bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-fraction high-dose-rate (HDR) brachytherapy boost and hypofractionated radiation for intermediate- and high-risk prostate cancer: A report of toxicity from a single center experience.
Authors: Arthur Claire , Alam Nooreen Sarah , Mandall Paula , Swindell Ric , Elliott P. Anthony , Tran Anna , Livsey Jacqueline E. , Choudhury Ananya , Logue John P. , Wylie James 
Published: February 2017

112 Background: Single-fraction HDR brachytherapy offers a highly conformal approach to dose escalation for intermediate and high risk prostate cancer and exploits the apparent low α/β ratio of prostate cancer cells. The potential benefit of improving tumour control must be balanced against the heightened risk of toxicity. We assessed and compared toxicity among patients receiving either 12.5 Gy or 15 Gy as a single fraction HDR boost prior to conformal external beam radiotherapy (EBRT). Methods: Between July 2008 and February 2011, 177 patients received HDR brachytherapy prior to conformal EBRT (37.5 Gy in 15 fractions). 95 patients in the early cohort received 12.5 Gy and 82 patients in the later cohort received 15 Gy. The median patient age at presentation was 67 (range 57 – 77) with a median PSA of 16.0 (range 0.29 – 102), median Gleason score 7 (range 6 – 10), clinical stages T1c to T4 and median baseline IPSS was 8 (range 0 – 27). Prospective patient questionnaires - IPSS, LENT SOMA and EPIC QoL - were completed prior to treatment and at regular intervals following EBRT (6 weeks, 6 monthly thereafter). Results: Both treatment groups had similar median IPSS values at 6 weeks (12.5 Gy = 10, 15 Gy = 11); there was no significant difference in values throughout follow-up. Mean LENT SOMA scores for bladder/urethra toxicity peaked at 6 weeks (12.5 Gy = 0.6, 15 Gy = 0.72) with no trend towards greater reporting of maximum values of ≥ 2 in the 15 Gy cohort. Rectum/bowel mean LENT SOMA scores peaked at 6 weeks (12.5 Gy = 0.30, 15 Gy = 0.39). Although a greater proportion of 15 Gy patients reported a maximum score of ≥ 2 at 6 weeks and 6 months compared with the 12.5 Gy patients, this returned to pre-treatment levels at 12 months. Conclusions: We conclude that dose escalation from 12.5 Gy to 15 Gy delivered in a single HDR fraction is not associated with a clinically significant increase in toxicity. We believe that the reported toxicity is acceptable at this level of dose escalation (2 Gy equivalent = 112 Gy, assuming an α/β ratio of 1.5). Ongoing follow-up is required to ascertain tumour control.
Changes in plasma metabolomic profiles during the first 3 months of androgen-deprivation therapy for prostate cancer.
Authors: Saylor Philip James , Karoly Edward D , Smith Matthew Raymond 
Published: February 2017

116 Background: Androgen-deprivation therapy (ADT) with a GnRH agonist is the foundational systemic therapy for prostate cancer but causes gain of fat mass, loss of muscle mass, adverse changes in serum lipid profile, and a decline in insulin sensitivity. It is unknown whether ADT causes a broader pattern of metabolic alterations. In order to better characterize the metabolic effects of ADT, we measured changes in plasma metabolomic profile during the first 3 months of ADT. Methods: Fasting plasma samples were drawn from 36 subjects at baseline and after 3 months (range: 71-112 days) of GnRH agonist therapy. Metabolomic analyses were performed by Metabolon, Inc (Durham, NC). Extracted samples were split into equal parts for analysis on the gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry platforms. Matched pairs t-test was used to identify biochemicals that differed between baseline and month 3. Results: Of the 504 identified metabolites, 88 changed significantly (p<0.05) from baseline to 3 months. Consistent changes in biochemicals were grouped as follows: (a) Multiple steroids were lower at 3 months, consistent with the effect of therapy on gonadal androgen synthesis. (b) Markers of lipid beta-oxidation (acetyl-carnitines and ketone bodies) and omega-oxidation were lower at 3 months. (c) Two previously-identified biomarkers of insulin resistance (2-hydroxybutyrate and branch chain keto-acid dehydrogenase complex products) were lower at 3 months. (d) Most bile acids and their metabolites were higher during treatment. Cholesterol levels changed very little (1.06 fold change, P = 0.029). Conclusions: Unbiased metabolomic analyses on fasting plasma samples from men receiving GnRH agonist therapy revealed expected, unexpected, and novel results. Steroid levels fell, consistent with the effects of ADT. Biomarkers of lipid metabolism and insulin resistance also fell, unexpected results given that ADT has previously been shown to decrease insulin sensitivity. Finally, we observed evidence of increased levels of bile acids and bile acid metabolites. Further investigation of this novel finding is warranted.
Impact of statin therapy on PSA kinetics during active surveillance of prostate cancer.
Authors: Rogers William , Rothschild Daniel , Bylund Jason R. , Venkatesh Ramakrishna , Demos Jon , Strup Stephen E. , Preston David , Crispen Paul L. 
Published: February 2017

