bluuebunny/crossref_metadata_2025_split huggingface dataset:
1.5-year post-treatment follow-up of radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase 3 ALSYMPCA study.
Authors: Nilsson Sten , Vogelzang Nicholas J. , Sartor A. Oliver , Bottomley David , Coleman Robert E. , Skjorestad Irene , Wahba Mona , Parker Chris 
Published: February 2017

9 Background: Ra-223 is a first-in-class alpha-emitting pharmaceutical recently Food and Drug Administration approved for treatment (tx) of patients (pts) with CRPC and symptomatic bone metastases (mets). In ALSYMPCA, Ra-223 significantly improved overall survival by 3.6 months versus placebo (pbo) (HR = 0.70; 95% CI, 0.58-0.83; P < 0.001) and was well tolerated. Reported here are long-term safety data ~1.5 years after the last pt’s final injection (inj) from the entire ALSYMPCA safety population. Methods: Eligible pts had progressive CRPC with ≥ 2 symptomatic bone mets and no known visceral mets, were receiving best standard of care, and had received docetaxel or were unfit for or declined docetaxel. Pts were randomized 2:1 to 6 inj of Ra-223 (50 kBq/kg IV; q 4 wk) or matching pbo. Only adverse events (AEs) considered tx related by the investigator were reported during follow-up. Long-term safety data were assessed by specific diseases, including acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or primary cancer in other organs. Results: ALSYMPCA safety population included 901 pts (Ra-223, n = 600; pbo, n = 301). Overall, 25 (4%) Ra-223 and 8 (3%) pbo pts had ≥ 1 tx-related AE (Table). During follow-up, primary cancer in other organs was reported in 5 pts (Ra-223, n = 2; pbo, n = 3). Conclusions: Ra-223 is an effective and well-tolerated tx for CRPC with symptomatic bone mets. No major safety issues were identified within ~1.5 years after tx in the ALSYMPCA safety population. Clinical trial information: NCT00699751. [Table: see text]
Clinical outcomes of patients (pts) age 80 or older treated with docetaxel (DOC) as first-line chemotherapy for castration-resistant prostate cancer (CRPC): Results of an Italian multicenter retrospective study (DELPHI study).
Authors: Veccia Antonello , Burgio Salvatore Luca , di Lorenzo Giuseppe , Ortega Cinzia , Scognamiglio Florinda , Aieta Michele , Zustovich Fable , Mattioli Rodolfo , Mansueto Giovanni , Facchini Gaetano , Procopio Giuseppe , D'Angelo Alessandro , Spizzo Gilbert , Donini Maddalena , Bortolus Roberto , Vicario Giovanni , Zucali Paolo A. , Basso Umberto , Lo Re Giovanni , Caffo Orazio ,   DELPHY Study Group
Published: February 2017

92 Background: Docetaxel (DOC) represents the treatment of choice in the first line treatment for patients (pts) with castration-resistant prostate cancer (CRPC). However, when CRPC is diagnosed in pts age 80 or older, the fear of high toxicity degree usually limits chemotherapy use due to both pts frailty and several comorbidities occurrence. The present retrospective study is aimed to assess the clinical outcomes in this very elderly CRPC population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all pts age 80 and older CRPC pts from participating institutions, treated with DOC in clinical practice, recording the pre- and post-DOC clinical history, the DOC treatment details and outcomes. Results: To date we collected a consecutive series of 115 pts from 28 Italian hospitals. The median age was 82 (range 80 to 90). The median baseline prostate-specific antigen (PSA) was 92 ng/ml (range 3 to 2,981); 83% of the pts had bone metastases, while nodal, lung and liver metastases were observed in 39%, 9%, and 8% of the pts, respectively. Median Cumulative Illness Rating Scale score was 3 (range 0 to 11), median Activity Daily Living index score was 0 (range 0 to 5), median Instrumental Activities of Daily Living score was 0 (range 0 to 5). The DOC was administered on 3 week or weekly schedule basis (43%/57%). A PSA reduction greater than 50% was observed in 55% of the pts; an objective response was observed in 15% of the 60 pts who underwent a radiological re-evaluation at the treatment end. Grade 3-4 toxicities were: anemia (2%), neutropenia (10%) , thrombocytopenia (2%), fatigue (10%), diarrhea (4%), nausea (2%), renal (2%), and febrile neutropenia (2%). The median progression-free survival (PFS) and overall survival (OS )were 7 months and 20 months, while the 1 year PFS and OS rates were 21.2% and 71.5%, respectively. Conclusions: This data suggests that selected very older (age 80 and older) CRPC pts may received DOC with a good toxicity profile. In this pts population the treatment, both on 3 week or weekly schedule, is able to produce survival outcomes comparable to pivotal trials (18 months).
Chromosome 8 alterations and PTEN loss in Gleason grade 3 tumor to predict the presence of unsampled grade 4 tumor: Implications for active surveillance.
Authors: Trock Bruce J. , Jenkins Robert B. , Said Jonathan W. , Fine Samson , Knudsen Beatrice , Fedor Helen L. , Gurel Bora , Lotan Tamara L , De Marzo Angelo M 
Published: February 2017

