bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein BIII-tubulin expression as a prognostic and/or predictive factor of response to docetaxel in patients with hormone-refractory prostate cancer.
Authors: Perez Quionia , Alvarez Carlos , Ruiz Lucrecia , Gutierrez Eduardo , Rodriguez David , Villanueva Noemi , Berros Jose Pablo , Fonseca Paula J. , Vieitez Jose Maria , Esteban Emilio 
Published: February 2017

84 Background: Docetaxel is a standard treatment for hormone-refractory prostate cancer. Preclinical-clinical studies suggest that the determination of the BIII-tubulin is associated with response to taxanes. This study analyzes the role of that subunit of microtubules in prostate biopsies of patients with HRPC treated with docetaxel. Methods: Thirty two patients with prostate biopsy who received docetaxel in first-line chemotherapy between 2006 and 2011 were included in this retrospective cohort analysis. The clinic-pathological characteristics, PSA response, progression-free survival (PFS) and overall survival (OS) were collected. The findings were correlated with the overexpression of BIII-tubulin protein measured by immunohistochemistry techniques (IHC) with a purified and monoclonal Ac mouse. Results: The median age and Karnofstky index (KI) were 68 years (range 49-77) and 80% (60-90) respectively. Five patients (15.6%) had received only one anti-hormone treatment, fifteen (46.8), two and twelve (37.5) more than two lines. Twenty patients (62.5) had only one metastatic localization. The median of PSA value before the docetaxel treatment was 302 (4-3745). With a median of eight cycles (3-10) of docetaxel (75mg/m2/ /3s) 41% of patients achieved biochemical response with a median PFS and OS of 4.9 and 19.6 months respectively. Moderate-intense overexpression of BIII-tubulin was identified in five patients (15.6) and minimal or absent in 27 (84.4). In univariate analysis, over-expression was correlated with KI, but not with Gleason score. PSA responses to docetaxel was observed in four patients (80%) with over-expression compared with 20% of those with minimal or absent BIII-tubulin staining. The median PFS and OS for patients with over-expression was 8.6 and 20 months respectively compared to 4.3 and 17 months for those with minimal or absent BIII-tubulin. Conclusions: Over-expression of BIII-tubulin in tumor prostate tissue, applying the present technique is unusual. Its presence appears to be related with higher biochemical response to docetaxel and improvement in PFS and OS. These findings are discordant with those previously published.
Skeletal events unrelated to bone metastasis in men with castration-refractory prostate cancer.
Authors: Kamoi Kazumi , Okihara Koji , Takaha Natsuki , Iwata Tsuyoshi , Kawauchi Akihiro , Miki Tsuneharu 
Published: February 2017

85 Background: The purpose of this study was to analyze skeletal events unrelated to bone metastasis in men with castration-refractory prostate cancer (CRPC). Methods: A total of 68 patients with CRPC treated by secondary hormonal therapy (dexamethasone) and/or chemotherapy including docetaxel were analyzed. Primary endpoint was skeletal related events (SREs) after PSA relapse. PSA relapse was defined as 3 consecutive PSA increase and serum PSA more than 4 ng/ml. Zoledronic acid was given for 31 patients with radiographic bone progression from the initiation of docetaxel-based treatment. For 37 patients without radiographic bone progression, no bone targeted agents or radioisotopes were administered during the observation period. Results: During median observation period of 17.5 months (range 1 to 76 months), SREs were observed in 17 of 68 patients (25%). In patients with bone progression, SREs was observed in 8 of 37 (22%) patients, whereas 9 of 31 (29%) patients without radiographic bone progression experienced SREs unrelated to bone metastasis. All patients without radiographic progression had been treated by oral steroids (dexamethasone), which might be related to osteoporotic change in these cases. Conclusions: For CRPC patients without radiographic bone progression, caution needs to be paid for SRE unrelated to bone metastasis. The administration of steroids may cause osteoporotic change, thus preventive administration of anti-osteoporotic agents would be mandatory.
Dose to the muscles of fecal continence during radiation therapy for prostate cancer.
Authors: Waggoner Adam , Brown Michael , Tinnel Brent , Halligan John B , Brand Timothy , Brooks Joseph P , Ninneman Stephanie , Hughs Grant , Macdonald Dusten 
Published: February 2017

