tbuckley/cabot-search huggingface dataset:
Phase I and pharmacokinetic study of the oral tris-(8-quinolinolato)gallium(III) complex (FFC11, KP46) in patients with solid tumors - a study of the CESAR Central European Society for Anticancer Drug Research - EWIV
Authors: C. Dittrich, A. Hochhaus, S. Schaad, C. Salama, U. Jaehde, M. A. Jakupec, M. Hauses, M. Gneist, B. K. Keppler
Journal: Journal of Clinical Oncology (2005)

3205 Background: FFC11 is an orally bioavailable gallium complex, which exerts its antitumoral activity via inhibition of ribonucleotide reductase, induction of S phase arrest and apoptosis. In preclinical models FFC11 proved to be a stronger anticancer agent than gallium nitrate and it was effective against a model of tumor-associated hypercalcemia. Methods: FFC 11 is administered orally for 14 days followed by a 14-days recovery period representing one cycle of therapy. The phase I trial is started at 30 mg/m2. Dose escalation (DE) is performed acc. to an accelerated dose titration design with escalation steps of 100%. The accelerated phase is finished when 1 pt exhibits dose limiting toxicity (DLT) or 2 pts experience toxicities ≥ grade (G) 2 NCI-CTC. Further DE will be done acc. to a modified Fibonacci scheme. Tumor response is assessed using the RECIST criteria. PK parameters were estimated assuming a one compartment model. Results: 7 pts were entered at the following dose levels (DL): 30 mg/m2, 60 mg/m2, 120 mg/m2, 240 mg/m2 and 480 mg/m2. Patient’s profile comprised the following tumor entities: parotid gland, stomach, renal cell (4) and ovarian cancer. Most pts were heavily pretreated. The adverse events for which a relationship to the study medication could not definitely be ruled out were neutropenia (G2 at DL1) (1pt) and anemia (G2 at DL1) (2pts), stomatitis and conjunctivitis (G1 at DL2) (1pt), dizziness, headache and acne (G1 at DL4) (1pt), fatigue (G1) and diarrhoea (G3) both at DL5 (1pt); the latter represented a DLT. Further enrolment on this DL was terminated due to feasibility reasons. In one out of the 4 pts with renal cell carcinoma (RCC) an unconfirmed partial response (PR) has been observed after 8 weeks and in a second pt with RCC the disease was stabilized for 29 weeks. Peak plasma levels were reached 5–7 h after intake. PK analysis revealed a long terminal half-life (28 h), a high CL/F (42 L/h) and a large V/F (1700 L). Conclusions: FFC11 has been well tolerated with some preliminary evidence of efficacy in RCC. FFC11 will be developed further after the production of higher dosed tablets. Supported by Faustus Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Faustus Cie
Psychosocial profile and morbidity in Indian patients with Chronic Myeloid Leukemia (CML)
Authors: P. Malhotra, N. Gupta, S. Dogra, S. K. Mahi, S. Varma, P. Kulhara
Journal: Journal of Clinical Oncology (2008)

20753 Background: CML is the commonest adult hematological malignancy in India, yet psychological aspects and psychiatric morbidity in these patients has not been evaluated earlier. We report our results from a cross-cultural perspective in a resource-constrained setting. Methods: It was a prospective cross-sectional study that included 93 CML patients (diagnosed using standard criteria) attending hematology outpatients at a teaching hospital in North India. Data were collected using socio-demographic and clinical profile sheets, Coping Strategies Check List, WHO Quality of Life (QOL) Scale-Bref, and General Health Questionnaire-12 (GHQ-12). Patients with GHQ-12 score of ≥ 3 were defined as GHQ positive group (GP1) while subjects with GHQ-12 ≤ 2 were defined as GHQ negative group (GP2). Data collection formed the study end-point. Chi-square and Mann-Whitney U tests were used to compare the socio-clinical variables and psychosocial profile between these two groups. Results: The socio-clinical profile of the overall CML group was: middle aged (45.5 ± 11.7 years, range = 13–73 years), 58.1% males, 94% married, 47% from nuclear family, 67.7% from rural background and mean duration of illness of 27.9 ± 25.8 (range = 2–136) months. Additionally, 93.6% were in chronic phase, and 3.2% each in accelerated and blast phase. Fifty-two subjects belonged to GP1 giving a psychological/psychiatric morbidity rate of 55.9% while 41 subjects belonged to GP2. Both groups were comparable on all socio-clinical variables, except that GP1 had significantly more females (p<0.05) and higher number of patients in accelerated/blast crisis (p<0.05). GP1 had a significantly poorer QOL (overall and on all domains, except social) despite using high number of coping strategies (p<0.001). Conclusions: Significant number of Indian patients with CML had psychiatric morbidity. The data suggests that poor QOL was associated with female gender and accelerated/ blast phase of disease despite use of coping mechanisms. These findings highlight the need for comprehensive psychosocial management of patients with CML even in a resource-constrained setting. No significant financial relationships to disclose.
Abstract 5846: Extranuclear Estrogen Receptor {alpha} Signaling Promotes Endothelial Monolayer Integrity but Not Breast Cancer or Uterine Growth in Mice
Authors: Qian Wu, Ken L Chambliss, Sarah C Oltmann, Michihisa Umetani, Ivan S Yuhanna, Kenneth S Korach, Gail D Thomas, Chieko Mineo, Sung Hoon Kim, Zeynep Madak-Erdogan, Adriana Maggi, Sean P Dineen, Christina L Roland, Rolf A Brekken, John A Katzenellenbogen, Benita S Katzenellenbogen, Philip W Shaul
Journal: Circulation (2009)

