tbuckley/cabot-search huggingface dataset:
Phase I trial of gemcitabine and epirubicin in patients with solid malignancies
Authors: D. Mahadevan, L. Dreisbach, D. Williams, D. Pilkington, C. Gebremarium, E. Martin, Y. Obregon, D. Von Hoff
Journal: Journal of Clinical Oncology (2004)

4190 Background: Gemcitabine (G) given as a standard 30-minute infusion is well tolerated with modest clinical activity, but new data suggest prolonged exposure may improve response. In vitro studies of G combined with epirubicin (E), have demonstrated >50% growth inhibition in human pancreatic cancer cell lines, whereas the drugs were relatively ineffective as single agents in the same cell lines. A Phase I study was undertaken to investigate whether a fixed-dose-rate infusion of G combined with E can be given safely to patients on a weekly schedule. Methods: 6 patients with solid malignancies received G 800 mg/m2 IV with E 10 mg/m2 on a weekly schedule (days 1, 8, & 15 of a 28-day cycle). No dose-limiting toxicities were noted. 3 subsequent patients were treated with 1000 mg/m2 G and 10 mg/m2 E on the same weekly schedule; they all experienced grade 3/4 leukopenia, grade 3/4 thrombocytopenia, and/or inability to complete treatment. The protocol was amended, changing the dosing to biweekly (days 1 & 15 of a 28-day cycle). On this schedule, 3 patients were treated with G 800 mg/m2 plus E 10 mg/m2 and 3 with G 1000 mg/m2 plus E 10 mg/m2. Results: A total of 15 patients were enrolled and 12 were evaluable for toxicity. Grade 3/4 toxicities included neutropenia (n = 6), thrombocytopenia (n = 1), fatigue (n = 4), and myalgia (n = 1). All occurred in the 9 patients who received weekly dosing; no Grade 3/4 toxicities were seen in patients receiving biweekly dosing. There was 1 death, attributed to non-treatment-related acute cardiopulmonary failure. 7 patients experienced stable disease for >16 weeks, and 1 patient with pancreatic cancer had a partial response for 32 weeks (G 800 mg/m2 and E 10 mg/m2 on the weekly schedule). Conclusions: The maximum tolerated dose of G (w/ 10 mg/m2 E) on day 1, 8 and 15 of a 28-day cycle is likely to be 800 mg/m2. When given on day 1 and 15 of a 28-day cycle, the combination is safe up to G 1000 mg/m2. Phase II studies are warranted to establish the efficacy of this combination. This clinical trial was supported by Pfizer Oncology. No significant financial relationships to disclose.
How breast cancer care is coordinated in hospitals serving predominantly minority women.
Authors: Ann Scheck McAlearney, Alexandra Moss, Rebeca Franco, Nina A. Bickell
Journal: Journal of Clinical Oncology (2013)

e17592 Background: Underuse of adjuvant breast cancer treatment results from system failures and occurs more commonly in minority women. We assessed organizational processes associated with care coordination prior to implementing an intervention. Methods: We interviewed 29 clinical and 20 administrative key informants from 6 hospitals with high volumes of minority breast cancer patients. We analyzed qualitative interview data using the constant comparative method. Results: Hospitals varied in approaches to coordinate adjuvant therapy delivery. All hospitals made a “basic” effort to follow up with patients who missed appointments (e.g., certified letters), but some sites included “extra” efforts such as clinician calls. Processes to coordinate handoffs among providers involved use of clerical staff to reach out across specialties in most sites; several sites also explicitly involved clinicians. Effective tracking and handoffs were hindered where electronic health record (EHR) systems were not fully integrated. A critical distinction was whether breast cancer care delivery was integrated within the hospital. Better integration appeared to facilitate communication among clinicians, as well as promote service coordination. Accountability was an important factor contributing to integration, particularly in sites that were less integrated. Conclusions: Appropriate delivery of adjuvant therapies to breast cancer patients appears to be facilitated by better integration of care and services within the hospitals we studied. A fully integrated EHR and enhanced processes for tracking no shows and supporting handoffs seemed to increase integration in these hospitals. Integration was further facilitated when there was accountability for results. Strong clinical leadership can promote integration, but its impact may be lessened if hospitals’ processes are integrated. [Table: see text]
Abstract 310: Vascular Endothelial Growth Factor and Endothelial Nitric Oxide Synthase-mediated Regulation of Cardiomyocyte Proliferation During Development in Humans and Mice
Authors: Carmine Gentile, Christine Y Chuang, Christopher J Drake, Michael J Davies
Journal: Circulation Research (2015)

