tbuckley/cabot-search huggingface dataset:
A proprietary multianalyte test for predicting extreme resistance to neoadjuvant 5-FU based chemoradiation (CTRT) in esophageal adenocarcinoma (EC).
Authors: Weiwei Shan, Natalie Lassen, Clare Johnson, Yaeli Biermann-Harrar, Kristen M. Oelschlager, Robert W. Cook, Daniel Rosen, Sunil S. Badve, Kenneth Kessler, Romil Saxena
Journal: Journal of Clinical Oncology (2014)

51 Background: Standard of care for localized EC is neoadjuvant CTRT followed by surgery. Although 5-FU based regimens are still commonly used, other regimens (CROSS) are also prescribed. Published EC studies report 20-25% of patients exhibit extreme resistance (exCTRT) to 5-FU based neoadjuvant treatment (NT); these patients may benefit from alternative treatment regimens. We have developed a proprietary assay using a training set of 167 patients to accurately identify patients with exCTRT (ROC 0.96). The results presented herein constitute an independent clinical validation. Methods: Biopsy samples from 71 pts diagnosed to have EC and who had undergone surgical excision following NT were obtained. IHC detection of NF-kB, SHH, and Gli-1 proteins in FFPE sections was performed in a CLIA approved lab. A GI pathologist and an expert clinical scientist blindly evaluated resection specimens and assigned a labeling index (LI) score. The LI for each case was compared to the established training set and the predicted response determined using a logistic regression algorithm. Blinded pathology scoring for exCTRT vs. non-exCTRT was performed for all samples using both CAP Tumor Response Grade (TRG) and the Rohatgi research scale. Results: Of the 71 EC cases in the clinical validation cohort, 24 had an outcome of exCTRT (&lt;50% reduction in tumor following neoadjuvant treatment; TRG 3) and 47 had an outcome of non-exCTRT (&gt;50% reduction in tumor; TRG 0-2). ROC for the validation cohort was 0.85. The positive predictive value for the validation study was 83%, reflecting an assay that can accurately predict those likely to have some degree of response to chemotherapy / radiation. Conversely, a negative predictive value of 83% with specificity of 94% was achieved indicating accurate identification of those not likely to benefit from neoadjuvant treatment. Conclusions: The analysis of NF-kB, SHH, and Gli-1 in EC tissue can accurately identify patients unlikely to respond to 5-FU based NT. These results are now confirmed using a CLIA accredited lab and a multicenter independent validation cohort of esophageal adenocarcinoma biopsies.
The influence of a composite hospital volume of upper gastrointestinal cancer resections on outcomes of gastric cancer surgery.
Authors: Linde A.D. Busweiler, Johan L. Dikken, Mark I. van Berge Henegouwen, Vincent K.Y. Ho, Daniel Henneman, Rob A.E.M. Tollenaar, Michel W.J.M. Wouters, Johanna W. van Sandick
Journal: Journal of Clinical Oncology (2016)

305 Background: There is a known volume-outcome association for complex surgial procedures such as oncologic gastric resections. The aim of this study was to describe the process of centralization for gastric cancer surgery in the Netherlands in relation to other types of upper gastrointestinal (GI) cancer resections and to investigate whether the quality of gastric cancer surgery is affected by the overall experience with those related complex surgical procedures. Methods: Data on all patients (n = 4251) who underwent surgical treatment for non metastatic invasive gastric cancer between 2005-2013 were obtained from the Netherlands Cancer Registry. Annual hospital volume categories were based on the overall volume of gastrectomies, esophagectomies and pancreatectomies together (composite hospital volume). Volume-outcome analyses were performed for lymph node yield, 30-day mortality, and overall survival. Results: The percentage of gastric cancer patients who underwent a resection in a hospital with a volume of at least 20 gastrectomies per year increased. At the same time, the percentage of gastric cancer patients who underwent surgery in hospitals with an annual composite hospital volume of at least 20 upper GI cancer resections, such as esophageal and pancreatic cancer resections, increased. A higher composite hospital volume was associated with a higher lymph node yield, a lower 30-day mortality, and an increased overall survival. Conclusions: In the Netherlands, an increasing proportion of gastric cancer resections is performed in hospitals that are high volume centers for esophagectomies and pancreatectomies for cancer. Experience with these complex surgical procedures has a favorable effect on the outcomes of gastric cancer surgery.
Evaluation of cardiac safety of lapatinib therapy for c-erbB2 amplified metastatic breast cancer.
Authors: E. Dogan, H. Yorgun, I. Petekkaya, N. Ozer, K. Altundag, Y. Y. Ozisik
Journal: Journal of Clinical Oncology (2011)

e11001 Background: Lapatinib (L) is a tyrosine kinase inhibitor (TKI) that has efficacy in breast cancer. This study assessed the cardiac safety of lapatinib in women with cerbB-2 amplified metastatic breast cancer. Methods: In this study, 26 patients who were previously treated with anthracyclines, taxanes and trastuzumab were assigned to receive lapatinib (L) plus capecitabine (C). Cardiac toxicity was assessed with symptoms, transthoracic echocardiography, electrocardiography (ECG), brain natriuretic peptide (BNP), creatine kinase (CK) and CK-MB at baseline and every 9 weeks until progression. Results: A total of 26 patients were treated with L+C for a median follow-up of 18 weeks. The median age was 48 (28-83) years. Among 25 eligible patients, 8 (30,8%) had ECG changes one of which was grade I QT prolongation and 2 (7.7%) had decreased left ventricular ejection fraction (LVEF) below critical level (>15% drop compared to baseline or below normal level). Although there were no clinically observed cardiac symptoms, lapatinib was stopped in one patient who had decreased LVEF. The patient showed recovery of LVEF after three cycles of capecitabine monotherapy. Lapatinib was restarted and L+C therapy was continued until progression. The other patient who also had decreased LVEF, contiuned L+C therapy. LVEF normalized after 3 cycles of L+C combination therapy. Both patients are alive without any cardiac problems. The patient with grade I QT prolongation continued the therapy and after 3 cycles QT distance turned to normal limits. Among eligible 21 patients, 2 had increased BNP, 1 had increased CK and 1 had increased CK-MB level compared to baseline. There were no symptomatic cardiac events which required monitorization and intervention. Statistically, there was no significant relationship between duration of lapatinib administration and LVEF changes, QT distance prolongation, BNP, CK and CK-MB level. Conclusions: Lapatinib is safe and has lower cardiac side effects than other TKIs. Thus cardiotoxicity is not a class effect of TKIs. Despite no clinically serious cardiac side effects of lapatinib were observed in this study, the incidence of cardiac side effects is higher than previously reported lapatinib studies.
Initial results of a first-in-man phase I study of EPC2407, a novel small molecule microtubule inhibitor anticancer agent with tumor vascular endothelial disrupting activity
Authors: S. P. Anthony, W. Read, P. J. Rosen, R. Tibes, D. Park, D. Everton, B. Tseng, J. Whisnant, D. D. Von Hoff
Journal: Journal of Clinical Oncology (2008)

2531 Background: EPC2407 is a 4-aryl-chromene single isomer microtubulin inhibitor which in preclinical models showed antitumor effects due both to direct tumor apoptosis and to tumor vascular endothelium disruption. Through Dec. 2007, 17 patients with advanced cancers received from 1 to 18 doses of EPC2407. Methods: The 17 patients included advanced adenocarcinomas of the prostate (4), G.I. tract (2), breast, pancreas, unknown origin, NSCLC (2), melanoma, neuroendocrine, anaplastic thyroid, parotid gland carcinoma, VIPoma, and leiomyosarcoma. All patients met enrollment criteria: ECOG PS of 0–1, three month expected survival and confirmed tumor progression on prior therapy. EPC2407 was infused over 1 hour on 3 consecutive days in 21 day cycles. A modified Fibonacci dose escalation started at 4 mg/m2. Results: The primary objective was to define DLT. At the fourth dose level of 21 mg/m2 anticipated transient vasoconstrictive effects were seen in 2 of 2 patients: one patient had cardiac ischemia and severe pain in the tumor bed and one patient had pain at the site of a pre-existing DVT. The MTD was determined to be 13 mg/m2. Most patients at all dose levels had transient increases in BP during infusion and for 1–4 hours after. QTc increased up to 50 msec and correlated temporally and quantitatively with dose and with BP changes. Several patients received 4 or more cycles and had stable disease for 3+ months. There was minimal nausea/vomiting or other acute symptoms; one patient had moderate alopecia. Two patients reported transient decrease in mental status and two reported dysphoria or anxiety. There were no dermal or pulmonary AE’s and no clinically significant myelosuppression, hepatic or renal toxicities. The PK profile for EPC2407 is similar to that predicted in toxicokinetic analyses. The T1/2 in plasma is 2–3 hours. The AUC is dose-proportional up to MTD. Conclusions: EPC2407 appears to be an effective new anticancer agent with an acceptable side effect profile. Based on this study and results from preclinical studies showing additive or synergistic activity with antiangiogenic or chemotherapeutic agents, further clinical development of EPC2407 is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Epicept Corp Epicept Corp Epicept Corp Epicept Corp
Efficacy and safety of hematopoietic stem cell (HSC) remobilization with plerixafor plus G-CSF in patients with non-hematologic malignancies.
Authors: M. Horwitz, J. Schriber, E. N. Libby, E. J. Gorak, P. Mody, S. Marulkar, P. R. Holman
Journal: Journal of Clinical Oncology (2010)

e15072
Circadian robustness as an independent predictor of prolonged progression-free survival (PFS) and overall survival (OS) in 436 patients with metastatic colorectal cancer (mCRC).
Authors: Francis Levi, Arti Parganiha, Abdoulaye Karaboué, Pasquale F. Innominato, Sylvie Giacchetti, Carlo Garufi, Garance Dispersyn, C. N. J. Focan, Stefano Iacobelli, Georg A Bjarnason, Thierry Moreau, Pierre Antoine Dugue, Jim Waterhouse
Journal: Journal of Clinical Oncology (2012)

464 Background: The rest-activity rhythm is a biomarker of the circadian timing system (CTS), whose disruption accelerates cancer progression in experimental models. Prior studies in cancer pts identified a reliable measure of CTS function in cancer pts based on non invasive wrist actigraphy monitoring. Methods: The prognostic value of I&lt;O, the ratio between activity counts in-bed vs out-of-bed, was explored for PFS and OS in mCRC. The rest-activity rhythm was recorded for &gt;48 h in 436 mCRC pts from 3 international cohorts. Data were stratified per cohort, and analyzed with Kruskall-Wallis ANOVA, log rank tests, and multivariate Cox analyses. Results: Median age was 59.2 y. Pts were mainly men (62.6%); had good performance status (PS = 0, 58.2%; 1, 33%); &gt; 2 metastatic sites (51.6%); metastases in liver (79%) or lung (38.8%); were chemotherapy-naïve (54.6%). After baseline actigraphy recording, pts received a median of 8 courses of oxaliplatin- or irinotecan-based chemotherapy, including chronomodulated schedules (chrono; 81.4%). Despite a strong correlation with PS (p&lt; 0.0001), I&lt;O independently influenced both PFS and OS. Thus, both median PFS and OS nearly doubled in the pts with I&lt;O above 97.5% (upper two quartiles) as compared to those with I&lt;O below 93.2% (lowest quartile). Median PFS ranged from 4.8 to 10.6 months (log rank, p&lt;0.001) and median OS from 10.1 to 20.6 months (p&lt;0.001). In multivariate analyses, I&lt;O ranked as the second best independent predictor of PFS, after metastases surgery, with a hazard ratio (HR) of 0.967 [95% C.L., 0.95-0.98] (p&lt;0.001). I&lt;O ranked as first independent predictor of OS, with a HR of 0.95 [0.94-0.97] (p&lt;0.001). Forrest plots revealed consistent HR of I&lt;O for PFS and OS in each cohort. Conclusions: The circadian biomarker indicator I&lt;O is a robust, consistent and independent quantitative predictor of both PFS and OS in mCRC pts. Rest-activity rhythm monitoring deserves further testing for helping accurate determination of mCRC prognosis. The biological significance of I&lt;O implies that specific treatments of circadian disruption could enhance survival in cancer pts.
Phase I trial of weekly cabazitaxel with concurrent intensity-modulated radiation therapy (IMRT) and androgen deprivation therapy (ADT) for the treatment of high-risk prostate cancer (PCa).
Authors: Jianqing Lin, Robert Benjamin Den, Timothy Norman Showalter, Jean H. Hoffman-Censits, Monica McGuire, Brooke Kennedy, Mark Hurwitz, Edouard John Trabulsi, Costas D. Lallas, Hushan Yang, Ruth C. Birbe, Inna Chervoneva, Adam Dicker, William Kevin Kelly
Journal: Journal of Clinical Oncology (2015)

26 Background: Cabazitaxel (C) improves overall survival and has been approved in second line chemotherapy for patients (pts) with metastatic castrate resistant PCa. We hypothesized that C is a radiosensitizer and performed a phase I trial of weekly C with standard IMRT and ADT for pts with high risk localized PCa. Methods: Conventional “3 + 3” design. Pts with newly diagnosed high risk PCa defined as either Gleason score (GS) 8 – 10, or T3/T4 with GS 7, or PSA &gt; 20 with GS 7 are eligible. Dose escalation occurred only after all the cohort pts completed weekly C ( 4 cohorts at the dose of 4, 6, 8 and 10 mg/m 2 ) and the total planned dose IMRT. ADT was started two months prior to C and IMRT then continued on for a total of 24 months. Daily bicalutamide started within 1 day to 2 weeks prior to LHRH agonist therapy and stopped on the last day of IMRT for approximately 4 month duration. IMRT is delivered to a total dose of 75.6 Gy at 1.8 Gy daily fraction for 8.5 – 9 wks. The primary objective of this study was to determine the safe dose of the combination of weekly C with IMRT and ADT . Results: At present, 14 pts of mean age 62 yrs (range 53 – 82), T2 - T4; mean PSA 89 (range 4 – 253); and median GS 9 (GS 7 – 10) were enrolled and 10 pts completed the chemo-radiation therapy. Grade 3 dose-limiting toxicites in the first two pts at the 8 mg/m 2 C dose level were diarrhea and elevated transaminase, thus the maximum tolerable dose (MTD) of C with IMRT was determined to be 6 mg/m 2 . An expansion cohort is ongoing. In this dose level, there were ≤ grade 2 toxicities only (diarrhea, hypophosphatemia and leukopenia). No long term toxicities are observed. Standardized measurement of health status and quality of life will be presented. Conclusions: Concurrent weekly C with current standard IMRT is feasible with no unexpected toxicity. In combination with IMRT and ADT, the MTD of weekly C is 6 mg/m2 in pts with newly diagnosed high risk PCa. Clinical trial information: NCT01420250.
Focal nodular prostatic peripheral zone enhancement on CT to predict clinically significant (Gleason 4+3 and higher) prostate cancer.
Authors: Daniel I. Glazer, Matthew S. Davenport, Richard H. Cohan, James H. Ellis, Elaine M. Caoili, Erica B. Stein, John C. Childress, William R. Masch, Jordan M. Brown, Brett J. Mollard, Jeffrey S. Montgomery, Ganesh S. Palapattu, Isaac R. Francis
Journal: Journal of Clinical Oncology (2014)

173 Background: CTs are insensitive for prostate cancer and inaccurate for local prostate cancer staging. However, enhancing peripheral zone nodules can be seen on a CT, and their significance is uncertain. The purpose of this study was to determine whether focal nodular enhancement within the prostatic peripheral zone on a CT is predictive of clinically significant prostate cancer. Methods: Institutional review board approval was obtained and informed consent waived for this Health Insurance Portability and Accountability Act-compliant retrospective study. Forty-three patients with high-grade prostate cancer (Gleason 4+3 [n=14], 3+5 [n=1], 4+4 [n=1], 4+5 [n=19], 5+4 [n=8]) and 96 with cystoprostatectomy-confirmed low-grade (Gleason 3+4 [n=24], 3+3 [n=23]) or absent (n=49) prostate cancer imaged with contrast-enhanced CT within nine months of histology (median: 18 days) comprised the study population. CT images were reviewed by 10 blinded radiologists (five attendings, five residents) who scored peripheral zone enhancement on a scale of 1 (benign) to 5 (malignant). Focal nodular enhancement was considered malignant. Likelihood ratios (LR) and specificities were calculated. Results: Scores of ‘5’ were strongly predictive of clinically significant prostate cancer (pooled LR+: 9.6 [95% CI: 5.8-15.8]) with rare false positives (pooled specificity: 0.98 [942/960, 95% CI: 0.98-0.99]). Attendings outperformed residents (LR+: 14.7 [95% CI: 5.8-37.2] vs. 7.6 [95% CI: 4.2-13.7]) with similar specificity (0.99 [475/480, 95% CI: 0.98-1.00] vs. 0.97 [467/480, 95% CI: 0.96-0.99]). Conclusions: Focal nodular peripheral zone enhancement on a CT is specific and predictive of clinically significant prostate cancer.
Role of New Tyrosine Kinase Inhibitors in Osteoblastogenesis
Authors: Daniele Tibullo, Cesarina Giallongo, Piera La Cava, Provvidenza Guagliardo, Maide Cavalli, Alessandra Romano, Concetta Conticello, Annalisa Chiarenza, Giuseppe A. Palumbo, Francesco Di Raimondo
Journal: Blood (2008)
Avoidance of futile treatment and adverse events by using angiogenesis-specific imaging for early detection of disease progression in patients with first-line metastatic renal cell carcinoma.
Authors: Stephen K. Gruschkus, Carolyn Bodnar, Amol Dhamane, Manan Shah
Journal: Journal of Clinical Oncology (2012)

