tbuckley/cabot-search huggingface dataset:
Natural history of rising serum PSA in men with castrate nonmetastatic prostate cancer
Authors: M. R. Smith, F. Kabbinavar, F. Saad, A. Hussain, Y.-J. Hei, E. Small, R. Cook, C. Higano
Journal: Journal of Clinical Oncology (2005)

4514 Purpose: To describe the natural history of nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy. Subjects and Methods: The 201 subjects in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to randomization, time from diagnosis to randomization, and PSA velocity. Results: At 2 years, 33% of subjects had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA > 10 ng/mL (relative risk 3.18; 95% CI 1.74, 5.80; p<0.001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI 2.30, 8.21; p<0.001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes. Conclusions: Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have an indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Oncology Novartis, Novartis Oncology Novartis Oncology Novartis Oncology Novartis Oncology Novartis Oncology
Number of lesions measured and the relative percent change in tumor burden and response rate.
Authors: C. S. Moskowitz, M. Gonen
Journal: Journal of Clinical Oncology (2010)

e16504 Background: In early-phase clinical trials and clinical practice, response to treatment is assessed by the relative percent change in overall tumor burden (RC) from baseline to follow-up visits. Patients frequently have multiple metastatic lesions, and there is some debate over the number of target lesions to include when calculating the RC. The recently updated Response Evaluation Criteria in Solid Tumors (RECIST 1.1) recommends including a maximum of five lesions, a decrease from the ten lesions previously recommended in RECIST 1.0. Methods: We derive an analytic expression for the distribution of the RC from baseline to follow-up. Using data from eight clinical trials studying therapies with varying degrees of activity, we calculate the expected RCs and response rates (RRs) for a range of number of lesions measured. Results: Average RCs and RRs changed based on the number of lesions measured. The magnitude of this difference depends upon the situation. In some cases, fewer than five lesions may be sufficient while in other cases it may be preferable to measure more than five lesions. For instance, in situations where there was a low RR together with a high correlation between baseline and follow-up measurements, we found less variation in the average RCs and RRs across the number of lesions measured than in other situations. Two different scenarios are presented in the Table. Conclusions: Knowing the distribution of the RC allows investigators to obtain an idea of the number of target lesions to measure when planning clinical trials. This number depends upon a variety of factors which are inputs to our analytic expression. Relative percent change from baseline to follow-up measurement Number of lesions measured 1 2 3 4 5 6 7 8 9 10 Scenario 1: Moderate response rate, moderate correlation between baseline to follow-up measurements Average -1% -7% - 10% -11% -12% -12% -13% -13% -13% - 13% SD 0.62 0.44 0.36 0.32 0.29 0.28 0.27 0.25 0.24 0.23 RR = Prob (RC ≤ -30%) 38% 34% 32% 32% 30% 29% 28% 26% 25% 24% Scenario 2: Very low response rate, high correlation between baseline to follow-up measurements Average 17% 15% 15% 14% 14% 14% 14% 14% 14% 14% SD 0.38 0.30 0.27 0.26 0.25 0.24 0.23 0.23 0.23 0.22 RR = Prob (RC ≤ -30%) 7% 4% 2% 2% 1% 1% 1% 1% 1% 1% No significant financial relationships to disclose.
Phase II consortium (P2C) study of gemcitabine and tanespimycin (17AAG) for metastatic pancreatic cancer.
Authors: Robert R. McWilliams, Nathan R. Foster, Andrea Wang-Gillam, Charles Erlichman, George P. Kim
Journal: Journal of Clinical Oncology (2013)