Our previous studies in early mouse embryonic development (E8.2) showing that vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) are expressed in embryonic endothelial cells, but not in embryonic cardiomyocytes, together with the findings by others indicating that NO is required for cardiomyocyte proliferation in mice, led us to investigate the relevancy of the VEGF/eNOS signaling pathway during cardiovascular development. First, wild type and NOS3 knockout mouse embryos between E8.0 and E17.0 were stained with antibodies against smooth muscle α-actin, phospho-histone H3 (PH3), VEGFR2 and PECAM, markers of cardiomyocytes, proliferating, progenitor and endothelial cells, respectively. Our confocal analysis showed hearts of E8.0 NOS3 nulls develop normally. However, E8.5 and E9.5 NOS3 nulls have reduced cardiomyocyte proliferation and impaired heart development. As consequence, hearts of E17 NOS3 nulls were approximately 20% smaller compared to wildtype hearts. To translate our findings to humans, we stained human heart specimens with antibodies against VEGFR2, eNOS, PH3 and sarcomeric α-actinin. Confocal analyses showed for the first time that VEGFR2 is highly expressed in the perinuclear region of human cardiomyocytes of a young donor. They also showed a correlation between eNOS expression and cardiomyocyte proliferation in humans. Consequently, we developed an in vitro three-dimensional co-culture model of human endothelial cells, cardiomyocytes and fibroblasts: “human cardiac tissue spheroids” (HCTSs). Our data showed that laminin and collagen type IV synthesis is increased in VEGF-treated HCTSs generated using CMs from an older donor compared to untreated cultures, suggesting a role for VEGF and eNOS in postnatal human heart development. In conclusion, our data showed that VEGF and eNOS play a similar role in mediating cardiomyocytes proliferation and heart regeneration in both mice and humans. Current studies are focusing on evaluating molecular targets of the VEGF/eNOS signalling pathway in human proliferating cardiomyocytes, which may have significant therapeutical impact for stem cell differentiation, and prevention of cardiovascular complications such as myocardial infarction.
Predictors of survival for younger patients (pts) less than 50 years of age with non-small cell lung cancer (NSCLC): A California Cancer Registry (CCR) analysis.
Authors: Matthew Stephen Lara, Ann Brunson, Ben Kent Tomlinson, Theodore Wun, Lihong Qi, Rosemary Cress, Primo Lara, David R. Gandara, Karen Kelly
Journal: Journal of Clinical Oncology (2013)

8049 Background: Lung cancer is often seen in older pts, with a median age at diagnosis of 70 years (yrs). Epidemiology and outcomes are reportedly different among younger NSCLC pts (&lt; 50 yrs). We hypothesized that these pts have longer cause-specific survival (CSS) and that baseline clinical features prognostic for CSS would be identified. Methods: NSCLC pts in the CCR diagnosed between 1/98 through 12/09 were included. The primary outcome was CSS. Hazard ratios (HR) for CSS were calculated using Cox Proportional Hazards (PH) models for all ages &amp; for pts &lt;50 years, adjusted for baseline variables. Results: We identified 132,671 lung cancer pts: 114,451 (86.3%) had NSCLC. 6,389 (5.6%) were &lt; 50 yrs (median, 46 yrs). Demographics: White (3,557, 56%); Histology: AdenoCA (AC) (3,406, 53%), Squamous (781, 12%), BAC (291, 4.6%); Stage IV (3,655, 57%). Fewer pts &lt; 50 yrs were diagnosed in later yrs: from 37% in ‘98-’01 to 29% in ‘06-‘09. Results of Cox PH models for all ages and &lt; 50 years are shown. Conclusions: The relative proportion of pts &lt; 50 yrs has declined by 22% over the past decade. Age &lt; 50 years was an independent predictor of improved CSS (HR 0.83, p&lt;0.001). In younger pts, AC histology was not prognostic for CSS (versus squamous) despite known differences in clinical and biologic behavior between subtypes.Importantly, clinical variables strongly prognostic for CSS were identified in pts &lt; 50 yrs. [Table: see text]
New thrombolytic strategy providing neuroprotection in experimental ischemic stroke: MMP10 alone or in combination with tissue-type plasminogen activator
Authors: Carmen Roncal, Sara Martinez de Lizarrondo, Agustina Salicio, Arnaud Chevilley, Jose A. Rodriguez, Anna Rosell, Pierre-Olivier Couraud, Babette Weksler, Joan Montaner, Denis Vivien, Jose A. Páramo, Josune Orbe
Journal: Cardiovascular Research (2017)

