tbuckley/cabot-search huggingface dataset:
Final efficacy results of a phase I/II trial of ixabepilone in combination with capecitabine in patients with metastatic breast cancer (MBC) previously treated with a taxane and an anthracycline
Authors: C. A. Bunnell, J. Klimovsky, E. Thomas
Journal: Journal of Clinical Oncology (2006)

10511 Background: Ixabepilone is an epothilone B analog that has demonstrated efficacy in taxane-sensitive and taxane-resistant MBC. Differing mechanisms of action and minimally overlapping toxicities provide the potential for synergy between ixabepilone and other cytotoxics. Methods: This open-label Phase I/II study was conducted to determine the recommended Phase II (and III) doses of ixabepilone and capecitabine using a 3-hour infusion of ixabepilone given on Day 1 (Schedule A) or a 1-hour infusion of ixabepilone given for 3 consecutive days (Schedule B) in combination with capecitabine given orally on Days 1–14 every 21 days in patients (pts) with MBC previously treated with a taxane and an anthracycline in the adjuvant or metastatic setting. Pts were excluded if they had received &gt;3 prior chemotherapy regimens in the metastatic setting. Tumor response was determined after every 2 cycles. Results from the 62 patients treated with ixabepilone 40 mg/m 2 as a 3 hr-infusion and capecitabine 2000 mg/m 2 are shown here. Results: 56/62 patients (90%) were aged &lt;65 yrs. 80% of pts had visceral disease and 44% were ER/PR/HER-2 negative. 44% of pts had received ≥2 prior chemotherapies in the metastatic setting. Pts received a median of 4 cycles (range 1–20). The overall response rate was 30% (15/50; 95% CI = 17.9–44.6%) comprised of one (2%) complete response and 14 (28%) partial responses. All 15 of the responders had extensive tumor metastases at baseline. Four of the 15 responders were triple negative for ER/PR/HER-2. The median time to response was 6 weeks (range 5–14 weeks), with most responders achieving an objective response by the end of Cycle 2. The median duration of response was 6.9 months (95% CI = 4.3–9.7 months). Conclusions: The recommended Phase II (and III) doses were 40 mg/m 2 ixabepilone (3-hour infusion on Day 1 every 21 days) and 2000 mg/m 2 capecitabine (2 doses on Days 1–14 every 21 days). This ixabepilone/capecitabine combination demonstrated promising synergistic antitumor activity and a manageable safety profile in pts with MBC previously treated with a taxane and an anthracycline. [Table: see text]
FAK/PYK2 inhibitors defactinib and VS-4718 enhance immune checkpoint inhibitor efficacy
Authors: Jennifer Ring, Yajuan Li, Irina Shapiro, Yan Wang, David Weaver, Jonathan Pachter
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Although durable responses to single agent immune checkpoint inhibitors have been reported, additional approaches are needed to extend this therapeutic benefit to a greater proportion of cancer patients. Accordingly, substantial efforts are ongoing to identify agents that can
RELATIONSHIPS BETWEEN ANTHELMINTIC EFFECTS AND BIOCHEMICAL AND PHYSIOLOGICAL MECHANISMS
Authors: HOWARD J. SAZ, ERNEST BUEDING
Journal: Pharmacological Reviews (1966)

The concept that the selective activity of anthelmintic agents is based on biochemical and physiological differences between the parasite and the host is supported by the results of investigations reviewed in this article. Such differences afford opportunities to design chemical agents that interfere with the functional integrity of the parasite without injury to the host. Up to the present, this possibility has remained a theoretical one, but further advances in our understanding of the physiology and biochemistry of parasitic worms could form the basis for the rational development of more effective and safer anthelmintic drugs.
Altered Brain Computed Tomography Perfusion in Patients With Fluctuating Lacunar Syndrome and Normal Magnetic Resonance Imaging
Authors: Salvatore Rudilosso, Xabier Urra, Oscar Chirife, Ángel Chamorro
Journal: JAMA Neurology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Study of vascular endothelial growth factor and endostatin in childhood leukemia and lymphoma
Authors: E. N. Ebeid, M. M. Kamel, N. G. Mohamed
Journal: Journal of Clinical Oncology (2004)

