective Rx Comparative Database (Premier, Inc., Charlotte, NC), which collects data from over 600 non-federal hospitals throughout the US. We identified patients who underwent radical cystectomy between 2003 and 2010 based on ICD-9 code (57.71). Primary outcome measure was 90-day major complication rates, defined as Clavien Classification System Grade 3-5, derived from ICD-9 codes. Multivariable logistic regression models were developed adjusting for clustering by hospitals and survey weighting to ensure nationally representative estimates to evaluate 90-day major complication for all patients (Model 1), patients ≥65 years (Model 2), and Medicare only patients (Model 3). Results: Our study cohort included 50,175 patients. The majority of patients were Caucasion (76%), men (83.5%), with Medicare (64.2%). Major complication rates were 16% for Caucasions, 17% for African American, 24% for Hispanics, and 16% for Other. Compared to Caucasians, the odds ratio (OR) of major complications for Hispanics was 1.9 (p=0.03) and 2.6 (p<0.0001) in Models 1 and 2, and 1.7 (p=0.1) for Model 3. None of the other racial groups had significantly different odds of major complications compared with Caucasians. Conclusions: In the United States, Hispanic patients are the least likely to undergo radical cystectomy but have the highest rate of major complication following surgery. Our analysis shows that this disparity is uniquely absent among Hispanic patients with Medicare suggesting that barriers to healthcare may underlie the observed phenomenon. Therefore, the worse outcomes for Hispanic patients with bladder cancer may be secondary to challenges in accessing medical treatment at earlier stages of disease arising from language differences and non-U.S. citizenship status.
Influence of age on incident diabetes (DM) and cardiovascular disease (CVD) among prostate cancer survivors receiving androgen deprivation therapy (ADT).
Authors: Morgans Alicia Katherine , Fan Kang-Hsien , Koyama Tatsuki , Albertsen Peter C. , Goodman Michael , Hamilton Ann S. , Hoffman Richard M. , Stanford Janet L. , Stroup Antoinette M. , Resnick Matthew , Barocas Daniel Ari , Derleth Christina Louise , Penson David F. 
Published: February 2017

31 Background: Androgen deprivation therapy (ADT) has been associated with an increased risk of developing diabetes (DM) and cardiovascular disease (CVD), though this is controversial, particularly for CVD. We prospectively assessed the relationship between ADT and incident DM and CVD in the Prostate Cancer Outcomes Study (PCOS), a population-based cohort of prostate cancer survivors followed longitudinally for 15 years from diagnosis. Methods: We identified men in the PCOS with non-metastatic prostate cancer diagnosed from 1994 to 1995 and followed through 2009 to 2010. We used multivariable logistic regression models to compare groups receiving short-term ADT (less than 2 years), prolonged ADT (2 years or more) and no ADT to assess the relationship between ADT exposure and subsequent diagnoses of DM and CVD (determined by patient report and cause of death data). We evaluated the effects of age at diagnosis, race, stage, and comorbidity on the development of DM and CVD. Results: Among 3,526 men with comorbidity and treatment data, 2,985 men without baseline DM and 3,112 men without baseline CVD constituted the DM and CVD cohorts, respectively. Regardless of duration of ADT exposure, there was not an increased risk of DM or CVD in men younger than 70 at diagnosis. Compared to no ADT exposure, prolonged ADT was associated with an increased risk of DM and CVD that increased steadily over age 76 at diagnosis for DM (OR 2.11 at age 74, 95% CI 1.02 – 4.36; OR 2.65 at age 80, 95% CI 1.09 – 6.47) and age 74 at diagnosis for CVD (OR 1.89 at age 74, 95% CI 1.02 - 3.49; OR 3.19 at age 80, 95% 1.25 – 8.17). Increasing comorbidity burden modified risk of DM and CVD (for 3 or more comorbidities vs. no comorbidities; for DM, OR 4.25, 95% CI 2.3 - 7.9; and for CVD, OR 8.1, 95% CI 4.3 -15.5 P<0.001). Conclusions: The relationship between ADT and development of CVD and DM may be dependent upon age at diagnosis in addition to length of ADT administration, with longer ADT exposure predominantly increasing risk among older men only. Men with greater comorbid burden had increased risk of developing DM and CVD. Closer monitoring for development of DM and CVD may be most important among older men receiving prolonged ADT, especially those with other comorbidities.