tbuckley/cabot-search huggingface dataset:
DNA vaccine encoding the androgen receptor ligand binding domain elicits MHC class I restricted T-cell responses in vivo
Authors: Brian Olson, Douglas McNeel
Journal: Cancer Research (2008)

2857  The androgen receptor (AR) is a steroid hormone receptor that plays a critical role in both androgen-dependent and -independent prostate cancer. In addition to its accepted role as a target in androgen-deprivation therapy, we’ve shown that the AR is also an immunological target antigen, identifying some prostate cancer patients that have concurrent antibody and cellular immune responses specific for the AR ligand-binding domain (LBD). Using in vitro primary human cell culture, we also found that some patients with prostate cancer have cytotoxic CD8+ T-cells specific for HLA-A2-restricted peptides derived from the AR LBD. In this report, we sought to determine whether these peptide-specific T-cell responses could be elicited or amplified in vivo through the use of vaccines. To conduct these studies, we utilized the HHDII transgenic mouse, a model that expresses the human HLA-A2 and HLA-DR1 molecules but not the endogenous murine MHC class I and II molecules, and a model in which the AR LBD is a self-antigen, identical in amino acid sequence to the human antigen. These mice were immunized with one of ten AR LBD HLA-A2 peptides, and were analyzed for the presence of peptide-specific immune responses. Immunization with at least 3/10 peptides was found to induce cytotoxic, peptide-specific T-cell responses. We then sought to determine whether a DNA vaccine, targeting the entire AR LBD, could be used to elicit these peptide-specific responses. This vaccine (pTVG-AR) was used to immunize HHDII mice, and was found to elicit or amplify peptide-specific immune responses against at least 5/10 identified AR LBD HLA-A2-restricted peptides without any demonstrable toxicity. These results show that not only can the AR LBD be safely targeted in vivo, but more significantly that vaccines targeting the AR LBD can be used to elicit or enhance HLA-A2 peptide-specific immune responses in vivo. This suggests that the AR LBD is a potentially attractive immunological target antigen, and that vaccines targeting the AR LBD in vivo may be a useful approach in developing immunotherapies to treat prostate cancer.
Medicine in Europe: The greying of Europe
Authors: J L C Dall
Journal: BMJ (1994)

About a quarter of the population of Europe is now of pensionable age. Facilities for caring for very old or disabled people differ throughout Europe in scope and means of funding, and the countries of the European Union are far from equity in the status of pensioners. Health expectations have increased in older people--most of the calculated gain in life expectancy is likely to be without disability. Most countries now have specialist geriatric medicine facilities, and international research programmes are under way.
Abstract 4545: Anticancer effects and mechanism of VR23, a novel chloroquine derivative
Authors: Hai-Yen Thi Vu, Sheetal Pundir, Raja V. Solomon, Hoyun Lee
Journal: Cancer Research (2014)

Abstract Chloroquine, a worldwide used drug in treatment of malaria, rheumatoid and other human diseases, has recently been focused as a potential anti-cancer drug as well as a chemo-sensitizer when given in combination with other anti-cancer drugs. In cancer treatment, chloroquine possesses a major potential therapeutic advantage in which it specifically targets cancer cells. Unfortunately, however, its anticancer activity is rather low. To further improve its efficacy and specificity in killing cancer cells, we created and characterized several chloroquine derivatives using a hybrid pharmacophore approach, which led us to identify VR23 as the most promising compound. Our in-vitro model of cancer cells shows that VR23 functions as a novel proteasome inhibitor. It also deregulates activity of cyclin E and other centrosomal proteins, resulting in induction of multiple centrosome amplification, abnormal spindle formation, uneven cytokinesis, irreversible mitotic arrests, and eventually apoptosis. These VR23-induced phenomena occur in cancer-specific manner and cause massive death in a variety of cancer cell types. The treatment of engrafted animals with VR23 (30 mg/kg) twice per week for three weeks effectively inhibits tumor growth. Interestingly, administration of VR23 following 24 hours pre-treatment with paclitaxel (20mg/kg/week) enhances paclitaxel's anti-tumor activity by 70%. Our histological data shows that VR23 causes substantial decrease in mitotic index, inhibition of tumor infiltration into surrounding tissues and remarkable reduction of tumor cell proliferation and angiogenesis. Most importantly, VR23 shows very low toxicity to vital organs (liver, spleen, kidney and lung) of non-tumor-bearing nude mice. In addition, VR23 seems to reduce paclitaxel-induced toxicity when used in combination. Taken together, VR23, our novel chloroquine derivative and newly discovered proteasome inhibitor, appears to be an effective and safe anticancer therapeutic alone or in combination with other anticancer agents. Citation Format: Hai-Yen Thi Vu, Sheetal Pundir, Raja V. Solomon, Hoyun Lee. Anticancer effects and mechanism of VR23, a novel chloroquine derivative. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4545. doi:10.1158/1538-7445.AM2014-4545
Pharmacokinetics (PK) of CR011-vcMMAE, an antibody-drug conjugate (ADC), in a phase (Ph) I study of patients (pts) with advanced melanoma
Authors: M. Sznol, O. Hamid, P. Hwu, H. Kluger, T. Hawthorne, E. Crowley, R. Simantov, A. Pavlick
Journal: Journal of Clinical Oncology (2009)