Early reperfusion with tissue-type plasminogen activator (tPA) is an effective therapeutic strategy to treat acute ischemic stroke, but only 1/3 of tPA-treated patients recover and are free from disability. tPA has also shown neurotoxicity in experimental models of cerebral ischemia. Considering that MMP-10 improves stroke injury, we have examined the therapeutic and protective effect of MMP10 and tPA/MMP10 as clot-dissolving and neuroprotective agent in an experimental model of ischemic stroke and studied in vitro the molecular pathways involved in MMP10-mediated effects. Cerebral ischemia was induced by the local injection of thrombin into the middle cerebral artery followed by reperfusion with MMP10 (6.5 µg/kg) and tPA (10 mg/kg) alone or in combination with MMP10. Cell cultures were also performed to determine the effect of MMP10 and tPA/MMP10 on brain endothelial cells and neurons. tPA/MMP10 significantly reduced the infarct size in the ischemic stroke model compared with tPA alone (P < 0.05). In vitro, MMP10 reduced the tPA-promoted endothelial ionic permeability, preserved the expression of claudin-5 and decreased ERK1/2 activation. Moreover, combination of tPA/MMP10 prevented tPA-mediated neuronal excitotoxicity and calcium influx. These effects were reversed by blocking MMP10 activity with a monoclonal antibody. These results show that MMP10, either alone or in combination with tPA, might represent a new strategy for thrombolysis in ischemic stroke, providing higher protection against cerebrovascular damage.
Neoadjuvant transarterial chemoembolization (TACE) using cisplatin with the combination of dose-dense intravenous administration of paclitaxel for the locally advanced cervical adenocarcinoma
Authors: H. Tsubamoto, R. Wada, R. Kanazawa, S. Komori, H. Maeda, S. Hirota, S. Adachi
Journal: Journal of Clinical Oncology (2009)

e16518 Background: Adenocarcinoma (including adenosquamous carcinoma) of the uterine cervix has a tendency to early lymph node metastasis and is resistant to radiation therapy, thus results in poor prognosis compared with squamous cell carcinoma. Neoadjuvant chemotherapy (NAC) followed by radical hysterectomy (RH) for bulky cervical adenocarcinoma seems to be an alternative therapy to primary radiation. Methods: P2 at the single institution. Eligible criteria were as follows: Histologically diagnosed cervical adeno or adenosquamous carcinoma with FIGO stage IB2-IVA, Age &lt; or equal to 75, PS 0–2, given informed consent. The NAC regimen consisted of paclitaxel (60mg/m2, iv, D1, D8, D15) and cisplatin (70 mg/m2, trans-uterine arterial infusion followed by embolization using the gelform, D2) repeated every 3 weeks for 2–3 cycles, followed by RH. Primary endpoints were clinical and pathological responses, and secondary endpoints were toxicities, relapse free survival (RFS) and overall survival (OS). Results: Enrolled patients: 22 (1998–2006), Age: median 51 (33–75), FIGO stage: IB2 (9), IIA-IIB (8), IIIB (3), IVA (2), adeno/adenosquamous: 16/6. Toxicities during NAC (CTCAE ver.3) were as follows: G3/G4 neutropenia 18% (4/22), G3/G4 anemia 14% (3/22), G3/G4 thrombocytopenia 0%, G2/G3 sensory neuropathy 0 %, G3/G4 creatinine elevation 0%, G2 alopecia 100%. Clinical response rate (RR: CR+PR) of the patients with stage IB2-IIB was 100%. 16 of 17 received RH, and no residual malignant cells were found pathologically (pCR) in 3. RR of the patients with stage IIIb-IVa was 80%, three patients completed RH with either modified anterior or posterior exenteration, and pCR was found in one patient. The rate of radiation therapy following either NAC or surgery among enrolled patients were 18% (3/17) with stage IB2-IIB and 40% (2/5) with IIIB-IVA. 5 year RFS/OS were 69%/68% with stage IB2-IIb and 60%/60% with stage IIIb-IVa. All 15 alive patients had RH. One patient with stage IVa had urostomy, and other 14 patients have no trouble in urination function. Conclusions: TACE with cisplatin and dose dense paclitaxel in the neoadjuvant setting is feasible and effective for cervical adenocarcinoma. [Table: see text]
Addition of bicalutamide 80 mg to LHRH-agonist monotherapy in patients with advanced prostate cancer: Impact on quality of life
Authors: S. Naito, M. Tachibana, T. Deguchi, M. Namiki, Y. Hirao, Y. Arai, H. Akaza, M. Usami, H. Kanetake, Y. Ohashi
Journal: Journal of Clinical Oncology (2004)

