tbuckley/cabot-search huggingface dataset:
Akt-mTOR pathway in uterine leiomyosarcoma.
Authors: G. Garg, A. Short, J. R. Liu, A. R. Munkarah, R. Morris, R. Ali-Fehmi
Journal: Journal of Clinical Oncology (2011)

5040 Background: The Akt-mTOR pathway is an important regulator of cell proliferation and survival, shown to be deregulated in many cancers. This study was undertaken to determine the activation status of the Akt pathway in uterine leiomyosarcomas compared to benign leiomyomas; to study the relationship between the expression of different component proteins of the Akt pathway in leiomyosarcomas; and to determine their correlation with select clinicopathologic characteristics. Methods: Immunohistochemical staining was performed with specific antibodies for the phosphorylated Akt, 4E-BP1, and S6 ribosomal protein on 22 leiomyosarcoma- and 20 benign leiomyoma specimens. Clinical information was obtained from medical records. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests. Results: Patients with leiomyosarcoma were significantly older than those diagnosed with leiomyoma (mean age in years: 53 vs. 44, p <0.05). Although, p-4E-BP1 staining did not differ between leiomyomas and leiomyosarcomas; both p-Akt and p-S6 were significantly more expressed in leiomyosarcomas compared with leiomyomas (p<0.05). Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between the expression of p-S6 and p-AKT (P<0.05), but not between p-4E-BP1 and p-S6 or p-Akt. Recurrences were noted in 18 patients (82%); 4 pelvic and 14 distant. The mean disease free interval was 11 months (95% CI: 3-21 months). Although, not statistically significant (p>0.05), a trend towards negative correlation was observed between disease free interval and expression of p-Akt and p-S6 in patients with leiomyosarcoma. Furthermore, the expression of p-S6 was significantly associated with the presence of distant metastasis in these patients (p<0.05). Conclusions: Our results demonstrate significantly high levels of phosphorylation of Akt and S6 ribosomal protein in leiomyosarcomas, which is indicative of the activation of the Akt/ mTOR /S6 ribosomal protein pathway in these cancers. These findings suggest that S6 ribosomal protein is a promising biomarker for targeted therapy with mTOR inhibitors in the treatment of this highly malignant disease.
Warburg science goes to the bedside: A phase I trial of 2-deoxyglucose in patients with prostate cancer and advanced malignancies
Authors: R. S. DiPaola, M. N. Stein, S. Goodin, S. Eddy, E. H. Rubin, S. Doyle-Lindrud, D. Dvorzhinski, S. Beers, W. J. Shih, E. White
Journal: Journal of Clinical Oncology (2008)

16087 Background: A profound, but therapeutically unexploited, difference between cancer and normal tissues is the preferential utilization of glycolysis (the ‘Warburg effect‘) for energy by cancer cells. Additionally, similar to mechanisms of chemotherapy resistance, potential mechanisms of cancer cell resistance to starvation have recently emerged. One pathway by which cells survive periods of metabolic stress is thought to be autophagy, which is a catabolic process of organelle digestion that creates ATP during periods of nutrient limitation and is regulated by the protein Beclin1. Methods: We developed this novel paradigm in pre-clinical models and a phase I clinical trial. Preclinically, we used immortalized mouse epithelial prostate cells, as well as PC-3 and LNCaP cell lines, and a transfected pEGFP-LC3 autophagy marker construct to assess cytotoxicity and autophagy induction by 2-deoxyglucose (DG). In the clinic, eligible patients receive DG orally on days 1–14 of a 21 day cycle in cohorts of 3 in a dose escalating manner. Planned correlative assessments in patients included PET scans at baseline and day 2, as a potential marker of DG uptake, Beclin1 in initial tumor blocks, and LC3 protein in peripheral blood mononuclear cells as a potential marker of autophagy. Results: In preclinical models, we demonstrated cytotoxicity and induction of autophagy, which was dependent on Beclin1 expression. To establish methods for the clinical trial, we stained a human prostate TMA (>35 patients) for Beclin1 by IHC. In the clinical study, 6 patients have been treated at doses 30 and 45 mg/kg/day orally and a 3rd cohort is accruing currently at 60 mg/kg. Therapy was well tolerated with no dose-limiting toxicity. Of three patients with prostate cancer, one patient has received more than 11 cycles with a stable PSA for over 6 cycles. Of three patients in which PET was performed at baseline and follow-up, one patient had marked decrease in tumor site SUV and a second patient a minor decrease. Accrual is ongoing. Additional PET and assessment of LC3 and Beclin1 correlatives are ongoing. Conclusions: These initial data support the safety of DG and translational advancement of the rapidly developing paradigm of targeting the metabolic fragility of cancer. No significant financial relationships to disclose.
Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius).
Authors: Sagar Lonial, Brendan M. Weiss, Saad Zafar Usmani, Seema Singhal, Ajai Chari, Nizar J. Bahlis, Andrew Belch, Amrita Y. Krishnan, Robert A. Vescio, María-Victoria Mateos, Amitabha Mazumder, Robert Z. Orlowski, Heather J Sutherland, Joan Blade, Emma Catherine Scott, Huaibao Feng, Imran Khan, Clarissa M. Uhlar, Tahamtan Ahmadi, Peter Michael Voorhees
Journal: Journal of Clinical Oncology (2015)