Although estrogen receptors (ER) function classically as transcription factors, a membrane-associated ER subpopulation initiates extranuclear responses in various cell types including endothelial cells (EC) and breast cancer cells. We investigated the basis and relevance of extranuclear ER function in endothelium using an estrogen-dendrimer conjugate (EDC) with 21 estrogen molecules stably conjugated to a large inert dendrimer that is excluded from the cell nucleus. Estradiol (E2) and EDC stimulated comparable EC growth and migration that was dependent on ER α , Src, G α i and endothelial NO synthase (eNOS) stimulation. The utility of EDC for in vivo studies was then examined. Ovariectomized female mice were given vehicle, E2, dendrimer, or EDC to yield estrogen-equivalent plasma concentrations for E2 and EDC of 10 −8M. In whole body imaging of estrogen-response-element-luciferase (ERE-Luc) reporter mice, E2 caused luciferase activation and EDC did not. Similarly, ER-regulated genes in mouse uterus were modified by E2 but not EDC. In addition, serum from EDC-treated mice did not activate ERE-Luc in HEK293 cells expressing ER α , but it stimulated nongenomic eNOS activation in EC. As such, EDC remains intact to specifically target extranuclear processes in vivo . Following perivascular electric injury of the carotid artery, E2 and EDC caused comparable 70 – 80% reendothelialization that was negated by the ER antagonist ICI 182,780 and was also absent in ER α −/− mice. In contrast, E2 elicited a uterotrophic response that was prevented by ICI 182,780, but EDC did not. Reendothelialization with E2 or EDC was prevented by pertussis toxin but not by B-oligomer. To study extranuclear ER signaling and breast cancer growth in vivo , MCF-7 cell tumor xenografts were established with E2 for 28d in SCID mice that were then treated with vehicle, E2, dendrimer or EDC for 21d. Whereas E2 caused further tumor growth, EDC did not, mimicking prior findings in cultured MCF-7 cells. Thus, EDC is a novel extranuclear selective ER modulator (SERM) in vivo , extranuclear ER α signaling is operative in vivo and promotes endothelial monolayer integrity, and these processes can potentially be harnessed to provide cardiovascular protection without increasing uterine or breast cancer risk.
Sequential Bacillus Calmette Guèrin and electromotive mitomycin-C versus Bacillus Calmette Guèrin alone for high-risk superficial bladder cancer: A prospective controlled study
Authors: S. M. Di Stasi, A. Giannantoni, R. L. Stephen, G. Capelli, A. Giurioli, G. Zampa, L. Storti, C. Pisanello, G. Vespasiani
Journal: Journal of Clinical Oncology (2004)