119 Background: Statin therapy has been associated with decreased serum PSA levels in men undergoing prostate cancer screening, lower rate of adverse pathologic features in radical prostatectomy specimens and decreased risk of biochemical recurrence following prostatectomy. Here we evaluate the impact of statin therapy on PSA kinetics during active surveillance of prostate cancer. Methods: A retrospective review of patients diagnosed with prostate cancer at our institution between the years 2000 and 2009 was performed. Patients undergoing at least 12 months of active surveillance were identified. PSA velocity and percentage change in PSA per year were compared between patients receiving and not receiving statin therapy during active surveillance. Subgroup analysis was performed on low risk patients (prebiopsy PSA <10, Gleason score <6, <cT2). Results: We identified 81 patients meeting our inclusion criteria, 43% (35/81) were on statin therapy during active surveillance. Prebiopsy PSA was significantly lower in patients receiving statin therapy (6.0 ng/ml) compared to controls (8.3 ng/ml), p = 0.005. There was no difference in duration of active surveillance, PSA velocity, and percentage change in PSA per year based on statin use in all patients. When evaluating the 41 low risk patients, 54% (22/41) were on statin therapy. Prebiopsy PSA was lower in low risk patients receiving statin therapy (4.9 ng/ml) compared to controls (6.4 ng/ml), p= 0.055. PSA velocity was significantly lower in low risk patients (0.02 ng/ml/year) compared to low risk controls (0.89 ng/ml/year), p=0.024. Percentage change in PSA per year was significantly lower in low risk patients receiving statin therapy (-1.7%/year) compared to low risk controls (11.6%/year), p=0.05. The percentage of low risk patients receiving definitive therapy following a period of active surveillance on statin therapy was 9% (2/22)compared to 26% (5/19) in controls, p = 0.14. Conclusions: PSA kinetics during active surveillance appear to be significantly altered by statin therapy in low risk patients. Further evaluation of the impact of statin therapy on PSA kinetics and clinical outcomes of men undergoing active surveillance for prostate cancer are warranted.
MR spectroscopy compared with DW-MRI and DCE-MRI at 3-tesla for the noninvasive prediction of short-term radiation response for patients with localized prostate cancer.
Authors: Crehange Gilles , Maingon Philippe , Gauthier Mélanie , Cochet Alexandre , Martin Etienne , Mirjolet-Didelot Céline , Cormier Luc , Bonnetain Franck , Vignon Nicolas , Brunotte Francois , Walker Paul M 
Published: February 2017

122 Background: PSA is not appropriate for assessing early radiation response for patients treated with and without hormones for prostate cancer. New biomarkers using multiparametric functional MR could be of value. To investigate the benefits of multiparametric functional MR for predicting radiation response during the first year after radiation therapy in prostate cancer patients. Methods: Between 01/2008 and 04/2010, 34 patients with a localized prostate cancer (T1-T3, N0) were prospectively enrolled in the ERIS trial. All patients underwent high dose IMRT with or without long term adjuvant hormonal therapy and were prospectively followed with MR spectroscopy, diffusion-weighted MRI and dynamic contrast-enhanced MRI at 3-Tesla without endorectal coil every 3 months up to 1 year. Patients were followed with DRE, PSA level every 3 months and with sextant-biopsy at 6 and 12 months following radiation. Choline and Citrate levels on MRS, apparent diffusion coefficient on DW-MRI and the slope of the contrast uptake on DCE-MRI were measured in the central gland and in the peripheral zone every 3 months over 12 months and compared with PSA nadir at 12 months (≤0.5 ng/mL vs. >0.5 ng/mL). Results: Cho, Cit and SCU significantly decreased over time whereas ADC remained stable. For the entire prostate at 3 months, the mean Cho level was higher in patients with PSA level >0.5 ng/mL at 1 year (10.1±3.0 vs. 6.6±2.5, p= 0.004). Similarly, Cit level was higher at 3 months for patients with PSA level > 0.5 ng/mL at 1 year (15.4±7.9 vs. 8.5±9.9, p= 0.0065). Neither ADC value nor contrast enhancement evaluated at each time interval was correlated with PSA at 1 year. Conclusions: Low Cho and Cit levels evaluated at 3 months are new markers for early success in prostate cancer patients treated with exclusive radiation therapy.
Calcium metabolism in patients with castration-resistant prostate cancer: Development of a quantitative urinary assay for extent of bone metastasis.
Authors: Pai Ashok P. , Hillegonds Darren , Lara Primo , Pan Chong-xian , Shelton David 
Published: February 2017

130 Background: In patients with metastatic castration-resistant prostate cancer (CRPC), the degree of perturbation from normal bone turnover provides a strong indication of risk for disease progression, skeletal complications and death. Biomarkers of bone cell function and bone collagen degradation provide an integrated index of the underlying disease for patients with bony metastases, but available bone markers are not precise or accurate. In this study, patients with CRPC with bony metastases will consume a single oral calcium-41 dose and the pharmacokinetics of this will be measured over an 18 month period. Participants will also be assessed clinically for time to progression, skeletal related events and death. Methods: Patients with metastatic castration-resistant prostate cancer and bony metastatses, as diagnosed via bone scintigraphy, who were on bisphosphonates were enrolled into the study. 12 consenting research subjects consumed a single 1.2 microgram 41Ca tracer dose and provided 30-250mL urine specimens (single voids) after dose on day 1 (6h after dosing), days 7, 14, 28, 42, 60, and monthly thereafter. Isotope ratios were measured via accelerator mass spectrometry. Results: Urinary 41Ca/Ca was significantly and inversely associated with increased skeletal tumor burdens suggesting that development of an isotopic urine test for bone metastasis extent is feasible, providing a non-invasive and quantitative measure of disease extent. A calculation of the area under the curve of the measurements between day zero and 14 were inversely correlated with disease extent at baseline. Clinical deterioration with worsening bony disease was associated with a significant decrease in the urinary 41Ca/Ca value. We are currently assessing correlations between bone turnover and outcomes such as therapy effectiveness, disease progression, skeletal related events and death. Conclusions: This work is the first direct measurement of long-term calcium metabolism in advanced prostate cancer, providing a basic scientific complement to cellular and collagen-based measures of bone formation and resorption rates as well as a correlation to clinically relevant outcomes.
Exclusive image-guided IMRT versus radical prostatectomy followed by postoperative IMRT for localized prostate cancer: A matched-pair analysis based on risk groups.
Authors: Azelie Caroline , Gauthier Mélanie , Mirjolet-Didelot Céline , Cormier Luc , Martin Etienne , Peignaux-Casasnovas Karine , Truc Gilles , Maingon Philippe , Crehange Gilles 
Published: February 2017

135 Background: To investigate whether patients treated for a localized prostate cancer require prior radical prostatectomy followed by postoperative radiotherapy or exclusive radiotherapy, in the modern era of image-guided IMRT. Methods: One hundred and seventy-eight patients with localized prostate cancer were referred for daily on-line exclusive image-guided IMRT (IG-IMRT), while 69 patients were referred for postoperative IMRT without image guidance after radical prostatectomy (RP+IMRT). The patients were matched in a 1:1 ratio according to their baseline risk group before any treatment. Late toxicity was scored using the CTV v3.0 scale. Biochemical failure was defined as a postoperative PSA ≥ 0.1 ng/mL followed by 1 consecutive rise in PSA for the postoperative group of patients and by the Phoenix definition (nadir+2 ng/mL) for the group of patients treated with exclusive radiotherapy. Results: A total of 98 patients were matched (49:49). Thirty patients had a low-risk (30.6%), 62 patients an intermediate risk (63.3%) and 6 patients a high risk (6.1%). In the RP+IMRT group, the median PSA value before radiotherapy in the RP+IMRT group was 0.28 ng/mL [undetectable-6.99]. The median radiation dose in the IG-IMRT group was 77.4Gy [73.0-79.8 Gy] whereas it was 66.0 Gy [31.4-70.3 Gy] in the RP+IMRT group. The duration of the hormones was similar in both groups (p= 0.438). From the start of any treatment, the median follow-up was 56.6 months (95% CI = [49.6-61.2], range [18.2-115.1]. No patients had late gastrointestinal grade ≥ 2 toxicity in the IG-IMRT group vs. 4% in the RP+IMRT group. Forty-two percent of the patients in both groups had late grade ≥ 2 genitourinary toxicity. The 5-year freedom from biochemical failure rates in the IG-IMRT group and in the RP+IMRT groups were 93.1% [80.0-97.8] and 76.5% [58.3-87.5], respectively (p= 0.031). Conclusions: Patients with localized prostate cancer treated with IG-IMRT had a better oncological outcome than patients treated with RP+IMRT. Further improvements in postoperative IMRT using image guidance and dose escalation need to be evaluated to determine whether it could eventually be superior to IG-IMRT.
The effect of acute and chronic exposure to acetaldehyde—a mutagenic metabolite of dietary ethanol—on prostate cancer cells: A potential source of race disparity disfavoring black men.
Authors: Banez Lionel Lloyds , Davidson Anthony Kyle , Etienne Wiguins , Allott Emma H , Calloway Elizabeth Ellen , Inman Brant Allen 
Published: February 2017

