tbuckley/cabot-search huggingface dataset:
Population profiles of extra-ovarian and ovarian serous adenocarcinomas: Comparisons with grade stratification
Authors: P. M. Grimley, R. Matsuno, W. F. Anderson
Journal: Journal of Clinical Oncology (2009)

e16506 Background: Molecular studies of ovarian serous adenocarcinomas (OSC) have linked distinct patterns of gene expression or mutations to high or low tumor grade. This heterogeneity appears to be mirrored in two population subgroups delineated by age-specific incidence rates (ASIR) stratified by grade. We aimed to determine whether serous adenocarcinomas of the peritoneum (PSC) or fallopian tubes (FSC) comprised grade-related subgroups comparable to OSC. Methods: Data for women with invasive OSC (25,997 cases), PSC (2,157), and/or FSC (618) registered in the NCI's Surveillance, Epidemiology, and End Results program (1976–2005) were analyzed. Incidence rates (IR) stratified by grade were compared by year or age of diagnosis. Descriptive analyses were supplemented with tests for trend or age interaction by grade. Cancer-specific survival also was compared by grade (Kaplan-Meier estimator). Results: We observed trend interactions by grade for OSC, PSC, and FSC (p &lt; 0.001); age-adjusted incidence rates rose more rapidly for high than low grade tumors over time. ASIR for OSC/PSC were higher for low than high grade tumors prior to age 40 years, after which rates became higher for high grade (p &lt; 0.001 for age interaction by grade). ASIR were similar for FSC but interpretation was limited by small sample sizes. Unilateral carcinomas were far more common for FSC than OSC (90.9% versus 40.6%). Actuarial cancer-specific cumulative survival was worse for high than low grade tumors (all anatomic sites). Conclusions: Trend and survival analyses both were consistent with a biologically significant high/low grade stratification of OSC, PSC, and FSC. For PSC, significant correlations to ASIR by high/low grade were consistent with two population subgroups as defined for OSC; and also appeared congruent with molecular models that project dual pathways of carcinogenesis. For FSC, definitive correlations will require larger sample sizes. No significant financial relationships to disclose.
Molecular pharmacodynamic (MPD) evaluation of dose and schedule of RAD001 (everolimus) in patients with operable prostate carcinoma (PC)
Authors: E. Lerut, T. Roskams, E. Goossens, D. Bootle, S. Dimitrijevic, M. Stumm, N. Shand, H. van Poppel
Journal: Journal of Clinical Oncology (2005)

3071 Background: RAD001(R) is a novel protein kinase mTOR-inhibitor. Activation of the PI-3K/AKT/mTOR pathway has been frequently associated with prostate cancer. This study aims to determine dose and dosing schedule effects of R on tolerability and MPD modifications of mTOR pathway signaling in patients with newly-diagnosed PC requiring prostatectomy. Methods: Consenting patients with newly-diagnosed, localized PC are treated for 4 weeks with R prior to radical prostatectomy in successive cohorts administered as either weekly (30mg, 50mg, or 70mg) or daily (5mg or 10mg) doses. Passage from one cohort to the next depends on the dose-limiting toxicity (DLT) rate during the 4 week treatment period. Diagnostic ultrasound-guided core biopsy (pre-treatment) and the whole prostatectomy (post-treatment) is processed and evaluated by immunohistochemistry (IHC) using a standardized methodology. Changes in IHC scores for total and phosphorylated forms of S6, AKT and 4E-BP1 between core biopsy and radical prostatectomy are evaluated by two pathologists blinded for patient identification. Exploratory multivariate analysis is applied to IHC Results: Results: Fifteen patients have completed treatment: 4 patients in each of the 30 and 50mg/week, 5mg/day cohorts, and 3 patients in the 10mg/day cohort. No DLT has been observed. Most frequently observed adverse events are CTC grade 1–2 stomatitis and rash. IHC analyses are ongoing. Current observations on first 15 patients indicate highly heterogeneous phospho-S6(PS6) staining in hyperplasia, intraepithelial neoplasia and cancer cells, no correlation between IHC score for PS6 and Gleason score or proliferation index and indication of a reduced IHC score of phospho-S6 staining after treatment with R. If present, staining is located in the periphery of the tumor and in penetrating, invasive strands (e.g. areas of extraprostatic extension and perineural invasion). Conclusions: R is tolerated by patients with localized PC at doses investigated. IHC evaluations are ongoing with early results indicating pharmacodynamic effect of R at molecular level in the prostate tissue. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharma AG Novartis Pharma AG
Quantitative aspects of failure mode and effects analysis (FMEA) scoring in a prospective safety study of a large academic radiation oncology department.
Authors: S. A. Terezakis, L. Myers, R. Bell, A. Souranis, D. Y. Song, R. C. Zellars, T. L. DeWeese, E. C. Ford
Journal: Journal of Clinical Oncology (2010)

6153 Background: Failure mode and effects analysis (FMEA) is used in multiple industries to prospectively evaluate system safety and reliability. Using FMEA, we performed a systematic risk analysis in the radiation oncology (RO) setting. Methods: A visual map of the external beam RO process was created and divided into four sub-processes: consultation (C), simulation (SM), treatment planning (TP) and treatment delivery (TX). An 11-member cross-sectional, department committee reviewed the map to identify possible failure modes. Each mode was scored by 10 individuals and assigned a risk probability number (RPN) based on severity (S), frequency (F), and detectability (D). A 10-point scale, determined by consensus, was used to score each category. Modes within the S sub-process were re-scored by committee consensus. A higher RPN correlated with importance of a failure. A two-tailed t-test was used for significance. Results: The process map consisted of 269 different nodes and 131 failure modes were identified with RPNs from 8 to 240. The mean (± standard deviation) RPNs calculated for the C, SM, TP, and TX were 79.4 (± 33.2), 73.1 (± 26.1), 76.7 (± 24.1), and 87.2 (± 25.0), respectively. The mean RPN for TX was significantly greater (p < 0.003) than all other sub-processes. For TX, the mean S, F, and D scores were 6.6 (± 1.2), 3.3 (± 0.6), and 3.9 (± 0.7) compared to 4.9 (± 1.2) (p < 0.001), 3.9 (± 0.7) (p < 0.001), and 4.1 (± 1.5) (p < 0.05) for all other sub-processes. For the S sub-process, the group and individual mean scores were concordant for S and F of the failure and the total RPN. The individual mean D score, 4.1 (± 1.2) was significantly greater than the group, 3.6 (± 2.0) (p < 0.006). Conclusions: This first analysis using the validated FMEA tool systematically and quantitatively identified vulnerabilities in a complex, academic RO process before an error occurred. Relative RPNs can prioritize the risk of system failures and select interventions for safety improvement. Such an analysis could be used in other process-intensive oncologic areas. This serves as the basis for ongoing work in the appropriate application and limitations of FMEA for error reduction in medicine. No significant financial relationships to disclose.
Paclitaxel injectable emulsion: phase 2a study of weekly administration in patients with metastatic or locally advanced unresectable or recurrent urothelial transitional cell cancer (TCC)
Authors: A. Gorelov, S. Gorelov, P. Karlov, O. Golubeva, M. Stewart
Journal: Journal of Clinical Oncology (2004)

4586 Background: Paclitaxel Injectable Emulsion (PIE; TOCOSOL™ Paclitaxel) is a convenient, ready-to-use, Cremophor®-free unmodified paclitaxel product administered over 15 min. Methods: As part of a Phase 2A program, a multicenter study of second line PIE was performed in taxane-naïve patients (pts) with metastatic or locally advanced, unresectable or recurrent TCC who progressed after cisplatin (cis)-based therapy. PIE was given IV over 15 min weekly to dose cohorts of 80, 100, and 120 mg/m2. Results: 27 pts were enrolled: median age = 65 yrs; 26/1 M/F; median ECOG PS=1; 3 Stage II, 16 Stage III, and 8 Stage IV (6 M1). Prior chemo: cis alone, 11 pts; MVAC or cis/gemcitabine, 12; cis + another agent, 4 pts. By study design, 6 pts received 80, 15, 100 and 6, 120 mg/m2/wk. Therapy is complete; follow-up for progression and survival continues. Grade 3–4 toxicities in more than 5% of pts across the entire Phase 2A program (n=145) included neutropenia (G3 17%; G4 16%; febrile 2%), anemia (G3 11%; G4 1%), peripheral neuropathy (G3 9%; G4 0%) and dyspnea (G3 4%; G4 1%). Infusion-related symptoms were generally mild and resolved without treatment if the infusion was interrupted for several min. In the TCC study, pts received PIE for 1 to 32 (median 16) weeks. PIE was dc'd in 3 pts who were treated surgically, in 8 for unspecified reasons, in 7 because of adverse events and in 2 due to investigator decision; 2 pts were lost to follow-up and 5 had progressive disease. Objective responses by RECIST are summarized in the table.Conclusion: PIE is well tolerated and shows encouraging efficacy given on a weekly schedule by 15-min infusion in pts with TCC who have progressed after platinum-based therapy. Objective responses are encouraging and have resulted in the initiation of a confirmatory, multicenter phase 2B trial under FDA Fast Track designation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PSI Pharma Support Intl; Sonus Pharmaceuticals Sonus Pharmaceuticals Sonus Pharmaceuticals Sonus Pharmaceuticals
An ENU Mutagenesis Screen of FLT3-ITD Knock-in Mice Identifies Novel Gene Mutations That Lead to an Exacerbated Myeloproliferative Neoplasm
Authors: Anna L Brown, Teresa Sadras, Grant A Engler, Robert Tunningley, Jennifer Kofler, Paul J Leo, Jesse Cheah, Adrienne Laskowski, Ann Frazier, David Stroud, Michael Ryan, David Thorburn, D Gary Gilliland, Ian D Lewis, Thomas J Gonda, Richard J D'Andrea
Journal: Blood (2014)
Extra-abdominal fibromatosis: Can aggressive management be avoided in a subgroup of patients?
Authors: S. Bonvalot, H. Eldweny, V. Haddad, G. Missenard, D. Vanel, P. Terrier, O. Oberlin, A. Le Cesne, C. Le Péchoux
Journal: Journal of Clinical Oncology (2007)

10077 Background: The objective was to evaluate the impact of surgery as first-line treatment on event -free survival (EFS) of primary aggressive fibromatosis. Methods: Treatments were categorized into: surgery with or without radiotherapy and non surgical strategies with systemic treatment alone or wait and see policy. Event-free survival curves were estimated using the Kaplan-Meier method. Results: The sex ratio was 39 males/73 females. The median age at the time of the first diagnosis was 30 years. The median size of the primary was 60 mm. Eighty-nine patients (79.5%) had initial resection of their primary tumor followed by postoperative radiotherapy in 13 cases. Twenty-three patients (20.5%) did not undergo surgery but received systemic treatment or watch and wait policy. Median follow-up was 76 months. Three years EFS was 49%. In the univariate analysis, patients with microscopically complete surgery had a similar outcome to that of patients in the non-surgery group (65% vs 68% for 3-yr EFS respectively). Gender, age, tumor size, treatment period and strategy (surgery versus no surgery) were not statistically significant. Quality of resection according to margins and the tumor site were the only prognostic factors. There was a significant correlation between the tumor site and the quality of surgery (p= 0.0002). Tumor site was the only prognostic factor that remained in the multivariate analysis. Conclusions: Surgical removal as initial treatment was not found to influence the outcome. A subset of patients could be managed with a non aggressive policy. When surgery is finally necessary, it should be performed with the aim of achieving negative margins. Predictive biological factors influencing tumor evolution have to be defined No significant financial relationships to disclose.
Phase I/II trial of the anti-idiotypic monoclonal antibody ACA125 in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer
Authors: F. Hilpert, P. Harter, S. Reinartz, J. Sehouli, S. Loibl, U. Canzler, A. Belau, A. Reuss, C. Jackisch, J. Pfisterer
Journal: Journal of Clinical Oncology (2005)

5018
Prognostic role of dendritic cells and T lymphocytes in the clinical outcomes of stage III ovarian cancer.
Authors: W. Ding, M. J. Maurer, K. Kalli, L. Murphy, L. C. Hartmann, K. L. Knutson, A. C. Clayton
Journal: Journal of Clinical Oncology (2010)

5069 Background: Effector T cells associate with better outcome in ovarian cancer while regulatory T cells associate with worse outcome. A prognostic role for other immune cells is unknown. Full understanding of the complex immune microenvironment may augment newer targeted therapies. Methods: Immunohistochemical staining for CD20, CD3, CD11c, and CD68 was performed on 52 frozen specimens obtained from high-grade serous stage III ovarian cancers treated with optimal cytoreductive surgery and paclitaxel-platinum chemotherapy. CD11c staining was graded in 6 different levels as shown in the Table. CD20, CD3, and CD68 staining were graded as 0, 1+, 2+, 3+ in both intratumoral and stromal regions by a gynecological pathologist who was blinded to patient outcome. Cox proportional hazards models were used to assess univariate relationships between immune markers and overall survival (OS). Results: Individual immune marker staining is shown in the attached table. Increased stromal CD11c+ dendritic cells was associated with poor OS [HR per category increase = 1.23, 95% CI: (1.00-1.52), p = 0.05]. The median survival for stromal CD11c+ cells less than 25% or more than 25% is 53 .1 or 31.5 months, respectively. In addition, patients with tumor- infiltrating T cells (tumor CD3 > 0) had improved OS [HR = 0.56, 95% CI: (0.28-1.09), p = 0.09] compared to patients with no tumor infiltrating T cells (tumor CD3 = 0). The median survival for the presence or absence of intratumoral T cells is 44.9 or 32.1 months respectively. Conclusions: Our results are consistent with previous finding that T cells have a key role in the antitumor immune response and also suggest that dendritic cells in the tumor stroma may contribute to the profound immune suppressive microenvironment in advanced ovarian cancer. Marker 0 1+ 2+ 3+ CD20 27 (52%) 20 (38%) 4 (8%) 1 (2%) Tumor Stroma 14 (27%) 30 (58%) 6 (12%) 2 (4%) CD3 12 (23%) 21 (40%) 15 (29%) 4 (8%) Tumor Stroma 2(4%) 17(33%) 19(36%) 14(27%) CD68 5 (10%) 20 (38%) 13 (25%) 14 (27%) Tumor Stroma 1 (2%) 6 (12%) 20 (38%) 25 (48%) Marker 0 <5% 5-10% 10-25% 25-50% 50-100% CD11c 1 (2%) 10 (19%) 18 (35%) 13 (25%) 7 (13%) 3 (6%) Tumor Stroma 1 (2%) 7 (13%) 10 (19%) 5 (10%) 16 (31%) 13 (25%) No significant financial relationships to disclose.
Randomized proteomic stratified phase III study of second-line erlotinib (E) versus chemotherapy (CT) in patients with inoperable non-small cell lung cancer (PROSE).
Authors: Chiara Lazzari, Silvia Novello, Sandro Barni, Michele Aieta, Filippo De Marinis, Tommaso De Pas, Francesco Grossi, Manlio Mencoboni, Alessandra Bearz, Irene Floriani, Valter Torri, Alessandra Bulotta, Julia Grigorieva, Joanna Roder, Claudio Doglioni, Heinrich Roder, Luisella Righi, Silvia Foti, Angela Bachi, Vanesa Gregorc
Journal: Journal of Clinical Oncology (2013)

LBA8005 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Implementing American Heart Association pediatric and adult nutrition guidelines: a scientific statement from the American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity and Metabolism, Council on Cardiovascular Disea
Authors: Samuel S Gidding, Alice H Lichtenstein, Myles S Faith, Allison Karpyn, Julie A Mennella, Barry Popkin, Jonelle Rowe, Linda Van Horn, Laurie Whitsel
Journal: Circulation (2009)
Preliminary efficacy and safety results of masitinib administered, front line in patients with advanced GIST. A phase II study
Authors: B. N. Bui, J. Blay, F. Duffaud, O. Hermine, O. Hermine, A. Le Cesne
Journal: Journal of Clinical Oncology (2007)

10025 Background: Masitinib mesylate (MM; AB1010) is a protein tyrosine kinase inhibitor (tki) which, in vitro, has greater activity and selectivity than imatinib mesylate (IM) against the wild-type c-Kit receptor and the mutated form in the juxtamembrane region. MM also inhibits the PDGF and FGFR3 receptors. A phase I trial has shown MM safety and tolerability in patients (pts) with different tumor types. One pathological complete response was observed in a pt intolerant to IM. This evidence led to a multicenter phase II trial in non pretreated GIST pts. Methods: Twenty-six pts with advanced or metastatic GIST tumors naive to IM treatment were recruited by the end of October 2006. MM was given orally at the dose of 7.5 mg/Kg/d. Results: Preliminary results are available from 21/26 pts enrolled so far. There were 13 male, 8 female) with a median age of 61 years (range 33–81). The mean tumor size was 104 mm (29- 254), primary tumor origin was in the stomach in 8 cases and small intestine in 9 cases. At pathological review one patient was found to have a low grade stromal uterine sarcoma. After a median follow up of 9 months (4–15), 11/21 (52.4%) patients achieved a partial response, 8(38.1%) are in stable disease; 2 (9.5%) were considered in progression. Three PR were observed in patients with a primary in the lower GI tract and 7 in patients with gastric primary GIST. The low grade uterine sarcoma also showed PR. The progression occurred after 8 weeks in a pt with primary gastric origin, who failed also IM treatment afterwards. The most frequent AEs related to the study drug were Asthenia (observed in 15% of patients), Periorbital oedema, Muscle spasm, Nausea (40% each), Abdominal pain (35%), Rash, Abdominal pain upper, Diarrhea (30 % each) and Vomiting (25 %). Two patients stopped treatment at 87 and 189 days due to skin toxicity G3. Conclusions: These preliminary results, obtained in a small homogeneous population of patients with GIST naïve to IM treatment, show high efficacy of MM and warrant further trials to confirm the efficacy and complete the safety evaluation of this promising TKI. Definitive results and analysis of KIT/PRGFR mutational status will be presented during meeting. No significant financial relationships to disclose.
Pegylated liposomal doxorubicin (PLD) plus cyclophosphamide as 1<sup>st</sup>-line therapy for metastatic breast cancer in patients previously treated with anthracyclines
Authors: M. E. Trudeau, L. Provencher, L. Panasci, L. Yelle, J. Latreille, T. Vandenberg, D. Rayson, A. Rodgers, J.-F. Pouliot
Journal: Journal of Clinical Oncology (2005)

745 Background: Anthracyclines are among the most active drugs used for the treatment of breast cancer. Utilization in advanced disease however, is limited by their intrinsic dose limiting cardio-toxicity and extensive exposure in the adjuvant setting. Pegylated Liposomal Doxorubicin (Caelyx/Doxil) has been shown to possess similar activity to conventional doxorubicin, with a more favorable toxicity profile and significantly less cardiotoxicity. Cyclophosphamide is commonly used in combination with anthracyclines, thus represents an interesting drug to use with PLD. Methods: We undertook a multi-center single arm phase II trial to assess the safety and efficacy of PLD 35mg/m2 in combination with cyclophosphamide 600 mg/m2 every 3 weeks. Eligibility criteria included: Measurable disease, prior anthracyclines exposure >12 months prior to study entry, adequate organ and bone marrow function. A 2 stage design was implemented with planned accrual of 70 patients if an objective response rate of ≥ 28% was observed in the first 25 patients in the absence of significant cardiac or other severe toxicities. Results: Previous adjuvant therapy included cyclophosphamide, doxorubicin, epirubicin, 5-Fu and taxanes in 90%, 59%, 41%, 30% and 27% of cases, respectively. Patients received a median of 4 cycles (4–10) of PLD and no major toxicity has been reported after the first 30 patients. Four patients experience asymptomatic >10% declines in LVEF that was reversible upon discontinuation of PLD. The incidence of hand foot syndrome (HFS) was relatively low (13%); only one patient stopped therapy due to grade 3 HFS. Other toxicities were uncommon and usually did not lead to discontinuation of therapy. An early efficacy analysis revealed a 32% objective response rate exceeding the predefined stopping rule. The study is now moving forward to the second stage. Conclusions: The combination of PLD with Cyclophosphamide given every 3 weeks is a safe and active combination in advanced breast cancer patients who relapse more then one year after completion of adjuvant therapy with anthracyclines. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Canada, Aventis, Pfizer, Roche Canada AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Pfizer, Schering Amgen Canada, AstraZeneca, Aventis, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Pfizer
Phase I dose escalation study and biomarker analysis of E7080 in patients with advanced solid tumors
Authors: K. Yamada, T. Hirata, Y. Fujiwara, H. Nokihara, N. Yamamoto, Y. Yamada, F. Koizumi, K. Nishio, N. Koyama, T. Tamura
Journal: Journal of Clinical Oncology (2008)

3527 Background: E7080 is an oral multi-targeted kinase inhibitor of VEGFRs, PDGFRs, FGFRs and c-kit. Methods: This study was designed to determine the safety, PK, PD and preliminary efficacy of E7080 in patients with advanced solid tumor. E7080 was orally given twice daily by 2 wks-on/ 1 wk-off in 1 cycle. Plasma angiogenic proteins (VEGF, PDGF, bFGF) and circulating endothelial cells (CEC) and progenitors (CEP) were measured for biomarker analysis. Results: 24 evaluable patients (10 males, 14 females, median age 53 yrs, all in PS 0 or 1) were enrolled. Tumor types included colorectal (7), sarcoma (7), non-small cell lung (4), and others (6). Dose was escalated from 1 mg/day to 2, 4, 8, 12, 18, 26 and 40 mg/day by conventional 3 patient cohort. No Gr3 or Gr4 toxicity was observed during cycle 1 at doses up to 26 mg/day. Gr3 thrombocytopenia was seen in 2 patients at 40 mg/day and the dose escalation was terminated. Gr2 or Gr3 thrombocytopenia was seen in 6 patients (25%) during all cycles and recovered during 1 wk-off period. Gr2 or Gr3 hypertension was seen in 15 patients (63%) and proteinuria in 9 patients (38%). Other toxicities included the increases of GOT, GPT, and gamma-GTP. Disease control for 6 cycles and more was seen in 8 patients (33%) including 1 PR in colorectal cancer at 4 mg/day. Pharmacokinetic analysis showed that Cmax and AUC increased linearly with dose. Plasma VEGF increased during 2-wk treatment at 12, 18 and 26 mg/day, but PDGF and bFGF did not. C- kit(+) CEP and c-kit(+) CEC decreased in most patients by 2-wk treatment at 1 to 26 mg/day, but c-kit(-) CEP and c-kit(-) CEC did not. Leukocytes did not change at these doses. Conclusions: E7080 has manageable toxicity profiles at doses up to 26 mg/day and shows preliminary activity for durable disease control. Modulation of plasma VEGF, c-kit(+) CEP and c-kit(+) CEC suggest drug activity consistent with anti-angiogenic activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eisai Co., Ltd. Eisai Co., Ltd.