4539 Background: Intravesical bacillus Calmette-Guèrin (BCG) and mitomycin C (MMC) are a theoretically attractive combination for the treatment of high risk superficial bladder cancer. We conducted a prospective, controlled study comparing BCG with sequential BCG + electromotive delivery MMC in patients with T1 bladder cancer. Methods: Following transurethral resection and multiple biopsies we randomized 175 patients with T1 bladder cancer into 2 groups. Group I received BCG 81 mg; 6 weekly instillations. Group II received sequential BCG and electromotive (intravesical electric current; 20 mA for 30 min.) MMC at weekly intervals thus: (BCG, BCG, MMC) x 3, totaling 6 BCG and 3 MMC instillations. Non responders received repeat courses at 3 months. All complete responders underwent maintenance regimens of monthly instillations. Group I: 10 BCG treatments. Group II: (MMC, MMC, BCG) x 3, treatments. Results: Group I vs Group II: median (IQR or 95% CI). Follow up (months): 64 (38–82) vs 71 (49–87); p = 0.054 Recurrence: 47% (36–58) vs 28% (19–39); p = 0.013 Months to Recurrence: 11 (6–19) vs 20 (16–33); p = 0.001 Progression: 20% (12–30) vs 14% (7–22); p = 0.312 Months to Progression: 17 (10–21) vs 46 (21–58); p = 0.002 % 5-years mortality by any cause: 11.6 (5.7–20.3) vs 4.5 (1.2–11.1); p = 0.099 % 5-years mortality by bladder cancer: 9.3 (4.1–17.5) vs 1.1 (0.02–6.1); p = 0.017 Side effects were numerous but mainly localized to the bladder. There were no treatment related deaths nor episodes of serious illness nor bladder contractures. Conclusions: Intravesical sequential BCG/electromotive MMC is superior to BCG alone in the treatment of high risk bladder cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Physion srl
Eleven Asian countries pledge tougher action on tobacco
Authors: Sanjeet Bagcchi
Journal: BMJ (2015)

Health ministers from 11 countries in the World Health Organization’s South-East Asia region have signed the Dili Declaration, pledging to accelerate “hard-hitting measures” to reduce the use of tobacco in the region. 

The declaration, which was signed at the 68th regional committee meeting of the WHO South-East Asia region in Dili, the capital of Timor-Leste, on 7 September,1 calls on governments of all the 11 member countries for quicker and stricter implementation of WHO’s Framework Convention on Tobacco Control. This is important to reach WHO’s post-2015 sustainable development goal …
<i>PIK3CA</i> as a molecular target in mantle cell lymphoma
Authors: S. Papageorgiou, A. Psyrri, E. Liakata, A. Scorilas, D. Rontogianni, C. Kontos, P. Argiriou, V. Pappa, N. Harhalakis, D. Pectasides, T. Economopoulos
Journal: Journal of Clinical Oncology (2008)

8612 Background: We sought to determine the contribution of PIK3CA gene alterations to the pathogenesis of mantle cell lymphoma (MCL). PIK3CA is known to be involved in the PI 3-kinase/AKT signaling pathway, which is activated in MCL. Methods: We analysed 35 primary MCL cases (14 frozen and 21 paraffin-embedded specimens) and 2 MCL cell lines (Granta, REC1). To search for PIK3CA mutations, we isolated genomic DNA from primary MCL cases and MCL cell lines and performed direct sequencing of the exons 9 and 20 of PIK3CA. We used real-time quantitative PCR to investigate genomic amplification of the PIK3CA gene. We also analyzed PTEN and phoshorylated Akt protein levels in primary cases and cell lines using western blotting and immunohistochemistry (IHC). Flow cytometry analysis was used to assess apoptosis after treatment of MCL cell lines and the Raji Burkitt lymphoma cell line with LY294002, a specific inhibitor of PI3KCA. Results: We found that 14 of 23 (58%) primary MCL cases with amplifiable β- globin and two of two cell lines harboured a gain (>3) of PIK3CA gene copy number. PIK3CA gene mutations were not identified. In addition, amplification of PIK3CA correlated with the status of Akt phosphorylation in 7 of 12 (58%) primary MCL cases and the two MCL cell lines. Inhibition of PIK3CA induced increased apoptosis in the MCL cell lines. PTEN protein expression was present in all 14 primary MCL cases and cell lines by western blotting whereas five of 33 (15%) cases tested by IHC had loss of PTEN protein expression. Only one of the 5 MCL cases with loss of PTEN expression harboured gain of PIK3CA gene copy number. Therefore, PI3KCA gene amplification and PTEN loss were nearly mutually exclusive. Conclusions: We conclude that PIK3CA is an oncogene in MCL and PIK3CA amplification may be linked to pathogenesis and survival in MCL. No significant financial relationships to disclose.
POGZ truncating alleles cause syndromic intellectual disability
Authors: Janson White, Christine R. Beck, Tamar Harel, Jennifer E. Posey, Shalini N. Jhangiani, Sha Tang, Kelly D. Farwell, Zöe Powis, Nancy J. Mendelsohn, Janice A. Baker, Lynda Pollack, Kati J. Mason, Klaas J. Wierenga, Daniel K. Arrington, Melissa Hall, Apostolos Psychogios, Laura Fairbrother, Magdalena Walkiewicz, Richard E. Person, Zhiyv Niu, Jing Zhang, Jill A. Rosenfeld, Donna M. Muzny, Christine Eng, Arthur L. Beaudet, James R. Lupski, Eric Boerwinkle, Richard A. Gibbs, Yaping Yang, Fan Xia, V. Reid Sutton
Journal: Genome Medicine (2016)

Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.
Abstract 268: Quantitative Performance Assessment of Simulated Pediatric Cardiopulmonary Resuscitation
Authors: Aaron Donoghue, Nancy Tofil, Linda Brown, Frank Overly, Adam Cheng
Journal: Circulation (2014)

Background: Methods to quantitatively measure performance during resuscitative care are lacking in published literature. Members of our group have previously published psychometric analyses of task-based scoring instruments used in educational research in pediatric resuscitation. These published investigations used instruments that were designed for specific cases in pediatric resuscitation, rather than for a more generalizable application. We hypothesize that a novel scoring instrument will reliably assess clinical performance during simulated cardiac arrest. Methods: This study was conducted at 11 pediatric centers in Canada and the US. Teams of pediatric providers performed a simulated cardiac arrest scenario (asystole for 6 minutes, VF for 6 minutes). A task-based scoring instrument was designed by investigator consensus using a 0, 1, or 2 point scoring system to rate performance during cardiac arrest. The items were chosen according to the essential steps in the pulseless arrest algorithm of the AHA Pediatric Advanced Life Support course and include CPR performance parameters (chest compression rate, depth, release, pauses), defibrillation (dose in J/kg, timing), and epinephrine (dose, timing). Multiple raters reviewed and scored a set of simulations. Overall interrater reliability was measured; a fully-crossed generalizability study with team and rater as facets was performed to determine the variance in scores ascribable to each facet; a decision study was done to determine the effect of additional raters and scenarios on the G coefficient. Results: Three raters scored four videos. Overall scores ranged from 53/90 (59%) to 73/90 (81%) possible points. Intraclass correlation coefficient was 0.77 (F 3,8 = 4.46, p = 0.04). Variance components were 21% for rater, 57% for scenario. G coefficient was 0.80; by D study this increased to 0.91 and 0.93 with 8 and 10 raters, respectively. Conclusions: A novel scoring instrument for quantifying performance during pediatric cardiac arrest showed modest reliability and generalizability. Future studies should examine the effect of a larger number of raters and/or scenarios on generalizability, as well as the utility of the instrument in assessing real clinical performance.
Variation of fetal hemoglobin and F-cell number with the LCR-HS2 polymorphism in nonanemic individuals [letter]
Authors: T Merghoub, M Maier-Redelsperger, D Labie, B Perichon, N Feingold, SP Dibenedetto, G Schiliro, P Samperi, r Ducrocq, J Elion, R Krishnamoorthy
Journal: Blood (1996)
Abstract 15206: Prognostic Value of Left Atrial Appendage Function for Maintenance of Sinus Rhythm After Catheter Ablation in Atrial Fibrillation
Authors: Miyuki Ariyama, Makoto Matsumura, Yoshie Nakajima, Tomomi Koizumi, Ritsushi Katoh, Toshihiro Muramatsu, Kazuo Matsumoto, Nobuyuki Komiyama, Nishimura Shigeyuki
Journal: Circulation (2012)

Purpose: We evaluated whether the left atrial appendage (LAA) function was associated with the prognosis after catheter ablation in the patients with atrial fibrillation (AF). Method: Transesophage...
Costs of managing side effects in the treatment of first line metastatic renal cell carcinoma (mRCC) in Germany, France, and UK: Bevacizumab (BEV) + interferon alpha-2a (IFN) compared with sunitinib
Authors: G. Mickisch, B. J. Escudier, M. E. Gore, S. Walzer, E. Sabaté, M. Nuijten
Journal: Journal of Clinical Oncology (2008)