LBA8512 Background: DARA, a human anti-CD38 IgG1κ mAb, has single agent activity and is well-tolerated in rel/ref MM (Lokhorst HM et al. ASCO 2014). This ongoing phase 2 study (NCT01985126) evaluated DARA monotherapy in the FDA breakthrough therapy designation population: MM patients with ≥ 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory to a PI and IMiD. Preliminary results are reported. Methods: MMY2002 is a 2-part, open-label, international, multicenter study. In part 1 stage 1, 34 patients were randomized to DARA 8 mg/kg (n = 18) q4w or 16 mg/kg (n = 16) qw x 8 wk, q2w x 16 wk, then q4w in a Simon-2-stage design to determine the most effective dose. Subsequently, 90 additional patients were enrolled in the 16 mg/kg DARA group. The primary endpoint was overall response rate (ORR) by independent review (IRC). Results: Data for the 16 mg/kg DARA group are presented (n = 106). Baseline characteristics: median time since diagnosis, 4.8 y; median prior treatment lines, 5; 75% ISS ≥ 2. Refractory to: last line of therapy, 96%; last PI and IMiD, 95%; pomalidomide, 63%: carfilzomib, 48%; alkylating agents, 78%. Adverse events (AE; ≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%), cough (20.8%). Infusion-related reactions (IRR, 42.5%) were mainly grade 1/2 during first infusion (grade 3 4.7%; no grade 4). No patients discontinued study due to IRRs; 5 (4.7%) discontinued treatment due to AEs. None of these AEs were assessed by the investigator to be DARA-related. ORR (IRC assessed) was 29.2%, with 3 sCR, 10 VGPR, and 18 PR with a 7.4 month median duration of response. ORR was consistent across clinically relevant subgroups. Median time to progression was 3.7 months. Median overall survival has not been reached and the estimated 1-year OS rate is 65%. After a median follow up of 9.4 months 14/31 (45.2%) of responders remain on therapy. Conclusions: In a heavily pre-treated MM population (95% refractory to last PI and IMiD), DARA at 16 mg/kg showed meaningful durable single agent activity, with deep responses and a favorable safety profile. Clinical trial information: NCT01985126.
Publication bias in translational research and number of polymorphisms analyzed in genetic association studies.
Authors: L. Tsali, A. Valachis, C. Neophytou, N. P. Polyzos, S. Drachtidi, L. Tsilidou, E. E. Skamagouli, V. Paparoupa, D. Mauri
Journal: Journal of Clinical Oncology (2010)

1539 Background: Due to advances in molecular targeted treatment technologies and the expansion of translational research, genetic association studies play a key role for clinical practice and development of new therapeutical targets. The number of genetic association studies in medical oncology is increasing rapidly and is expected to have an exponential growth over the next decades. Nonetheless genetic association reports are prone to potential biases which may influence the reported outcome. Aim: we hypothesized that positive outcome for a determined polymorphism might be over reported across genetic association studies analysing a small number of polymorphisms when compared to studies analysing a higher number of polymorphisms. Methods: Systematic review and analysis of published reports on the association of single nucleotide glutathione s-transferase (GST) polymorphisms and cancer outcome. Results: We identified 79 eligible trials. Most of the studies examined the GSTM1, GSTP1 Ile105Val and GSTT1 polymorphisms (n = 54,57 and 46 respectively). Studies analysing 1-3 polymorphisms (n = 39) were significantly more likely to present positive outcomes compared to studies examining more than 3 polymorphisms (n = 40) p = 0.004; this was particularly evident for studies analysing GSTM1 polymorphism p = 0.001. We found no significant associations between journal impact factor, number of citations and probability of publishing positive studies or studies with 1-3 polymorphisms examined. Conclusions: We propose a new subtype of publication bias in genetic association studies. Articles which examine 1-3 polymorphisms are more likely to present positive outcome for a determined polymorphism when compared to studies dealing with more polymorphisms. Thereafter positive results for genetic association studies analysing a small number of polymorphisms (n = 1-3) should be evaluated cautiously and considered at a lower level of evidence. Since medical oncologists are frequently called to review genetic association studies in translational research they should be aware about this potential reporting bias. No significant financial relationships to disclose.
Mechanisms for Congenital Transmission of Avian Leukosis Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Henry S. di Stefano, Robert M. Dougherty
Journal: JNCI Journal of the National Cancer Institute (1966)