93 Background: A key eligibility criterion in many active surveillance (AS) programs is that the biopsy exhibit only Gleason pattern 3 (G3) for a Gleason score of 6 or less. However, 25 to 35% of biopsy Gleason 6 is upgraded to Gleason 7 or higher in the prostatectomy (RP) specimen. Thus, there is a great need for biomarkers that, when measured on G3 tissue in a Gleason 6 biopsy, can predict the presence of unsampled higher grade tumor in the whole prostate. We evaluated PTEN loss by immunohistochemistry (IHC), and PTEN deletion, chromosome 8q (MYC) gain and 8p (LPL) loss by fluorescence in situ hybridization (FISH) for their ability to predict unsampled G4 tumor. Methods: A tissue microarray (TMA) was constructed of RP tissue from three groups of patients (n=50 per group) whose prostates exhibited only Gleason 3+3, only 3+4, or only 4+3 tumor, matched on age, year of RP, and race. In each patient, multiple cores sampled only from areas of G3 were evaluated for PTEN deletion by FISH, PTEN loss by IHC, and chromosome 8p/8q alterations by FISH. Biomarker results were compared between Gleason 6 versus 7 tumors using conditional logistic regression. Results: Patients underwent RP in 2001 to 2009, had median age 60, and median prostate-specific antigen 5.2; 63% of tumors were organ confined. In univariate analyses 8q gain (odds ratio OR=8.9, p<.0001), 8p loss (OR=6.9, p<.0001), PTEN loss by IHC (OR=5.7, p=.025), but not PTEN deletion by FISH (OR=1.5, p=.477) were significantly more common in G3 cores from Gleason 7 tumors than G3 cores from Gleason 6 tumors. In multivariable analyses, 8q gain (OR=6.2, p=.002) and 8p loss (OR=5.2, p=.0002) remained highly significant. At least one high risk biomarker (8q gain, 8p loss, PTEN loss, or PTEN deletion) was found in 35.7% of Gleason 3+3 versus 77.1% of Gleason 3+4 versus 91.3% of Gleason 4+3 tumors, p<.0001. Adjustment for confounding factors did not change the results. Conclusions: Chromosomal 8q gains (MYC), 8p loss (LPL), and PTEN loss measured in Gleason G3 TMA cores strongly differentiate whether the core comes from Gleason 6 or Gleason 7 tumor. If validated in biopsy Gleason 6 cores to predict prostatectomy Gleason 7 tumor these biomarkers could facilitate safe selection of men for active surveillance.
Highly functional natural killer (NK) cells as predictive biomarkers associated with long response to castration in newly diagnosed metastatic prostate cancer.
Authors: Pasero Christine , Gravis Gwenaelle , Guerin Mathilde , Rocchi Palma , Thomassin Jeanne , Walz Jochen , Salem Naji , Dermeche Slimane , Brunelle Serge , Olive Daniel 
Published: February 2017

95 Background: Immunotherapy is now investigated as a promising alternative treatment for patients (pts) with metastatic prostate cancer (PC). Natural killer (NK) cells are powerful effector cells with antitumoral activity and their role have been explored in solid tumors but not yet in prostate cancer. NK cell cytotoxicity is regulated by a balance between activating and inhibitory receptors. Here, we performed a restrospective study to evaluate the link between NK cells and the time of castration response in newly diagnosed PC patients with metastases. Methods: Newly diagnosed metastatic PC pts were divided according the time of castration response, with an 18-months cutoff value: 18 pts with long castration response (LCR, median = 64.6 months), and 14 pts with short castration response ([SCR] median = 11.2 months), with a median overall survival of 97.7 months and 33.8 months respectively. Circulating NK cells from these patients were studied by flow cytometry to evaluate the expression of activating receptors and the NK cell functionality. Results: We observed thatNK cells from LCR pts express higher levels of the maturation marker CD57 (43.3% vs. 23.3% positive cells, p= 0.002), the receptor CD16 involved in cytotoxicity (29,124 vs. 16,806 MFI, p= 0.02), and the activating receptors NKp46 and NKp30 (17.5 vs. 11.4 RMFI, p= 0.0146 , and 10.9 vs. 6.3 RMFI, p = 0.0128 respectively) than NK cells from SCR pts. This suggests that LCR pts have powerful NK cells. Indeed, NK cells from LCR pts are highly efficient in CD107 functional assay than NK cells from SCR pts (28.9% vs. 19.4%, p =0.002). In vitro blocking experiments show that NKp46 is precisely one of the NK cell receptors involved in the NK-mediated recognition of prostate tumor cells, thus higher expression of NKp46 would help to control PC progression. Conclusions: Together our results show for the first time that efficient NK cells are associated to a long response to castration and prolonged survival in newly diagnosed metastatic PC. NK cell receptors might be useful as predictive biomarkers in metastatic PC, to help in stratification of patients and to design NK cell–based immunotherapeutic strategies for PC.
Leveraging RB status to define therapy for castrate-resistant prostate cancer.
Authors: de Leeuw Renee , Comstock Clay de , Pollutri Daniela de , Schiewer Matthew Joseph , Ciment Stephen J , Mankame Tanmayi de , Ostrander William , Den Robert Benjamin , Kelly William Kevin , Gomella Leonard G. , Dicker Adam , Hussain Maha , Knudsen Karen E. 
Published: February 2017

96 Background: Loss of retinoblastoma (RB) tumor suppressor is overrepresented in castrate-resistant prostate cancer (CRPC) compared to primary PCa. We previously showed using analyses of human tissue and in vitro and in vivo modeling that RB constrains androgen receptor (AR) function, and that loss of RB is sufficient promote resistance to castration and AR antagonists. Thus, novel strategies are needed to treat RB-deficient tumor. By contrast, in tumors retaining RB, suppressing enhancing RB activity would be of therapeutic advantage, and may be accomplished through next-generation Cdk4/6 inhibitors. Methods: Stable isogenic pairs of prostate cancer cell lines either retaining RB or RB depleted (by shRNA) were assessed in vitro and in xenografts for response to Cdk4/6 kinase inhibitors or the cabazitaxel. In addition, using an ex vivo explant assay, fresh tumor tissue samples from radical prostatectomy were exposed to the Cdk4/6 inhibitor or cabazitaxel for up to 7 days, and evaluated by IHC for Ki67, Caspase-3, and AR. Results: Cdk4/6 inhibition blocks tumor cell proliferation dependent on RB status. This was further confirmed ex vivo, as evidenced by a marked reduction in Ki67 staining in Cdk4/6 inhibitor treated explant tissue from two prostate cancer patients. Conversely, in vitro studies revealed a modest sensitization of RB-depleted tumors to cabazitaxel that was dramatically enhanced in vivo and after castration. Cabazitaxel, like docetaxel, targets the cell architecture and induces cell death, but also induces a distinct gene expression profile that may partially explain efficacy in docetaxel-resistant tumors. Neither taxane showed affects on AR nuclear localization using in vivoor explant studies. Conclusions: These results strongly support our hypothesis that RB status can be used as a metric to define therapeutic response to cabazitaxel, as such that loss of RB function induces sensitization taxanes, whereas RB proficient tumors give an enhanced response to Cdk4/6 kinase inhibitors.
Impact of prior response to abiraterone acetate (AA) on subsequent activity of docetaxel (D) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Azad Arun , Lester Renee , Heng Daniel Yick Chin , Eigl Bernhard J. , Chi Kim N. 
Published: February 2017

97 Background: Questions about optimal sequencing of systemic agents in mCRPC and whether cross-resistance occurs between agents remain largely unanswered. Recently, it was reported that D is inactive in mCRPC pts who did not have a ≥ 50% PSA decline on prior AA (Ann Oncol 2012; 23(11):2943-7). To investigate this further, we evaluated the activity of D in mCRPC pts who had previously received AA. Methods: Cancer registries at two Canadian centers were used to identify mCRPC pts treated with D after AA. Outcomes from D treatment were compared between AA responders (≥ 50% PSA decrease with prior AA) and AA non-responders (< 50% PSA decrease with prior AA). Progression-free survival (PFS) (Prostate Cancer Working Group 2 criteria) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Of 40 eligible pts, 14 (35%) were classified as AA responders and 26 (65%) as AA non-responders (including 16 pts who had no PSA decline on AA). The median number of cycles of D administered to AA responders and non-responders was 6 (range: 1-10) and 4 (range: 1-13) respectively. Thirty (75%) pts had also received D prior to AA. Notably, among 39 pts evaluable for PSA response, no difference was seen in the proportion of AA responders and non-responders who had PSA falls ≥ 50% (p=0.72; Fisher’s exact test) or ≥ 30% (p=0.75; Fisher’s exact test) on D (Table). Analysis of survival outcomes from date of initiation of D also revealed similar median PFS (p=0.54; log-rank) and median OS (p=0.93; log-rank) in both groups (Table). Conclusions: PSA response rates to D did not differ between AA responders and non-responders. These data suggest that the anti-tumor activity of D in mCRPC may be independent of prior response to AA and that chemotherapy is still a therapeutic option in patients who do not respond to AA. Prospective studies evaluating optimal sequencing of AA and D in mCRPC are warranted. [Table: see text]
Evaluation of length, maximum Gleason score, and extension of disease at positive surgical margins during radical prostatectomy.
Authors: Djaladat Hooman , Alemozaffar Mehrdad , Day Christina , Aron Manju , Cai Jie , Campanelli Tracy , Lieskovsky Gary , Daneshmand Siamak 
Published: February 2017

98 Background: Positive surgical margin (PSM) found following radical prostatectomy (RP) is known to affect subsequent recurrence and survival. The extent of PSM has been shown to impact clinical outcomes. We examined the effect of length of PSM, extent of disease at PSM and maximum Gleason score at PSM on oncologic outcomes. Methods: A retrospective review of 3971 patients undergoing RP for prostate cancer at our institution between1978-2009 revealed 1053 patients with PSM, out of whom 814 received no hormone therapy. The initial 175 patients were selected to maximize available follow-up, and their slides were re-reviewed for following parameters: length of PSM (mm), maximum Gleason score at PSM, and maximal extension of PSM (intraprostatic incision vs. extracapsular extension). Data was available in 107 patients who are the subject of this study. Multivariable Cox regression models were used to evaluate the impact of above features as well as age, preoperative PSA, pathologic Gleason score, stage and adjuvant radiotherapy on biochemical and clinical recurrence-free survival (RFS), and overall survival (OS). Results: Median follow-up was 17.6 years. Maximum extension of PSM was limited to intraprostatic incision in 63 (58.9%) and extracapsular in 44(41.1%) patients. Median length of PSM was 4 mm (range 1-55 mm); 41 (38.3%) with <3mm and 66 (61.7%) with >4mm. Maximum Gleason score at PSM was <6 in 70 (66.0%) and >7 in 36 (34%) patients. 10-yr PSA RFS, clinical RFS, and OS were 60.2%, 80.7%, and 60.2%, respectively. Multivariable Cox regression modeling showed the length of PSM >4mm and extracapsular extension as independent predictors of PSA RFS and clinical RFS. Age and extracapsular extension were independent predictors of OS. Conclusions: PSM >4mm and extracapsular extension have a higher risk of PSA and clinical recurrence after RP. These findings can help decision-making regarding adjuvant therapy in patients with PSM and should be reported by pathologists in addition to the presence of PSM. [Table: see text]
Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study.
Authors: Beer Tomasz M. , Armstrong Andrew J. , Sternberg Cora N. , Higano Celestia S. , Iversen Peter , Loriot Yohann , Rathkopf Dana E. , Bhattacharya Suman , Carles Joan , De Bono Johann S. , Evans Christopher P. , Joshua Anthony M. , Kim Choung-Soo , Kimura Go , Mainwaring Paul N. , Mansbach Harry H. , Miller Kurt , Noonberg Sarah B. , Venner Peter M. , Tombal Bertrand 
Published: February 2017

LBA1^ Background: Enzalutamide, an orally administered androgen receptor inhibitor, improved overall survival (OS) in men with mCRPC who had received prior docetaxel therapy (Scher et al, NEJM 367:13, 2012). This study examined whether enzalutamide could prolong OS and radiographic progression-free survival (rPFS) in asymptomatic or mildly symptomatic chemotherapy-naive men with mCRPC. Methods: In this randomized, double-blind, placebo-controlled, multinational phase 3 study (NCT01212991), chemotherapy-naive patients with mCRPC were stratified by site and randomized 1:1 to enzalutamide 160 mg/day or placebo. OS and rPFS were co-primary endpoints and analyzed for the intent-to-treat population. Planned sample size was 1,680 with 765 deaths to achieve 80% power to detect a target OS hazard ratio (HR) of 0.815 with a type I error rate of 0.049 and a single interim analysis at 516 (67%) deaths. The co-primary endpoint of rPFS had sufficient power to detect a target HR of 0.57 and a type I error rate of 0.001 with a minimum of 410 events. Results: A total of 1,717 men were randomized (1,715 treated) between September 2010 and September 2012. The interim analysis at 539 deaths showed a statistically significant benefit of enzalutamide over placebo with a 30% reduction in risk of death (OS: HR 0.70; 95% CI: 0.59-0.83; P< 0.0001) and an 81% reduction in risk of radiographic progression or death (rPFS: HR 0.19; 95% CI: 0.15-0.23; P< 0.0001). At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died. Estimated median OS was 32.4 months (mo) (95% CI, 31.5–upper limit not yet reached [NYR]) in the enzalutamide arm vs 30.2 mo (95% CI, 28–upper limit NYR) in the placebo arm. Median rPFS was NYR (95% CI: 13.8–upper limit NYR) in the enzalutamide arm vs 3.9 mo (95% CI: 3.7-5.4) in the placebo arm. Seizure events were reported in two patients. The Independent Data Monitoring Committee considered the benefit-risk ratio to favor enzalutamide and recommended stopping the study and crossing placebo patients to enzalutamide. Secondary endpoints and safety analysis will be presented. Conclusions: Treatment with enzalutamide significantly improves OS and rPFS in men with chemotherapy-naive mCRPC. Clinical trial information: NCT01212991.
Breast cancer survivorship in urban India.
Authors: Gadgil Pranjali V , Nag Shona Milon , Mane Anupama Dutt , DeSouza Rebecca , Sivaram Rama , Gupta Sudeep 
Published: February 2017

108 Background: With increasing breast cancer burden, there is need for survivorship programs in developing countries. The Indian Breast Cancer Survivors Conference is a unique initiative, to address this need in urban India. A survey of participants at this meet was conducted to aid planning of future events. Methods: Participants filled a 3-page bilingual questionnaire. Data gathered included demographics, education, treatment and side effects, health behaviors, and social impact of diagnosis. Results: Demographic: 205 breast cancer survivors registered from 5 cities. 190 participated in the study. Mean age was 51.5 years (27-79). 61.6 % reported having one or more college degrees and 86.5% were married. Diagnosis and Treatment: Mean age at diagnosis was 47.5 yrs (22-72). Median time from diagnosis was 36 m (3m-19 yrs). Mastectomy was reported as the surgical treatment by 52.1% (6% reconstruction), 72.9 % reported lymph node removal and 10.8% could not specify surgical details. 90% received chemotherapy; 76.8% underwent radiation (97.3% in lumpectomy pts); 61% took endocrine therapy and 5.1 % interrupted it before 5 years. Side Effects:Arthralgia (64%) and anxiety (60.9%) were most frequent self- reported problems followed by surgical site pain (56.1%), depression (53.9%), cognitive deficits (52.2%), skin/ hair/ nail problems (48.2%), hot flashes (48.2%), arm swelling (48.2%) and vaginal dryness (38.2%). Social Impact:Survivors whowere married or in a relationship described their relationship as stronger after diagnosis in 57.8%, unchanged in 37.4% and weaker in 4.7%. Two were married after diagnosis and none reported separation or divorce. Health Behaviors: Regular surveillance visits were reported by 93.3 % (168/180) of participants (65 with their medical oncologist, 50 with surgeon, 23 with both) 5.5% had not seen their oncologist in 2 years. Alternative medical treatment was used by 29.1% (53/182); 26 used Ayurvedic, 13 homeopathic and 14 other. This was discussed with an oncologist by 62.3%. Regular exercise at least 3 times/week was reported by 73.7% and walking (88.8%) or yoga (22.2%) were preferred. Conclusions: The presented data highlights aspects of breast cancer survivorship in urban Indian women that can be used to plan survivorship programs in future.