tbuckley/cabot-search huggingface dataset:
Efficacy and safety of long-term administration of temozolomide monotherapy in patients with anaplastic astrocytoma at first relapse
Authors: R. Nishikawa
Journal: Journal of Clinical Oncology (2008)

13017 Background: Efficacy and safety of temozolomide (TMZ) were examined in a multicenter phase II study in 32 patients with anaplastic astrocytoma at first relapse. Methods: 32 pts were enrolled. After completing 6 cycles of TMZ (Step 1), the pts experiencing “no change” or better effect were allowed to continue to receive treatment in Step 2. TMZ was administered for 5 consecutive days in a 28-day cycle. The dose for the first cycle was 150 mg/m2/day. From the second cycle, the dose was 100, 150, or 200 mg/m2/day based on a dose adjustment criteria. Results: The response rate up through Cycle 6 was 34%, including 3 pts with “complete response” (CR), and the response rate at the end of the study was 44%, with the number of CR pts increased to 6. All of the additional 3 CR pts achieved CR in Step 2 from “partial response”. Pts were also observed who had transient “progressive disease” in Step 1 who had a reduction in tumor in Step 2. Fourteen pts discontinued treatment during Step 1. The reason for discontinuation was the onset of an adverse event in 2 pts, disease exacerbation in 11, and change in hospital in 1. Eighteen pts progressed to Step 2, and 1 pt received 7 cycles, 8 received 4, 1 received 9, 2 received 11, 1 each received 12, 13, 14, 16, and 23, 3 received 24, and 1 each received 27 and 35 cycles. The reason for discontinuation in Step 2 was disease exacerbation in 9, market availability of TMZ in 3, duration of treatment exceeding 2 years in 3, and for other reasons such as partner’s pregnancy in 3. No pt discontinued due to an adverse event. Adverse events judged to be CTC Grade 4 were observed in 9% (3 pts), all of which were observed in Step 1. One pt had pancytopenia, respiratory failure, septicemia, and renal failure, the second pt had intracranial hemorrhage, and the third pt had blood glucose and calcium decrease. The pt who developed decreased blood glucose and calcium discontinued treatment due to PD response and not to these adverse events. Conclusions: There are pts with anaplastic astrocytoma at first relapse for whom long-term treatment with TMZ beyond 6 cycles (with the duration of treatment at times exceeding one year) is clinically meaningful. No accumulation-type adverse events were observed, and the long-term administration of TMZ was considered possible. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough K.K.
Evolution of osteoporosis
Authors: T. J ASPRAY, R. M FRANCIS, A. PRENTICE, D W PURDIE
Journal: Annals of the Rheumatic Diseases (1997)

Professor Purdie’s article on the influence of ethnicity on osteoporosis was fascinating.1 However we cannot support the argument that evolution has determined racial differences in bone mass and thus a low prevalence of osteoporosis in certain racial groups.

As the article points out, there are differences in bone mass and fracture incidence between white and black women in North America.2 The data on male fracture incidence are more contentious and the references cited relate to studies of black residents of mental institutions and hip fractures in a small population in Charlottesville, USA, with an incidence of fewer than 25 fractures per annum.3-5 However, Farmer reports no difference in fracture incidence in North America between black men, black women, or white men.2 In Africa, many women have multiple pregnancies, prolonged lactation periods, and low dietary calcium intakes. Despite these factors, …
COPD exacerbations occur more frequently in the presence of cardiovascular and pulmonary comorbidities and increase serum lipids
Authors: David Jungck, Susanne Blum, Inga Isbruch, Jürgen Knobloch, Andrea Koch
Journal: European Respiratory Journal (2014)

