tbuckley/cabot-search huggingface dataset:
Abstract P3-06-39: Anaplastic lymphoma kinase (ALK) protein overexpression is not a feature of inflammatory breast cancer
Authors: Cecile Colpaert, Melike Marsan, Peter Vermeulen, Luc Dirix, Steven Van Laere
Journal: Cancer Research (2015)

Abstract Recent studies suggest that anaplastic lymphoma kinase (ALK) could serve as a therapeutic target for inflammatory breast cancer (IBC) and that strategies targeting ALK should be considered for evaluation in clinical trials. Reverse phase protein arays revealed activation of the ALK receptor tyrosine kinase and biochemically-linked downstream signalling molecules in pre-clinical models of IBC. ALK genetic abnormalities have been reported in 80% (20/25) of IBC patients with a high prevalence of ALK alterations in basal-like IBC (Robertson F. et al., 2013). However, ALK protein expression has not been studied in human IBC samples. Immunohistochemical detection of the ALK protein is increasingly being used as a screening tool to test samples for ALK rearrangements. The biological premise is that the genetic abnormality of the ALK gene leads to overexpression of the ALK protein and therefore overactivity of the ALK tyrosine kinase; since this kinase is the target of crizotinib, it makes sense to assess the drug target directly. Formalin fixed paraffin embedded tissue samples from pre-treatment surgical biopsies of 79 consecutive IBC patients were immunohistochemically (IHC) tested for ALK protein over-expression using a validated IHC test (NCL-ALK, clone 5A4) with a sensitivity of 93% and a specificity of 100% when the Vysis ALK-FISH break apart test is used as a gold standard. Stained tissue sections were evaluated using the IHC histoscore proposed by Thunnissen E. et al., 2012, assessing both the proportion of tumor cells showing cytoplasmic staining and the staining intensity. Cytoplasmic staining of appendiceal ganglion cells was used as an on-slide external positive control; weak to moderate cytoplasmic staining of macrophages was used as an internal positive control. In 75 of the 79 tissue samples none of the tumor cells showed any ALK immunoreactivity. One tumor showed moderate cytoplasmic staining in a few cells (&amp;lt;1%, score 2+); ALK (2p23) FISH showed no rearrangement. This tumor was hormone receptor negative and HER2 negative. Three tumors showed minimal cytoplasmic staining in a few cells (&amp;lt;1%, score 1+). These results demonstrate that ALK protein overexpression is not a feature of IBC. Although genetic abnormalities of ALK without protein overexpression are not excluded, our results show that ALK IHC cannot be used to identify IBC patients eligible for enrollment in clinical trials evaluating ALK targeted therapeutics. Citation Format: Cecile Colpaert, Melike Marsan, Peter Vermeulen, Luc Dirix, Steven Van Laere, Inflammatory Breast Cancer International Consortium. Anaplastic lymphoma kinase (ALK) protein overexpression is not a feature of inflammatory breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-39.