245 Background: Gemcitabine (GEM) monotherapy for PDA has modest activity. 17-N-Allylamino-17-demthoxygeldanamycin (Tanespimycin/17AAG), is an HSP90 inhibitor, which results in degradation of a number of client proteins such as RAF and Akt. Arlander et al (J Biol Chem. 2003 278:52572-7) have demonstrated that 17AAG targeting of HSP90 leads to Chk1 degradation. Chk1 is upregulated with GEM treatment which affects cell survival (Karnitz et al. Mol Pharmacol. 2005 68:1636-44). In vitro, the combination demonstrated in vitro synergy. Thus the potential clinical activity in pancreatic cancer of the combination was explored. Methods: A phase II multicenter prospective study was performed using GEM 750 mg/m2 d1,8 and 17AAG 154 mg/m2 d2,9 on a 21 day cycle, as defined in a previous phase I trial. Patients with stage IV PDA, with adequate liver, kidney function and counts, ECOG 0-2 and no prior therapy for metastatic disease were eligible. The primary endpoint of 60% overall survival at 6 months was considered of clinical interest. Sixty-six patients were planned for accrual, and an interim analysis was planned after 25 evaluable patients. Informed, written consent was obtained from all pts. Results: Due to lack of drug availability and failure to achieve the planned endpoint, accrual was halted at 21 pts, enrolled from 5/08 to 9/10, of which 20 were evaluable (1 cancelled prior to treatment). Median age was 61.5 yrs., 55% were male, PS 0 (50%), 1 (45%), 2 (5%); 95% were non-Hispanic white, 1 was African American. Two had received adjuvant therapy for PDA. Tolerability was moderate, with 13 pts (65%) having &gt; grade 3 adverse event (AE), with 15% gr 4 AEs and 0% gr 5. Nausea (20%), vomiting (20%), constipation (15%), dehydration (15%), and anorexia (10%), were the most common non-heme AEs. Lymphopenia (15%), leukopenia (10%) and neutropenia (10%) were common grade 3 hematologic AEs. No complete or partial responses were seen. 40% of patients were alive at 6 months, with a median OS of 5.4 months. Conclusions: HSP 90 inhibitor 17AAG in combination with GEM does not show activity for treatment of PDA. Further trials should not be pursued with this combination. Supported by N01-CM-62205. Clinical trial information: NCT00577889.
Adjuvant chemotherapy with or without concurrent radiotherapy in stage IB patients with gastric cancer: Subgroup analysis of the adjuvant chemoradiotherapy in stomach tumors (ARTIST) phase III trial.
Authors: Haa-na Song, Jinhyun Cho, Ki Sun Jung, Su Jin Lee, Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang
Journal: Journal of Clinical Oncology (2016)

95 Background: To evaluate the risk of recurrence in patients with pathologically staged Ib, according to the American Joint Committee on Cancer (AJCC) 2002 staging system, gastric cancer (GC) in the phase III adjuvant chemoradiotherapy in stomach tumors (ARTIST) trial. Methods: Among 458 GC patients enrolled in ARTIST, 99 had stage Ib (T2N0 or T1N1) disease. Patients were randomly assigned to receive adjuvant chemoradiotherapy with capecitabine plus cisplatin (XP, n = 50)) or chemoradiotherapy (XPRT, n = 49). Kaplan-Meier method was used to calculate disease-free survival (DFS). Cox proportional hazard models were employed to determine associations between the addition of radiotherapy to XP and DFS after adjustment for patient and disease characteristics. Additionally, analyses were performed according to the AJCC 2010 staging system. Results: With 7 years of follow-up, there were 18 recurrences. The 5-year DFS rates were 88% and 84% in XP and XPRT patients, respectively (P = 0.537). When we reviewed the pathologic stages of the patients according to the AJCC 2010 system, stage migration from Ib to II occurred in 71% of the patients: 98% of the T2N0 patients were reclassified as T3N0, and 42% of the T1N1 patients were reclassified as T1N2. The patients classified as stage Ib according to the AJCC 2002 system and reclassified as stage II exhibited worse, although statistically insignificant, prognosis than the patients who remained in stage Ib (5-year DFS 83% vs. 93%, P = 0.183, HR 1.178, 95% CI 0.420-3.311, P = 0.158). When we compared 5-year DFS in 70 stage II (AJCC 2010 system) patients, the addition of radiotherapy to XP chemotherapy resulted, although again statistically insignificant (P = 0.234), in worse outcome in XPRT arm (77%) than in XPRT arm (88%). Conclusions: This subgroup analysis confirms the clinical relevance of the AJCC 2010 staging system in GC. The role of adjuvant chemotherapy in stage II GC warrants further investigation.
Effect of surgical resection (SR) of primary tumor in advanced colorectal cancer (CRC) on outcome: A Canadian province’s experience
Authors: S. Ahmed, R. Shahid, T. Zhu, K. Haider, R. Alvi, F. Arnold, A. Sami, S. Yadav, M. Brigden, K. Harding, I. Ahmad
Journal: Journal of Clinical Oncology (2008)