Background:  The numerous and frequent comorbidities of COPD pose a considerable threat to patients and are responsible for the majority of deaths. However, their influence on exacerbations is unclear.   Hypothesis:  Comorbidities of COPD increase the frequency of exacerbations.   Methods:  Multiple parameters of 605 COPD patients at Bergmannsheil University Hospital in Bochum, Germany, are being assessed and presented as preliminary data.   Results:  In 463 patients a diagnosis of COPD was confirmed (mean age 69.7 years, 34.6% women, mean number of pack years 48.8, average FEV 1  45.4%). 94.8% of patients had comorbidities, more than 50% had at least 3. Cardiovascular comorbidities at 77.3% were the most common (arterial hypertension 67.4%, coronary artery disease 25.7%, atrial fibrillation 17.06%). 67.2% of patients had pulmonary comorbidities (pneumonia 50.5%, obstructive sleep apnea 14.7%). 60.9% of patients had endocrinologic comorbidities, 21.2% suffered from neurologic and 14.9% from gastroenterologic comorbidities. In contrast to endocrinologic, neurologic and gastroenterologic comorbidities, cardiovascular and pulmonary comorbidities led to significantly more frequent exacerbations (both pl0.05). The level of serum high density lipoprotein (HDL) was positively correlated with COPD severity and the number of exacerbations in the previous year (each pl0.05).   Discussion:  Serum HDL needs to be further investigated as a possible marker of exacerbation risk but may be influenced by use of corticosteroids. These data highlight the importance of COPD comorbidities and suggest a particularly careful examination with regard to cardiovascular and pulmonary comorbidities.
Multidrug resistance in lymphomas.
Authors: A R Yuen, B I Sikic
Journal: Journal of Clinical Oncology (1994)

PURPOSE To discuss the significance of multidrug resistance (MDR) in human lymphomas and to review recent and ongoing clinical trials using MDR modulators. DESIGN A medical literature search was used to identify articles that reported results on the expression or modulation of MDR in human lymphomas. This review summarizes the various methods for detecting expression of the mdr1 gene in tumor specimens, the patterns of expression in lymphomas, and recent and upcoming clinical trials using modulating agents to reverse MDR. RESULTS There is considerable variation in the assays used to evaluate the expression of mdr1 in lymphomas. Current methodology includes reverse transcriptase polymerase chain reaction (rt-PCR) for assay of mdr1 mRNA, and immunohistochemistry or flow cytometry for detection of the multidrug transporter, P-glycoprotein (P-gp). The preponderance of evidence suggests that mdr1 expression is relatively low in untreated patients (10% to 20% of lymphomas positive), but increases in patients with recurrent disease (50% to 70% positive). Some evidence suggests that mdr1 expression is a prognostic factor for response to chemotherapy, as well as for subsequent survival. Verapamil and cyclosporine (CsA) have been used as competitive inhibitors of the multidrug transporter P-gp in early clinical trials. Although these studies show some activity in modulating clinical MDR, both verapamil and CsA manifest considerable toxicities at doses below those required for complete inhibition of P-gp function. CONCLUSION MDR due to the expression of the mdr1 gene is an important factor in the course of patients with lymphomas. Continued clinical trials with more potent and less toxic modulators are needed to define the ultimate benefit of modulating MDR in lymphomas.
Expression of transforming growth factor β (TGFβ) receptor, CD105, is declined in Th1 interstitial lung diseases (ILDs)
Authors: Andrzej Dyczek, Jerzy Szczeklik, Barbara Balicka-Slusarczyk, Joanna Chorostowska, Adam Szpechcinski, Ewelina Pόlgesek, Marek Jankowski, Piotr Kopinski
Journal: European Respiratory Journal (2011)

Background:  TGFβ, as the most potent activator of lung fibrosis, stimulates fibroblast proliferation and induces secretion of collagen and other extracellular matrix proteins. It reveals its profibrotic effect by receptor complex, including CD105 molecule.   Methods:  TGFβ levels was examined by ELISA in bronchoalveolar lavage (BAL) supernatants. CD105 expression was tested on BAL macrophages and lymphocytes in pulmonary sarcoidosis (PS, n=16), idiopathic pulmonary fibrosis (IPF, n=9), non-specific interstitial pneumonitis (NSIP, n=6) and extrinsic allergic alveolitis (EAA, n=7). CD105 appearance was also assessed in model lung cell lines: pneumocytes type 2 (A549) and fibroblasts (HLF-1).   Results:  IPF was the only disorder with significantly increased TGFβ level. CD105 expression is common on HLF-1 (98%), A549 (63%, median of 5 trials) and alveolar macrophages. In PS significantly decreased CD105 expression on BAL lymphocytes was found (all lymphocytes: 7.2±0.6%; Th cells: 4.6±0.4%, Tc cells: 1.8±0.3%, resp. control values: 13±3.4%, 6.6±2.6% and 4.7±1.1%, median±SEM, p   Conclusions:  TGFβ receptor, CD105, is frequently present in lower airways. Lower BAL CD105+ lymphocyte percentage in IPF, and higher one in PS and EAA, may reflect different Th1/Th2 polarization pattern. Summarizing, the key role of diverse lower airway cell reactivity to TGFβ in ILDs should be considered.
Identification By Gene Expression Profiling Of CIITA-Dependent HLA Class II Transcriptional Downregulation As a Novel Mechanism Of Leukemia Immune Escape and Relapse After Allogeneic HSCT
Authors: Cristina Toffalori, Michela Riba, Matteo Barcella, Orietta Spinelli, Lara Crucitti, Jacopo Peccatori, Massimo Bernardi, Chiara Bonini, Davide Cittaro, Dejan Lazarevic, Alessandro Rambaldi, Cristina Barlassina, Elia Stupka, Fabio Ciceri, Katharina Fleischhauer, Luca Vago
Journal: Blood (2013)
Breast cancer chemoprevention Phase IB evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator
Authors: C. J. Fabian, B. F. Kimler, J. Anderson, O. W. Tawfik, M. S. Mayo
Journal: Journal of Clinical Oncology (2004)