FRI0046 Anti-Carbamylated Protein Antibodies Precede the Onset of Symptoms of Rheumatoid Arthritis in A Swedish Biobank Cohort
Authors: M. Brink, M.K. Verheul, J. Rönnelid, R.E. Toes, L. Klareskog, L.L. Trouw, S. Rantapää Dahlqvist
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Antibodies against citrullinated peptides of several specificities (ACPAs) have been found to predate the onset of symptoms of rheumatoid arthritis (RA) by years. The presence of a new auto-antibody system, anti-carbamylated protein (anti-CarP) antibodies has been identified in rheumatoid arthritis (RA) even predating the disease onset. Anti-CarP antibodies were associated with RA irrespectively of ACPA status. <h3>Objectives</h3> The presence of anti-CarP antibodies was evaluated in samples from individuals who subsequently developed RA before symptoms of joint disease and also after disease onset. <h3>Methods</h3> 223 individuals, with 423 samples, who were identified before onset of symptoms of RA (median 5.2years IQR 2.6 – 8.9 years), as donors to the Medical Biobank of Northern Sweden. 192 of them were also sampled at the time of diagnose, and 197 population controls were identified from the Medical Biobank for analysis of anti-CarP IgG antibodies with ELISA as previously described (1). All samples were also analysed for anti-CCP2 antibodies with ELISA (Euro-Diagnostica). Cut-off levels were identified by receiver operating characteristic (ROC) curves with 97% specificity for anti-CarP. <h3>Results</h3> The concentration of anti-CarP was significantly increased in the pre-symptomatic individuals compared with controls (median (IQR) 44.0 (142.6) AU/mL vs. 7.9 (43) AU/mL, p&lt;0.001) and increased significantly after disease onset to 198.9 (379.1) AU/mL. The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals including all samples was 13.9% (95%CI 11-17.6%,) as compared to 42.2% (95%CI 35.4-49.3,) after RA was diagnosed. The concentration of antibodies increased significantly the closer to disease onset the sample was collected. Sensitivity, less than 3 years before symptom onset, was 18.6% (95%CI 12.8-26.3). 5.1% of the anti-CCP negative pre-symptomatic individuals were anti-CarP ab positive and 10.4% of the anti-CCP negative RA-patients were anti-CarP positive. The frequencies of anti-CCP antibodies was in the pre-sympomatic individuals 35.7% (95%CI 31.3-40.4) and 74.6% (95%CI 67.9-80.3) in the RA patients <h3>Conclusions</h3> These results indicate that the anti-CarP antibodies could be involved in the pathogenesis of RA independent of anti-CCP antibodies <h3>References</h3> Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GMC, van Veelen PA, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc. Natl. Acad. Sci. U. S. A. 2011;108(42):17372-7. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4530
Dronabinol treatment of delayed chemotherapy-induced nausea and vomiting (CINV)
Authors: E. Meiri, H. Jhangiani, J. Vredenburgh, L. Barbato, H. Yang, D. Li, V. Baranowski, N. Tse
Journal: Journal of Clinical Oncology (2005)

8018 Background: Dronabinol (MARINOL), synthetic tetrahydrocannabinol, binds to cannabinoid receptors and has antiemetic activity. To explore if this novel mechanism would be of benefit in delayed CINV, dronabinol was added to the prophylactic regimen for acute CINV and continued after chemotherapy. Methods: Subjects receiving moderate to high emetogenic chemotherapy were randomized to double-blind, placebo-controlled, flexible-dose treatment. All subjects received dexamethasone 20mg PO and ondansetron 16mg IV pre-chemotherapy. Subjects receiving dronabinol (D), ondansetron (O) or dronabinol+ondansetron (DO) also received dronabinol 2.5 mg pre- and post-chemotherapy (Day 1); the placebo (P) group did not. Treatment continued through Day 5; symptoms were assessed daily. Primary efficacy was total response (TR- nausea intensity <5mm on visual analog scale [VAS], no vomiting/retching, no rescue antiemetic). Secondary measures included nausea occurrence, nausea intensity (VAS) and vomiting/retching episodes. Active treatments were compared with each other and P (Days 2–5) and significance was p≤0.05(unadjusted). Results: Sixty-four subjects were randomized and 61 analyzed for efficacy. TR was comparable for the D and O groups. All