Chick embryos free from resistance-inducing factor (RIF) were given intravenous injections of avian leukosis virus (ALV) and allowed to hatch. Virologic and morphologic examination of older embryos and chicks established that all embryos given injections were infected with ALV and all hatched chicks were viremic at hatching. With the same procedures, uninfected RIF-free control embryos proved free of infectious virus, and no virus particles were found when sections of pancreases were examined with the electron microscope. In the infected birds, persistence of viremia was confirmed at various intervals after hatching (from 24 hours to 68 weeks). Samples of reproductive organs from hens of various ages and physiological states were examined with the electron microscope, and virus multiplication (budding particles) was evident in all. The largest concentrations of free virus particles and budding forms were in the albumen-secreting glands of the magnum during the ovulatory phase. These observations were confirmed in a second generation of hens derived from those initially infected with ALV, in which the congenital infection took place under natural conditions. Mechanisms for congenital transmission of ALV, based on infection of eggs in the reproductive systems of shedding hens, are discussed.
Survival of differentiated thyroid carcinoma studied in 500 patients.
Authors: H Lerch, O Schober, T Kuwert, H B Saur
Journal: Journal of Clinical Oncology (1997)

To analyze the factors that influence survival of patients with differentiated thyroid carcinoma treated by surgical thyroidectomy, radioactive iodine, and early surgical reintervention with compartment-oriented lymphadenectomy in the case of locoregional recurrence.The survival of 500 patients with differentiated thyroid carcinoma was analyzed retrospectively with regard to mortality and survival rate (Kaplan-Meier). A total of 301 patients had papillary and 199 follicular thyroid carcinoma. The mean age of the 380 women and 120 men was 46.8 +/- 16.4 years at presentation. All patients were treated by surgical thyroidectomy, high-dose radioactive iodine, and early surgical reintervention with compartment-oriented lymphadenectomy in cases of locoregional recurrence, without routine adjuvant external radiotherapy of the neck. Patients were monitored up to 23 years, with a median follow-up time of 5.6 years.Twenty-nine of 500 patients died, 19 of thyroid cancer. The corrected overall 5-year survival rate (Kaplan-Meier) was 0.92. Among patients with tumor stage pT1-3NO-1MO (low risk), none died of thyroid carcinoma (5-year survival rate, 0.97); in patients with tumor stage pT4 and/or M1 (high risk), the 5-year survival rate was 0.83. The cause of death was locoregional recurrence in eight and metastatic disease in 11. Using multivariate analysis, risk factors that significantly influence survival were local invasion (pT4), metastatic disease (M1), and age.In differentiated thyroid carcinoma, the use of total surgical thyroidectomy followed by high-dose radioiodine therapy and early surgical reintervention in case of locoregional recurrence yields high survival rates, even without adjuvant external radiotherapy of the neck.
Assessment of left ventricular function in COPD
Authors: Jayanta Mallik, Kaushik Saha, Supriya Sarkar, Arpita Bannerjee
Journal: European Respiratory Journal (2012)

INTRODUCTION/BACKGROUND:

To evaluate the left ventricular (LV) function in chronic obstructive pulmonary disease (COPD) in absence of known LV disease by echocardiography.

METHODS:

The study was an observational cross sectional study including 50 cases of stable COPD patients. Confirmation of cases for COPD were done by GOLD criteria and staged accordingly. Known cases of LV disease diagnosed on the basis of history, clinical findings, electrocardiography and other investigations were excluded from the study. All cases were subjected to 2D echocardiography for LV evaluation.