1015 Background: Arzoxifene (LY353381.HCl) is a new selective estrogen receptor modulator, SERM, with strong breast antiestrogen activity and absence of uterine agonist activity that is being explored as a potential breast cancer chemoprevention agent. We performed a multi-institutional Phase IB evaluation of the effects of arzoxifene on serum and tissue biomarkers in women with newly diagnosed DCIS and T1/T2 invasive cancer who received study agent in the interval between core biopsy and definitive re-excision. Methods: Post-menopausal women were randomized (2:1) to 20 mg of arzoxifene daily vs. matched placebo. Women discontinued hormone replacement therapy (HRT) prior to entry on study. Tissue from biopsy and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1; PCNA) and other biomarkers potentially related to drug effect. Only subjects with an ER+ and/or PR+ tumor at biopsy, with tumor tissue available from both biopsy and re-excision, were evaluated for biomarker modulation. Results: 74 subjects entered the study. For 58 subjects evaluable for tissue biomarker analysis, a change in ER expression (median decrease of 6% positive cells) was observed for subjects receiving arzoxifene, that was statistically significant (p=0.0068) compared to the placebo group (median change = 0%). However, the changes in proliferation indices (median decreases: Ki-67 = 1.5%, PCNA = 3%) were not statistically different from the placebo group (median decreases: Ki-67 = 1.1%, PCNA = 0%). This may be due to the large number (46%) of subjects who discontinued HRT in the peri-biopsy period, resulting in decreases in proliferation independent of an arzoxifene effect. Conclusions: We have demonstrated the feasibility of accrual to a multi-institutional biomarker modulation trial utilizing women with newly-diagnosed breast cancer. Given a favorable side effect profile and the modulations of tissue (ER and proliferation) biomarkers associated with risk of breast cancer development, arzoxifene remains a candidate for continued evaluation as a breast cancer chemoprevention agent. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NCI
Off-label drug use in women with breast cancer
Authors: W. Dean-Colomb, S. Fang, W. Smith, L. Michaud, G. N. Hortabagyi, S. Giordano
Journal: Journal of Clinical Oncology (2009)

1016 Background: Despite reports of widespread use of off-label agents in cancer treatment, little is known about the off-label use of agents in the treatment of breast cancer patients. Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) - Medicare linked database to identify 2082 persons older than 65 years who were diagnosed with distant stage breast cancer between 1991 and 2002 and who were treated with chemotherapy between diagnosis and death. Off versus on-label classification was based upon FDA-approved indication in the treatment of breast cancer. We calculated the percentage of patients receiving off-label chemotherapy and used multivariate logistic regression models to estimate predictors of off-label chemotherapy use. We also evaluated the appropriateness of off-label chemotherapy drugs using DRUGDEX classifications. Results: Overall, 34.9% of patients were treated with off-label chemotherapy drugs. Of the thirty-six agents that were used to treat these patients, only 8 (22%) were FDA-approved for use in the treatment of breast cancer. Off-label use was least common in patients age 80 years and older (OR 1.93, 95% 1.35–2.76 for 80+ vs. 66–70 years) and varied by diagnosis year and geographic region. The most commonly used off-label agents were vinorelbine and gemcitabine, with 16.0% and 8.4% of patients receiving these agents, respectively. While 71% of the drugs used off-label lacked supporting evidence for their use in the treatment of breast cancer, these drugs were used in a small number of patients. Only 6.7% of patients were treated with drugs considered inappropriate for use in the treatment of breast cancer. Conclusions: Off-label chemotherapy use is widespread among patients with metastatic breast cancer. However, the majority of patients who received off-label chemotherapy received drugs with scientific data supporting such use. No significant financial relationships to disclose.
Irinotecan (I), carboplatin (C), and imatinib (IM) in the first-line treatment of extensive-stage small cell lung cancer (SCLC): A phase II trial of the Minnie Pearl Cancer Research Network
Authors: D. S. Thompson, J. D. Hainsworth, D. R. Spigel, M. A. Toomey, M. S. Rubin, M. T. Schreeder, S. Mateer, F. A. Greco
Journal: Journal of Clinical Oncology (2005)