active treatments were statistically better than P in absence of nausea and nausea intensity. Nausea intensity and vomiting/retching were lowest in group D. There were no statistical differences among active treatments. Study treatments were well tolerated. Efficacy at Endpoint (LOCF) Conclusions: Dronabinol was comparable to ondansetron in total response and but was more effective in reducing nausea intensity and vomiting/retching. Results for the combination of DO were similar to either agent alone. These results support conducting a larger study since D could become an attractive alternative to serotonin receptor antagonists in treating delayed CINV. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Solvay Quintiles, Solvay Solvay
Effects of Angiotensin on the Central Nervous System
Authors: Walter B. Severs, Anne E. Daniels-Severs
Journal: Pharmacological Reviews (1973)

In the article, Effects of Angiotensin on the Central Nervous System by Walter B. Severs and Anne E. Daniels-Severs, Vol. 25, No. 3, 1973, page 421, line 2 from the bottom of the left hand column should read rat brain associated with the microsomal and page 434, line 12 from the bottom of the right hand column should read microsomal Na-K ATPase of rat hypo-
Retraction
Authors: Emilio Di Lorenzo, Rosario Sauro, Attilio Varricchio, Giannignazio Carbone, Giuliana Cortese, Michele Capasso, Tonino Lanzillo, Fiore Manganelli, Ciro Mariello, Francesco Siano, Maria Rosaria Pagliuca, Giovanni Stanco, Giuseppe Rosato, Giuseppe De Luca
Journal: Circulation (2009)

Drug-eluting stents may offer benefits in terms of repeat revascularization that may be counterbalanced by a potential higher risk of stent thrombosis, especially among ST-segment elevation myocardial infarction (STEMI) patients. No data have been reported so far on the long-term benefits and safety of drug-eluting stents in STEMI. Thus, the aim of the present study was to evaluate the short- and long-term benefits of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) compared with bare metal stents (BMS) in patients undergoing primary angioplasty.Consecutive STEMI patients admitted within 12 hours of symptom onset and undergoing primary angioplasty and stent implantation at a tertiary center with 24-hour primary percutaneous coronary intervention capability were randomly assigned to BMS, PES, or SES. All patients received upstream glycoprotein IIb/IIIa inhibitors. The primary end point was target lesion revascularization at the 1-year follow-up. Secondary end points were death and/or reinfarction, in-stent thrombosis, and major adverse cardiac events (combined death and/or reinfarction and/or target lesion revascularization) at long-term follow-up (up to 4 to 6 years). Cumulative incidence of end points was investigated. No patient was lost to follow-up. From October 1, 2003, to December 31, 2005, 270 patients with STEMI were randomized to BMS (n=90), PES (n=90), or SES (n=90). Procedural success was obtained in 93% to 95% of patients. Follow-up data were available for all patients. Compared with BMS (14.4%), both PES (4.4%; hazard ratio, 0.29; 95% confidence interval, 0.095 to 0.89; P=0.023) and SES (3.3%; hazard ratio, 0.21; 95% confidence interval, 0.06 to 0.75; P=0.016) were associated with a significant reduction in target lesion revascularization at the 1-year follow-up (primary study end point). At the long-term follow-up (4.3 years; 25th to 75th percentile, 3.7 to 5 years), no difference was observed in terms of death, reinfarction, and combined death and/or reinfarction, but compared with BMS (22.2%), both PES (6.7%; hazard ratio, 0.27; 95% confidence interval, 0.11 to 0.68; P=0.005) and SES (5.6%; hazard ratio, 0.22; 95% confidence interval, 0.083 to 0.59; P=0.003) were associated with a significant reduction in target lesion revascularization.This study shows that among STEMI patients undergoing primary angioplasty, both SES and PES are associated with significant benefits in terms of target lesion revascularization at the long-term follow-up compared with BMS with no excess risk of thrombotic complications. Thus, until the results of further large randomized trials with long-term follow-up become available, drug-eluting stents may be considered among STEMI patients undergoing primary angioplasty.
Abstract 19354: Management and Outcomes of Acute Type B Dissection in IRAD Treated with Open Surgery, Endovascular Flap Fenestration or TEVAR
Authors: Nathaniel I Costin, Peter Levanovich, Eduardo Bossone, Mark D Peterson, Truls Myrmel, Patrick O’Gara, Toru Suzuki, Stuart Hutchison, Kevin Greason, Khaled Abdul-Nour, Santi Trimarchi, Daniel G Montgomery, Eric M Isselbacher, Christoph A Nienaber, Kim A Eagle, Himanshu J Patel
Journal: Circulation (2014)

Background: The debate for the optimal treatment of complicated Type B Acute Aortic Dissection (TBAAD) is primarily focused upon open surgical intervention versus thoracic endovascular aortic repair (TEVAR). The technique of fenestration with stenting has been proposed to resolve malperfusion. This study evaluated post-procedural outcomes of all three approaches for TBAAD. Methods: TBAAD patients enrolled in the International Registry of Acute Aortic Dissection were stratified by management type: TEVAR, fenestration and stenting, and surgery. Results: Of the 552 patients with TBAAD, 231 (41.8%) underwent TEVAR, 214 (38.8%) standard open surgery, and 107 (19.4%) fenestration and stenting. TEVAR or fenestration and stenting were more likely to be performed in classic double barrel aortic dissection when compared to open surgery (73.2%, 76.6%, 52.8% respectively; p&lt;0.001). Patients treated with open repair were less likely to have distal extension into the abdominal aorta than those with TEVAR or fenestration and stenting (47.7%, 62.7%, 86.4%, respectively; p&lt;0.001). In-hospital mortality was similar between groups (11.7% TEVAR, 14.0% fenestration and stenting, 15.9% surgery). At five years, Kaplan-Meier post-discharge all-cause survival estimates were highest for TEVAR, followed by endovascular fenestration and finally open surgical intervention (85.2%, 78.3%, 67.2%, respectively; p=0.039). Conclusion: Patients treated by endovascular approaches, whether with flap fenestration or thoracic endovascular aortic repair, had lower five year mortality when compared to patients who required open repair in the setting of TBAAD. Either endovascular approach may be helpful in the treatment of TBAAD. Further research is needed to determine how much of the observed difference represents patient selection versus differential effects of treatment.
Lapatinib and gemcitabine for metastatic pancreatic cancer: A phase II study
Authors: H. Safran, T. Miner, N. Bahary, S. Whiting, C. Lopez, W. Sun, K. Charpentier, K. Charpentier, J. Shipley, E. Anderson, B. McNulty
Journal: Journal of Clinical Oncology (2009)

e15653 Background: To determine the overall survival for patients with metastatic pancreatic cancer treated with lapatinib and gemcitabine. Methods: Patients with metastatic pancreatic cancer received lapatinib, 1,500 mg/day, and Gemcitabine, 1 gm/m 2 /week for 3 weeks followed by 1 week off, until disease progression. This multicenter phase II study was planned to enter 125 patients to evaluate if the treatment regimen could achieve a 1-year survival of 30% and a median survival of 7 months. An additional subset of 20 patients were to receive 2 months of single agent lapatinib followed by lapatinib and gemcitabine. Results: At a planned 6 month analysis, the Brown University Oncology Group Data Safety Monitoring Board terminated accrual after 29 patients due to futility analysis. The median survival was 4 months (95% CI, 2.0–5.5 months). The four patients who received single agent lapatinib all progressed at 1 month. Conclusions: Lapatinib is not effective in pancreatic cancer. Evaluation of HER2 inhibitors in pancreatic cancer is not warranted. [Table: see text]
Phase II trial of neoadjuvant docetaxel (T), cisplatin (P), and cetuximab (E) followed by concurrent radiation (X), P, and E in locally advanced head and neck cancer (HNC)
Authors: A. E. Argiris, M. K. Gibson, D. E. Heron, R. P. Smith, R. L. Ferris, S. Y. Lai, S. W. Kim, B. F. Branstetter, J. T. Johnson, J. R. Grandis
Journal: Journal of Clinical Oncology (2008)

6002 Background: We incorporated E, a chimeric IgG1 monoclonal antibody against the epidermal growth factor receptor, into the induction therapy and subsequent chemoradiotherapy of HNC. Methods: Patients (pts) had previously untreated, stage III/IV squamous cell or undifferentiated carcinoma of the HN, ECOG PS 0–1, and adequate laboratory parameters. Induction consisted of T 75 mg/m² day 1, P 75 mg/m² day 1, and E 250 mg/m² days 1,8, and 15 (after an initial dose of 400 mg/m² on cycle 1, day 1), repeated every 21 days x 3 cycles, with prophylactic antibiotics. Subsequently, pts received 70 Gy (2 Gy/day) with concurrent P 30 mg/m² and E 250 mg/m² weekly, followed by maintenance E for 6 months. Sample size was 39 pts; target overall response rate (ORR) to TPE: 80%. Results: From 1/06 to 10/07, 39 pts were enrolled: median age 52 (21–74); male: 34; stage IV: 35; primary site: oropharynx, 23; larynx, 5; hypopharynx, 3, oral cavity, 3; nasopharynx, 3; and unknown, 2. 36 pts received all 3 cycles of TPE (2 pts discontinued treatment due to infusion reactions and 1 due to complications); 34 pts received XPE with median of 7 weekly P doses; 2 pts were switched to carboplatin. In 37 pts evaluable for response using RECIST, the ORR to TPE was 32/37 (86%); CR 2, PR 30, SD 5; in the primary, 19/26 (73%) had CR by clinical exam and 13/22 (59%) by PET. After XPE (n=28), the ORR was 100%; CR 8, PR 20; in the primary, 22/22 (100%) had CR by exam and 19/22 (86%) by PET. 3 pts underwent neck dissection for presumed residual disease; 2/3 had pCR. With a median follow-up of 12 months (3–23), 4 pts progressed (3 local, 1 distant); 1 pt had salvage surgery and remains disease free. 4 pts died (1 due to myocardial infarction and 3 of disease progression). Serious toxicities during TPE included grade (G) 3/4 neutropenia, 8/20; neutropenic fever, 4; G 3 infection, 3; G 3 anemia, 2; G 3 thrombocytopenia, 1; G 3/4 hypomagnesemia, 3/1; G 3 rash, 1; G 3 mucositis, 1; G 3 diarrhea, 2. During XPE (n=30): G 3 mucositis, 15; G 3/4 dermatitis, 8/1; G 3/4 hypomagnesemia, 5/6; G 3 infection, 7; neutropenic fever, 2. Conclusions: TPE followed by XPE has manageable toxicities and substantial activity in HNC. Early survival results are promising. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb
Phase II study of biweekly XELOX (capecitabine and oxaliplatin) as first line chemotherapy in elderly patients with metastatic colorectal cancer
Authors: C. Grande, G. Quintero, J. R. Mel, G. Huidobro, B. Campos, S. Candamio, J. C. Méndez, M. Salgado, E. Álvarez, J. Casal
Journal: Journal of Clinical Oncology (2009)

e15053 Background: Analysis of efficacy and toxicity of biweekly XELOX as first line monotherapy in elderly patients (pts) with metastatic colorectal cancer (MCRC), based in results of W. Scheithauer (J Clin Oncol 2003; 21: 1307). Methods: From March/06 to November/08, 28 chemonaïve elderly pts (&gt;75 years old) with MCRC, PS: 0–2, and adequate renal, hepatic and bone marrow functions, were included in a phase II study of: oxaliplatin 85 mg/ m 2 / day 1 plus capecitabine 2000/ m 2 / in 2 divided doses/ days 1–7 every 2 weeks. Treatment was continued until 12 cycles, tumour progression or innaceptable toxicity. Response evaluation every 6 cycles and toxicity every cycle was performed. At present 28 pts for toxicity and 24 pts for response are evaluable. Results: Median age: 78.2 years (range: 73.5–79.5). Male/Female: 14/14. Rectal/Colon: 9/19. Metastatic sites 1/2/&gt;2: 15/6/6. Liver 78.6%, Lung 32.1%, Local tumour 7.1%, Retroperitoneum 14.2%, Peritoneum 10.7%. and Bones 7.1 %. Previous adjuvant with 5-FU regimens to 4 pts. Comorbidity grade by Charlson index 0–1/2/&gt;2: 60.8%/ 28.6% / 10.7%, respectively. Median number of cycles for oxaliplatin and capecitabine were 8 (5.25–12) and 8 (5.25–11.75). Response rate: 2 pts complete response (8.3%), 8 pts partial response (33.3%),10 pts stable disease (41.7 %) and 4 pts progression (16.7%). The main CTC toxicity was Asthenia G2+3 in 6 (21.5%), Nausea and emesis G2 in 7 (25%), Diarrhea G2+3 in 7 (25%) and Hand-foot syndrome G1+2 in 5 pts (17.8%). No G4 toxicity or toxic deaths were observed. Median time to progression was 8.6 months.Median overall survival will be given updated at the congress. Conclusions: Preliminary results suggest that bi-weekly XELOX is an effective first line treatment for MCRC in elderly pts with an acceptable toxicity profile (especial surveillance of diarrhea is necessary) and protocol cumpliment. Combination with bevacizumab should be considered. No significant financial relationships to disclose.
Effect of mTOR inhibition on sensitivity of triple-negative breast cancer cells to epidermal growth factor inhibition
Authors: T. Liu, R. Yacoub, T. Graham, L. Yang, M. Tighiouart, R. M. O'Regan
Journal: Journal of Clinical Oncology (2009)

1055 Background: The outcome for patients with triple negative (TN) cancers is poor at least in part because of a lack of targeted therapies. Although 50% of TN breast cancers over-express EGFR, the use of EGFR inhibitors as single agents in patients with unselected and TN metastatic breast cancers has produced disappointing results. Likewise, mTOR inhibitors have modest activity as single agents in metastatic breast cancer. mTOR inhibitors have been demonstrated to activate the Akt pathway by a possible feedback mechanism, which could potentially sensitize TN breast cancer cells to upstream inhibitors. We have previously demonstrated that EGFR inhibitors in combination with rapamycin (RAPA) decrease cell survival, increase apoptosis, and are synergistic in TN breast cancer cells, compared to any of the agents alone (AACR 2008). We, therefore, evaluated the combination of mTOR and EGFR inhibition in vivo. Methods: Athymic mice were inoculated with TN (MDA-MB-231) breast cancer cells. One week after cell inoculation, mice were treated with vehicle, lapatinib 75mg/kg by mouth daily, RAPA 3mg/kg IP biweekly, or the combination. After 4 weeks of treatment, mice were sacrificed and tumors were assessed for target proteins by Western blotting and immunohistochemistry Results: The combination of RAPA and lapatinib resulted in a significant decrease in TN breast tumor volume (76 mm 3 ), compared to rapamycin alone (133 mm 3 , p = 0.01), lapatinib alone (183 mm 3 , p &lt; 0.0001) or control (188 mm 3 , p = 0.005). Neither lapatinib nor RAPA alone inhibited tumor growth significantly compared to control (p &gt; 0.05). Interestingly, in contrast to our findings in vitro, the increase in pAkt noted in RAPA treated tumors was not decreased by lapatinib, despite the significant decrease in tumor size in tumors treated with the combination. Conclusions: These studies demonstrate that the combination of mTOR inhibition and lapatinib significantly inhibit TN breast cancer growth, compared with either agent alone. Given the lack of targeted therapies in TN breast cancers, these data support the possibility that mTOR inhibition can sensitize TN breast cancers to EGFR inhibitors. A clinical trial evaluating the combination of lapatinib and RAD001 as second-line therapy for TN metastatic breast cancer is planned. [Table: see text]
Best providers should win contracts irrespective of their ownership
Authors: B. Hassel
Journal: BMJ (1996)

EDITOR,—Although J Grimley Evans's editorial on long term care in later life raises important issues, some of his assumptions and emotive language undermine the spirit of the open and informed debate that we so desperately need on the future of long term care in Britain.1 Although it is useful for commentators to acknowledge the diversity and …