15016 Background: Advances in anticancer therapy have led to improved outcomes for patients with advanced CRC. The potential benefit of SR of primary tumor in these patients remains unknown. We have recently demonstrated that SR of primary tumor in patients with newly diagnosed advanced CRC has been associated with survival benefit irrespective of chemotherapy (ASCO 2008 GI Symposium). We present here an update analysis. Methods: Medical records of patients with metastatic CRC diagnosed from 1992–2000 in Saskatchewan province were reviewed. Patients with unresectable T4M0 disease were excluded. A multivariate analysis was done using Cox regression model and various clinicopathologic variables were tested for their prognostic significance. Kaplan-Meier curves were used to determine survival. Results: A total 813 eligible patients were identified. Patients median age was 71 yrs (24–98) and M: F was 56:44. Five hundred-ninety four (73%) patients underwent SR of the primary tumor. Among 594 patients, 248 (41%) were operated for tumor related symptoms. Thirty-nine (6.5%) died within 30 days of surgery. Of 813 patients, 314 (39%) patients received 5FU-based chemotherapy and 84 (10%) received a second line therapy. Median overall survival (OS) of all patients was 7.3 months. Patients who received chemotherapy had a median OS of 14.8 months compared with 4.1 months if they did not receive chemotherapy (p<0.0001). Patients who underwent SR of primary tumor had a median OS of 9.7 months compared with 3.3 months in patients who did not have surgery (p<0.0001). Patients who had SR and received chemotherapy had a significantly better median OS of 16.7 months compared with 8.7 months if they received chemotherapy but did not have surgery (P<0.0001). On multivariate analysis 5FU-based chemotherapy (HR 0.48; 95% CI: 0.40–0.56), SR of primary tumor (HR 0.49; 95%CI: 0.42–0.59), and metastectomy (HR 0.58; 95% CI: 0.46–0.71) were correlated with a better survival in patients with advanced CRC. Conclusions: SR of primary tumor in patients with advanced CRC has been associated with significant improvement in survival independent of systemic chemotherapy. A future prospective trial is warranted to assess the role of SR of primary tumor in the era of targeted therapy. No significant financial relationships to disclose.
Circulating tumor cells (CTC) as potential biomarkers in neoadjuvant chemotherapy of muscle invasive bladder cancer (MIBC).
Authors: Ajjai Shivaram Alva, Stephanie Daignault-Newton, Tamara Huebner, Melanie Clark, Maha Hussain, Cristian Ionescu, Mike Schwartz
Journal: Journal of Clinical Oncology (2015)

330 Background: Biomarkers to assess early response to cisplatin based neoadjuvant chemotherapy (NAC) in MIBC is a clinical need. We hypothesized that CTC enumeration and genomic profiling using a novel microfluidic immunomagnetic assay IsoFlux (Fluxion Biosciences Inc., CA) could provide novel biomarkers in individual patients during NAC. Methods: Peripheral blood was drawn at baseline and after one cycle (3-4 weeks) of NAC in patients (pts) with locally advanced resectable bladder cancer in an IRB approved prospective study at the University of Michigan. CTCs were enumerated by the CellSearch and IsoFlux assays in parallel and by IsoFlux in duplicate samples. We correlated CTC numbers with pStage at cystectomy, a known prognostic variable for survival. We assessed gene expression by RT-PCR and gene mutational status by Ion Torrent sequencing on CTCs. Results: We analyzed 21 pts with localized muscle invasive bladder cancer (cT2-T4aNx). Mean age was 65 yrs with 84% male. Clinical stage was 71% cT2N0, 14% cT3N0, 10% cT4N0, 5% cT4aN1. NAC was GC in 9 pts and MVAC in 12 pts. The IsoFlux assay detected more CTCs per sample than CellSearch at baseline (median =10 vs. 0, n=5) and after 1 cycle (5.5 vs. 0, n=4). IsoFlux assay in parallel tubes had 80% of samples with &lt;5 CTC difference between the pairs. Baseline CTC concordance with pStage was 75% (12/16) (concordance=either &lt;pT1N0 with &lt;10 CTCs or ≥ pT1N0 with ≥10 CTCs). On the other hand, concordance of cStage with pStage was only 62.5% (10/16). PDGFRA, PIK3CA and MET mutations were detected on CTCs. Interrogation of CTCs for gene expression by RT-PCR and application of next generation sequencing (NGS) to CTCs were feasible. Conclusions: IsoFlux detects more CTCs than CellSearch in patients undergoing NAC. Baseline CTC number is a potential prognostic variable superior to cStage. However, changes in CTC number before and after 1 NAC cycle do not appear to reflect benefit in individual patients. Gene expression and genomic profiling of CTCs are feasible. CTCs are potential liquid biopsies in patients undergoing NAC in bladder cancer.
Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis
Authors: Mark Martin Jensen, Wanjian Jia, Kyle J. Isaacson, Austin Schults, Joseph Cappello, Glenn D. Prestwich, Siam Oottamasathien, Hamidreza Ghandehari
Journal: Journal of Controlled Release (2017)
Individualized chemotherapy in the advanced NSCLC patients based on the mRNA level of BRCA1 and RRM1.
Authors: S. Ren, S. Zhou, L. -. Zhang, X. Chen, C. Zhou
Journal: Journal of Clinical Oncology (2011)

e18029 Background: Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin and RRM1 overexpression enhances resistance to gemcitabine. In order to further investigate the effect of BRCA1 and RRM1 mRNA levels on outcome in advanced NSCLC, we performed this phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. Methods: RNA was isolated from fresh tumor tissue. The chemotherapy regimen that patients received was based on their BRCA1 and RRM1 mRNA levels: both low, cisplatin plus gemcitabine (GP); both high novelbine plus cisplatin (NP); BRCA1 low and RRM1 high, cisplatin plus docetaxel (DP); BRCA1 high and RRM1 low, novelbine plus gemcitabine (GN). Results: From Dec 2005 to Nov 2008, 94 metastatic or local advanced NSCLC patients in our institute were enrolled into this study. The median age was 58 years old and 76% were male. Among them, 21 patients received GP, 30 patients received TP, 43 patients received NP and no patient received NP chemotherapy. GP group got a numerically higher response rate, longer median time to progression and median overall survival time than the other 2 group. The response rate in the GP,TP and NP group were 42.9%, 36.7% and 27.9% respectively (P=0.568), Median time to progression was 5.6,5.0,4.8 months (P=0.975)and median overall survival was 12.5, 11, 9.7 months (P=0.808) respectively. Conclusions: Chemotherapy customized according to BRCA1 and RRM1 expression levels is associated with numerically higher response rate and longer TTP and OS time in the GP group, which may be caused the controversial function of the BRCA1 and RRM1 mRNA at the initiation period of this trial, and suggested that BRCA1 and RRM1 mRNA levels could be used as biomarker in individual therapy in NSCLC. Efficacy of patients according to the treatment group. Regimen N Response TTP OS PR SD PD GP 21 9 9 3 5.6 12.5 TP 30 11 10 9 5.0 11 NP 43 12 19 12 4.8 9.7 Total 94 32 38 24 5 11 Abbreviations: PR, partial response; SD, stable disease; PD, progression disease.
Influence of ischemia on tissue androgens in eugonadal and androgen-deprived men treated with prostatectomy.
Authors: Robert B. Montgomery, Michael Christopher Risk, Daniel W. Lin, Alvin M. Matsumoto, Brett Marck, Jonathan L. Wright, Peter Nelson, Elahe A. Mostaghel
Journal: Journal of Clinical Oncology (2013)

118 Background: Optimizing tissue androgen suppression may provide a higher rate of complete pathologic response in patients with localized prostate cancer (PCa). The ability to accurately assess tissue androgens may be influenced by ischemic time and catabolism after devascularization. This study was performed to determine if ischemia influences tissue androgen in eugonadal men and in men treated with various types of neoadjuvant androgen deprivation (ADT). Methods: Eugonadal men (n=12) or men treated with neoadjuvant ADT using LHRH agonist and Casodex or LHRH agonist with Dutasteride, Casodex or all three with Ketoconazole (n=34) underwent prostatectomy for localized PCa. Tissue was acquired by needle biopsy at the time of ligation of the vascular pedicles, at prostate removal and at 30 minutes after prostate removal. Prostate tissue was flash-frozen and tissue dihydrotestosterone (DHT) and testosterone (T) were determined by LC/MS/MS. Change in tissue androgens from clamp was assessed at each time point. Trends in androgen levels were assessed by ANOVA for eugonadal men and within each treatment group Results: Average time from clamp to removal was 23 minutes (± 8) and from removal to subsequent biopsy 32 minutes (± 2). There was no evidence for a significant change in T or DHT over the time intervals tested (one way ANOVA p&gt;0.05 for all measures) except in patients treated with LHRH agonist and Casodex alone. In this group of patients, T declined by 34%by the time of prostate removal, and by 83% at 30 minutes after removal when compared to levels at clamp (one way ANOVA p=0.017, test for linear trend =0.007). In all other treatment groups, both T and DHT were stable for 60 minutes. Conclusions: Assessment of DHT levels in prostate tissue at prostatectomy is not compromised by ischemia. Tissue sampling from 30-60 minutes after vascular clamping yields a stable measure of tissue DHT in the majority of patients. In the absence of SRD5A blockade, testosterone sampling in castrate men is sensitive to ischemia, and delayed sampling underestimates tissue androgen levels due to ischemia-related metabolism. These results lend important insight into clinical trial design and translational endpoints.
Does the choice of hormone therapy affect medium-term outcomes following radical external beam radiotherapy for localized prostate cancer?
Authors: Ciara Lyons, Jaine K. Blayney, Darren M. Mitchell, Jacqueline A. Harney, Jonathan McAleese, Lin Shum, David P. Stewart, Suneil Jain, Joe M. O'Sullivan
Journal: Journal of Clinical Oncology (2016)

e16588 Background: Multiple randomized controlled trials (RCTs) have demonstrated the benefit of the addition of androgen deprivation therapy (ADT) to external beam radiotherapy (EBRT) in the treatment of localized prostate cancer (PC). Anti-androgens (AA) may have a better toxicity profile than luteinizing hormone-releasing hormone agonists (LHRHa). However, no RCT has directly compared these agents in combination with radical EBRT. We evaluated outcomes for men with localized PC treated with EBRT in conjunction with either LHRHa or AA therapy. Methods: Clinical data from 477 consecutive PC patients treated with radical EBRT (70-74 Gy) between 2005 and 2009 in Northern Ireland were reviewed. Detailed clinical information was obtained via an electronic medical record, a radiological results system and a pathological results database. Baseline and treatment characteristics analysed comprised age at diagnosis, clinical T stage, initial PSA, Gleason score, age-adjusted Charlson Comorbidity Index (aCCI), ADT type and EBRT dose. Outcomes of interest included biochemical progression-free survival (bPFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Results: Complete data for 409 patients were available. At a median follow-up of 75 months, 5-year bPFS was 81%, PCSS was 98% and OS was 95% in the AA group and 92%, 98% and 88% respectively in the LHRHa group (p = 0.158 for the biochemical failure (BF) group and 0.25 for the OS group; insufficient events to assess PCSS). Men receiving LHRHa were significantly more likely to be older and have a higher iPSA. Conclusions: In this retrospective study, we found that an aCCI ≥ 4 was the only independent factor for poorer OS. While there was a significantly increased rate of BF in the AA group, there was a trend towards poorer OS in the LHRHa group. These data suggest that AA may be a reasonable alternative to LHRHa therapy in men with localized PC treated with radical EBRT and ADT. MVA HR CI P-value BF Clinical T Stage 1 1 2 1.21 0.58 – 2.53 0.61 ≥ 3 2.69 1.38 – 5.27 0.004 ADT Type AA 1 LHRHa 0.53 0.31 – 0.90 0.02 OS aCCI 0 – 2 1 3 1.71 0.85 – 3.47 0.13 ≥ 4 4.47 2.27 – 8.80 1.49e-05 ADT Type AA 1 LHRHa 1.83 0.9151-3.681 0.09
High-Resolution Genomic Profiling of Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukaemia (ALL) Identified Novel Recurrent Copy Number Variations Involved in Both Pathogenesis and Resistance to Tyrosine Kinase Inhibitors.
Authors: Ilaria Iacobucci, E. Ottaviani, A. Astolfi, S. Soverini, N. Testoni, S. Paolini, P.P. Piccaluga, C. Papayannidis, D. Cilloni, A. Pession, F. Pane, A. Vitale, S. Chiaretti, R. Foà, M. Baccarani, Giovanni Martinelli
Journal: Blood (2007)