9063 Background: CR011-vcMMAE, an ADC of fully-human monoclonal anti-GPNMB antibody (Ab) with monomethylauristatin E (MMAE), is in Ph I/II trials in pts with melanoma and breast cancer. We report PK and toxicity data from a Ph I study in melanoma pts treated every (q) 3 weeks (w), qw, or 2 of 3w. Methods: Enzyme-linked immunosorbent assays were used to measure ADC, total Ab (TA), soluble GPNMB (sGPNMB), and anti-ADC Ab in pt samples. Free MMAE was measured by liquid chromatography/mass spectrometry. Results: Initially, 32 pts were treated in 9 cohorts of 0.03 to 2.63 mg/kg iv q3w using standard 3+3 dose escalation. Noncompartmental PK analysis showed dose-proportional TA, ADC and free MMAE levels. As previously reported, maximum tolerated dose (MTD) was 1.88 mg/kg iv q3w; dose limiting toxicity (DLT) was rash. At MTD (n=15), terminal phase half life (T½) of TA was 41 ± 25h and T½ of ADC was 29 ± 13h. Mean maximum plasma concentrations of free MMAE was 1.3–2.9% of TA concentration across all doses. Mean sGPNMB at baseline was 12 ng/ml (range 1.3–32 ng/ml), corresponding to 0.024 % of TA concentration at MTD. Anti-ADC Ab were detectible in 8/240 (3.3%) samples (n=54). Based on the T½, two additional dose schedules (qw and 2 out of 3w) were initiated (n=14). Pts received 0.75 mg/kg (n=3) and 1.0 mg/kg (n=5) in the qw schedule and 1.25 mg/kg (n=3) and 1.5 mg/kg (n=3) in 2 of 3w. The most common adverse events (AEs) were rash (n=6), pruritus (n=5) and fatigue (n=4). 1 DLT (Gr 3 rash) was observed at 1.0 mg/kg qw. Enrollment is ongoing in both schedules. Conclusions: The relatively short T½ of CR011-vcMMAE (∼40h) does not appear to be due to immunogenicity or sGPNMB-mediated clearance. Preliminary data suggest that weekly dosing is tolerated at higher per-cycle cumulative doses than the q3w schedule. [Table: see text]
Double-blind, placebo-controlled trial of toremifene for the prevention of prostate cancer in men with high-grade prostatic intraepithelial neoplasia
Authors: D. Price, B. Stein, E. Goluboff, P. Sieber, D. Bostwick, G. Barnette, R. Boger, M. S. Steiner
Journal: Journal of Clinical Oncology (2005)

1003 Background: Toremifene, a selective estrogen receptor modulator (SERM) marketed for the treatment of breast cancer, appears to have promise in preventing prostate cancer. A randomized, double-blind, placebo-controlled study was conducted to determine the incidence of prostate cancer in men with high-grade prostatic intraepithelial neoplasia (PIN) treated with toremifene. Methods: 514 patients with high-grade PIN and no evidence of prostate cancer at study entry were randomized to oral toremifene 20, 40, or 60 mg or placebo QD for 12 months. Patients were rebiopsied at 6 and 12 months (minimum 8 cores per biopsy). Initial and subsequent biopsies were evaluated by a central pathologist (Bostwick Laboratories) for diagnosis of high-grade PIN and prostate cancer. Cumulative risk reduction and 12-month point-estimate risk reduction were compared between each toremifene group and placebo with Mantel-Cox and Cochran-Mantel-Haenszel, respectively, stratified by study center. Results: The number of evaluable patients (defined as having one on-study biopsy and being compliant with the protocol) was 447. Prostate cancer was diagnosed among significantly fewer patients taking toremifene 20 mg compared with placebo during the study based upon both 6-month and 12-month biopsy data (24.4% vs. 31.2% cumulative incidence, p<0.05). The cumulative incidence of cancer with 40 mg and 60 mg doses was lower than with placebo but not statistically different (28.2% and 28.1%, respectively). The number of cancers prevented per year with toremifene 20 mg over placebo was 6.8 per 100 persons treated. Among patients with no evidence of prostate cancer on baseline and 6-month biopsies, the incidence of prostate cancer was reduced by 48% with toremifene 20 mg compared with placebo on 12-month biopsy (9.1% vs. 17.4% 12 month point estimate, p<0.05). For the 40-mg and 60-mg doses, cancer incidence at 12 months was reduced by 14.3% and 13.0%, respectively, compared with placebo (not statistically significant). Conclusions: Toremifene 20 mg significantly reduced the incidence of prostate cancer at 1 year in a high-risk population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GTx
Late-breaking abstract: Effectiveness of easy smoking cessation clinic in tertiary health care settings: Observational study of cohorts
Authors: Ratapum Champunot, Maneewan Waikasikorn, Pranomm Maweha, Aninchata Pongphot, Mataneeya Poohkesorn, Jirawat Suwannakit, Sunee Jirasmitha
Journal: European Respiratory Journal (2011)