8560 Background: Angiogenesis is an important component in the progression and metastasis of solid tumors. Angiogenesis is also critically involved in the pathogenesis of hematologic malignancies. Current data suggest important prognostic and therapeutic implications of angiogenesis in a variety of malignancies of the hematopoietic system, including acute and chronic leukemias, myeloproliferative diseases, multiple myeloma, non-Hodgkin's lymphomas, and Hodgkin's disease. This study aims at clarifying the role of angiogenic factors, vascular endothelial growth factor (VEGF) and endostatin in the pathogenesis of leukaemia and lymphoma in children, and to asses if these factors can be used as a prognostic factor for leukaemia and lymphoma. methods:The present study examined the levels of VEGF and endostatin using ELISA technique in 40 cases, 20 cases presenting with acute leukemia (13 with ALL and 7 with AML) and 20 cases presenting with lymphoma (13 with NHL and 7 with HD). Results: Serum levels of VEGF and endostatin were significantly higher at diagnosis and after complete remission than controls. Serum levels of VEGF have significant correlation with platelets, WBCs, Hb concentration and endostatin at diagnosis in cases of leukemia and lymphoma, but have no significant correlation with age. Serum levels of endostatin have significant correlations with Hb concentration and VEGF, but have no significant correlation with age, platelets count and WBCs. No significant differences could be found in serum VEGF and endostatin in different types of leukemia and lymphoma and patients with organomegaly or without organomegaly. Conclusions: These data suggest that VEGF and endostatin expression ascribes an important role in children with leukemia and lymphoma.They may have a prognostic role for follow up of cases with leukemia and lymphoma. No significant financial relationships to disclose.
Clinical behavior of retroperitoneal sarcomas that express HIF-1α, PHD2 and/or VEGF
Authors: D. Han, G. C. Karakousis, J. Huang, E. Bartlett, T. L. Pasha, F. S. Lee, P. J. Zhang, D. L. Fraker
Journal: Journal of Clinical Oncology (2008)

10589 Background: Tumor hypoxia is correlated to poorer prognosis in certain cancers but few studies have assessed hypoxia in retroperitoneal sarcomas (RS). Here, we correlate clinical behavior of RS to tumor expression of hypoxia related proteins (HRPs): hypoxia inducible factor 1α (HIF-1α), prolyl hydroxylase domain protein 2 (PHD2) and vascular endothelial growth factor (VEGF). Methods: RS were resected in 56 patients (April 1996 to July 2005) with 43 patients having complete clinical and pathology data. A retrospective review was done looking at age, gender, local (pain/distension) and systemic (fever/weight loss) symptoms, tumor pathology and operative details. Immunohistochemistry was performed on sections from all 43 RS staining for HIF-1α, PHD2 and VEGF. Sections were scored as positive if ≥10% of cells stained positively. Staining patterns were correlated to clinical variables. Statistical analysis was done using ANOVA and 2 tailed chi-square tests. Results: Mean age was 64 years and 49% of patients were female. There were 29 liposarcomas (LPS), 12 leiomyosarcomas (LMS) and 2 other sarcoma histologies. Tumors positive for HIF-1α, PHD2 or VEGF were associated with higher rates of local and systemic symptoms compared with tumors negative for the same marker, but a significant increase was seen for local symptoms in HIF-1α positive tumors compared with HIF-1α negative tumors (87% vs. 54%, P<0.05). Tumors positive for HIF-1α and either PHD2 or VEGF or tumors positive for all 3 HRPs were high grade in 100%, were either LMS (56%, mean size 11±0.2 cm) or de-differentiated LPS (44%, mean size 22±1 cm), had a smaller overall mean tumor size compared with tumors negative for the same markers (15±1 vs. 24±1 cm, P<0.05) and required an abdominal organ resected in 96%. Negative staining for all markers (6 cases) was associated with no systemic symptoms, high grade in only 17%, larger mean tumor size (28 cm) and organ resection in only 33%. Conclusions: RS expressing HIF-1α, PHD2 and/or VEGF tend to be higher grade and smaller sized tumors that are associated with more symptoms and a greater need for organ resection. These results suggest that staining for HRPs could be prognostic by defining clinically aggressive forms of RS. No significant financial relationships to disclose.
High incidence of diarrhea in patients on long term therapy with lenalidomide and dexamethasone for multiple myeloma
Authors: L. Simpson, S. V. Rajkumar, A. Dispenzieri, M. Q. Lacy, S. Hayman, V. Roy, K. Stewart, M. A. Gertz, P. R. Greipp, S. Kumar
Journal: Journal of Clinical Oncology (2008)

8586 Background: Several phase II and III trials have demonstrated high response rates and improved survival and excellent tolerability with lenalidomide (Len) and dexamethasone (Len-Dex) in newly diagnosed myeloma (NMM). Therefore many pts continue on therapy for prolonged periods which might be associated with unexpected side effects. Methods: We reviewed the frequency of diarrhea with Lenalidomide in NMM, on two trials utilizing Len-Dex at MAyo. and in MM009/MM010 phase III trials. Toxicity data was prospectively collected using NCI CTCAE v 3.0. Results: Sixty seven NMM pts in Mayo trials and 703 pts in MM 009/010 trials were studied. In Mayo trials, the median duration of follow up and therapy was 28.6 mos and 8.5 mos (range, 1–47 mos) respectively. Eighteen pts (27%) reported diarrhea.Median duration of therapy for patients with diarrhea was 31 mos (range, 9–43) compared to 5 mos (range, 1–47) without diarrhea; (P < 0.001). No diarrhea was observed with therapy < 8 mos. Median time to diarrhea onset was 19 mos. One pt had grade 3 persistent diarrhea; all others had grade 1 or 2. One pt with grade 2 diarrhea required dose reduction of Len and one with grade 3 diarrhea required treatment cessation for palliation. Others benefitted from a conservative approach with Imodium as needed. We analyzed MM009/010 trials to estimate baseline diarrhea risk and risk with Len addition. The incidence of diarrhea was 38.8% and 28% in the Len-Dex (n=353) and Dex arm (n=350) respectively( excess risk of 10%). Multivariate logistic regression was done including therapy duration and treatment arm. Only duration of therapy was significant in this analysis (P<0.001); treatment with Len-Dex was not significant (P=0.4).We examined a cohort of pts in MM009/010 trials receiving 9–15 mos of therapy to further understand the effect of treatment duration. With adjustment for treatment duration, the incidence of diarrhea was identical; 42.3% (Len-Dex) and 42.5% (placebo-Dex). Discussion: We report diarrhea as an unexpected side effect in a significant proportion of patients with prolonged Len-Dex combination therapy. Most of the risk can be attributed to long-term Dex therapy. Most patients respond to conservative treatments with spontaneous resolution at treatment cessation. No significant financial relationships to disclose.
The Epidemic of Cardiovascular Disease in the Developing World: Global Implications
Authors: Bernard Gersh
Journal: Circulation (2012)

Recent data highlight that cardiovascular disease accounts for approximately 16.7 million of total global deaths of 57 million. 87% of worldwide cardiovascular deaths occur in the developing countries and at a younger age than the developed world. In contrast, total deaths due to HIV, tuberculosis, and malaria were approximately 5 million. Future projections are a concern in that it is estimated that death rates from stroke and coronary heart disease in the developing countries would be two to threefold greater than in the developed world. The cost of countries dealing with the dual burdens of communicable and degenerative diseases in terms of loss of productivity and the impact upon the public and private sector is enormous and could be catastrophic. It is likely that the pace of the “epidemiologic transition” underlying at the epidemic will vary according to the rapidity of economic development or the lack thereof and the role of genetic vulnerability needs to be determined. Nonetheless, the combination of a hostile cardiovascular environment as defined by changing diet, tobacco, lack of exercise, an aging society, air pollution, and the psychosocial and economic stresses in the developing worlds in conjunction with limited national resources and possible genetic vulnerability (the thrifty gene) is likely to lead to an explosion of the epidemic in the next 20 years. The key question is whether population-based strategies based upon community public health programs and high risk clinic-based strategies can stem the tide or even halt the epidemic. It is likely that the epidemic will involve all developing countries in the future, but the time course is unpredictable, and there is a dire need for prospective data since the implications for resource allocation are profound. Not all developing nations are at the same stage of the “epidemiologic transition“ and the shifting of resources from dealing with communicable diseases to cardiovascular disease needs to be based upon actual as opposed to perceived needs. The low priority of cardiovascular and chronic diseases on the global health agenda is a cause for concern and integrating the treatment and prevention of chronic diseases into health systems dealing with communicable diseases will contribute to the strengthening of weak health systems and overall community health.
Abstract 15015: Multimodal <i>in vivo</i> Computed Tomography and Optical Imaging for Simultaneous Functional, Metabolic and Molecular Myocardial Analysis
Authors: Elza D van Deel, Yanto Ridwan, Sasha Belenkov, Jeroen Essers
Journal: Circulation (2014)

Introduction and Hypothesis: The prevalence of myocardial infarction increases with the average age of the population and is currently the leading cause of death worldwide. In order to define anatomical changes and biomarkers related to cardiac infarction, we tested the use of combined computed tomography (CT) and near infrared fluorescent (NIRF) probes to facilitate non-invasive imaging of processes concerned with tissue degeneration/regeneration. This development of new non-invasive diagnostic methods will lead to better treatment options in the future. Methods: Mice were subjected to left anterior descending artery (LAD) ligation inducing an acute myocardial infarction and subsequently imaged in vivo using fast and low dose microCT scanning (QuantumFX, Perkin Elmer) and near infrared (NIRF) probes to monitor MMP activity (MMPsense680). Immediate contrast enhanced CT imaging using eXIA160 during its blood-pool phase allowed registration of changes in ventricular anatomy and function of important global parameters, like end-diastolic volume (EDV), end-systolic volume (ESV). These were used to calculate stroke volume (SV), and left ventricular ejection fraction (LVEF). Delayed eXIA160 contrast uptake during its myocardial phase, subsequently allowed analysis of the infarct size and infarct healing. In addition, in vivo molecular MMPsense localization was combined with micro-CT imaging for accurate 3D co-registration. Results: Changes in ventricular anatomy and myocardial viability were assessed 3 hours and 2 months post LAD occlusion in the same animal, demonstrating the feasibility of monitoring myocard viability over time. The decreased uptake of eXIA160 in the myocardium was subsequently quantitated. A concomitant increase in MMP activity, as determined by fluorescence mediated tomography using MMPsense680, could be localized to the infarcted site. Conclusions: Non-invasive imaging, using NIRF probes, enables longitudinal imaging of processes concerned with myocard infarction. Consequently, disease progression can be monitored over time and the effect of (new) pharmacotherapy can be studied.
Association of Age at Menopause and Duration of Reproductive Period With Depression After Menopause
Authors: Marios K. Georgakis, Thomas P. Thomopoulos, Andreas-Antonios Diamantaras, Eleni I. Kalogirou, Alkistis Skalkidou, Stella S. Daskalopoulou, Eleni Th Petridou
Journal: JAMA Psychiatry (2016)

Estrogens have neuroprotective and antidepressive effects; however, associations between indices of reduced endogenous estrogens and risk for postmenopausal depression have not been systematically explored.To investigate the association of age at menopause and the duration of the reproductive period with the risk for depression among postmenopausal women with naturally occurring menopause.A search strategy for use of MEDLINE was developed (through January 1, 2015) using the key terms menopause, climacteric, reproductive period, depression, and mood disorders. References of included studies and reviews were also screened; authors were contacted to maximize synthesized evidence.A total of 12,323 articles, without language restriction, were screened by pairs of reviewers to identify observational studies related to the study hypothesis; 14 studies were eligible for meta-analysis.Pairs of reviewers independently extracted information on study design and type of analysis by participants' characteristics and methods of depression ascertainment. Study quality was assessed using the Newcastle-Ottawa Scale, and fixed- or random-effects models were implemented.Pooled-effect estimates for depression, defined by psychiatric evaluation or validated instruments, by age at menopause and duration of the reproductive period.The 14 studies included in the meta-analysis represented 67,714 women. An inverse association (reported as odds ratio [OR]; 95% CI of 2-year increments) with depression in postmenopausal women was shown for increasing age at menopause (0.98; 0.96-0.99 [67,434 unique participants; 13 studies]) and duration of the reproductive period (0.98; 0.96-0.99 [54,715 unique participants; 5 studies]). Menopause at age 40 or more years compared with premature menopause was associated with a 50% decreased risk for depression (3033 unique participants; 4 studies). Pooling of studies examining severe depression showed a 5% decrease in risk of severe depression with increasing (2-year increment) age at menopause (52,736 unique participants; 3 studies); sensitivity analysis of studies controlling for past depression revealed similar results for age at menopause (0.98; 0.96-1.00 [48,894 unique participants; 3 studies). No heterogeneity or publication bias was evident in the main analyses.Longer exposure to endogenous estrogens, expressed as older age at menopause and longer reproductive period, is associated with a lower risk of depression in later life. Identifying women at higher risk for depression due to early menopause who could benefit from psychiatric intervention or estrogen-based therapies could be useful in the clinical setting.
Correlation of number of tumor infiltrating FOXP3-positive cells after primary systemic chemotherapy with anti-tumor response in breast cancer patients
Authors: T. Aruga, E. Suzuki, S. Horiguchi, S. Sekine, D. Kitagawa, S. Saji, N. Funata, M. Toi, K. Kuroi
Journal: Journal of Clinical Oncology (2008)

22219 Background: FOXP3-positive cells are known as regulatory T cells (Tregs) which inhibit activity of cytotoxic T lymphocytes (CTLs). It has been reported that some chemotherapeutic agents might selectively inhibit the Tregs preserving the activity of CTLs and result in antitumor response in many animal studies. Therefore, we hypothesized that primary systemic chemotherapy (PST) might inhibit FOXP3-positive cells and correlate with the antitumor response in breast cancer patients. Methods: To test the hypothesis, between September 2000 and January 2005, surgically resected tumor specimens (n=93) after primary systemic chemotherapy were stained with FOXP3 monoclonal antibody, and numbers of tumor infiltrating FOXP3-positive cells were counted in 5 randomly chosen high power fields (×40 objective and ×10 eyepiece; 0.13 mm2 per field). A median cutoff of > 6.6 defined patients with high numbers of Tregs. All patients were treated with anthracyclin containing therapy (EC or FEC) and 81% (n=75) of them were added taxanes sequentially. Results: Numbers of Tregs were significantly higher in lymphvessel invasion positive tumors (P=0.01) and ER negative tumors (P=0.02). There was no correlation between lymph node involvement and numbers of Tregs (P=0.8). Importantly, a low number of Tregs in tumors after PST correlated with clinical response (CR+PR) measured by Response Evaluation Criteria in Solid Tumors (RECIST) (P=0.03) although there was no correlation between numbers of Tregs and pathological response. Conclusions: These findings suggest that Tregs might be an important therapeutic target for breast cancer and that some chemotherapeutic agents could be a potential inhibitor of the Tregs in tumor and show antitumor effects addition to their direct cytotoxicity against cancer cells. No significant financial relationships to disclose.
Telling patients of incidental genetic findings is questionable, researchers warn
Authors: Jacqui Wise
Journal: BMJ (2016)

Patients with genetic variations linked with cardiac disorders often have no symptoms of the conditions, a study published in JAMA has shown. The researchers said that this raised the question of whether patients should always be notified about incidental genetic findings discovered during gene sequencing.1

Sequencing of selected gene sets and whole genomes is increasingly used for research and clinical care and can often identify incidental findings of potential clinical relevance. The American College of Medical Genetics and …