bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of zoledronic acid and biochemical relapse in treatment-naive patients with bone-metastatic prostate cancer.
Authors: Matsuyama Hideyasu , Nozawa Masahiro , Inagaki Takeshi , Nagao Kazuhiro , Hara Isao , Uemura Hirotsugu ,   Kis-BoP Group
Published: February 2017

136 Background: Recent reports suggest that zoledronic acid have anti-proliferative activity, and that bone metabolism markers predict patient outcome in prostate cancer. Aims of this study are if bone metabolism markers may predict patient outcome who are treated with zoledronic acid concomitant with androgen deprivation therapy (ADT), and if zoledronic acid has oncological benefit in patients with metastatic prostate cancer. Methods: A multi-institutional prospective phase II study was conducted for 54 treatment-naïve patients with bone-metastatic prostate cancer who were treated with zoledronic acid concomitant with ADT (ADT-Z group). Median age, baseline PSA of the patients were 72, and 249ng/ml, respectively. Patients were treated with zoledronic acid (4 mg iv every 4 weeks) in combination with bicalutamide (80mg po) and goserelin acetate (10.8mg sc every 3 months), and followed with a median follow-up of 24.6 months. Serum bone metabolism markers, including bone-specific alkaline phosphatase (BAP) and cross-linked C-terminal telopeptides of type I collagen (I-CTP) and urine levels of cross-linked N-terminal telopeptides of type I collagen (NTx), were measured before treatment followed by every 3 months thereafter, and were compared with biochemical relapse (BCR). BCR of those patients was compared with that of 180 patients who were treated with ADT alone (ADT group) as historical control. Results: Baseline NTx (>100), baseline PSA (>225), EOD (>2) were significantly linked with BCR. Baseline NTx (>100) was an independent predictor for BCR in multivariate analysis (p=0.02). Time to BCR was significantly longer in ADT-Z group than that in ADT group (p<0.0001, median TTP: not reached in ADT-Z vs. 15.4 months in ADT). Conclusions: Zoledronic acid may improve patient prognosis, and baseline NTx may be a useful predictor for BCR in treatment-naïve metastatic prostate cancer patients with zoledronic acid combined with ADT.
Diet, supplements, and lifestyle factors and risk of progression in contemporary active surveillance patients.
Authors: Trock Bruce J. , Feng Zhaoyong , Landis Patricia , Carter Ballentine 
Published: February 2017

138 Background: Men diagnosed with prostate cancer frequently change their diet or lifestyle in an effort to decrease their risk of developing aggressive disease. Men managed with active surveillance (AS) may feel a greater need to modify risk factors because their cancer is untreated. However, no data on post-diagnosis diet and lifestyle factors from large prospective cohorts with long-term follow-up have been reported. We evaluated the influence of diet and lifestyle on the risk of prostate cancer biopsy progression in the largest prospective AS cohort in the US. Methods: Diet and lifestyle questionnaire completed by AS participants at enrollment. Progression determined by occurrence of Gleason score>7 or increase in tumor volume at annual surveillance biopsy. Analysis focused on 28 nutrients, 10 food groups, 9 supplements, 7 medication variables, and 2 lifestyle variables with a priori hypotheses. Data were analyzed by Wilcoxen test and logistic regression, with calorie adjustment by the residual method. Results: There were 723 men in the analysis, of whom 187 (26%) progressed. Median follow-up was 2.7 years. Men who progressed were significantly older, had higher PSA density, and higher biopsy tumor burden at diagnosis. In multivariable analyses, men who progressed had higher PSA density (OR=1.34 per 0.1 ng/ml/cc, p=0.017), were more likely to have >1 positive biopsy core (OR=2.9, p<0.0001), had higher percentage core involved with tumor (OR=1.04, p<0.0001), and were more likely to be current smokers (OR=4.1, p=0.004); duration of NSAID use and history of prostatitis approached significance. Conclusions: Cigarette smoking was significantly associated with risk of progression. This association must be viewed with caution due to the large number of variables tested. It is likely that many men considered to have progressed represent undersampling of the initial biopsy, rather than true biologic progression; this misclassification may obscure risk relationships. Ongoing analyses will be presented that explore whether associations differ for early vs late progression events. We believe this is the first report that smoking is associated with progression in men managed by AS.
Effect of thalidomide on the TGFβ-1-mediated synthesis of testosterone from DHEA in prostate cancer.
Authors: Sissung Tristan , Kirkland C. Tyler , Reece Kelie M , Arnold Julia T , Figg William Douglas 
Published: February 2017

141 Background: TGFβ-1 induces conversion of DHEA to testosterone in prostate cancer stromal cells. We hypothesized that thalidomide would inhibit TGFβ-1-mediated formation of testosterone from DHEA. Methods: We grew LAPC4 or LNCaP prostate cancer epithelial cells and 6S primary prostate stromal cells in mono-/co-culture with DHEA (100nM) and/or TGFβ-1 (40 or 100pM). Testosterone and PSA concentration in media were ascertained using ELISA and corrected for cell count using CCK8 (%DHEA controls). Results: TGFβ-1 and DHEA induced a dose-dependent increase in the formation of testosterone over controls (∼5-6 fold; P<0.0001). Thalidomide (100μM) inhibited the formation of testosterone in cocultured cells treated with DHEA and TGFβ-1 (40pM) by 35% (P=0.0008). The thalidomide analogues, CPS49 (10μM) and lenalidomide (10μM) also had activity; CPS49 inhibited testosterone synthesis by 54% (P=0.010) while lenalidomide reduced testosterone by 15% (P=0.011). However, only thalidomide and CPS49 decreased median PSA secretion (40% and 93% respectively; P≤0.031). Other angiogenesis inhibitors (i.e., suramin (10μM) and sorafenib (500pM)) had no effect on testosterone synthesis (P>0.05). Therefore, anti-androgen activity was not a class effect of antiangiogenesis agents. Ketoconazole also did not have activity suggesting that TGFβ-1-induced testosterone synthesis from DHEA evades standard therapies designed to inhibit androgen synthesis enzymes (i.e. CYP3A4 and CYP17 inhibitors). We assessed the phosphorylation status of TGFβ-1 pathway constituents (i.e., SMAD2/3, p38, JNK, and ERK) in cocultured cells treated as above. Thalidomide inhibits the phosphorylation of ERK without affecting total ERK levels; however, neither MEK inhibition (via U0126) nor Raf inhibition (via sorafenib) resulted in anti-androgenic effects in these cells suggesting that the canonical RAF/MEK/ERK pathway is not responsible for the difference in testosterone secretion phenotype. Conclusions: These results indicate that thalidomide and its analogues have anti-androgen activity and may explain the success of thalidomide and its analogues in clinical treatment of hormone-dependent and castration-resistant prostate cancer.
An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study.
Authors: Nabhan Chadi , Gomella Leonard G. , DeVries Todd , Whitmore James Boyd , Frohlich Mark Walter , George Daniel J. 
Published: February 2017

144 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Our previous analyses on the effect of salvage crossover treatment with a product constructed from previously frozen cells (APC8015F) on OS in the control arms of mCRPC studies of sipuleucel-T suggested a positive treatment effect with salvage therapy (George DJ et al. JCO 2011;29:abstr 139). To quantify how treatment with APC8015F might have impacted the OS of the IMPACT study, we performed an exploratory analysis adjusting for the potential bias that salvage APC8015F might have had in estimating the OS advantage of sipuleucel-T. Methods: After objective disease progression, patients (pts) in the control arm were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. A rank-preserving structural failure time (RPSFT) model, as previously described, was applied to adjust the sipuleucel-T treatment effect. Results: In the 512-pt IMPACT study, there was a 4.1-month median improvement in OS (25.8 vs 21.7 months) for sipuleucel-T compared to control (HR=0.78; 95% CI: 0.61, 0.98; p=0.032). 109/171 (64%) of control pts received APC8015F; other post-progression interventions were balanced. Median OS was 23.8 months for control pts receiving APC8015F and 11.6 months for control pts not receiving APC8015F. Using the RPSFT model, and assuming APC8015F was equally as effective as sipuleucel-T, the estimate of median OS for control was 18.0 months (HR=0.60, 95% CI: 0.41, 0.95), representing a 7.8-month median improvement in OS in favor of sipuleucel-T. Results from extensions of the RPFST model, where APC8015F is assumed to have less treatment effect than sipuleucel-T, will be presented. Conclusions: Adjusting for a positive effect of APC8015F in the control arm resulted in a sipuleucel-T OS treatment benefit in the IMPACT study ranging from 4.1 to 7.8 months. These results support a greater treatment effect of sipuleucel-T than reported in the IMPACT study and should be factored into future studies without APC8015F crossover.
Early detection of high-grade prostate cancer using digital rectal examination in men with a normal PSA and risk of death.
Authors: Hattangadi Jona Ashok , Chen Ming-Hui , Sun Leon , D'Amico Anthony Victor 
Published: February 2017