4703 Background: Bicalutamide (‘Casodex’) 80 mg (licensed dose in Japan) is being evaluated as part of combination therapy in patients (pts) with previously untreated advanced prostate cancer in an ongoing Japanese double-blind Phase III trial. Interim analysis after all pts had completed at least 6 months' follow-up (median follow-up 15 months) showed that first-line treatment with bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist significantly improved the prostate-specific antigen normalization rate at 12 weeks and reduced the risk of treatment failure and disease progression compared with LHRH-agonist monotherapy, without compromising tolerability (Proc Am Soc Clin Oncol 2003; 22: 422 [abs 1695]). We now report quality-of-life (QoL) findings during the first 24 weeks of treatment. Methods: Pts with previously untreated advanced (stage C/D) prostate cancer were randomized to receive bicalutamide 80 mg od (n=102) or placebo (n=101), in addition to an LHRH agonist. QoL was assessed using the Japanese version of the Functional Assessment of Cancer Therapy (FACT), a general questionnaire (FACT-G) assessing physical, social/family, emotional and functional wellbeing, plus a disease-specific subscale for prostate cancer symptoms (FACT-P); this was completed at baseline and at Weeks 1, 5 and 24. Results: The questionnaire collection rate at Week 24 was 93.1% in the bicalutamide 80 mg group and 89.1% with placebo. Total FACT scores showed no clear improvement in QoL in either treatment group at each time point. Mean FACT-P scores (specific to prostate cancer symptoms) increased by 4.64 and 3.10 from baseline to Week 24 in the bicalutamide 80 mg and placebo groups, respectively (difference 1.54;95%CI-1.03,4.11). Analyses of FACT-P scores using generalized estimating equations revealed a greater overall improvement with bicalutamide 80 mg compared with placebo (p=0.051). Conclusions: Compared with LHRH-agonist monotherapy, bicalutamide 80 mg in combination with an LHRH agonist improves symptom-related QoL in pts with previously untreated advanced prostate cancer. ‘Casodex’ is a trademark of the AstraZeneca group of companies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Around 30 pharma companies including AstraZeneca Around 30 pharma companies including AstraZeneca AstraZeneca
Effect of zoledronic acid (ZA) versus placebo on bone mineral density (BMD) in androgen-deprived prostate cancer patients with and without bone metastases (mets)
Authors: C. W. Ryan, D. Huo, M. Hanson, W. M. Stadler, N. J. Vogelzang
Journal: Journal of Clinical Oncology (2004)

