tbuckley/cabot-search huggingface dataset:
Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein, on chemotherapy-induced multilineage myelosuppression in patients with sarcoma.
Authors: S Vadhan-Raj, N E Papadopoulos, M A Burgess, K A Linke, S R Patel, C Hays, A Arcenas, C Plager, A P Kudelka, W N Hittelman
Journal: Journal of Clinical Oncology (1994)

PURPOSE To evaluate the clinical safety and ability of PIXY321, a novel fusion protein of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), to ameliorate chemotherapy-induced multilineage myelosuppression. PATIENTS AND METHODS PIXY321 was administered by subcutaneous injection twice daily (25 to 1,000 micrograms/m2/d) over 14 days to 24 chemotherapy-naive patients with sarcoma in a phase I/II study. Three weeks from the initiation of PIXY321, the first cycle of chemotherapy with cyclophosphamide, doxorubicin, and dacarbazine (DTIC) (CyADIC) was administered over 3 days. Four weeks later, a second cycle of CyADIC was administered, followed by 14 days of PIXY321. RESULTS Treatment with PIXY321 was well tolerated. Local skin reactions and constitutional symptoms were the main side effects. The dose-limiting toxicity was not encountered; however, headache and fatigue were more frequent at the highest dose (1,000 micrograms/m2). PIXY321 before chemotherapy elicited a modest increase in the WBC count (consisting mainly of mature neutrophils), platelets, and corrected reticulocyte counts (all P &lt; .001). Following chemotherapy, PIXY321 at effective doses (500 to 1,000 micrograms/m2/d), significantly reduced both the degree (mean nadir, 70 v 310/microL; P = .016) and duration (mean days &lt; 500/microL, 6.6 v 3.9 days; P = .002) of neutropenia. Cumulative thrombocytopenia was not observed during the first two cycles of CyADIC (mean nadir platelet count, 103 v 95 x 10(3)/microL, in cycles no. 1 and 2, respectively; P = NS). Compared with our historic control data, the mean nadir platelet count in cycle no. 2 was significantly higher after PIXY321 (1.7-fold, P &lt; .05) than with CyADIC alone or with GM-CSF support. There was a suggestion for a dose response, since the mean percentage change in nadir platelet values from cycle no. 1 to cycle no. 2 increased with the PIXY321 dose (P &lt; .02), with the peak effect observed at 750 micrograms/m2/d. CONCLUSION These results suggest a potential clinical role for PIXY321 in attenuating the cumulative multilineage hematopoietic toxicity of chemotherapy.
A phase III, randomized, double-blind, placebo-controlled study of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated subjects with locally advanced or metastatic, nonsquamous, non-small cell lung cancer (NSCLC) .
Authors: A. Sandler, J. H. Schiller, V. Hirsh, L. V. Sequist, J. Soria, J. Von Pawel, Q. Wang, A. U. Pande, B. E. Schwartz, E. G. Garmey, I. Gorbatchevsky, G. Scagliotti
Journal: Journal of Clinical Oncology (2011)

TPS217 Background: ARQ 197 (A) is a selective, oral, non–ATP-competitive, small-molecule inhibitor of the c-MET receptor tyrosine kinase, which is implicated in tumor cell migration, invasion, proliferation, and metastasis. The EGFR tyrosine kinase inhibitor (TKI), erlotinib (E) is approved for the treatment of advanced or metastatic NSCLC after failure of ≥ 1 prior chemotherapy regimen. Resistance to EGFR TKI in EGFR mutation-positive NSCLC is associated with amplification of c-MET. A + EGFR TKI showed greater preclinical antitumor activity than either drug alone. A randomized, placebo-controlled, phase II study in previously-treated metastatic NSCLC patients (pts) showed that E + A prolongs progression free survival, overall survival (OS), and delays the onset of new metastases compared to E alone in pts with non-squamous NSCLC (J Clin Oncol 28:18s, 2010 (suppl; abstr LBA7502). Methods: A follow-up phase III trial has been initiated. Eligible patients must have locally advanced unresectable or metastatic non-squamous NSCLC previously treated with 1 or 2 lines of systemic anticancer therapy, of which one must be platinum-doublet therapy; pts must be EGFR TKI naïve; have ECOG performance status ≤ 1, adequate organ function; measurable disease by RECIST, and archival tumor tissue available for histology, EGFR, KRAS, and c-MET testing. Pts treated with only adjuvant therapy are eligible if progression occurred < 6 months after completion of treatment. Pts with clinically unstable CNS metastases are excluded. 988 pts are planned to be stratified by the number of prior therapies, gender, smoking history, EGFR and KRAS mutation status. Pts are randomized 1:1 to receive E+A or E + placebo until progression, unacceptable toxicity or other discontinuation criterion is met. This study is powered to detect a significant improvement in median OS in the E+A arm over E alone. Radiographic efficacy assessments will occur every 8 weeks. Pts discontinued from study treatment will be followed for survival. The study is sponsored by Daiichi Sankyo Inc. in collaboration with ArQule, Inc.
Abstract 12520: Baseline Mechanical Dyssynchrony is Associated with Improvement in Mitral Regurgitation and Left Ventricular Reverse Remodeling after Cardiac Resynchronization Therapy
Authors: Tetsuari Onishi, Toshinari Onishi, Josef Marek, Mohamed Ahmed, Stephanie C Haberman, Samir Saba, John Gorcsan
Journal: Circulation (2012)

Background: Mitral regurgitation (MR) is a marker of poor outcome in patients with chronic heart failure. Cardiac resynchronization therapy (CRT) has been shown to improve MR and left ventricular (...
In Vitro and In Vivo Activity of SKI-606, a Novel Abl/Src Inhibitor, Against Imatinib Resistant BCR-ABL+ Neoplastic Cells.
Authors: Miriam Puttini, Addolorata M.L. Coluccia, Frank Boschelli, Anna Franceschino, Lucia Tornaghi, Shaheen Ahmed, Sara Redaelli, Rocco Piazza, Vera Magistroni, Federica Andreoni, Leonardo Scapozza, Franca Formelli, Carlo Gambacorti
Journal: Blood (2006)
Cigarette smoking and early neonatal death [letter]
Authors: Nicholl Jp, OCathain A
Journal: BMJ (1988)

Dr Sven Cnattingius and colleagues (23 July p 258) have provided evidence that maternal smoking during pregnancy is a risk factor not only for late fetal death but also for early neonatal death.  As a result of an extensive secondary analysis of data from the United Kingdom multicenter study of postneonatal mortality funded by the Foundation for the Study of Infant Deaths we believe that the increased risk associated with maternal smoking during pregnancy may last at least until the 8th week of life.  A multiple logistic regression analysis of the multicenter study data on 303 sudden infant deaths and control infants showed that maternal smoking during pregnancy was the largest risk factor for the sudden infant death syndrome in infants under 8 weeks of age (estimated relative risk=1.55 for every 5 cigarettes smoked daily 95% confidence interval 1.11-2.14) but was not a risk factor for sudden infant death syndrome in infants over 24 weeks.  On the other hand when paternal smoking in the absence of maternal smoking was studied there was no significantly increased risk for the young infants with sudden infant death syndrome.  The older infants who died were however at a significantly increased risk of sudden infant death syndrome if their fathers smoked (estimated relative risk=2.81 for every 5 cigarettes smoked daily 95% confidence interval 1.11-7.15).  There are 2 types of explanation for how smoking could be causally related to postnatal deaths; smoking during pregnancy may leave the newborn infant more vulnerable or postnatal passive smoking by the infant may increase the risk of death.  These data provide some evidence for the passive smoking mechanism in older infants but not in younger infants in whom maternal smoking during pregnancy appears to be an important factor lasting well beyond the neonatal period.  (full text)
Capecitabine (Cap) and oxaliplatin (Ox) in elderly and/or frail patients with metastatic colorectal cancer: The FOCUS2 trial
Authors: M. T. Seymour, T. S. Maughan, H. S. Wasan, A. E. Brewster, S. F. Shepherd, M. S. O'Mahoney, B. R. May, L. C. Thompson, A. M. Meade, R. E. Langley
Journal: Journal of Clinical Oncology (2007)

9030 Background: Elderly/frail patients, though commonly treated, are under-represented in clinical trials. Evidence is needed to guide choices of drugs and doses in this population. Methods: FOCUS2 is a multicenter, 2x2 factorial randomized trial for patients with unpretreated metastatic colorectal cancer judged unfit for full-dose combination chemotherapy. After comprehensive health assessment (CHA), randomization was to: (A) simplified LV5FU2 infusional fluorouracil/leucovorin (FU); (B) OxFU; (C) Cap; or (D) OxCap. In each case, starting doses were 80% standard, with an option to escalate to full-dose at 6 weeks (wk). The factorial questions were: (A+B v C+D) - does replacing FU with Cap improve quality of life (QL)? (primary endpoint: improved global QL at 12 wk [QLQ-C30]); and (A+C v B+D) - how much does Ox improve efficacy in this population? (primary endpoint: progression-free survival (PFS). Results: 460 patients were randomized, 22% &lt; 70 yrs; 35% 70–75 yrs; 43% &gt; 75 yrs. 22% were performance status (PS) 0; 49% PS1; 29% PS2. Primary comparisons: (see table ): global QL did not favor Cap over FU. Comparison of PFS favored the addition of oxaliplatin but did not reach significance (HR 0.87, 95% CI 0.71–1.06, p=0.16). Secondary comparisons: Compared with FU, Cap did not affect RR, PFS or 60-day mortality, but it increased the risk of gr =3 toxicity. Oxaliplatin significantly improved RECIST response (RR) by wk 12, did not increase gr =3 toxicity or 60-day mortality, but reduced the chance of improved QL at 12 wk. Conclusion: In this frail elderly population, substituting Cap for FU did not improve overall QL or efficacy, and significantly increased toxicity. Addition of Ox gave significantly higher anticancer activity without increasing toxicity, but at the cost of some reduction in QL at 12 wk. Planned analyses include correlating baseline CHA with treatment outcome. [Table: see text] [Table: see text]
Phase I dose-escalation study of daily BMS-754807, an oral, dual IGF-1R/insulin receptor (IR) inhibitor in subjects with solid tumors.
Authors: J. Desai, B. J. Solomon, I. D. Davis, L. R. Lipton, R. Hicks, A. M. Scott, J. Park, P. L. Clemens, T. A. Gestone, F. G. Finckenstein
Journal: Journal of Clinical Oncology (2010)