RESULTS:

LV diastolic dysfunction was noted in 84% cases and both systolic and diastolic dysfunction was recorded in 2% case. We found statistically significant positive correlation of the LV diastolic dysfunction with the age of the patients, duration of symptoms and stage of diseases. But we did not find any significant co-relation between LV dysfunction with nature of symptoms and chest x-ray findings.

CONCLUSIONS:

We concluded that there was a definite association between LV diastolic dysfunction and COPD even if the known causes of LV disease were excluded. We suggested that left ventricular function should be evaluated in COPD patients not responding to usual management even in absent of clinical evidence of LV disease.
춘계학술대회 : 특강 ; GSK 학술상 발표 및 시상 : 제한효소분절질량다형성(RFMP)를 이용한 라미부딘 내성 B형간염바이러스의 검출
Authors: 황성규, 홍선표, 김남근, 정현재, 김석준, 한진희, 김형태, 임규성, 강명서, 유왕돈, 김수옥
Journal: Clinical and Molecular Hepatology (2005)

배경/목적: 만성B형간염의 치료에 사용되는 뉴클레오사이드 유도체인 라미부딘은 지속 사용시 B형간염바이러스 (HBV)의 중합효소인 P 유전자에 돌연변이를 유발하게 되는데, 중합효소의 활성 부위인 tyrosine, methionine, aspartate, aspartate (YMDD) motif의 M552I (YIDD)와 M552V (YVDD)가 내성을 유발하는 주요 돌연변이로 보고되고 있다. 현재 제한효소분절길이다형성 (RFLP), 염기서열분석 및 hyb
The Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitor SAHA Sinergistically Inhibit Proliferation and Induce Apoptosis of Megakaryoblastic MO7-e Cells.
Authors: Sara Galimberti, Martina Canestraro, Simone Pacini, Rita Fazzi, Enrico Orciuolo, Letizia Mattii, Paola Collecchi, Ami Sen, Fabio Presutti, Maura Brugiatelli, Mario Petrini
Journal: Blood (2006)
Extracellular Ribonucleic Acids (RNA) Enter the Stage in Cardiovascular Disease
Authors: Alma Zernecke, Klaus T. Preissner
Journal: Circulation Research (2016)

Inflammatory and ischemic cardiovascular diseases, especially atherosclerosis and myocardial infarction, remain the number one cause of death in the Western world, whereas the therapeutic options currently available are still limited. Several recent findings have indicated that nucleic acids, particularly extracellular ribosomal RNA and micro-RNAs, significantly contribute to the adverse outcome of atherosclerosis, myocardial infarction, and other cardiovascular diseases. Extracellular RNAs act as novel danger-associated molecular pattern signals and potent cofactors in cardiovascular inflammation and thrombosis, particularly when accumulating in the extracellular space under tissue-damaging or pathological conditions. In this concise review article, the different entities of extracellular RNAs, their cellular sources, and their putative functional contribution to the pathogenesis of cardiovascular diseases will be discussed. In fact, it remains a tightrope walk for these polyanionic molecules outside cells to promote defense reactions on the one side but to provoke cardiovascular disease development on the other side, dependent on their concentration, the environmental conditions, and the cellular stimuli engaged. Thus, we will discuss the mechanisms and cellular responses by which extracellular RNAs operate between defense and disease. Finally, natural counteracting molecules, such as RNase1, will be focused on to elaborate their protective functions in the context of inflammatory and ischemic cardiovascular diseases with the possibility to apply them as novel interventional strategies.
Long-term follow-up (FU) of patients with durable complete response (DCR) after chemotherapy (CT) and trastuzumab (T) for HER2-altered (HER2+) metastatic breast cancer (MBC).
Authors: Giuseppe Gullo, Monica Zuradelli, Francesco Sclafani, Josephine Ballot, Anne Marie Defrein, Armando Santoro, John Crown
Journal: Journal of Clinical Oncology (2012)

