tbuckley/cabot-search huggingface dataset:
Abstract 3360: Macrophages promote resistance to pegylated arginine deiminase in malignant pleural mesothelioma
Authors: Melissa M. Phillips, Ramsay Khadeir, Laura Tookman, Fiona McCarthy, Jeremy Steele, John Bomalaski, Essam Ghazaly, Peter W. Szlosarek
Journal: Cancer Research (2015)

Abstract Background Approximately 50% of all malignant pleural mesotheliomas (MPM) are deficient in argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine biosynthesis, and are therefore sensitive to arginine deprivation. This discovery in MPM has been translated into the clinic using the arginine depletor pegylated arginine deiminase (ADI-PEG20) which showed a halving in the risk of disease progression in a randomized phase II study (Szlosarek et al, ASCO 2014). However, unstudied to date, stromal resistance to ADI-PEG20 may reduce its efficacy. Here, we studied the effect of macrophages, which are abundant in mesothelioma, on the tumor cytotoxicity of ADI-PEG20. Methods ASS1 negative MPM cell lines treated with ADI-PEG20 were analysed using the Affymetrix Human Genome U133 Plus 2.0 array, with validation of genes involved in stromal-tumor cell communication. Additional studies involved using tumor-macrophage co-culture experiments, mass spectrometry and an MPM xenograft model. Results A distinct pro-inflammatory cytokine gene expression signature involved in macrophage recruitment and activation was identified in the ADI-PEG20-treated ASS1 negative MPM cell lines. Notably, a significant increase in ASS1 negative MPM cell viability was seen upon co-culture with macrophages in the presence of ADI-PEG20. This was accompanied by a significant increase in ASS1 expression in co-cultured macrophages, with a corresponding increase in argininosuccinate lyase (ASL) expression in co-cultured tumor cells and a doubling in levels of the arginine precursor, argininosuccinate, in cell supernatant. The addition of argininosuccinate to tumor cell media rescued ASS1 negative MPM cells from ADI-PEG20 cytotoxicity, while the macrophage-mediated resistance to ADI-PEG20 was abrogated following ASL knockdown in MPM cells. Finally, xenograft studies demonstrated a significant reduction in tumor volume in mice treated with ADI-PEG20 in combination with macrophage depletion, compared with ADI-PEG20 monotherapy. Conclusion Collectively, our data indicate that as a result of metabolic ‘cross-talk’ between macrophages and ASS1 negative MPM cells, macrophages mediate MPM resistance to ADI-PEG20 via the provision of argininosuccinate. Our studies provide a rationale for combining ADI-PEG20 with an inhibitor of macrophage recruitment in the treatment of ASS1-deficient mesothelioma. Citation Format: Melissa M. Phillips, Ramsay Khadeir, Laura Tookman, Fiona McCarthy, Jeremy Steele, John Bomalaski, Essam Ghazaly, Peter W. Szlosarek. Macrophages promote resistance to pegylated arginine deiminase in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3360. doi:10.1158/1538-7445.AM2015-3360
Neoadjuvant IMC-A12 and combined androgen deprivation with prostatectomy for high-risk prostate cancer: A phase II trial.
Authors: J. P. Dean, S. R. Plymate, B. L. Dalkin, W. J. Ellis, D. W. Lin, J. L. Wright, J. M. Corman, L. D. True, P. H. Lange, R. B. Montgomery
Journal: Journal of Clinical Oncology (2010)

TPS251 Background: IMC-A12 is a fully human monoclonal antibody which targets the insulin-like growth factor receptor 1 (IGF-1R) to inhibit ligand binding and receptor signaling. Preclinical data from the treatment of androgen-dependent human prostate cancer xenografts in immunodeficient mice suggests that the combination of androgen deprivation and IMC-A12 is much more effective than either treatment alone. Nuclear localization of androgen receptor is reduced in treated xenograft tissues, suggesting one potential mechanism for the synergy between androgen deprivation and IMC- A12. We designed a clinical trial to test the benefit of neoadjuvant IMC-A12 and androgen deprivation prior to radical prostatectomy as treatment for prostate cancer. Methods: Eligible men are those with high-risk localized prostate cancer as defined by any one of the following factors: Gleason score ≥8, Prostate-specific antigen ≥20, Clinical stage ≥T2c, or risk for relapse exceeding 50% as defined by the Kattan nomogram. Men are treated for 3 months with goserelin, bicalutamide, and biweekly IMC-A12 infusions (10 mg/kg). All men receive a pre-treatment prostate biopsy for the purpose of research tissue acquisition. Serum and DNA are collected before, during, and at the end of treatment. The primary objective of the trial is to determine the rate of pathological complete response. Secondary objectives include positive surgical margin and apoptosis rates, as well as androgen receptor localization. Insulin-like growth factor, IGF-1R, and insulin levels in tissue and serum will be examined.The availability of pre- and post-treatment prostate tissues is critical for determination of treatment-related changes in histology, senescence, gene expression, and prostate tissue hormone levels. Accrual of 28 men will provide 80% power to detect a pathological complete response rate of 20%, compared to historical controls of 5% with androgen deprivation alone. To date, 16 men have accrued and 8 men have completed prostatectomy. The scientific and clinical integration of this trial will yield valuable insights into the efficacy and mechanisms of IMC-A12 in localized and advanced prostate cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImClone Systems
Abstract 12554: The Association of Electrocardiographic Findings With Outcomes in Cardiac Amyloidosis
Authors: Nicole B Cyrille, Jeff Goldsmith, Julissa Alvarez, Mathew S Maurer
Journal: Circulation (2013)