3104 Background: BMS-754807 is a potent reversible inhibitor of IGF-1R and IR family kinases (IGF-1R, IR; Ki <2nM). Methods: CA191002 is an ascending dose study of once daily BMS-754807 in subjects with solid tumors. Study objectives include determination of maximum tolerated dose, assessment of safety, effects on metabolic parameters, pharmacokinetics, and pharmacodynamics. Antitumor activity is assessed by radiological responses and FDG- and FLT-PET imaging. Results: To date 19 subjects (12 M, 7 F, median age 59 yr) have been treated at daily doses of 4, 10, 20, 30, 50 or 70 mg. Dosing duration was 17 - 233 d. Fatigue (G1, n=3) and hyperglycemia (≤ G3, n=3) were the most frequent related adverse events (AEs). One related AE (reversible asymptomatic postprandial hyperglycemia) was G3; all other related AEs were ≤ G2. Metabolic AEs were managed by diet and/or comedication. No dose limiting toxicities have been observed and further dose escalation continues. BMS- 754807 exposure increased in relation to dose; mean accumulation index was 1.2 - 1.5. Minimum effective exposures (MEE) for Rh41 xenograft (IGF-1R dependent) tumor growth inhibition were achieved in all subjects. 15/16 subjects dosed with ≥ 10 mg achieved MEE for GEO xenografts (less IGF-1R dependent). Dose related increases of plasma glucose, insulin and C-peptide were observed at 2h post-dose and demonstrate pharmacological activity. Partial metabolic response and stable metabolic disease on FDG-PET by D56 was achieved by 1/12 and 11/12 evaluable subjects respectively. Reduction of FLT uptake by > 25% by D10 was observed in 4/16 evaluable subjects. To date stable disease (SD) > 100 d by radiological assessment was achieved in 7 subjects, including subjects with SCLC (168 d) and osteosarcoma (≥ 2 prior chemotherapy regimens, 225 d). Conclusions: Daily dosing of BMS-754807 resulting in exposures exceeding preclinical MEE is feasible and safe. Effects on blood glucose were manageable and did not lead to discontinuation of dosing. PD effects of IR inhibition were observed and differentiate BMS-754807 from IGF-1R specific agents. PET results and prolonged SD suggest anti-tumor activity. MTD has not been reached and accrual is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
Progesteron receptor status as a predictor of progression-free survival and overall survival in patients with early breast cancer.
Authors: T. Latiano, C. D'Addetta, R. Murgo, A. Piano, M. Morritti, V. Valori, L. Lombardi, P. Parrella, M. Copetti, E. Maiello
Journal: Journal of Clinical Oncology (2010)

677 Background: The frequency of small (pT1a,b,c) node negative invasive breast cancers (BC) is increasing because of wider implementation of BC screening. When cancer is detected early, patients (pts) show an overall better prognosis than pts with more advanced disease, however, even in this group a subset of pts will experience local or distant recurrences. The aim of our study was to evaluate in this subgroup of BC cases the association between disease-free survival (DFS), overall survival (OS) and pts clinicopathological characteristics. Methods: Six hundred twenty eight pts with early BC (pT1a,b,cN0M0) were observed between March 1996 and December 2007 (median follow-up 80 months - IQR 45-118) and were retrospectively investigated in our Institution. Tumours were classified histologically according to the WHO histological classification on BC. Tumour grading was assessed according to Elston and Ellis. Estrogen receptor (ER) and progesteron peceptor (PgR) status and HER2neu overexpression were evaluated immunocitochemically. The threshold for ER and PgR positivity was 10%. Results: The analysis of survival by Kaplan Meier method showed that PgR negative cases were associated with worst DFS (p > 0.02 Log rank test) and OS (p > 0.02) as compared with PgR positive patients. These results were confirmed by univariate and stepwise multivariate Cox proportional regression model. It is of note that PgR-negative status was still a predictor of worst DFS (P=0.01 Log rank test) when survival analysis was limited to the first 2 years of follow-up. This association was confirmed by both univariate (p > 0.012 HR 4.04 CI95 1.24-5.64) and multivariate (p > 0.03 HR 4.9 CI95 1.19-20.05) stepwise Cox proportional regression model. We also evaluated whether the combination between ER and PgR status was able to affect survival. The ER-positive/PgR-negative BC subgroup showed the worst DFS (p > 0.02 log rank test) and OS (p > 0.02 log rank test). Conclusions: Although the overall prognosis of pts with early stage BC is excellent, we observed that the PgR negative status was a predictor of worst DFS and OS. No significant financial relationships to disclose.
An open-label multicenter phase II study of oral lapatinib (GW572016) as single agent, second-line therapy in patients with metastatic colorectal cancer
Authors: A. L. A. Fields, D. A. Rinaldi, C. A. Henderson, C. J. Germond, L. Chu, K. J. Brill, L. H. Leopold, M. S. Berger
Journal: Journal of Clinical Oncology (2005)

3583 Background: Lapatinib is an orally active, reversible inhibitor of the tyrosine kinase activity of ErbB1 (EGFR) and ErbB2 (HER-2/neu). This multicenter, open-label, phase II study was designed to evaluate the safety and efficacy of single-agent lapatinib in patients with metastatic colorectal carcinoma, whose tumors progressed on first-line therapy with 5-fluorouracil in combination with irinotecan or oxaliplatin. Methods: Eighty-six (86) patients received 1250mg of oral lapatinib daily until disease progression or unacceptable toxicity. Safety and efficacy assessments were performed at 4-week and 8-week intervals respectively. Tumor response was determined by an independent review committee using RECIST guidelines. Results: The median age was 60 years (22–83) and median KPS was 90 (70–100). Patients were not selected based on ErbB expression; however, 54.2% and 44.1% of the patients had positive expression (+1, +2, +3) for ErbB1 and ErbB2, respectively. The most commonly encountered adverse events were: diarrhea (45% grade 1, 2, 5% grade 3), rash (33% grade 1, 2, 2% grade 3), fatigue (27% grade 1, 2, 2% grade 3), nausea (20% grade 1, 2, 1% grade 3), anorexia (16% grade 1, 2, 2% grade 3), and vomiting (14% grade 1, 2). In addition, 3 (3%) patients experienced a drug-related Grade 2 (≥20%) decrease in LVEF. All decreases in LVEF were asymptomatic and resolved within three weeks after discontinuation of lapatinib. One (1%) patient experienced a confirmed partial response; however, five patients experienced a minor response with cytoreduction of 20%, 22.4%, 22.8%, 26.8%, and 34% at week 8. Overall, five patients experienced clinical benefit with stable disease for ≥20 weeks. The median TTP and overall survival were 8 and 42.9 weeks respectively. Conclusions: Lapatinib was well tolerated, but demonstrated limited activity as second-line monotherapy in patients with recurrent metastatic colorectal cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Secretoneurin is a Novel Endogenous CaMKIId Inhibitor That Regulates Cardiomyocyte Calcium Handling and is Closely Associated With Mortality in Patients With Acute Heart Failure
Authors: Anett Hellebo Ottesen, William Edward Louch, Cathrine Carlson, Ole Jorgen Bjarnason Landsverk, Rune Forstrom Johansen, Morten Moe, Arne Didrik Hoiseth, Hilde Jarstadmarken, Stale Nygard, Magnar Bjoras, Mats Stridsberg, Torbjorn Omland, Geir Christensen, Helge Rosjo
Journal: Circulation (2013)

Secretoneurin is a Novel Endogenous CaMKIId Inhibitor That Regulates Cardiomyocyte Calcium Handling and is Closely Associated With Mortality in Patients With Acute Heart Failure
Aerosolized sargramostim for the treatment of metastatic melanoma to the lungs
Authors: S. N. Markovic, V. J. Suman, P. Schaefer, R. Morton, K. M. Rowland
Journal: Journal of Clinical Oncology (2007)

8565 Background: Previous studies using low-dose (250 ug/dose) aerosolized sargramostim (granulocyte macrophage colony stimulating factor: aero-GM-CSF) for the treatment of metastatic melanoma, revealed anecdotal clinical responses that appeared to correlate with an increase in the number of tumor specific cytotoxic T lymphocytes (CTL) in blood. Herein, we address whether or not further dose escalation of aero-GM-CSF is safe, results in greater increase of melanoma specific CTLs, and affects clinical outcomes. Methods: A 5+5 dose escalation clinical trial was conducted to determine the dose of aero-GM-CSF that would increase in the frequency of peripheral blood melanoma specific CTLs in HLA-A2 + patients with metastatic melanoma to the lungs. Aero-GM-CSF was administered twice daily on days 1–7 and 15–21 of a 28 day cycle at doses of: 500, 750, 1,000, 1,250, 1,500, 1,750, and 2,000 ug per cohort. If at most 2 of 5 patients at a dose level reported a 5-fold increase in CTLs, dose escalation occurred. If not, 5 additional patients were treated at that dose. Dose escalation continued until =2 of 5 patients at a dose level developed severe toxicity, at least 7 of the 10 patients at a dose level reported a 5-fold increase in CTLs, or all dose levels were exhausted. Results: The study accrued 40 patients from August 2002 to July 2006. Four patients cancelled participation prior to treatment. One patient was replaced (500 ug) as he died within 13 days of registration. Among the 35 remaining patients, median age was 58 (23–84), 72% were male, and 72% had a PS=0. Dose escalation was not terminated due to toxicity. Toxicities = grade 3 (at least probably treatment related) included: grade 3 fatigue (1) at 1,000 ug; and grade 3 cough (1), and grade 4 dyspnea (1) at 1,750 ug. At the 2,000 ug dose, most patients (4 of 5) exhibited a greater than 2-fold increase in melanoma specific CTLs. Two of these patients remain on treatment: one with partial response at 14.0 months and the other with stable disease at 6.5 months. A 5-fold increase in tumor specific CTLs was not achieved in any patient. Conclusions: Aero-GM-CSF therapy administered at up to 2,000 ug/dose appears safe and seems to correlate with increased frequencies of tumor specific CTLs in a dose-dependent fashion. Further dose escalation followed by clinical efficacy testing is warranted. No significant financial relationships to disclose.
Phase II study of oral S-1 in pretreated patients with recurrent or metastatic head and neck cancer
Authors: S. Park, S. Lee, J. Park, E. Cho, D. Shin, J. Lee
Journal: Journal of Clinical Oncology (2008)

17007 Background: Based on the potential antitumor effect of fluoropyrimidines against head and neck cancer (HNC), we conducted a phase II study to evaluate the efficacy and toxicity profile of S-1 given as second-line treatment in patients with recurrent or metastatic HNC. Methods: Patients with measurable HNC, progressive after prior chemotherapy and/or chemoradiotherapy, were treated with oral S-1 40 mg/m2 twice daily as an intermittent regimen of 4 weeks of treatment followed by a 2-week rest. Treatment was repeated every 6 weeks until disease progression or unacceptable toxicity. The study endpoints were clinical response rate and toxicity. Results: A total of 33 HNC patients who had relapsed after cisplatin-based chemoradiotherapy and/or palliative chemotherapy for advanced disease were registered. Primary sites included the larynx, oral cavity/tongue, nasopharynx, tonsil, nasal cavity, maxillary sinus and salivary glands. A total of 92 treatment cycles were delivered (median 2, range 1–6). The patients’ median age was 6059 years (range 42- 75) and all had a symptomatic disease (ECOG performance status 2 in 8 patients). Two complete (CR) and 7 partial responses (PR) were observed, yielding an overall response rate of 27%. Seven additional patients showed stable disease (SD) with symptomatic improvements. The median time to progression and overall survival were 4.2 months (95% CI 3.2–5.2) and 6.7 months (95% CI, 3.9–9.5), respectively. Although fatigue and stomatitis were the most frequently encountered toxicities, toxicity profiles were generally mild and easily manageable. Grade≥2 hand-foot syndrome was observed in only 2 patients. One patient died during the first cycle due to a massive upper gastrointestinal bleeding. Conclusions: Oral S-1 is an effective chemotherapy for patients with recurrent or metastatic HNC. Moreover, this regimen is well tolerated with mild, and easy to treat, toxicity. No significant financial relationships to disclose.
Long-term effect of strontium ranelate on serum C-terminal propeptide of type I Procollagen (PICP) and urine cross-linked N-telopeptide (U-NTX) in women with postmenopausal osteoporosis
Authors: Olivier Bruyère, Julien Collette, Jean-Yves Reginster
Journal: Annals of the Rheumatic Diseases (2010)