134 Background: Although sunitinib is effective first-line therapy (1LT) for metastatic renal cell carcinoma (mRCC), ~20% of patients experience rapid progressive disease (PD). Traditional RECIST monitoring often does not detect PD until 90 days after 1LT initiation. Investigational angiogenesis-specific imaging (AI) may identify PD as early as 14 days post-1LT initiation, thus allowing a switch to a potentially more effective second-line therapy and avoiding unnecessary risk of AEs. This study’s goal was to quantify the potential reduction in futile 1LT length, AEs, and costs by using AI for early detection of PD. Methods: Decision modeling with a 90-day horizon evaluated a comparator arm using RECIST monitoring at 90 days and an intervention arm using AI at 14 days. Sunitinib costs were $21,250 for the comparator arm and $13,282 for the intervention arm. RECIST costs were $619 and AI costs were tested as a breakeven analysis. A literature review quantified AE rates associated with 1LT sunitinib and claims data were used to determine costs. Early PD detection was estimated based on a 20% rapid PD rate. Results: For AI sensitivity of 50% to predict rapid PD, a 38-day reduction in futile 1LT could be achieved per PD patient by using AI vs. RECIST (AI sensitivity of 75%/100% yielded 57/76 fewer days). The potential number of AEs avoided through early PD identification is shown below. Costs saved per 1,000 mRCC patients were $684,566 for AEs and $3,187,400 for futile 1LT. Based on these results, $3,872 per mRCC patient would be freed up for AI. Conclusions: Continuing 1LT after PD brings unnecessary risk of AEs and delays potentially effective 2nd-line therapy. Results of this study indicate that early PD identification using AI may improve quality of care by minimizing duration of futile 1LT and avoiding unnecessary AEs. [Table: see text]
Antagonist effect of the androgen-receptor activity and IKKe expression in prostate cancer xenograft growth.
Authors: B. Péant, Y. Huon, A. Poisson, K. Leclerc-Desaulniers, N. Delvoye, A. Mes-Masson, F. Saad
Journal: Journal of Clinical Oncology (2011)

e15183 Background: The androgen receptor (AR) is central to the initiation and growth of prostate cancer (Pca) as well as to its response to androgen deprivation therapy. We have previously shown that CR PCa cell lines lacking AR expression (PC-3 and DU145) exhibit high constitutive IKKe expression, whereas only very low IKKe expression is observed in HS PCa cell lines (LNCaP and 22Rv1). We also found that TNF-alpha-induced IKKe expression is inhibited by an androgen-analog (R1881) in HS PCa cells. Based on these results, we put forth the hypothesis that the IKKe-AR interaction is important in the control of PCa progression. Methods: We developed a sub-cutaneous xenograft PCa model expressing IKKe following the induction with doxycycline (dox). This model makes use of the dox-inducible 22Rv1-6TR-pTrexIKKe cells, as well as pTrexLacZ-inducible controls. The cells were mixed with matrigel prior to injection into the flank of SCID mice to limit their spread and to allow the formation of better-defined tumors. Half of the studied mice were castrated one week prior to tumor cell injection. Dox was delivered through dox-supplemented food (625 mg/kg) to minimize stress. Mice were sacrificed when the tumor volume reached 2,500 mm3, in accordance with institutional guidelines. Results: We performed a large-scale experiment (108 mice) to study the effect of androgen depletion on the in vivo proliferation of HS 22Rv1-pTrexIKKe cells. No dehydration or weight loss due to the diet was observed. We did not find any difference in the proliferation rate of 22Rv1-pTrexIKKe and 22Rv1-pTrexLacZ cells injected in castrated mice fed with normal or dox-supplemented diet. As expected, 22Rv1-pTrexIKKe and 22Rv1-pTrexLacZ cells injected in castrated mice had a lower proliferation rate than cells injected in uncastrated mice fed with normal diet. Surprisingly, we observed an important decrease in the growth rate of the 22Rv1-pTrexIKKe xenografts in uncastrated SCID mice fed with the dox-supplemented diet compared to all the other groups. Conclusions: These results provide the first evidence for the opposing role of IKKe and AR in HS PCa cell proliferation and survival. These observations may be significant in the development of CR PCa.