Introduction: Classically, electrocardiogaphic (EKG) findings in patients with cardiac amyloidosis include low voltage and pseudoinfarcts. While these findings may be clues to the diagnosis, the as...
A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a continuous schedule in patients with advanced solid tumours
Authors: D. B. Agus, E. Terlizzi, P. Stopfer, A. Amelsberg, M. S. Gordon
Journal: Journal of Clinical Oncology (2006)

2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: BIBW 2992 was administered orally as a continuous once daily dose starting at 10 mg daily and doubled in successive cohorts until observation of drug-related adverse events (AE) ≥ CTC grade 2. Thereafter, escalation steps of no more than 50% were allowed. All pts underwent pharmacokinetic sampling. The enrolled patient population included a variety of advanced solid malignancies, historically known to express EGFR and/or HER2. After reaching DLT, the MTD dose group was expanded to a total of 18 treated at that dose level. Results: To date in this continuing study, twenty-two patients have been included (13 M/ 9 F). Median age: 61.5 (range: 34–80). Administered doses (patients) were 10 (5), 20 (3), 40 (11), and 60 (3) mg in a once daily schedule. Ten pts who completed the initial 28 treatment days were eligible to continue treatment beyond the first treatment cycle. Duration of treatment is up to 7 cycles so far in this ongoing study. A total of three dose-limiting toxicities (DLT) were observed. DLT events were diarrhea (CTC grade 3) and patients recovered fully upon cessation of the drug. The 60 mg dose level was considered dose-limiting with the occurrence of two DLT. The dose level below (40 mg) was expanded to a total of 18 patients. A pharmacokinetic interim analysis (9 pts) showed, in general, increasing exposure to BIBW 2992 with increasing doses at steady state. A high inter-patient variability in all PK parameters was detected. Conclusions: BIBW 2992, in an oral once daily administration of 40mg, is well tolerated with an acceptable toxicity profile. The further evaluation of BIBW 2992 in Phase II clinical trials is warranted. [Table: see text]
Prevalence and severity of chronic diseases in adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study
Authors: K. C. Oeffinger, A. C. Mertens, C. A. Sklar, T. Kawashima, M. M. Hudson, A. Meadows, N. Marina, N. Kadan-Lottick, W. Leisenring, L. L. Robison
Journal: Journal of Clinical Oncology (2005)

9 Background: Survivors of childhood cancer experience a variety of chronic diseases, defined as physical late effects with a potential for serious disability. This analysis was conducted to determine the incidence of chronic diseases in adult survivors of childhood cancer and determine the relative risk compared to sibling controls. Methods: The Childhood Cancer Survivor Study is a retrospective cohort study tracking health outcomes of long-term survivors (> 5 years) who were diagnosed 1970–1986 and a comparison group of siblings. The incidence of chronic diseases occurring in adult (≥ 18 years of age) survivors (N=10397) and siblings (N=3034) were calculated. A severity score, using the Common Terminology Criteria for Adverse Events, v3.0 (grades 1–4), were assigned to each chronic disease. For example, grade 4 diseases included: second malignant neoplasm (excluding non-melanoma skin and thyroid cancer), myocardial infarction or coronary artery bypass surgery, heart transplant, dialysis or kidney transplant, mental retardation requiring special education, and paralysis of an extremity. Cox proportional hazards models were used to estimate hazard ratios, reported as relative risks (RR) and 95% confidence interval (95% CI) of developing a chronic disease between survivors and siblings. Results: Survivors were a mean age of 9.7 years at diagnosis and 26.7 (range, 18–48 years) at evaluation; siblings were 29.2 (range, 18–56 years) at evaluation. Eighty-five percent (8828/10397) of survivors had at least one chronic disease. The cumulative incidence of chronic disease at age 45 in survivors was: 57.1% grade 3 and 37.4% grade 4. In contrast, the cumulative incidence at age 45 in siblings was: 18.2% grade 3 and 4.6% grade 4. The relative risk of a survivor having a grade 3 or 4 chronic disease, adjusted for age at study and gender, was 5.0 (95% CI, 4.7–5.4) compared with siblings. Conclusions: Chronic diseases are common following childhood cancer, with over one-third having a life-threatening illness or chronic disease by age 45. Interventions are needed to reduce the morbidity and mortality associated with long-term survivorship. No significant financial relationships to disclose.
Phase 1/2a study of EKB-569, an irreversible inhibitor of epidermal growth factor receptor, in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) in patients with advanced colorectal cancer (CRC)
Authors: S. Tejpar, E. Van Cutsem, E. Gamelin, D. Machover, P. Soulie, A. Ulusakarya, S. Laurent, J. M. Vauthier, S. Quinn, C. Zacharchuk
Journal: Journal of Clinical Oncology (2004)

3579 Background: EKB-569 is an orally active, low molecular weight, selective, irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase. In animal models, EKB-569 in combination with different chemotherapy agents shows at least additive effects on growth inhibition of colorectal and other tumors. Methods: This open-label, dose-escalation study evaluates the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-tumor activity of EKB-569 in combination with the FOLFOX-4 regimen in patients (pts) with previously untreated advanced CRC. Pts (3–6 per cohort) were to receive EKB-569 (25, 35, 50, or 75 mg/day orally) starting on day 3 in combination with the FOLFOX-4 regimen (day 1: oxaliplatin 85 mg/m2 and leucovorin [LV] 200 mg/m2, 120 min, simultaneously, followed by 5-fluorouracil [FU] 400 mg/m2, bolus, and FU 600 mg/m2, 22-h continuous infusion; day 2: LV and FU as on day 1). Dose escalation was based on safety evaluations after 2 treatment cycles (14 days/cycle). Treatment continues until evidence of disease progression or unacceptable toxicity. Results: Twenty nine pts were enrolled; enrollment is complete. Median age was 61 yrs (range, 46–70); ECOG performance status was 0: 71% and 1: 29%. Dose-limiting toxicities within the first 2 treatment cycles were grade 3 diarrhea (1 pt) and grade 3 febrile neutropenia (1 pt) in the 35-mg cohort. Thus, the MTD was 25 mg EKB-569, FOLFOX-4. For 25 pts, treatment-emergent adverse events (TEAEs), all grades, with frequency ≥ 30% were diarrhea (76%), paresthesia (60%), nausea (48%), and neutropenia (40%). Grade 3 or 4 TEAEs with frequency ≥ 5% were neutropenia (32%) and diarrhea (8%). Of 11 pts who completed ≥ 4 treatment cycles, 4 had partial response (PR), 6 had stable disease (2 pts for ≥ 6 mos, 1 pt with unconfirmed PR), and 1 had progressive disease (RECIST guidelines). Conclusions: EKB-569 at an oral dose of 25 mg in combination with the FOLFOX-4 regimen is generally well tolerated and shows promising antitumor activity in pts with previously untreated advanced CRC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Research Wyeth-Lederle
Weekly cisplatin-epirubicin-paclitaxel (PET) with granulocyte-colony stimulating factor support versus tri-weekly epirubicin-paclitaxel in locally advanced breast cancer: Final comprehensive and subgroup analysis of a SICOG phase III study
Authors: G. Frasci, G. D’Aiuto, P. Comella, R. Thomas, G. Botti, M. Rubulotta, G. Iodice, R. Costanzo, M. Di Bonito, G. Comella
Journal: Journal of Clinical Oncology (2006)

572 Background: We previously reported the preliminary pathological response data of a phase III trial comparing a weekly dose-dense approach (PET) to a standard epirubicin-paclitaxel q3wk combination, in LABC pts. (ASCO 2004; abstr.511). In the present abstract, we report the final data on response and PFS, and a subgroup analysis according to the hormone-receptor, and HER2/neu status. Methods: Overall, 200 patients with stage IIIB disease were randomised to receive either 12 weekly cycles of cisplatin 30 mg/m 2 , epirubicin 50 mg/m 2 , and paclitaxel 120 mg/m 2 (PET) plus granulocyte-colony stimulating factor support, or 4 cycles of epirubicin 90 mg/m 2 + paclitaxel 175 mg/m 2 (ET) every 3 weeks. Results: Overall, a pCR in both breast and axilla occurred in 16 (16%) PET patients and in 6 (6%) ET patients (P=0.02). The higher activity of PET was evident only in ER negative (27.5% vs 5.4%; P=0.026), and in HER/neu 3+ (31% vs 5%; P=0.037) tumours. The 2 arms yielded similar pCR rate in ER positive (PET/ET=7.5%/7.1%) and HER/neu negative (PET/ET=10%/6%) patients. At a 45 months median follow-up, 78 patients showed a progression or relapse (PET= 32 vs ET= 46). The 5-year Failure-free survival rates in PET/ET arms were: Total =27%/21%; ER+= 26%/23%; ER- =25%/9%; HER2+=.18%/11%; HER2- =29%/25%. Conclusions: The PET weekly regimen is superior to ET in terms of pCR rate in LABC patients. The advantage of such an aggressive approach is limited to ER negative and HER2 positive pts. A large randomised trial comparing weekly PET to a standard regimen in ER- LABC pts., with FFS as the main end-point, is highly recommendable. No significant financial relationships to disclose.
Characteristics and prognosis of gastric cancer according to <i>Helicobacter pylori</i>.
Authors: Ji Yeon Seo, Eun Hyo Jin, Hyuk Yoon, Hyun Jin Jo, Cheol Min Shin, Young Soo Park, Nayoung Kim, Hyun Chae Jung, Dong Ho Lee
Journal: Journal of Clinical Oncology (2015)

14 Background: Different features of gastric cancer according to Helicobacter pylori(Hp) infection is still under debate. The aim of this study was to compare clinical, pathologic characteristics and prognosis of gastric cancer between Hp-positive (HpP) and Hp-negative (HpN) gastric cancer. Methods: Patients diagnosed as gastric cancer in Seoul National University Bundang hospital from June 2003 to December 2010 were reviewed. Status of Hp was evaluated by histology and rapid urease test (RUT). Patients who had positive histology and/or positive RUT were classified as HpP. Patients who had atrophic gastritis and/or intestinal metaplasia from histology were also classified as HpP. Patients who had both negative histology and RUT were defined as HpN. Results: The number of patients with HpP and HpN were 852 (62.6%) and 509 (37.4%), respectively. Antral location was more common in gastric cancer with HpP than in those with HpN (51.8% vs 44.9%, P = 0.003). Stage of gastric cancer was higher in patients with HpN than in patients with HpP (stage IV 17.9% vs 9.6%, P &lt; 0.001). Age, sex of patients and Lauren classification of gastric cancer was not different according to Hp status. Recurrence and mortality was significantly higher in patients with HpN gastric cancer than those in HpP gastric cancer (P = 0.002 and P= 0.001). Conclusions: Gastric cancers have different clinical and pathologic features according to the Hp status. Patients with HpN gastric cancers have poorer prognosis than those with HpC or HpP gastric cancers.
A phase I trial using the proteasome inhibitor bortezomib and concurrent temazolomide and radiotherapy for high grade gliomas
Authors: A. Dicker, M. Werner-Wasik, M. Machtay, G. Mallon, M. Ramirez, D. Andrews, W. J. Curran
Journal: Journal of Clinical Oncology (2007)

2061 Background: Improving the response of patients with high-grade astrocytomas continues to remain a challenge despite advances in chemoradiation. Preclinical studies have demonstrated the importance of the NF-kappaB pathway treatment resistance and enhancement of radiosensitivity by proteasome inhibition. This open-label, phase I study evaluated the safety of 3 dose levels (0.7, 1.0, 1.3 mg/m 2 /dose) of intravenously administered bortezomib, a reversible proteasome inhibitor with unique properties in combination with chemoradiation. Methods: Eligible patients had a diagnosis of high-grade glioma. Other requirements included performance status 0–1 and adequate hematologic reserve. Previous radiotherapy and/or chemotherapy was allowed. Patients received fraction sizes of XRT that ranged from 1.8–3.5 Gy/day for total doses between 35–66 Gy. During radiotherapy, temozolomide was administered continuously at a daily dose of 75 mg/m 2 . The starting dose level of bortezomib was 0.7 mg/m 2 / days 1, 4, 8, 11 of 21-day cycle for up to 2 cycles. This was followed by 1.0 mg/m 2 and 1.3 mg/m 2 dose levels. The primary endpoint of the study was dose-limiting toxicity (DLT), defined as any Grade 4–5 toxicity or Grade 3 toxicity(ies) requiring hospitalization and/or XRT interruption. Response was also assessed (1-month post-XRT brain MRI). Results: A total of 27 patients were enrolled. There were no DLTs observed in any dose groups. Grade 1 and 2 toxicities consisted of stomatitis, erythema, and alopecia. Of 24 patients evaluable for response, 1 patient had no evidence of disease, 3 patients had a PR; 9 patients had stable disease and 11 patients had progressive disease. Conclusions: Bortezomib can be combined at full dose with concurrent temozolomide and radiation therapy with minimal adverse effects. Correlative translational endpoints are still pending. The results observed justify further evaluation in a phase II setting. [Table: see text]
Clinical evaluation of a side entry access port: a novel dual-lumen venous access device.
Authors: T S Ravikumar, J Hollingshead
Journal: Journal of Clinical Oncology (1990)

The initial clinical experience with a low-profile side entry access (SEA) dual-lumen implantable venous access port for cancer chemotherapy administration is summarized in this report. The catheter material is polyurethane. The overall experience in 35 patients in this study was a total of 6,224 patient days, with a mean of 178 days per patient. A variety of chemotherapeutic agents, biologic response modifiers, and antibiotics were administered. In 26% of the patients, the device chambers were in simultaneous use during the treatment period. A 6% incidence of clinical subclavian vein thrombosis was noted. There was no infectious complications. Inconsistencies in blood withdrawal and temporary catheter dysfunction were comparable to other access ports in clinical use. The novel design of this side entry port and the catheter material of low thrombogenicity make this device a good option in patients requiring a low-profile system and dual access. Nursing staff should be made aware of the side entry design and that in-service training for accessing the septum is required in centers where such devices are not routinely used.
The importance of imatinib dose intensity in imatinib plus combination chemotherapy in newly diagnosed Ph+ ALL.
Authors: S. Lim, K. Lee, Y. Joo, W. Lee, S. Yoon, S. Sohn, S. Bae, M. Hyun, H. Kim, H. Eom
Journal: Journal of Clinical Oncology (2010)

6563 Background: Several studies showed that a higher CR rate and longer CR duration could be achieved when imatinib was added to the combination chemotherapy for Ph+ALL. Optimum use of imatinib in Ph+ALL, however, remains to be defined. Methods: In November 2005 we initiated a multicenter trial, where patients with newly diagnosed Ph+ALL were administered with remission induction of daunorubicin (DNR), vincristine (VNC), and prednisolone (PD) along with imatinib 600 mg/day from 8th day of chemotherapy. Upon achieving CR, patients with a suitable donor underwent hematopoietic cell transplantation (HCT) after 0-5 cycles of consolidation containing DNR, VNC, PD, etoposide, cytarabine, or methotrexate. Imatinib was given continuously until HCT or throughout the consolidation, then for 2 years. Results: Of 89 patients enrolled, 2 were not evaluated (one CML; one early follow-up loss). The median age of 87 evaluated patients (54 male) was 41 years (range, 16- 71). During induction, 44 patients (51%) had their imatinib dose withheld (48 episodes) or reduced (9 episodes) due to myelosuppresion ± infections (n=23), GI toxicities (n=18), protocol violation (n=6), or others (n=10). Eighty-two achieved CR (94%). Five died during induction (2 sepsis; 3 bleeding). After a median follow-up of 24 months (range, 6-45), 29 patients relapsed giving leukemia-free survival (LFS) of 40%. In all, 38 patients died giving overall survival (OS) of 39%. Univariate analyses showed that age, WBC count at diagnosis, and imatinib dose-intensity during induction were significant factors affecting LFS and OS. Multivariate analyses identified the independent prognostic factors seen in the Table. Conclusions: Our study showed that about a half of patients with newly diagnosed Ph+ALL could not take continuous dosing of imatinib 600 mg/day when given additionally to combination chemotherapy. Imatinib dose-intensity during remission induction was an independent prognostic factor. LFS OS HR (95% CI) P HR (95% CI) P Age, ≥ 60 yrs 1 1 < 60 yrs 0.031 (0.01-0.12) <0.001 0.34 (0.13-0.89) 0.027 WBC at diagnosis, > 50 x 109/L 1 ≤ 50 x 109/L 0.31 (0.10-0.95) 0.040 Not significant Imatinib dose-intensity, <90% 1 1 ≥90% 0.26 (0.11- 0.60) 0.002 0.46 (0.23-0.94) 0.032 No significant financial relationships to disclose.