86 Background: Radiation therapy for prostate cancer can lead to loss of fecal continence; our understanding of the dose-volume relationships of this late toxicity continues to develop. The external anal sphincter (EAS), internal anal sphincter (IAS), and the three parts of the levator ani muscle, the puborectalis (PRM), the pubococcygeus (PCM), and the illiococcygeus (ICM), all contribute to fecal continence. We developed a reproducible method for contouring these muscles and in this preliminary study evaluate whether decreased planning target volume (PTV) margins lead to potentially clinically significant decreases in dose to these muscles during definitive radiation therapy for prostate cancer. Methods: Muscles involved in fecal continence were contoured for 10 consecutive patients on a prospective study of reduced PTV margins for treating low-to-intermediate risk prostate cancer with intensity-modulated radiation therapy (IMRT) using an electromagnetic localization system. IMRT plans to a prescribed dose of 7740 cGy were developed using 10mm PTV margins (5mm posteriorly), and compared with actual treatment IMRT plans using 3mm circumferential PTV margins. Decreases in dose were evaluated for statistical significance using an unpaired t-test. Results: Reducing PTV margins decreased the mean PTV volume from 176.2 ml to 91.9 ml. Mean doses to the EAS, IAS, and rectum (REC) decreased significantly; from 11.0 Gy to 4.1 Gy (p=0.005), from 30.5 Gy to 15.0 Gy (p = 0.004), and from 43.7 Gy to 35.6 Gy (p=0.006) respectively. Decrease in the mean dose to the PRM was nearly statistically significant, 48.7 Gy to 34.6 Gy (p = 0.055). Decreases in mean doses to the PCM and ICM were not statistically significant; from 61.9 Gy to 55.2 Gy (p = 0.107), and from 40.7 Gy to 34.8 Gy (p = 0.176), respectively. Conclusions: Using electromagnetic tracking to reduce PTV margins leads to a significant decrease in dose to the muscles of fecal continence, with mean dose decreases in a range that may be clinically significant.
Neoadjuvant hormone therapy for radical prostate radiotherapy: A case-matched study comparing bicalutamide to LHRH agonist therapy.
Authors: O'Hare Jolyne , McGivern Ursula , McDowell Cliona , Mitchell Darren M. , Corey Gemma , O'Sullivan Joe M. 
Published: February 2017

88 Background: To assess and compare the biochemical failure free survival (BFFS), PSA kinetics and absolute PSA responses in men receiving radical radiotherapy for localized prostate cancer (RT) receiving either neoadjuvant bicalutamide or neoadjuvant LHRH agonist therapy. Methods: A retrospective review of consecutive cases with prostate cancer treated with BC monotherapy prior to radical radiotherapy was individually case matched to men treated with neoadjuvant LHRHa monotherapy from April 2004 to December 2008. PSA kinetics and absolute pre-RT, post neo-adjuvant hormone PSA (PRPH-PSA) level and subsequent BFFS were analyzed. Results: 65 men treated with BC monotherapy were individually matched with 65 men treated with LHRHa. The median follow-up was 44 months and 54 months respectively. There were no significant differences in pre-treatment patient or tumour characteristics. Statistically significant differences were noted between groups in the PRPH-PSA with a geometric mean of 2.0ng/ml (range 0.1 – 11.2ng/ml) for BC patients and 1.0ng/ml (range 0.1 – 11.1ng/ml) for LHRHa patients (p<0.001). The geometric mean PSA halving time during the neo-adjuvant period of 14.6weeks (range 2 – 160weeks) in the BC treated group was statistically significantly different when compared to the mean of 16.1 weeks (range 2.1-96.8 weeks) for LHRHa patients (p=0.056). There were however no differences in PSA velocity. A PRPH-PSA of <1.0ng/ml and <0.1ng/ml was seen in 16(24.6%) and 2 (3%) of the BC patients and 34(52.3%) and 3(4.6%) of LHRHa patients respectively. Phoenix biochemical failure was seen in 10(15.4%, 95%CI [8.6%, 26.1%]) and 8(12.3%, [6.4%, 22.5%) of BC and LHRHa patients respectively. Neither PRPH-PSA level nor PSA kinetics during the neo-adjuvant period predict for subsequent BFFS at this duration of follow-up. Conclusions: In this case-matched study, we found that although neo-adjuvant BC therapy did not result in equivalent PRPH-PSA suppression when compared to neo-adjuvant LHRHa alone, there was no difference in biochemical failure rates between the cohorts at an overall median follow-up of 44 months. Longer follow-up is required.
Predictive factors for acute and late urinary toxicities after permanent prostate brachytherapy.
Authors: Tanimoto Ryuta , Bekku Kensuke , Kobayashi Yasuyuki , Ebara Shin , Araki Motoo , Katayama Norihisa , Nasu Yasutomo , Kumon Hiromi 
Published: February 2017