7049 Background: The tyrosine kinase c-kit has variable expression in SCLC and may be a poor prognostic factor. IM targets c-kit expression, providing rationale for studying its role in combination with chemotherapy in SCLC. Methods: The primary endpoints of this multicenter phase II study were to assess the safety and response rate (RR) of IM 600mg PO QD and concurrent C AUC=4 IV D1 and I 60mg/m2 IV D1, 8, 15 Q 28D for 4 cycles, in patients (pts) with untreated extensive-stage SCLC. Pts were restaged after cycles 2 and 4, and every 4 months thereafter. Pts without progression or undue toxicity receive imatinib for 2 years. Eligibility criteria included: measurable disease, ECOG PS 0–1, adequate organ function, no active brain metastases, and informed consent. Results: Sixty-eight pts were enrolled between 09/02 and 05/04. The range of follow-up is 6–26 months. Baseline characteristics include: median age 62 years (37–81); male/female, 58%/42%; ECOG PS 0,1,2: 23%/75%/2%. Grade(G) 3 non-hematologic toxicity included: anorexia (9%), dyspnea (6%), edema (6%), nausea (25%), diarrhea (25%), and fatigue (26%). G4 non-hematologic toxicity was limited to infection in 1 pt. G3/4 hematologic toxicity included: neutropenia (10%/6%), anemia (13%/1%), and thrombocytopenia (4%/0%). There were no treatment-related deaths. Response data are available for 60 pts. Complete/partial RR were observed in 5 pts (8%)/35 pts (58%), respectively, for an overall RR of 67%. Eight percent of pts had stable disease, and 10% had progressive disease (15% were unevaluable because of intercurrent illness, poor compliance, or treatment toxicity.) Median progression-free (PFS) and overall survival (OS) were: 5.7 months (95% CI, 3.7–5.9) and 6.3 months (95% CI,4.7-not reached), respectively. Analyses of correlations of treatment to RR, response duration, PFS, and OS with c-kit expression are in progress. Conclusions: I/C/IM is a safe and well-tolerated regimen with acceptable RR in the first-line treatment of extensive-stage SCLC. Pending correlative studies of c-kit expression will be important in understanding the impact of imatinib in the treatment of SCLC. No significant financial relationships to disclose.
FOLFIRNOX for advanced pancreatic cancer (aPDAC) according to schedule and dose modifications: Clinical feasibility and impact of supportive care.
Authors: Vanja Vaccaro, Isabella Sperduti, Davide Melisi, Emilio Bria, Enrico Vasile, Matteo Santoni, Guido Giordano, Paola Bertocchi, Eleonora Lucchini, Maria Simona Pino, Marco Russano, Carlo Garufi, Daniele Santini, Alberto Zaniboni, Antonio Febbraro, Stefano Cascinu, Alfredo Falcone, Giampaolo Tortora, Francesco Cognetti, Michele Milella
Journal: Journal of Clinical Oncology (2015)

372 Background: Although FOLFIRINOX is considered one of the standards for aPDAC, concerns emerged with regard to the safety profile in clinical practice. Thus, we investigated the impact of dose/schedule modifications and additional supportive measures. Methods: The clinical charts of 292 aPDAC patients (pts) receiving classic (group 1) or modified (m)FOLFIRINOX (group 2) were retrieved at 8 Institutions. Results: Table summarizes pts’ characteristics;82/709 and 188/1127 pts/cycles were analyzed for groups 1 and 2, respectively. Overall toxicity was mild; significant differences in G2-4 toxicities between the two groups: asthenia (12.5% vs 6%, p&lt;0.0001), anemia (6.1% vs 3.1%, p=0. 003), diarrhea (6.5% vs 4%, p=0.02), and thrombocytopenia (5.4% vs 0.5%, p&lt;0.0001), favouring group 2, and neutropenia (4.7% vs 12.3%, p&lt;0.0001), favouring group 1. G-CSF was used more frequently in group 1 (80% vs 36%, p&lt;0.0001). Dose delays were comparable between the two groups; dose reductions were more common in group 2 (39% vs 28%, p&lt;0.00001). No differences in the complete control of nausea/vomiting at cycle 1 (no N/V) with or without aprepitant were observed (50% vs 45%, respectively). The presence of a biliary stent did not appear to significantly worsen toxicity. Overall ORR and disease control rate (DCR: PR+SD) were 40% and 62%, respectively, without significant differences between the two groups. Median PFS was 7 mos for both groups. Median OS, however, was significantly longer in group 2 (12 vs 18 mos, respectively; p=0.01). Conclusions: Both schedulesare easily manageable and well tolerated and may be safely administered on an outpatient basis in pts carrying biliary stents as well. The minimal differences in toxicity and efficacy obtained with mFolfirinox require additional investigation. [Table: see text]
Lung cancer cells promote self-survival by co-activation of EGFR by opioid receptors and secretion of growth and survival promoting factors
Authors: Kalpna Gupta, Julia Nguyen, Vinita Gupta, Teena Pasrija, Katherine Johnson, Robert Kratzke, Brittany Stinson
Journal: Cancer Research (2008)

2378  Epidermal growth factor receptor (EGFR) is overexpressed in 62% of non-small cell lung cancers (NSCLC). EGFR based therapies are of limited success and associated with resistance to therapy, suggesting that EGFR may not be the sole determinant of lung cancer progression. Therefore, we aimed to identify additional targets that activate cell growth and survival. We hypothesized that mu opioid receptor (MOR), in the cancer cells and cytokines secreted by the NSCLC impart a growth and survival promoting signaling and microenvironment, in an autoregulatory manner. Therefore, we examined if MOR co-activates, EGFR mediated signaling in human NSCLC, HL2009, HL1299 and HL460 and Beas2B a control cell line. We observed that HL2009 cells showed a 3-5 fold higher expression of MOR (by RT-PCR) as well as constitutive activation of phospho-EGFR and phospho-MAPK/ERK as compared to HL1299 and HL460. Morphine (100 nM) a MOR agonist, stimulated the phosphorylation of EGFR, MAPK/ERK and Akt in a time-dependent manner similar to that of 10 nM EGF, in HL2009 but not in HL460 cells. Morphine as well as EGF-induced phosphorylation was accompanied by translocation of phospho-EGFR to the nucleus in HL2009 but not in HL460 cells. Naloxone, an opioid receptor (OR) antagonist inhibited the morphine-induced translocation of phospho-EGFR to the nucleus but not that stimulated by EGF, suggesting that morphine acts via an OR-specific mechanism. We next examined the secretion of cytokines by H2009 and Beas2B cells in culture medium using a BioPlex array system utilizing color coded beads coupled to cytokine specific antibodies. H2009 and Beas2B were incubated for 48h in the absence or presence of morphine (100 nM) and medium was analysed for follistatin, HGF, IL8, GCSF, PDGF-BB, VEGF, leptin and PECAM1. Control wells without cells were incubated with medium alone. We observed a 37-, 15- and 11-fold increase in IL8, G-CSF and VEGF, respectively in H2009 conditioned medium as compared to Beas2B conditioned medium (p
Abstract 18027: Effects of Prolonged Exercise in Patients with Systemic Right Ventricles
Authors: Keri M Shafer, Graeme Carrick-Ranson, Sina Rahmani, M Dean Palmer, Kara Boyd, Naoki Fujimoto, Sheryl Livingston, M Beth Brickner, Lisa W Forbess, Benjamin D Levine
Journal: Circulation (2012)

INTRODUCTION Cardiac fatigue is described in healthy participants after ultraendurance competitions often disproportionately affecting the right ventricle. Patients with systemic right ventricles a...