147 Background: A digital rectal examination (DRE) is less commonly practiced in the PSA screening era. Whether detection of high-grade prostate cancer (PC) while still clinically localized on DRE can improve survival in men with a normal PSA is unknown. Methods: From the Surveillance, Epidemiology and End Results database, 166,498 men with PC diagnosed between 2004-2008 were identified. Logistic regression was used to identify factors associated with the occurrence of palpable, PSA-occult (PSA <2.5 ng/ml) and Gleason score (GS) 8-10 PC. Factors examined included age at and year of diagnosis and race. Fine and Grays and Cox multivariable regression were performed to analyze whether these factors, treatment and known prognostic factors were associated with the risk of PC-specific mortality (PCSM) and all-cause mortality (ACM), respectively. Results: Of 166,498, 685 men (0.4%) had palpable, PSA-occult and GS 8 to 10 PC. Median age and PSA at diagnosis in this group were 68 years [IQR: 61-75] and 1.5 ng/ml [IQR: 1-2], respectively. Most (83%) men were white. Both increasing age (adjusted odds ratio (AOR): 1.02 [95% confidence interval (CI) 1.01-1.03]; p<0.0001) and white race (AOR: 1.26 [95% CI 1.03-1.54]; p =0.03) were associated with palpable, Gleason 8 to 10 PC with normal PSA. Significant factors associated with an increased risk of PCSM and ACM in this cohort are shown in the table. For these 685 men, detecting locally advanced as compared to localized PC on DRE was associated with a significantly lower survival (p = 0.0001). Conclusions: Detecting PSA-occult high-grade PC with DRE while disease remains clinically localized amongst high-risk men (over age 68 and white race) has the potential to improve survival. [Table: see text]
Prospective determination of long-term toxicity and quality of life (QoL) of patients with prostate cancer after intensity-modulated radiotherapy (IMRT).
Authors: Goineau Aurore , Marchand Virginie , Bourdin Sylvain , Rio Emmanuel , Campion Loic , Lisbona Albert , Mahe Marc-Andre , Supiot Stephane 
Published: February 2017

151 Background: To determine prospectively long-term toxicity and quality of life (QoL) of prostate cancer patients after intensity-modulated radiotherapy (IMRT). Methods: 55 patients with localized prostate adenocarcinoma were treated by IMRT (76 Gy) between February and November 2006. Physicians scored acute and late toxicity using the Common Terminology Criteria for Adverse Events version 3.0. Patients assessed general and prostate-specific QoL before IMRT (baseline) and at 2, 18 and 54 months using European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-PR25. Results: Median age was 73 years (range 54-80 years). Risk categories were 18% low risk, 60% intermediate risk, and 32% high risk. The incidence of urinary and bowel toxicity immediately after IMRT (n=55) was, respectively, 36.8% and 23.7% (grade 1), 5.3% and 5.3% (grade 2), 2.6% and none (grade 3). At 18 months (n=55), it was 23.7% and 10.3% (grade 1), 26.3% and 13.2% (grade 2) and none and 2.6% (grade 3). At 54 months (n=38), it was, 34.2 and 23.7% (grade 1), 5.3% and 15.8% (grade 2) and 5.3% and none (grade 3). After 54 months, there was a statistically significant worsening of QoL with regards to 11 items among the 19 studied. However, the scores were clinically relevant (decrease > 10 points) only for physical functioning, role functioning, social functioning, fatigue, pain, dyspnea and constipation. No statistical differences were shown between 54 months and baseline for general health, bowel symptom, treatment related symptoms and sexual activity. Concerning urinary symptoms, there was a statistically significant deterioration but not clinically relevant (difference < 10 points). Conclusions: High-dose IMRT to the prostate with accurate positioning does not induce any clinically relevant deterioration in long-term urinary and gastrointestinal QoL. Deterioration in functioning items may also be related to age and comorbidities. To our knowledge, our study is the only prospective study regarding quality of life following prostate IMRT with a very long follow-up of 54 months.
Palliative radiotherapy for prostate cancer: Outcomes of a weekly schedule of 6 fractions of 5 or 6Gy.
Authors: Tolan Shaun P. , Mbanu Peter , Walshaw Richard C. , Robson Peter , Eswarvee Chinnamani , Ibrahim Azman , Malik Zafar , Littler John , Syndikus Isabel 
Published: February 2017

160 Background: In the current era of PSA screening and advances in image guided intensity modulated radiotherapy, not all patients with carcinoma of the prostate (CaP) are suitable for radical radiotherapy (RT). Some patients have locally advanced disease and are unfit for radical RT or have significant local symptoms with coexisting metastatic disease. The outcomes of a weekly palliative RT schedule of 6 x 5 or 6Gy fractions are reported. Methods: This retrospective analysis identified 80 patients with CaP who received palliative prostate RT between 2003 and 2007. 62 patients received six, weekly fractions of 3D conformal RT and are included in this study. Clinico-pathological data of the cases are presented along with the clinical outcomes and survival data. Median follow up was 16.5 months. Results: 62 patients (median age 70 yrs), received 30Gy (87%) or 36Gy (10%) in 6 fractions over 6 weeks. Two patients received 27Gy. Gleason score at diagnosis was ≤6, 7, or 8–10 in 21%, 16% and 45% of cases respectively and was associated with a median PSA of 53ng/ml, and T3/4 stage in 59%. The median time from diagnosis to RT was 15.9 months and prior to RT, treatment included hormone therapy (100%), TURP (60%) and chemotherapy (13%). Disease was metastatic in 68% and castrate resistant in 77% of cases. ECOG performance status was 0–1 in 44% and 2–3 in 24%. No patients with PS 4 were treated over 6 weeks. Indications for RT were obstructive urinary symptoms (69%), pain (44%), haematuria (35%), obstructive bowel symptoms (23%), and rectal bleeding (2%). At 3–6 months post-RT the frequency of these symptoms was 27%, 13%, 4%, 17% and 2% respectively. RTOG grade 3 or 4 bladder toxicity was 18% and grade 3 or 4 bowel toxicity was 6%. Median overall survival after RT was 16.0 months and on multivariate analysis lower pre-RT PSA and prior use of chemotherapy were predictive of improved survival. Conclusions: A weekly fractionation schedule of 5 or 6Gy over 6 weeks provides effective palliation, particularly for the symptoms of urinary obstruction, pain and haematuria, and is associated with acceptable toxicity. The prognosis of this group of patients remains poor, but can be improved by the use of chemotherapy if clinically appropriate.
A phase II study evaluating the toxicity and efficacy of single-agent temsorilmus (TEM) in chemotherapy-naive castration-resistant prostate cancer (CRPC): First report of suggested activity.
Authors: Nabhan Chadi , Kruczek Kimberly , Tolzien Kathy , Galvez Angel G. , Lestingi Timothy M. 
Published: February 2017

165 Background: PTEN tumor suppressor gene is mutated in CRPC allowing for downstream protein activation including mammalian target of rapamycin (m TOR) leading to tumor cell growth and survival. We investigated TEM; an mTOR inhibitor, in chemotherapy-naïve CRPC patients (pts). Methods: Eligible pts received TEM at 25 mg weekly until disease progression. Responses were assessed every 8 weeks and toxicity every 4 weeks using CTCAE v.3. Quality of life (QOL) data were collected every cycle using two previously validated scales. Primary end point: Clinical Benefit (CB) [sum of complete response (CR), partial response (PR), and stable disease (SD)]. Secondary end points: Toxicity, time to next treatment (TTNT), time to radiographic and PSA progression (TTP and TTP-PSA respectively), impact on QOL, and overall survival (OS) Results: To date, 18 pts have been enrolled. Median age was 75 (57–89) with Gleason ≥7 in 14 (77%), and median PSA 211.3 (10.8-1,449). Ten pts (55.5%) had bone and visceral disease. Median time on androgen deprivation therapy (ADT) was 60 months (17–240). Previous therapy included: surgery 3, brachytherapy 3, external radiation 5, ADT 7. All pts were evaluable for toxicity and 16 for response. Six pts (33%) were taken off study without progression (2 withdrew, 3 persitsant thrombocytopenia, 1 non-compliance). Biochemical response data was available for 15 pts (2 not evaluable, 1 refused), of which 4 (26%) had PSA decline and 1 (6%) had >50% drop in PSA. TTP-PSA was 2 months (2-12). Sixteen pts were evaluable by RECIST; 2 PR and 9 SD for a CB of 69% (11 of 16). TTP or event (toxicity that took pts off study was an event) was 3 months (3–10) and TTNT was 4 months (2–11). With a median follow up of 18 months, 8 pts (44%) remain alive for a median OS of 13 months. Most commonly reported grade 3/4 toxicities: Thrombocytopenia (22%), hyperglycemia, hypophosphatemia, and fatigue (17% each), pneumonia and anemia (12% each). TEM did not impact QOL adversely without treatment-related mortality. Conclusions: TEM has activity in CRPC; some pts have CB without adverse impact on QOL. TEM should be further investigated in combination therapy in CRPC.
Metabolomics and histology on exactly the same ex vivo prostate biopsy.
Authors: Troyer Dean A , Shuster Jeffrey R , Lance Raymond S. 
Published: February 2017

166 Background: Histopathology is the standard method for diagnosis and histological grading and staging of cancer. Molecular biomarkers are associated with cancer aggressiveness. One drawback to some molecular studies is that the portion of the tissue to be analyzed is processed in a manner that is destructive to the tissue. We present here a new method for performing analysis of small molecule biomarkers and histology in exactly the same biopsy tissue. The process, molecular Preservation by Extraction and Fixation (mPREF), allows traditional histological examination to be combined with qualitative and quantitative analysis of small molecule biomarkers. Methods: 18 gauge core biopsies were obtained ex vivo from prostatectomy specimens. One core biopsy/specimen container was immersed in aqueous alcohol. After 12-24 hrs, biopsies were transferred to UMFIX, and the original alcohol retained. Histologic sections of biopsies were stained by routine methods and the immunohistochemical (IHC) stain, PIN4. Small molecular weight molecules in the retained alcohol were examined by a mass spectrometry-based method. Results: Light Microscopy: Tumor and grade were evaluable and IHC for PIN4 performed well. Metabolomics of Retained Alcohol: From a single core biopsy, 260 named biochemical compounds and their relative concentrations WERE detected. 83 were different between the cancer and non-cancer biopsy extracts (p< .05). 18 of the 20 common amino acids, and a number of long chain fatty acids and phospholipids were increased. Highest fold changes, 4- to 6-fold, were observed in cysteine, dihomo-linoleate, docosapentaenoate, N-acetylaspartate, N-acetylglucosamine, uracil, xanthine, and 1-stearoylglycerophosphoinositol. A sub-set of candidate biomarkers were differentially expressed in pT3 vs pT2 disease. Conclusions: MPREF allows for both histology and detection of small molecules in exactly the same tissue. The results suggest a higher metabolic state in cancer as compared with non-cancer containing biopsy tissues. Differential expression of small molecules from pT2 vs pT3 disease suggests that quantitative prognostic molecular and histologic data can be obtained from a single core biopsy.
Patterns of second-line chemotherapy for metastatic prostate cancer in the United States.
Authors: Wang Hongwei , Liao Laura , Obi-Tabot Eliot , Sands Robert , Rose Mathieu , Zhang Quanwu 
Published: February 2017

169 Background: Patients with prostate cancer progressing from 1st line (1L) docetaxel had limited treatment options available. This study is to evaluate patterns of 2nd line (2L) chemotherapy in US managed care between 2004 and 2010. Methods: Patients with metastatic prostate cancer (mPC) and treated with docetaxel as 1L chemotherapy after July 1, 2004 were ascertained from the OptumInsight database. We evaluated type and timing of chemotherapy and relationships between patient characteristics, physician specialty, healthcare costs and geographic region 6 months prior to 1L docetaxel and choice of 2L chemotherapy. Results: Patients (n=1,173) were on average 71 years old at the onset of 1L docetaxel. During a mean follow-up period of 18 months, 38% patients received 2L treatment. Out of the patients received 2L therapy, 32% received mitoxantrone (MITO), 24% with docetaxel rechallenge (RECH), 14% carboplatin (CARB), and 12% paclitaxel (PAC), plus 11% on combo therapy. An examination of the 2L treatment groups showed that during the 6 months prior to 1L docetaxel, the RECH group (n=101) was older (73yrs), had fewer hospital admissions (12%), lower comorbidity burden (Charlson Comorbidity Index (CCI)=7.4), lower total healthcare costs ($10,083), and 78% patients seeing an oncologist; relative to MITO group (n=143) with 70 years of age, 16% hospital admissions, CCI of 7.5, total healthcare costs of $12,074, and 80% seeing an oncologist. The combo group (n=52) was 66 years old, with 19% hospital admissions, CCI of 8, total healthcare costs of $20, 505, and 92% seeing an oncologist. Median time to MITO from the start of 1L docetaxel was 184 days, 309 days to RECH and 223 days to combo therapy. Midwest (36%) and West (37%) were more frequently using MITO than Northeast (26%) and South (31%), while RECH was more frequently used in Northeast. Conclusions: Patients with mPC in US were most frequently treated with MITO or RECH as 2L chemotherapy after 1L docetaxel. MITO was also given sooner than RECH, hence a valid comparator for comparative effectiveness evaluation on new 2L therapy. Rechallenge with docetaxel increased with time and was given to patients with lower disease burden and healthcare costs than the MITO or Combo group.