143 Background: We recently reported that the ADH1B*3 allele, which is specific to African Americans (AA), when combined with ethanol intake may constitute a gene-environment interaction leading to elevated prostate cancer (CaP) and potentially aggressive CaP risk among AA men possibly through intra-prostatic acetaldehyde accumulation. Indeed, studies have shown microsomes from rat ventral prostates biotransform ethanol to acetaldehyde that further metabolizes into oxidative stress-inducing acetyl radicals. In addition, acetaldehyde has been previously shown to enhance proliferation of colon cancer cells. Whether acetaldehyde has the same effect on CaP is unknown. Methods: We subjected DU-145 CaP cells to varying concentrations of acetaldehyde using acute and chronic models of exposure and measured tumor proliferation using MTS assay. Proliferation was measured over 4 days of acetaldehyde treatment in acute and after 2 weeks of treatment in chronic exposure experiments. All experiments were conducted in triplicate. Results were expressed as mean values for each treatment referenced to untreated cells. Doubling times were calculated using least squares fitting exponential regression. Results: In the acute exposure model, proliferation of DU-145 cells was inhibited by 150 uM acetaldehyde by 28% while 1,500uM and higher concentrations resulted in complete inhibition of proliferation. After chronic exposure to acetaldehyde, proliferation of DU-145 cells was inhibited by 500 uM acetaldehyde by 19%. In contrast, chronic exposure with 1,000 uM acetaldehyde resulted in increased proliferation by 9% and shortened tumor doubling time. Conclusions: Acute exposure to acetaldehyde resulted in inhibition of CaP cellular proliferation. Chronic exposure to high acetaldehyde concentrations promoted tumor proliferation likely through selection for more robust CaP cells that survive the repeated chemical insult. Our results suggest that chronic acetaldehyde exposure of existent CaP may potentially promote disease aggressiveness. Uncovering mechanisms for enhanced CaP cell proliferation by acetaldehyde are warranted.
A gene expression signature to predict high-grade prostate cancer response to oxaliplatin.
Authors: Pourquier Philippe , Puyo Stephane , Richaud Pierre , Robert Jacques , Houede Nadine 
Published: February 2017

150 Background: Prostate cancer (PCa) is one of the leading causes of death from cancer in men. High Gleason grade prostate cancers are characterized by aggressive tumors with poorly differentiated cells and a high metastatic potential. They are often refractory to chemical castration but still treated with hormone therapy to which docetaxel or cabazitaxel are added when they become resistant to the anti-androgen. Despite many clinical trials with other chemotherapeutic agents, response rates remain low. Moreover, none of these trials took into account the tumor grade. Methods: We used an in silico approach to screen for drug candidates that could be used as an alternative to taxanes, based on a 86 genes signature which could distinguish between low-grade and high-grade tumors. We extracted from the NCI60 panel databases the expression profiles of the 86 genes across 60 human tumor cell lines and the corresponding in vitro cytotoxicity data of 152 drugs and looked for correlation between their expression level and cell sensitivity to each of these drugs. Results: Among the 86 genes, we identified 9 genes (PCCB, SHMT2, DPM1, RHOT2, RPL13, CD59, EIF4AI, CDKN2C, JUN) for which expression levels across the 60 cell lines was significantly correlated (p< 0.05) to oxaliplatin but not to cisplatin sensitivity. This signature was validated at the functional level since repression of each of these genes conferred a significant change in the sensitivity of PCa cell lines to oxaliplatin but not cisplatin. Conclusions: Our results provide a proof of concept that gene expression signature specific from high grade PCa could be used for the identification of alternative therapies to taxanes. They could also be used to select patients for further clinical trials and as predictive markers of response to these drugs, which represents a further step forward towards personalized therapy of PCa.
The impact of neoadjuvant weekly ixabepilone for high-risk prostate cancer: A phase I/II clinical trial.
Authors: Layton Jodi Lyn , Plette Angela Marie , Renzulli Joseph F. , Miller E. Bradley , Safran Howard , Mega Anthony E. 
Published: February 2017

158 Background: Potential benefits of neoadjuvant chemotherapy are tumor downstaging and treatment of micrometastatic disease. A prior study using docetaxel yielded no pathologic complete responses and concerns for increased operative morbidity. In Phase II studies, ixabepilone has promising activity in metastatic prostate cancer. Our study is a Phase I/II clinical trial evaluating neoadjuvant, weekly ixabepilone in men with high-risk prostate cancer opting for radical prostatectomy. Methods: Men with high risk prostate cancer defined as either Gleason 8-10, cT3 disease, high volume Gleason 4+3 and a palpable nodule or a PSA>20 ng/ml were eligible. Men received weekly ixabepilone 16-20/m2 for 12-16 weeks prior to surgery. Fifteen men underwent robotic prostatectomy; one patient who had an open prostatectomy. Initial PSA response, post-operative PSA values, pathology, and evaluation of adverse events were recorded. Results: We enrolled 16 men with a mean follow-up of 15.25 months at time of review. All had pretreatment Gleason scores of 4+3 or higher. With neoadjuvant treatment, PSA values decreased in 14/16 men (mean 46.8%); increased in 2/16 men. None reached an undetectable pre-operative PSA. Nine men experienced an adverse event requiring dose modification or cessation of chemotherapy (neuropathy or allergic reaction). Only 5/16 men completed planned treatment. Mean operative time, EBL, and hospital stay were 189 minutes, 184mL, and1.5 days, respectively; all consistent with institutional and national norms. Post surgery 15/16 (94%) had pT3 disease, 8/16 (50%) had a positive surgical margin and 2/16 (12.5%) had positive regional lymph nodes. There were no pathologic complete responses. Only 1/16 (6.25%) had a biochemical relapse. Conclusions: While a PSA response is achieved, there is substantial toxicity with neoadjuvant weekly ixabepilone. Men were able to undergo prostatectomy without increased morbidity after neoadjuvant therapy. Extracapsular extension and positive surgical margins remained common in this population with high-risk disease. Assessment of biochemical recurrence rates and time to treatment failure will require longer, planned follow-up.
Impact of 36 months of androgen-deprivation therapy (ADT) on physical function and quality of life (QOL) in men with nonmetastatic prostate cancer.
Authors: Alibhai Shabbir M.H. , Breunis Henriette , Timilshina Narhari , Tomlinson George A. , Duff Canning Sarah , Fleshner Neil Eric , Krahn Murray , Tannock Ian , Warde Padraig Richard , Naglie Gary 
Published: February 2017

16 Background: Use of ADT has been shown to adversely affect physical function and QOL within 3 months of initiation; declines persist at 12 months. Few studies have examined physical function with ongoing ADT use beyond 12 months. Methods: In this extension of our prior study, men age 50 or older with non-metastatic prostate cancer (PC) who were on continuous ADT were followed along with two control groups (PC, no ADT; healthy controls) matched on age, education, and baseline function. Physical function was assessed with the 6-minute walk test (6MWT), grip strength, and the Timed Up and Go (TUG) test, representing endurance, upper extremity strength, and lower extremity strength, respectively. Aggregate physical and mental QOL were measured with the Medical Outcomes Study SF-36. Assessments were done at baseline and at 3, 6, 12, 18, 24, 30, and 36 months. Mixed effects regression models were used, adjusting for age, baseline function, and other covariates. Results: 87 patients on ADT, 86 PC controls, and 86 healthy controls were enrolled (mean age 69.4 y, range 50-87). At baseline, all three groups were similar in age and physical function (all ANOVA p>0.05) and most subjects were otherwise quite healthy. 6MWT distance improved in both control groups but remained unchanged in ADT users (p=0.0379). Grip strength declined sharply in the ADT group by 3 months and remained stable up to 36 months (p<0.001), whereas both control groups were stable over time. There was a slight worsening of TUG scores in the ADT group over 36 months (p=0.0003) but were unchanged in both control groups (p>0.10). Aggregate physical QOL continued to decline in ADT users over time (p=0.0002) but remained stable in both control groups over 36 months, whereas aggregate mental QOL was stable in all groups over time. Most declines were evident within 3-6 months of ADT initiation. Conclusions: Initial declines with continuous ADT use in both physical function and aggregate physical QOL persist for 36 months but generally did not decline further beyond one year despite ongoing ADT use. Early exercise interventions and/or intermittent ADT use may improve these outcomes.