Introduction: Tobacco treatment programs should be offered in clinical settings for all smokers who need to quit smoking. We have co-operated with every units and departments in hospital and changed our service patterns of smoking cessation clinic into easy way. Cessation assistance was provided on working time every day except holiday. It requires approximately 20-30 minutes to complete and involves asking patients about smoking behavior and acting to help them quit. Telephone helpline was used to follow up and encourage smokers trying to continue quit smoking.

Methods: This is an observational study of cohorts of participants in smoking cessation clinic, Buddhachinnaraj hospital during June 1 to November 30, 2009. The main outcome measurements were self report abstinence rate at 6 and 12 months, and cost per quit.

Results: Over a period of 6 months, a cohort of 315 smokers were enrolled in this study.The self report abstinence rate at 6 and 12 months was 33.7% (106/315) and 27.9% (88/315).The mean cost per quit was 3,145 baht (70 Euro).Lost follow up rate by telephone helpline at 6 and 12 months was 18.4% and 27.6%.

Conclusions: Easy smoking cessation clinic is the intervention that are simple, cheap, and effective.Strategies for incorporating effective smoking cessation clinic into routine clinical care needs to become a key part of routine intervention for managing smoking cessation.
Parenteral Iron Therapy: A Single Institution's Experience Over a 5-Year Period
Authors: Christopher A. Laman, Scott B. Silverstein, George M. Rodgers
Journal: Journal of the National Comprehensive Cancer Network (2005)

Many patients require parenteral iron therapy for optimal correction of anemia, including cancer patients who require erythropoietic drugs. Available parenteral iron therapy options include iron dextran, iron gluconate, and iron sucrose. The purpose of this study is to summarize our institution's experience with parenteral iron therapy over a 5-year period, with a focus on comparative safety profiles. All patients receiving parenteral iron therapy over this period were included in the analysis. Chi-squared test and Fisher's exact test were used to compare the adverse event rates of each product. A total of 121 patients received 444 infusions of parenteral iron over this period. Iron dextran was the most commonly used product (85 patients) and iron sucrose was the least used (2 patients). Iron gluconate was used by 34 patients. Overall adverse event rates per patient with iron dextran and iron gluconate were 16.5% and 5.8%, respectively ( P = .024). Premedication with diphenhydramine and acetaminophen before infusions of iron dextran reduced adverse event rates per infusion from 12.3% to 4.4% ( P = .054). Test doses of iron dextran were used 88% of the time for initial infusions of iron dextran. All adverse events for all parenteral iron products were mild or moderate. There were no serious adverse events and no anaphylaxis was observed. Our results suggest that, if test doses and premedications are used, iron dextran is an acceptable product to treat iron deficiency.
Tamoxifen, hot flashes, and breast cancer recurrence: Support for pharmacogenetics
Authors: J. Mortimer, S. Flatt, B. Parker, E. Gold, J. P. Pierce
Journal: Journal of Clinical Oncology (2007)