90 Background: To describe the frequency of acute and late Radiation Therapy Oncology Group (RTOG) urinary toxicity associated with predictive factors and International Prostate Symptom Score (IPSS) in consecutive prostate brachytherapy patients. Methods: From January 2004 to April 2011, 466 patients underwent permanent 125I-seed brachytherapy (median follow-up, 48 months). The IPSS and RTOG toxicity data were prospectively collected. The prostate volume, IPSS before and after brachytherapy and postimplant analysis were examined for an association with urinary toxicity which was defined as urinary RTOG toxicity 1 or more. Logistic regression analysis was used to examine the factors associated with urinary toxicities. Results: The rate of RTOG urinary toxicity Grade 1 or more at 1, 6, 12, 24, 36, 48 months was 67%, 40%, 21%, 31%, 27%, 28%, respectively. Grade 2 or more urinary toxicities were less than 1% at an each point. IPSS was highest at 3 months and returned to normal level at 12 months after brachytherpapy. On univariate analysis, patients with larger prostate size, greater baseline IPSS, the higher post V100 (volume of the prostate covered by 100% of the dose), higher post V150 and higher post D90 (dose that 90% of the target volume received) had more acute urinary toxicities 1 month as well as 12 months after brachytherapy. On multivariate analysis, the significant predictors for urinary toxicities were a greater baseline IPSS and post V100 one month as well as 12 months after brachytherapy (shown below). Conclusions: Most urinary symptoms were tolerated and resolved within 12 months after prostate brachytherapy. Acute and late urinary toxicities after brachytherapy were strongly related with baseline IPSS and the post V100.
Safety, efficacy, and pharmacodynamics of the investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase I/II study.
Authors: Agus David B. , Stadler Walter Michael , Shevrin Daniel H. , Hart Lowell , MacVicar Gary R. , Hamid Omid , Hainsworth John D. , Gross Mitchell E. , Wang Jingyuan , Webb Iain James , MacLean David , Dreicer Robert 
Published: February 2017

98 Background: The investigational agent orteronel (TAK-700) is a selective 17,20 lyase inhibitor that down regulates androgenic steroid production in vitro and in vivo. Since phase 1 data in patients (pts) with mCRPC were promising, this open-label, multicenter study was expanded to gather additional data on safety and antitumor activity. Methods: The phase 2 portion of this study included four additional dose cohorts. Pts had no prior chemotherapy, and had baseline testosterone <50 ng/dL and prostate-specific antigen (PSA) ≥5 ng/mL. Results: 97 pts received orteronel 300 mg BID (n=23), 400 mg BID + prednisone 5 mg BID (n=24), 600 mg BID + prednisone (n=26), or 600 mg QD (n=24). At data cut-off (23 May 2011), 62% of pts had withdrawn (including 19% due to AEs and 19% for disease progression [PD]). Most common AEs were fatigue (76%), nausea (47%), and constipation (38%); most common grade ≥3 AEs were fatigue (12%) and hypokalaemia (8%). PSA response rates (≥50% decrease) at 12 wks were 63%, 50%, 41%, and 60% in the 300 mg BID, 400 and 600 mg BID + prednisone, and 600 mg QD groups. Of 51 RECIST-evaluable pts, 10 had partial responses (of which 5 confirmed), 22 stable disease, and 15 PD. At 12 wks, median testosterone decreased from baseline in all groups: (ng/dL, 12 wks/baseline) 0.98/8.50 (300 mg BID), 0.30/9.90 (400 mg BID +prednisone), 0.07/7.33 (600 mg BID + prednisone), 0.49/6.31 (600 mg QD). Similarly, at 12 wks, median dehydroepiandrosterone sulfate (DHEA-S) decreased from baseline in all groups: (µg/dL, 12 wks/baseline) 8.65/53.0 (300 mg BID), 0.10/36.3 (400 mg BID + prednisone), 0.10/51.7 (600 mg BID + prednisone), 5.30/31.5 (600 mg QD). Overall, mean circulating tumor cell numbers decreased from 16.6 (per 7.5mL blood) at baseline to 3.9 at 12 wks. Conclusions: Orteronel ≥300 mg BID appears active and well tolerated in pts with mCRPC, with similar efficacy ± prednisone. PSA response rates suggest that testosterone, rather than DHEA, may be a more reliable marker of lyase inhibition efficacy. Preclinical data and changes in pharmacodynamic parameters in this study suggest partially selective 17,20 lyase inhibition. Final data will be reported.
Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma
Authors: Weber Jeffrey S. , Hodi F. Stephen , Wolchok Jedd D. , Topalian Suzanne L. , Schadendorf Dirk , Larkin James , Sznol Mario , Long Georgina V. , Li Hewei , Waxman Ian M. , Jiang Joel , Robert Caroline 
Published: February 2017

Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit.
Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia
Authors: Sopper Sieghart , Mustjoki Satu , White Deborah , Hughes Timothy , Valent Peter , Burchert Andreas , Gjertsen Bjørn T. , Gastl Günther , Baldauf Matthias , Trajanoski Zlatko , Giles Frank , Hochhaus Andreas , Ernst Thomas , Schenk Thomas , Janssen Jeroen J.W.M. , Ossenkoppele Gert J. , Porkka Kimmo , Wolf Dominik 
Published: February 2017

Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry–based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α–converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.
Impact of Extent of Resection on Local Control and Survival in Patients From the COG A3973 Study With High-Risk Neuroblastoma
Authors: von Allmen Daniel , Davidoff Andrew M. , London Wendy B. , Van Ryn Collin , Haas-Kogan Daphne A. , Kreissman Susan G. , Khanna Geetika , Rosen Nancy , Park Julie R. , La Quaglia Michael P. 
Published: February 2017

Purpose This analysis of patients in the Children’s Oncology Group A3973 study evaluated the impact of extent of primary tumor resection on local progression and survival and assessed concordance between clinical and central imaging review–based assessments of resection extent. Patients and Methods The analytic cohort (n = 220) included patients who had both central surgery review and resection of the primary tumor site. For this analysis, resection categories of < 90% and ≥ 90% were used, with data on resection extent derived from operating surgeons’ assessments (all patients), as well as blinded central imaging review of computed tomography scans for a subset of 84 patients; assessment results were compared for concordance. Treatment outcomes included event-free survival (EFS), overall survival (OS), and cumulative incidence of local progression (CILP). Results Surgeon-assessed extent of resection was ≥ 90% in 154 (70%) patients and < 90% in 66 (30%). Five-year EFS, OS, and CILP (± SE) were 43.5% ± 3.7%, 54.9% ± 3.7%, and 11.9% ± 2.2%, respectively. EFS was higher with ≥ 90% resection (45.9% ± 4.3%) than with < 90% resection (37.9% ± 7.2%; P = .04). Lower CILP ( P = .01) was associated with ≥ 90% resection (8.5% ± 2.3%) compared with < 90% resection (19.8% ± 5.0%). On multivariable analysis, ≥ 90% resection was associated with longer EFS after adjustment for MYCN amplification or diploidy but had no significant effect on OS. Concordance between surgeons’ assessments of resection extent and central image–guided review was low, with agreement of 63% (< 90% v ≥ 90%; simple κ = −0.0301). Conclusion Despite discordance between clinical assessment of resection extent and assessment via central imaging review, a surgeon-assessed resection extent ≥ 90% was associated with significantly better EFS and lower CILP. Improving OS, however, remains a challenge in this disease. These findings support continued attempts at ≥ 90% resection of the primary tumor in high-risk neuroblastoma.
Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation
Authors: Iyengar Neil M. , Gucalp Ayca , Dannenberg Andrew J. , Hudis Clifford A. 
Published: February 2017

Purpose There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. Methods We review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. Results Locally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. Conclusion The tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.