5110 Background: The combination of BEV + IFN has been shown to prolong the time to progression-free survival (PFS) [Escudier 2007] and to have comparable efficacy to sunitinib in patients with mRCC [Motzer 2007]. One key difference between the two regimens is the type and frequency of side effects. In this situation the management of side effects and their cost is an important factor to consider for physicians, patients and healthcare payers, when selecting treatment options. Methods: A linear decision analytic model was developed to compare the management cost of grade 3 and 4 side effects for BEV + IFN versus sunitinib from the perspective of the health care purchaser in 2007 in Germany, France and the UK. Data sources used included published cost literature and clinical trials, official price/tariff lists and country specific cost databases. Results: The side effect management costs for sunitinib were higher than those for BEV + IFN in Germany, France and UK. The total costs were €925, €834 and €246 for BEV + IFN and €1,677, €2,224 and €566 for sunitinib in Germany, France and UK, respectively. The main drivers (∼80% of all management costs) were dependent on the country but in general these were for sunitinib the management of leucopenia/neutropenia, thrombocytopenia, fatigue, hand-foot syndrome and diarrhoea. In comparison, the main costs in most of the countries for BEV + IFN were the management of neutropenia, thrombocytopenia, anaemia and fatigue. The difference in management costs between the two regimens were mainly due to the higher incidence of neutropenia and thrombocytopenia with sunitinib versus BEV + IFN and the high management costs for diarrhoea and nausea/vomiting. Hypertension is a common side effect in patients with mRCC treated with sunitinib or BEV + IFN and is inexpensive to treat. Conclusions: The costs of managing the side effects of sunitinib treatment are two to three times greater than those for BEV + IFN in Germany, France and the UK. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Bayer, Inate Pharma, Pfizer, Roche, Wyeth Roche Antigenics, Bayer, Genentech, Novartis, Pfizer, Roche, Wyeth Pfizer, Roche Roche Pfizer, Roche
Abstract 12939: Platelet Activation is Less Enhanced in Edwards Sapien 3 Valve Compared to Its Precursor Model
Authors: Suzanne Fateh-Moghadam, Sabrina Voesch, Meinrad Gawaz, wolfgang bocksch
Journal: Circulation (2014)

Background:  Due to a different design of the Cobalt chromium alloy frame and the additional outerskirt to minimize paravalvular leakage one might imagine that the extent of platelet activation (PA) of new Edwards Sapien 3 valve (ESV3) might differ from the Edward Sapien XT valve (ESVXT).  Aim of the study:  The aim of our study was to compare platelet aggregation (Agg) and platelet activation (PA) of the ESV-XT with the newer ESV-3 in pts undergoing TAVI on dual antiplatelet therapy .   Methods:  Pts scheduled for TAVI were loaded with 600 mg Clp and 500 mg ASA the day before intervention.  Platelet Agg were evaluated in all pts by the Multiplate system (Dynabyte, Munich, Germany) before (T0), directly after intervention (T1) and on T2 (day1), T3 (day2) , T4 (day3) . PA was simultaneously assessed with the use of immunologic markers of PA as CD62P and PAC-1 by flow cytometry.   Results:  43 pts (age 81.3 +1.2 years ) with severe aortic stenosis and high surgical risk (log Euroscore 18.1 +1.3 %) underwent successfully TAVI with the ESV-XT and 29 pts (age 82.6 + 1.2 years, log Euroscore 21.5 +2.9 %) underwent TAVI with the ESV-3. .  Platelet Agg was inhibited to the same extent in both valve types directly after TAVI under dual antiplatelet therapy [ESV-XT (T1) versus ESV-3 3 (T1) : AggADP, (AUC): 16 (11-24) versus 16 (10-20); p=0.514; AggTRAP (AUC): 61(41-81) versus 69(52-79);p=0.244; AggASPI (AUC): 13(5-19) versus 11 (5-17); p=0.436. ] There was no significant difference in platelet drop between both valve types between day 0 and day3. [ESV-XT (T0T3) versus ESV-3 (T0T3): 55.2 ± 4.2 versus 63.5± 8.1; p=0.364. ]  However there was an enhanced expression of PA markers (CD62P and PAC-1) directly after implantation in pts with ESV-XT compared to pts with the ESV-3. [ESV-XT versus ESV-3 :median (25th;75th percentile) mean immunofluorescence : CD62P : 7.4 (6.8-8.6) versus 6.6 (6-7.9), p=0.014; PAC-1 : 4.2(3.6-4.7) versus 3.4 (3.2 -4.9), p=0.045.]   Conclusion:  Our results show that dual antiplatelet therapy inhibits platelet Agg in both valve types to the same extent. However PA is less enhanced in pts with the ESV-3, than in pts the ESV-XT directly after implantation