4760 Background: Bisphosphonates can prevent BMD loss in prostate cancer patients receiving androgen deprivation. Previous studies of ZA and BMD in this population excluded patients with bone mets because of concern that mets may interfere with DEXA results. Methods: We performed a double-blind, placebo-controlled, randomized study of ZA in prostate cancer patients with and without bone mets on androgen deprivation for < 12 months. Patients were randomized to receive either 4 mg ZA or normal saline placebo IV every 3 months for 4 treatments. BMD of the femoral neck (FN) and lumbar spine (LS) were measured by DEXA at 0, 3, 6, 9, and 12 months. Results: From 1/00 through 12/02, 42 of a planned 80 patients were randomized. Accrual was stopped due to initiation of a multi-center study that is currently ongoing. BMD data are available for 18 patients who received placebo and 21 who received ZA. Baseline characteristics were well-balanced between the 2 groups (placebo vs. ZA): mean FN BMD 0.998 g/cm2 (SD 0.126) vs. 0.979 g/cm2 (SD 0.196); mean LS BMD 1.385 g/cm2 (SD 0.274) vs. 1.344 g/cm2 (SD 0.207). 9 patients in each arm had bone mets detected by bone scan. A random effect model was used to examine change in BMD over one year. The mean change in BMD per year (slope, g/cm2/year) is shown in the table below. Results are shown for all patients and for patients excluded based on bone scan abnormalities detected in the region of BMD measurement. Conclusions: When all patients were analyzed, no statistically significant difference in the mean change per year of BMD was detected. When patients with scintigraphic evidence of bone mets at the site of DEXA measurement were excluded, the expected benefit of ZA therapy became apparent. Mets detected in the region of DEXA measurement can interfere with interpretation of ZA effect. Bone marker analysis for this study is pending. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis
2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis
Authors: Lisa G Rider, Rohit Aggarwal, Angela Pistorio, Nastaran Bayat, Brian Erman, Brian M Feldman, Adam M Huber, Rolando Cimaz, Rubén J Cuttica, Sheila Knupp de Oliveira, Carol B Lindsley, Clarissa A Pilkington, Marilynn Punaro, Angelo Ravelli, Ann M Reed, Kelly Rouster-Stevens, Annet van Royen-Kerkhof, Frank Dressler, Claudia Saad Magalhaes, Tamás Constantin, Joyce E Davidson, Bo Magnusson, Ricardo Russo, Luca Villa, Mariangela Rinaldi, Howard Rockette, Peter A Lachenbruch, Frederick W Miller, Jiri Vencovsky, Nicolino Ruperto
Journal: Annals of the Rheumatic Diseases (2017)

To develop response criteria for juvenile dermatomyositis (DM). We analysed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique. Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute per cent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (p=0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (p<0.006). The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute per cent change in core set measures, with thresholds for minimal, moderate, and major improvement.
Single agent gefitinib in poor performance status patients with previously untreated advanced non-small cell lung cancer: A Minnie Pearl Cancer Research Network phase II trial
Authors: N. R. Dickson, J. D. Hainsworth, D. R. Spigel, H. A. Burris, D. A. Yardley, M. Thomas, S. F. Jones, D. C. Scullin, J. E. Bradof, F. A. Greco
Journal: Journal of Clinical Oncology (2004)

7086 Background: Gefitinib has single agent activity and excellent tolerability in patients (pts) with refractory non-small cell lung cancer (NSCLC) and may be of benefit to previously untreated poor performance status (PS) pts. Methods: The objectives were to evaluate the feasibility/toxicity, response rate, and symptom response (SR) of gefitinib in a total of 60 poor PS untreated pts. Eligible pts had no prior systemic therapy; ECOG PS 2, 3; stage IV or IIIB NSCLC; adequate organ function. Gefitinib 250 mg/day was given orally until disease progression, with initial evaluation at 8 weeks. Symptoms were evaluated at baseline and SR weekly using the Lung Cancer Subscale (LCS) of the FACT-L. Results: Twenty-five pts of the required 60 pts have enrolled to date (male/female 17/8); median age 64 (range 58–84); ECOG PS 2/3 20/5; stage IIIB/IV 7/18; bronchioalveolar/adenocarcinoma/squamous/large cell/or other 2/8/8/6/1. The median treatment duration was 3 months (range 1–7) and duration of follow-up 1.2 months (range 0.5–6 months). Grade 3/4 toxicities included: rash (1/10), diarrhea (0/0), elevated liver function test (0/0), dry skin/pruritis (0/0), and stomatitis (0/0). Eighteen pts are now evaluable for response. No partial responses have been seen. Eleven pts (61%) had stable disease and 8 of these 11 pts remain on study. Seven pts (39%) had progressive disease. Six of the 11 pts with stable disease had improved SR. Of the 25 pts enrolled, 8 have expired. Conclusions: Gefitinib is safe, well-tolerated and useful for symptom improvement as first-line therapy for some pts with poor PS. Further follow-up and additional evaluable pts will be provided. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca