tbuckley/cabot-search huggingface dataset:
Effect of a germline polymorphism in the manganese superoxide dismutase (MnSOD) gene on the association of clinically aggressive prostate cancer with plasma selenium levels
Authors: W. Xie, W. K. Oh, M. M. Regan, M. Abe, P. W. Kantoff, J. Chan
Journal: Journal of Clinical Oncology (2008)

5057 Introduction: We previously identified modified risk of prostate cancer by antioxidant levels and polymorphism in the MnSOD gene (rs4880) (Cancer Res 2005;65:2498). We further explore interaction between this polymorphism, plasma selenium levels and clinically aggressive prostate cancer. Methods: 778 patients with localized prostate cancer and pretreatment plasma was identified from a single institution. MnSOD polymorphism (rs4880) was genotyped in 764 subjects. Plasma selenium levels were measured in 499. Aggressive disease was stage ≥T2b, PSA>10ng/mL or Gleason≥7. Relative risk (RR) and 95% CI were calculated. Results: A total of 489 patients had clinical, selenium and genotype data. Median age was 62 years (range 43–86). Median PSA was 6 ng/mL (range 0.7–575.8). Biopsy Gleason score ≥7 and T stage ≥T2b were noted in 35.7% and 2.4%, respectively. 43% of patients had aggressive disease at diagnosis. There was no overall association of aggressiveness with MnSOD genotype or plasma selenium levels (p>0.05). However, the rs4880 polymorphism significantly modified the relationship between disease risk with selenium levels (P-value for interaction=0.02; Table). Among men with genotype AA, higher selenium levels (quintile 5 vs1) were associated with lower risk for aggressive prostate cancer (RR=0.6, 95% CI: 0.32∼1.12, P-trend=0.05). By contrast, there was a positive correlation between higher selenium levels and aggressive disease in men with VV/AV genotype (P-value for trend < 0.05). Conclusions: The association between aggressive prostate cancer and pretreatment selenium levels was modified by a polymorphism in MnSOD. Men with genotype AA were less likely to develop aggressive prostate cancer with higher selenium levels. Interestingly, a reverse relationship was observed in men with VV/AV genotypes suggesting that for them, higher selenium levels may be deleterious. Relative risk of aggressive prostate cancer by selenium and MnSOD variant Genotype (rs4880) No. of patients Quintile I (low) II III IV Quintile V (high) P-value (trend) P-value (interaction) VV 107 1.00 (reference) 1.58 (0.64∼3.85) 1.95 (0.83∼4.58) 1.73 (0.74∼4.06) 2.48 (1.07∼5.71) 0.043 0.018 VA 252 1.00 (reference) 0.80 (0.47∼1.35) 1.09 (0.70∼1.71) 1.20 (0.77∼1.87) 1.59 (1.07∼2.35) 0.004 AA 130 1.00 (reference) 0.95 (0.57∼1.59) 0.65 (0.32∼1.30) 0.71 (0.39∼1.31) 0.60 (0.32∼1.12) 0.056 No significant financial relationships to disclose.
Characteristics and outcomes of elderly patients with systemic prostate cancer (PCa) treated with peripheral androgen blockade (PAB).
Authors: Deepak Kilari, Chintan Pandya, Chunkit Fung, Deepak M. Sahasrabudhe, Ralph Anthony Brasacchio, Edward M. Messing, Lynn Sievert, Supriya Gupta Mohile
Journal: Journal of Clinical Oncology (2013)

226 Background: The side effect profile of androgen deprivation (ADT) warrants exploration of alternative options for elderly patients with systemic PCa. In phase 2 trials, the combination of anti-androgen and 5 alpha reductase inhibitor (PAB) demonstrated efficacy with low morbidity in the fit population. The objective of this retrospective study was to evaluate the characteristics and outcomes of elderly patients treated with PAB in lieu of ADT. Methods: We reviewed records of patients ≥65 yrs who received PAB in the geriatric oncology program from 2007-2012. Patients were evaluated with a validated comprehensive geriatric assessment (CGA) prior to PAB. Descriptive statistics were used to evaluate PAB type, characteristics of patients and their cancers, as well as PCa –specific and overall outcomes Results: Twenty-one asymptomatic PCa patients received PAB (bicalutamide alone-57%, or bicalutamide and finasteride-43%) in lieu of ADT. Indications for treatment were metastatic disease (53%) or biochemical relapse with PSA doubling time≤ 6 months (47%). Median age at the initiation of PAB was 86 years (range 65-94) and 76 % had ECOG PS≥ 2. By CGA, 57 % were vulnerable, 33% frail and 10% fit. 76% had contraindications for standard ADT (e.g., dementia, falls, etc.); the rest declined ADT due to concern about adverse effects (AE). The median PSA at PAB initiation was 14.78 (range 0.9-165.8). PSA nadir (i.e. 1 st of 3 consecutive PSA levels where values were within 90%) was reached in 57% of patients at the time of analysis with the remainder demonstrating a continuing decline. Median PSA at nadir was 0.86(range 0.02-11.24). The median follow up time was 11 months (range 1-30). The median time to PSA nadir was 5 months; (range 1-19). PSA nadir was maintained for median of 10.5 months (range 3-24).The median % decline in PSA was 92 % (range 13-99%).No patients reported AE or required treatment interruption. Two fit patients of the 4 who progressed on PAB responded to subsequent ADT. Conclusions: These results provide evidence that PAB is feasible, active and well tolerated in patients for whom ADT may be contraindicated. A prospective phase II study for an older vulnerable patient population is planned.
Sensitivity of PTEN-deficient prostate carcinoma cells to ionizing radiation through inhibition of treatment-induced CXCL8 signaling.
Authors: Chris Armstrong, Jonathan Coulter, Pamela Maxwell, Silvia Berlingeri, Joe M. O'Sullivan, Kevin Prise, David J. Waugh
Journal: Journal of Clinical Oncology (2013)

154 Background: We recently demonstrated that loss of PTEN in CaP cell lines increases expression of the pro-inflammatory chemokine CXCL8. Increased expression and signalling of this chemokine is detectable in PIN-foci and increases with disease progression. Our objective was to determine how induction of CXCL8 signalling affects the sensitivity of PTEN-deficient CaP cells to radiotherapy, a major treatment modality used in locally-confined CaP. Methods: Established cell-based models of CaP with differential expression of PTEN were subjected to ionizing radiation (IR) under normal or hypoxic culture conditions. Changes in chemokine expression in CaP cells were analyzed by real-time PCR, immunoblotting, and ELISA. siRNA- or shRNA-directed strategies were used to repress PTEN expression and/or attenuate autocrine CXCL8 signalling by down-regulating CXCR1 and CXCR2 gene expression.The effects of modulating chemokine signaling on cell viability following exposure to clinically-relevant doses of IR were assessed by colony formation assays, cell proliferation analysis, and analysis of apoptosis and/or cellular senescence. Results: Exposure to IR (3 Gy) in normoxic and hypoxic cells increased gene expression of CXCL8 and its receptors CXCR1 and CXCR2, a response potentiated in PTEN depleted cells. Loss of PTEN had different effects on the sensitivity of CaP cell lines; shRNA-mediated loss of PTEN conferred increased radioresistance in DU145 cells but increased the sensitivity of 22Rv1 cells to IR. However, despite these variable responses, siRNA-mediated repression of CXCR1/2 expression increased the sensitivity of all PTEN-depleted cell-based models to IR, under both normal and hypoxic conditions. Interestingly, inhibition of CXCL8 signalling reinforced IR-induced senescence in PTEN-depleted 22Rv1 cells (Tp53 WT) but increased apoptosis in PTEN-depleted DU145 cells (Tp53 mutant). Conclusions: Targeting IR-induced autocrine CXCL8 signalling is a novel therapeutic strategy to enhance the sensitivity of PTEN-deficient CaP cells to IR, taking on added significance in cells harbouring mutations or loss of Tp53 expression.
Identification of a predictive factor of metastatic castration-resistant prostate cancer patients’ response to alternative antiandrogen therapy with flutamide.
Authors: Masato Yasui, Shuko Yoneyama, Koichi Uemura, Takashi Kawahara, Yusuke Hattori, Jun-ichi Teranishi, Jun-ichi Ohta, Yumiko Yokomizo, Masahiro Yao, Masataka Taguri, Hiroji Uemura, Yasuhide Miyoshi
Journal: Journal of Clinical Oncology (2016)

321 Background: Recently, new androgen pathway inhibitors, abiraterone and enzalutamide, are demonstrated to improve overall survival for metastatic castration-resistant prostate cancer (mCRPC). In Japan, alternative antiandrogen (AA) as second-line hormonal therapy for mCRPC that relapses after initial hormone therapy have been commonly used before new androgen pathway inhibitors. In this study, we attempted to identify the predictive factors for efficacy of AA as second-line hormone therapy. Methods: We identified consecutive 65 mCRPC patients treated with AA as second-line hormonal therapy. All patients were treated with maximum androgen blockade (MAB) initially and evaluated antiandrogen withdrawal syndrome after relapse. We analyzed the correlations between progression-free survival (PFS) of AA and clinicopathological characteristics, including patients’ age, initial PSA levels, PSA levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease (EOD) classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB. Results: The median duration of prostate cancer sensitivity to MAB was 11.3 months (range: 1.5-53.0 months). In multivariate analysis, four significant risk factors for poor PFS were identified; initial PSA levels ( &gt; 263 ng/mL vs ≤ 263; HR 0.53, p = 0.038), N stage (1 vs 0; HR 3.00, p = 0.001), EOD classifications (3-4 vs 1-2; HR 2.50, p = 0.007), and the previous duration of prostate cancer sensitivity to MAB ( &lt; 12 months vs ≥ 12; HR 2.16, p = 0.026). We stratified the patients into two cohorts with low risk (0-2 risk factor present) and high risk (3-4 risk factors present). We found a significant difference in PFS among risk groups (median PFS 7.3 months vs 1.5, p &lt; 0.000). Conclusions: Initial PSA, N stage, EOD classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB were the significant predictive factors for efficacy of AA as second-line hormone therapy in patients with mCRPC. These findings might support that decision-making of when to start the new AR pathway inhibitors.
Phase I trial of biweekly S-1, leucovorin, oxaliplatin, and gemcitabine (the SLOG regimen) in metastatic pancreatic adenocarcinoma (mPDAC).
Authors: Nai-Jung Chiang, Kelvin K. Tsai, Jen-Shi Chen, Shih-Hung Yang, Chiun Hsu, Yan-Shen Shan, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2016)

369 Background: Gemcitabine and S-1 had been approved as the frontline treatment for mPDAC in Taiwan and Japan. Our previous study showed biweekly gemcitabine plus modified FOLFOX4 (the GOFL regimen) was a moderate active and well-tolerated regimen in mPDAC. To explore whether oral S-1/LV can be a substitute for infusion 5-FU/LV in combination with gemcitabine and oxaliplatin as “the SLOG regimen” to improve treatment efficacy and convenience. To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and preliminary anti-tumor efficacy of SLOG in patients with chemo-naïve mPDAC. Methods: Enrolled patients would receive intravenous infusion of 800 mg/m 2 gemcitabine (fixed-dose rate infusion, 10 mg/m 2 /min) followed by 85mg/m 2 oxaliplatin (2 hours) on D1 and escalating dose of oral S-1 and 20 mg/m 2 leucovorin, twice daily D1-D7, every 14 days. DLTs were evaluated during the first 2 cycles of treatment. The treatment was continued until disease progression, unacceptable toxicity or withdrawal of informed consent. Results: 19 patients were enrolled into four dose levels of S-1, 20 mg/m 2 (three), 30 mg/m 2 (seven), 35 mg/m 2 (six) and 40 mg/m 2 (three). At 30 mg/m 2 dose level, one patient who withdrew consent after one cycle treatment was replaced with another one. DLTs were observed in three patients, one at 30 mg/m 2 (grade 3 diarrhea) and two at 40 mg/m 2 (grade 3 hypersensitivity reaction and diarrhea in one each). MTD of S-1 was determined as 35 mg/m 2 . The median treatment duration was 8 cycles (ranged, 1-26). Of the 16 evaluable patients, the objective response rate and disease control rate were 37.5% (6 partial response, PR) and 81.3% (6 PR + 7 stable disease, SD), respectively. The median progression-free survival (PFS) was 4.6 months. At MTD dose level, there were 4 PR and 2 SD, with 6.7 months of PFS. The most common grade 3-4 adverse events included neutropenia (26.4%), diarrhea (15.8%), ALT increased (10.5%) and anemia (10.5%). Conclusions: The MTD of S-1 was 35 mg/m 2 in the SLOG regimen. Extension phase II study in mPDAC is ongoing. Clinical trial information: NCT 01415713.
Sponsor/research ethics boards (REB) communications about informed consent (IC) and time to local activation (LA): An NCIC CTG pilot study.
Authors: M. Walker, A. Szeto, Z. Meng, B. E. Chen, R. M. Meyer
Journal: Journal of Clinical Oncology (2011)

6131 Background: Communications between sponsors, investigators and REBs about IC details may affect a centre’s LA time. We evaluated factors associated with these communications and LA times for a series of NCIC CTG trials. Methods: A sample of NCIC CTG sponsored phase III trials (P3T) was selected based on mandatory compliance with regulatory requirements and NCIC CTG central ethics review (initiated in 2003). Two independent and trained reviewers systematically extracted data. We assessed LA times, number of IC communications between NCIC CTG and centre/REB, and IC elements leading to communication. Results: Between Apr 2003-Dec 2008, 63 P3Ts were activated by NCIC CTG; 16 (25.4%) were selected for inclusion, including 15 requiring Health Canada (HC) approval. A mean of 4.5 trials/centre (TC) were activated among 15 centres (range 1-10), resulting in 72 data sets. Median LA time was 11.3 mos with variation by centre (interquartile range [IR] = 0.66–21.78 mos) and trial (IR= 0.36–21.62 mos) and was 19.2 mos in 2003-05 and 10.1 mos in 2006-08 (p=0.006). Median LA times were 11.9, 9.2, 12.1, 14.6 and 21.5 mos for number of communications = 1, 2, 3, 4 and 5 (p-trend = 0.007). The number of IC elements requiring communication per TC trended towards longer LA time (0.3 mo/additional element; p=0.06). The top 5 IC elements leading to at least one communication per TC were: tissue banking language (39), confidentiality terms (25), risk frequency categorization (24), description of trial details (18), and risks to the subject (13); 3 of these are HC regulatory requirements. An exploratory analysis assessing all 65 elements found only communication about “subject responsibilities” (e.g., questionnaires) to be associated with longer LA time (7.5 mos; p=0.04 [corrected for multiple comparisons]). Conclusions: For NCIC CTG trials, LA times are longer than desired, may have reduced over time and are associated with more frequent communications between NCIC CTG and REB and possibly with more IC elements needing review. Systematic evaluations may assist in identifying elements associated with sponsor/REB interactions. Processes to standardize consent language may help reduce LA times.
Syngeneic Donor Hematopoietic Stem Cell Transplantation Is Associated with High Rates of Engraftment Syndrome
Authors: John Koreth, Melinda Biernacki, Julie Aldridge, Haesook T Kim, Edwin P Alyea, Philippe Armand, Corey Cutler, Vincent T. Ho, Catherine J Wu, Joseph H. Antin, Robert J Soiffer
Journal: Blood (2010)
Health-related quality of life in patients with metastatic colorectal cancer treated with panitumumab in first- or second-line treatment.
Authors: L. Bennett, Z. Zhao, B. Barber, X. Zhou, M. Peeters, J. Zhang, F. Xu, J. S. Wiezorek, J. Douillard
Journal: Journal of Clinical Oncology (2011)

e19500 Background: Panitumumab in combination with chemotherapy was evaluated in two pivotal clinical trials in 1st- and 2nd-line treatment of metastatic colorectal cancer (mCRC), respectively. Significant improvement in progression-free survival (PFS) with panitumumab+chemotherapy over chemotherapy alone was observed in patients with wild-type KRAS mCRC in both trials. This analysis compared the health related quality of life (HRQoL) of patients with or without panitumumab in the two trials. Methods: Patients with mCRC were randomized to FOLFOX (1st-line) or FOLFIRI (2nd-line) ± panitumumab. The EuroQoL 5-Dimensions Health State Index (EQ-5D HSI) and Visual Analogue Scale (EQ-5D VAS) were assessed at baseline and monthly follow-ups until disease progression. Patients with wild-type KRAS mCRC with baseline and at least one post-baseline EQ-5D score were included in this analysis. Average difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models. Results: In the 1st-line trial, 576 patients with wild-type KRAS mCRC (284 panitumumab+FOLFOX4 and 292 FOLFOX4 alone) were included in the HRQoL analyses; while 530 patients with wild-type KRAS mCRC were included in the 2nd-line trial analyses (263 panitumumab+FOLFIRI and 267 FOLFIRI alone). In 1st-line, based on linear mixed models, the treatment difference in the estimated least squares mean (LSM) of the change from baseline for EQ-5D HSI was -0.005 (95% CI -0.032–0.022) and for EQ-5D VAS was -0.653 (95% CI -2.925–1.618). The respective treatment difference in 2nd-line was -0.024 (95% CI -0.054–0.006) for EQ-5D HSI and -1.266 (95% CI -3.280–0.749) for EQ-5D VAS. Significantly more panitumumab patients dropped out late or completed the study than chemotherapy alone patients in both trials. Pattern-mixture analyses showed similar results of no treatment difference as the linear mixed models in both trials. Conclusions: The addition of panitumumab to FOLFOX4 or FOLFIRI in 1st- or 2nd-line treatment of wild type KRAS mCRC significantly improved PFS without compromising HRQoL.
Changes in opioid type and dose among cancer patients referred to outpatient palliative care.
Authors: Ali Haider, Joseph Baidoo, Yee Choon Meng, Donna S. Zhukovsky, Kimberson Cochien Tanco, Holly A Stewart, Tonya Edwards, Manju P Joy, Leela Kuriakose, Zhanni Lu, Diane D Liu, Janet L. Williams, Eduardo Bruera
Journal: Journal of Clinical Oncology (2016)

106 Background: Opioid prescriptions are regulated at both federal and state levels. Examples of such regulations include use of risk evaluation and mitigation strategies (REMS), mandatory sharing of prescription data with state prescription drug monitoring programs and the reclassification of hydrocodone as schedule II opioid in October 2014. One possible consequence of such changes would be earlier referral to palliative care (PC) for opioid management. Alternatively, primary oncologist may treat patients with weak opioids or use strong opioids with lower daily dose. We hypothesized that during the last six years, the number of referrals to outpatient PC has increased and the morphine equivalent daily dose (MEDD) has decreased. Methods: We reviewed 750 randomly selected patients who were seen as a new consultation from the year 2010 to 2015. Data was collected on demographics, cancer type and stage, referring specialty, symptom assessment, cancer pain classification, performance status, opioid type and MEDD. Data were also collected on first subsequent PC visit among eligible patients. MEDD over the 6 years was evaluated using general linear regression method, adjusted for covariates. Results: Hydrocodone was the most common opioid prescribed by the referring team throughout the six-year period. After reclassification, its use declined from 43% in 2014 to 33% in 2015. Tramadol use increased from 9% in 2014 to 19% in 2015 (p &lt; 0.0001). Median MEDD upon referral was 78mg/day in 2010 and progressively decreased to 40mg/day in 2015 (p &lt; 0.0001). Year to year referral increased 24% in the first quarter of 2015 (after hydrocodone rescheduling), compared to 17% in 2014 (p 0.0014). Conclusions: Over the past 6 years, there has been an increase in number of referrals to PC and a decline in MEDD upon referral. Likewise, an increase in weak opioids like tramadol has also been observed. These findings suggest oncologists are sending early referrals before further opioid dose titration and rotations are considered. Further opioid regulations will likely impact the integration of PC services in comprehensive cancer care.
Impact of bone and liver metastases (BM, LM) in patients with metastatic renal cell carcinoma (mRCC) treated with molecularly targeted agents (MTAs): Results from the International mRCC Database Consortium (IMDC).
Authors: Rana R. McKay, Nils Kroeger, Wanling Xie, Jae-Lyun Lee, Jennifer J. Knox, Georg A. Bjarnason, Mary J. MacKenzie, Lori Wood, Sandy Srinivas, Ulka N. Vaishampayan, Sun Young Rha, Sumanta Kumar Pal, Frede Donskov, Srinivas Tantravahi, Brian I. Rini, Daniel Yick Chin Heng, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2013)

394 Background: The skeleton and liver are frequently involved sites of metastases in patients with mRCC. Their impact on survival outcomes of patients treated with currently approved MTAs is largely unknown. The purpose of this study was to analyze patient outcomes based on the presence or absence of BM and/or LM in the era of MTAs. Methods: We conducted a review from the IMCD of 2,027 patients with mRCC treated from April 2003 to August 2012. Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: Median follow-up was 21 months. 1,978 were treated with first-line VEGF targeted therapy and 49 were treated with first-line mTOR inhibitors. Presence of BM was 34% overall and 27%, 33%, and 43% in favorable, intermediate, and poor-risk disease, respectively, by IMDC criteria (p &lt; 0.001). Presence of LM was 19% overall and higher in poor-risk patients (23%) compared to favorable (20%) or intermediate-risk groups (16%) (p = 0.003). Other sites of metastases include lung, lymph node, adrenal, soft tissue, and/or brain. Among patients with a single metastatic site, those with BM or LM had a worse overall survival (OS) when compared to metastases at other sites (Table). Among patients with ≥ 2 sites of metastases, those with BM and LM had a shorter time to treatment failure (4.2 vs. 7.3 months, p &lt; 0.0001) and worse OS (Table) when compared to patients with metastases at other sites. In multivariable analyses adjusting for IMDC criteria, BM and LM independently predicted poorer survival (HR=1.38 for BM vs. other metastases, 1.37 for LM vs. other metastases, and 1.82 for concomitant BM and LM, respectively, p &lt; 0.0001). Conclusions: BM and LM in mRCC patients have significant clinical relevance and may possibly be used for risk-stratification of patients with mRCC. [Table: see text]