500 Background: Knowledge of the pharmacogenetics of the CYP2D6 enzyme has been shown to correlate with the efficacy of adjuvant tamoxifen. Women who are ‘extensive metabolizers” of CYP2D6 have an improved relapse free survival and experience more hot flashes than women who have impaired metabolism (Goetz, JCO 2005;23:9312–18). We hypothesized that the development of hot flashes on adjuvant tamoxifen was an indicator of drug metabolism and would correlate with a more favorable outcome than women who did not experience hot flashes. Methods: The WHEL trial enrolled 3,088 breast cancer survivors with stages I (T1c)-IIIA breast cancer, within 2–48 months of initial diagnosis, and age &lt; 75 years to either a dietary intervention (n=1,537) or a control group (n=1,551). Data on the primary tumor, cancer treatment, disease status, and quality of life measures were collected at baseline and annually. Bivariate associations of vasomotor symptoms with age, race/ethnicity, menopausal status, cancer stage, ER and PR status, and time since diagnosis were tested using chi-square tests for categorical and t-tests for continuous variables. A left-truncated Cox proportional hazards model tested the association between recurrence-free survival and hot flashes, adjusting for tumor stage and grade and patient age. Women who died without a new breast cancer event were censored at their date of death; those without a new breast cancer event were censored at December 1, 2006 or the date of their most recent self-report of their breast cancer status. Results: The study sample includes 864 women treated with adjuvant tamoxifen 78% who reported hot flashes, and 69% of those reporting hot flashes also reported night sweats; 4% reported night sweats without hot flashes, and 18% reported neither hot flashes nor night sweats. A delayed entry Cox proportional hazards model adjusting for tumor stage and grade showed that those reporting hot flashes had a hazard ratio of 0.51 of recurrence during the follow-up period (95% CI 0.32–0.79) and that hot flashes were more predictive of outcome for tamoxifen treated patients than were age, grade, hormone receptor status, or stage II cancer. Conclusions: Our results contribute to the data that suggest tamoxifen side effects and efficacy may relate to an individual’s pharmacogenetics. No significant financial relationships to disclose.
Madreporique Stemmed Total Hip Replacement: Five Years' Clinical Experience
Authors: Gerald A Lord
Journal: Journal of the Royal Society of Medicine (1982)

Between February 1975 and December 1980, 1214 total hip arthroplasties were performed with a new type of rough surface implant. The results, pitfalls and complications are presented with special reference to the first 173 cases which have had a complete clinical and radiological follow up for at least five years. The indications for operations in both primary and revision arthroplasties are defined.
Brentuximab Vedotin Monotherapy in DLBCL Patients with Undetectable CD30: Preliminary Results from a Phase 2 Study
Authors: Nancy L. Bartlett, Mitchell R. Smith, Ranjana Advani, Tatyana Feldman, Kerry J. Savage, Maria Corinna Palanca-Wessels, Tanya Siddiqi
Journal: Blood (2014)
Capnogram phase III slope and dead space parameters: Comparison of main- and sidestream capnography techniques
Authors: Jozsef Tolnai, Balint Ladjanszki, Ferenc Petak, Barna Babik
Journal: European Respiratory Journal (2014)

Rationale:  Analyses of expired CO 2  concentration by capnography provides useful non-invasive bedside information about heterogeneity of lung emptying and ventilation dead spaces. Although the recording of capnogram can be achieved by using mainstream (MS) and sidestream (SS) devices, the capnogram indices supplied by these approaches has not been systematically compared.   Methods : To relate the parameters provided by these techniques, capnogram curves were recorded by using MS and SS techniques simultaneously in anaesthetized, mechanically ventilated patients undergoing elective heart surgery (n=39). Time capnography was used to assess phase III slope (S III,T ). Volumetric method was applied to estimate phase III slope (S III,V ), volume of CO 2  eliminated per breath (VCO 2 ), along with dead space parameters according to Fowler (V DF ), Bohr (V DB ) and Enghoff (V DE ) methods. Partial pressure of CO 2  in the arterial blood was also measured.   Results : Excellent correlation and good agreement was observed in S III,T  measured by MS and SS techniques (table). However, SS significantly underestimated S III,V  and VCO 2  and overestimated V DF , V DB  and V DE .   Conclusions:  Side stream time-capnography provides reliable estimates for the phase III slope, whereas application of a mainstream device is mandatory to assess volumetric parameters (slope, dead spaces and eliminated CO 2  volume) reliably.  Grant: TAMOP-4.2.4.A/2-11/1-2012-0001, OTKA 81179.
Etiology and outcome of bronchiectasis in children
Authors: B. Melki, B. Hamdi, A. Berraies, R. Bey, J. Ammar, A. Hamzeoui
Journal: European Respiratory Journal (2014)

The target of this retrospectivestudy is to illustrate the epidemiological characteristics, clinical features, underlying etiologic factors (EF), and outcome of children with bronchiectasis   Methods   Forty two children with bronchiectasis were admitted between January 2009 and December 2013. All patients underwent a comprehensive examination to identify EF. Data analysis in terms of age at onset, initial presenting symptoms, underlying etiology, distinct change in treatment, distribution of pulmonary involvement on computed tomography, and bronchal flora was performed.  RESULTS:  Mean age at diagnosis was 9,29 years (2 -15). Persistent cough and bronchorrhea were the most common symptoms. 9% of patients complain about exercise dyspnoea, together with chest deformation and/or finger clubbing. Haemoptysis was noted in 28% of cases. Mean time to diagnosis from symptom onset was 3,33 years (range: 0 to 10). The underlying etiologies were identified in 66% of patients: primary ciliary dyskinesia (40%) previous severe pneumonia (16%), and immunodeficiency (11%) were the most common causes. Bacteriologic tests isolated  H. influenza  in 66% of cases,  S. pneumonia  in 30% of cases and  Pseudomonas aeruginosa  in 16% of cases. Only 4 patients required surgery. Regardless of the cause, the treatment of bronchiectasis associated physiotherapy and antibiotics for exacerbations. 11% of the patients developed chronic respiratory failure and two of them died.   CONCLUSIONS:  All children with bronchiectasis should be comprehensively investigated because identifying underlying causes may have a major impact on the management as it argues against surgical resection.
Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV): A randomized phase III trial.
Authors: R. M. Navari, S. E. Gray, A. C. Kerr
Journal: Journal of Clinical Oncology (2010)

9020 Background: Olanzapine (OLN) has been shown to be a safe and effective agent for the prevention of CINV. In combination with other antiemetics, aprepitant (APR) has been approved for the prevention of acute and delayed CINV in patients receiving highly emetogenic chemotherapy (HEC). Methods: A phase III trial was performed for the prevention of CINV in chemotherapy naïve patients receiving HEC (cisplatin, ≥70 mg/m2 or doxorubicin, ≥50 mg/m2) comparing OLN to APR in combination with palonosetron (PALO) and dexamethasone (DEX). The OLN regimen was 10 mg of oral OLN, 0.25 mg of intravenous (IV) PALO, and DEX 20 mg IV on the day of chemotherapy, day 1, and 10 mg/day of oral OLN alone on days 2-4 after chemotherapy. The APR regimen was 125 mg of oral APR, 0.25 mg IV PALO, and 12 mg IV DEX, day 1, and 80 mg oral APR, 4 mg DEX BID, days 2-3. Fifty patients (median age 58 yrs, range 39-81; 29 females; ECOG PS 0,1) consented to the protocol and all were evaluable. Results: Complete response (CR) (no emesis, no rescue) was 100% for the acute period (24 h post-chemotherapy), 75% for the delayed period (days 2-5 post-chemotherapy), and 75% for the overall period (0-120 h) for 27 patients receiving the OLN regimen. CR was 87% for the acute period, 70% for the delayed period, and 70% for the overall period in 23 patients receiving the APR regimen. Patients without nausea (0, scale 0-10, M.D. Anderson Symptom Inventory) was: OLN: 88%, acute; 65%, delayed; and 65%, overall; APR: 88%, acute; 38%, delayed; and 38% overall. There were no Grade 3 or 4 toxicities. CR and control of nausea in subsequent cycles of chemotherapy (45 patients, cycle 2; 41 patients cycle 3; 33 patients, cycle 4) were equal to or greater than cycle one for both regimens. Conclusions: OLN was comparable to APR in the control of CINV in patients receiving HEC. Nausea was better controlled with OLN. No significant financial relationships to disclose.
Melanoma cytoplasmic humoral antibody test.
Authors: P.W.M. COPEMAN, P.G. ELLIOTT
Journal: British Journal of Dermatology (1976)

Detecting a high titre of antibody directed against the cytoplasm of malignant melanoma cells can help: To diagnose pigmented skin lesions with awkward histopathological signs. The test is positive in about half of the early primary malignant melanomas and in all actively regressing halo naevi. It is negative in benign juvenile melanoma. To prognosticate and provide a continuing assessment of the course of the disease in patients with known malignant melanoma. The test becomes negative when malignant melanoma metastasizes. To alert patients in danger, such as those who have extensive pigmented naevi or have a family history of malignant melanoma, of the supervention of the disease.
Time To Hematologic and Renal Improvements In Atypical Hemolytic Uremic Syndrome Patients With Long Disease Duration and Chronic Kidney Disease (CKD) Treated With Eculizumab
Authors: Christoph Licht, Petra Muus, Christophe Legendre, Yahsou Delmas, Maria Herthelius, Camille L. Bedrosian, Chantel Loirat
Journal: Blood (2013)