615 Background: Durable CT-induced complete response (DCR) of MBC is reported only anecdotally. The addition of monoclonal antibody T to conventional CT results in significant increase in response rates and prolonged survival for patients (pts) with HER2+ MBC. Though CRs are reported in most phase II and III clinical trials of CT+T, there is lack of data about clinical features and long-term outcome of these pts. Methods: We retrospectively reviewed all pts with HER2+ MBC treated at our Institutions with any CT+T and identified cases who achieved DCR. HER2 positivity was defined as 3+score at immunohistochemistry and/or amplification at FISH test. DCR was defined as a CR according to RECIST 1.0 criteria lasting &gt;36 months. Results: We identified 13 pts with HER2+ MBC who met criteria for DCR following CT+T. Their characteristics are: median age: 56yrs (range 30-65), stage at diagnosis: M0 54%/M1 46%, histology: ductal 84%/mixed ductal-lobular 8%/unknown 8%, tumour grade: G3 54%/G2 23%/unknown 23%, oestrogen receptors (ER): neg 62%/pos 38%, sites of metastatic disease: liver only 54%/other visceral 15%/bone and soft tissues only 31%, chemotherapy regimen: taxane+carboplatin 54%/single-agent taxane 23%/docetaxel+lapatinib 15%, capecitabine 8%. Metastatic disease was biopsy-proven in 54% of pts. All pts received maintenance T. Median follow-up (FU) is 6.5 yrs (range 3.0-11.6). Median duration of T was 59 months (17-121). At database cut-off date 12 pts (92%) are alive. Five pts (38%) had disease relapse (3 on maintenance T, 2 after T discontinuation), 2 of whom had radical surgery. In 8 pts (62%) disease has not relapsed (characteristics: all 1st-line therapy, ER negative 75%, liver only distant disease 75%). Conclusions: This is the largest series to our knowledge analyzing long-term FU of HER2+ MBC pts with DCR following CT+T. DCR pts appear to have prolonged survival and a substantial subgroup of them have no further disease relapse. These pts are usually treated in the 1st-line setting, have more frequently ER-negative disease and liver-only metastases. We are currently investigating the molecular profile of this subset of pts.
Personalized end-of-life care: Associations between patient preferences and treatment intensity near death
Authors: A. A. Wright, J. W. Mack, E. D. Trice, T. A. Balboni, S. D. Block, H. G. Prigerson
Journal: Journal of Clinical Oncology (2009)

6516 Background: Medical treatment at the end-of-life (EOL) should be responsive to patient values, but research shows it may instead reflect the regional supply of health services and/or physician practice patterns. We sought to determine whether patients' preferences are associated with EOL medical care and place of death. Methods: Coping with Cancer is an NCI/NIMH-funded, multi-site prospective, longitudinal cohort study of patients with advanced cancer, conducted from September 2002-February 2008. Analyses were based upon 317 deceased patients interviewed at baseline and followed until death, a median of 4.4 months later. EOL care was obtained from chart review, and regressed on patients' baseline preferences for life-extending therapy. Analyses were adjusted for significant confounds; i.e., socio-demographics, cancer type, patient denial, EOL discussion, do-not resuscitate (DNR) order, and treatment center. A sub-analysis examined EOL care within three different medical centers to determine whether patients' preferences and treatment intensity varied by region/practice type. Results: 90 of 317 patients (28.4%) reported a desire to receive life-extending therapy at baseline. Patients' preferences did not differ by proximity to death or performance status, but patients who preferred life-extending therapy had higher rates of denial (75.0% vs. 55.6%, p = 0.002) and were less likely to report having an EOL conversation (24.4% vs. 48.9%, p = 0.0002) or a DNR order (24.4% vs. 48.9%, p &lt; 0.0001). These patients were more likely to undergo ICU admission (AOR 4.6, 95% CI 1.9–11.1) and ventilation (AOR 3.0, 95% CI 1.2–7.3), and die in an ICU (AOR 6.7, 95% CI 2.4–18.7) instead of at home (AOR 0.6, 95% CI 0.3–0.9). A sub-analysis of patients treated at Yale, Parkland, and New Hampshire Oncology-Hematology confirmed that patients' preference for life-extending treatment was associated with higher rates of ICU admission in all three centers. Conclusions: Advanced cancer patients' treatment preferences may play a more important role in determining the intensity of medical care at the EOL than previously recognized. Future research should determine whether these preferences are informed and thus reflect patients' true values for EOL care. No significant financial relationships to disclose.
The Local-Regionally Advanced Nasopharyngeal Carcinoma Jigsaw Puzzle: Where Does the Chemotherapy Piece Fit?
Authors: Danny Rischin, Lester J. Peters
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.8.1968 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11956253 The Local-Regionally Advanced Nasopharyngeal Carcinoma Jigsaw Puzzle: Where Does the Chemotherapy Piece Fit? Danny RischinxDanny RischinSearch for articles by this author , Lester J. PetersxLester J. PetersSearch for articles by this author Show More Peter MacCallum Cancer Institute, Melbourne, Australia https://doi.org/10.1200/JCO.2002.20.8.1968 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology