tbuckley/cabot-search huggingface dataset:
Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Marion Delcroix, Irene Lang, Joanna Pepke-Zaba, Pavel Jansa, Andrea M. D’Armini, Repke Snijder, Paul Bresser, Adam Torbicki, Sören Mellemkjaer, Jerzy Lewczuk, Iveta Simkova, Joan A. Barberà, Marc de Perrot, Marius M. Hoeper, Sean Gaine, Rudolf Speich, Miguel A. Gomez-Sanchez, Gabor Kovacs, Xavier Jaïs, David Ambroz, Carmen Treacy, Marco Morsolini, David Jenkins, Jaroslav Lindner, Philippe Dartevelle, Eckhard Mayer, Gérald Simonneau
Journal: Circulation (2016)

Background— Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension. Methods and Results— A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90–95), 91% (95% CI, 87–93), and 89% (95% CI, 86–92) in operated patients (n=404), and only 88% (95% CI, 83–91), 79% (95% CI, 74–83), and 70% (95% CI, 64–76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension–targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1.49–11.62; P =0.0065 and HR, 4.76; 95% CI, 1.76–12.88; P =0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95–1.90; P =0.0992 and HR, 1.50; 95% CI, 1.20–1.88; P =0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36–6.69; P =0.0065 and HR, 2.15; 95% CI, 1.18–3.94; P =0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension–targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients. Conclusions— The long-term prognosis of operated patients currently is excellent and better than the outcome of not-operated patients.
Genetic alterations predicting the response of high risk breast cancer patients to Taxol-based adjuvant chemotherapy
Authors: G. Fountzilas, U. Stropp, E. Razis, R. Wirtz, D. Skarlos, H. Gogas, N. Pavlidis, H. P. Kalofonos, D. Pectasides, A. M. Dimopoulos
Journal: Journal of Clinical Oncology (2005)

9574 Objectives: In an effort to identify predictive markers that may have the potential to identify patients who are likely to respond to paclitaxel in a dose-dense sequential chemotherapy regimen we analyzed DNA alterations in fixed tumor tissues obtained from the adjuvant breast cancer trial HE 10/97. This is a two-arm trial (E-CMF vs. E-T-CMF) investigating postoperative dose-dense sequential chemotherapy with epirubicin (E) followed by CMF with or without paclitaxel (T). Disease -free survival (DFS) was the primary study endpoint. Methods: DNA from fixed tumor tissues was isolated employing an experimental method based on magnetic beads from Bayer HealthCare Diagnostics. The amplification of genes with putative relevance to breast cancer was verified by TaqMan™ PCR analyses. The amplification status of candidate genes was then used to identify differences in DFS in subgroups of patients. Results: By analyzing fixed tumor tissues from 270 patients, we found that amplification of genomic DNA frequently occurred as an overexpression of multiple (10–180) neighboring genes. We therefore named these genomic regions ARCHEONs (“Amplified Regions of Chromosomal Expression Observed in Neoplasia”). Notably, patients with ARCHEONs on chromosome 2q 33–34 or 4q34.1–3 that were treated with paclitaxel had a DFS rate of 84% at 48 months, which was significantly higher (p=0,006) than the 70% DFS rate observed in patients that had the ARCHEONs but were not treated with paclitaxel, or a rate of 68% seen in patients that were treated with paclitaxel but did not have the ARCHEONs. Conclusion: The described ARCHEONs appear therefore to influence the response of high-risk breast cancer patients to dose-dense sequential chemotherapy and to have predictive value in identifying patients that can benefit from paclitaxel. Identification of such ARCHEONs prior to the initiation of chemotherapy could help physicians determine whether to add paclitaxel to an adjuvant anthracyclin-based treatment. No significant financial relationships to disclose.
Cell-free multi-layered collagen-based scaffolds demonstrate layer specific regeneration of functional osteochondral tissue in caprine joints
Authors: Tanya J. Levingstone, Ashwanth Ramesh, Robert T. Brady, Pieter A.J. Brama, Clodagh Kearney, John P. Gleeson, Fergal J. O'Brien
Journal: Biomaterials (2016)
Cat, dog and horse allergens in day care centres in Uppsala, Sweden, associations with FeNO and dyspnea
Authors: Dan Norbäck, Nina Fabjan, Guihong Cai, Ivan Kreft, Erik Lampa, Gunilla Wieslander
Journal: European Respiratory Journal (2011)

Aim: To study associations between FeNO, FEV1 and dyspnoea in day care centre staff and levels of cat, dog and horse allergens in day care centres.

Methods: 62 staff in 5 day care centres in Uppsala participated in a study performed 3 times in each subject in spring, in connection with a diet study. Dust was collected by vacuum cleaning and analysed for cat (Fel d1), dog (Can f1) and horse (Equ cx) allergens by ELISA. Amount of allergens per ALK-filter was calculated by multiplying concentration with amount of fine dust. Airborne allergens were sampled in Petri dishes for 1 week. Exhaled NO was measured by NIOX MINO and FEV1 by dynamic spirometry. Dyspnoea was rated from 0-100%. FeNO and dyspnoea were log-transformed and associations analysed by multiple linear regression, adjusting for age, atopy, smoking, and body mass index (BMI). All were females.

Results: There were no pets in any building, but all allergens were common. Geometric mean (GM) (ng/g) were 1199 Fel d1, 666 Can f1 and 478 Equ cx. Fel d1 was found in 100% (GM=29.8 ng/m2 and day), Can f 1 in 33% and Ecu c x in 13% of Petri dish samples. FeNO was higher at higher amount of Fel d1 (p=0.04) and Can f1 (p=0.04) and lower at higher amount of Equ cx (p=0.01). No associations were found for FEV1 or dyspnoea and allergen levels.

Conclusion: Cat, dog and horse allergens were common in the day care centres, due to track in by clothes or hair. Cat and dog allergens in day care centres can be a risk factor for airway inflammation, measured as FeNO. The negative association for horse allergen remain unclear. It could be due to co-variance with some protective indoor factor, or a healthy life style related to horse riding.
Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma
Authors: Jesus Delgado-Calle, Judith Anderson, Meloney D. Cregor, Masahiro Hiasa, John M. Chirgwin, Nadia Carlesso, Toshiyuki Yoneda, Khalid S. Mohammad, Lilian I. Plotkin, G. David Roodman, Teresita Bellido
Journal: Cancer Research (2016)

In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3-dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma.
Interim results of a randomized phase 2 study of docetaxel with ramucirumab versus docetaxel in second-line advanced or metastatic urothelial carcinoma.
Authors: Daniel Peter Petrylak, Scott T. Tagawa, Manish Kohli, Shande Tang, Hui Zhang, Oday Hamid, John S. Kauh, Richard A. Walgren, Kim N. Chi
Journal: Journal of Clinical Oncology (2015)

295 Background: Patients (pts) with metastatic urothelial carcinoma (UC) progressing after first-line chemotherapy have limited treatment options. Ramucirumab (Ram), a human VEGFR2-targeted mAb, has demonstrated clinical activity in several solid tumors. Preclinical testing supports a role for Ram-taxane combinations in UC. Study JCDC is an open-label, multicenter, randomized phase 2 study of docetaxel (Doc) alone or combined with Ram or icrucumab (Icr) in locally advanced or metastatic platinum-resistant UC. We report on a planned interim analysis for Doc + Ram vs Doc; Icr results will be reported later. Methods: Eligible pts with advanced UC and ECOG PS 0-1 who relapsed ≤ 1 year from a platinum-regimen were randomized to receive Doc 75 mg/m 2 IV alone or with Ram 10mg/kg IV on Day 1 of repeating 21-day cycles. A sample size of 46 pts per arm enabled 71% power to demonstrate statistical significance of 4.5 mo (Doc + Ram) vs 3 mo (Doc) at a 1-sided α= 0.1. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed PFS with RECIST v1.1, analyzed by K-M methods. A planned interim analysis was performed after 75% of the PFS events. Results: 44 pts received Doc and 46 received Doc + Ram. Study arms were well matched with a mean age of 67 yr (29-84), and a 4:1 male to female ratio. 58.7% (Doc + Ram) vs 61.4% (Doc) had ECOG PS 1. 58.7% (Doc + Ram) vs 52.3% (Doc) had visceral metastases. Doc + Ram reduced the risk of disease progression, stratified HR = 0.388; 95% CI: 0.222, 0.677; log-rank p = 0.0005, improving median PFS (5.1 vs 2.4 mo). The ORR for Doc + Ram was 19.6 vs 4.5% for Doc (p= 0.0502), and the disease control rate was 67.4 vs 43.2%. OS maturity is pending. The most common adverse events in the Doc + Ram arm (all grades) were fatigue (80.4% Doc + Ram v 75.0% Doc), decreased appetite (54.3 v 43.2%), nausea (54.3 v 25.0%), and neuropathy (50.0 v 38.6%). Grade (G) ≥3 febrile neutropenia (19.6 v 11.4%), pneumonia (13 v 9.1%), hypertension (4.3 v 0%) were higher with Doc + Ram. One G3 hematuria was observed in each arm. Conclusions: Results support a statistically significant improvement in PFS for Doc + Ram in second-line UC. Final results are expected in 2015. Clinical trial information: NCT01282463.
Changing the behavior of breast cancer.
Authors: G Lawrence
Journal: Journal of Clinical Oncology (1996)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1996.14.1.321 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8558214 Changing the behavior of breast cancer. G LawrencexG LawrenceSearch for articles by this author https://doi.org/10.1200/JCO.1996.14.1.321 PDF "Changing the behavior of breast cancer.." Journal of Clinical Oncology, 14(1), pp. 321–322© 1996 by American Society of Clinical Oncology
Mutation and copy number discordance in primary versus metastatic colorectal cancer (mCRC).
Authors: Scott Kopetz, Michael J. Overman, Ken Chen, Agda Karina Lucio-Eterovic, Bryan K. Kee, David R. Fogelman, Arvind Dasari, Kanwal Pratap Singh Raghav, Eduardo Vilar Sanchez, Jonathan Phillips, Imad Shureiqi, Chris R. Garrett, Robert A. Wolff, Keyur Patel, Kenneth D. Aldape, Rajyalakshmi Luthra, Mark Routbort, Dipen M. Maru, Funda Meric-Bernstam, Cathy Eng
Journal: Journal of Clinical Oncology (2014)

3509 Background: Molecular profiling for CRC commonly utilizes formalin-fixed tissue of convenience, which may include tissue obtained from primary or metastatic tumors. While the alterations in KRAShave been shown to have a high degree of concordance, a detailed survey of other commonly mutated genes, copy number variations, and the influence of intervening treatment in CRC has not been conducted. Methods: Primary and metastatic tissue underwent sequencing on a 46 or 50-gene hotspot AmpliSeq panel (IonTorrent) in a CLIA-compliant setting. For a subset of patients, targeted resequencing of a panel of 202 genes by HiSeq 2000 (Illumina) to an average depth of 800 was performed by the MDACC Institute of Personalized Cancer Therapeutics, with single nucleotide variations and copy number called by in-house algorithms. Results: Sequencing was successfully completed on 115 pairs of primary and metastatic tumors (N=107 for 46/50-gene, and N=17 for 202-gene). Forty-six high level amplifications (>4 copies) were found in 28 genes in 11 of 17 pairs, with discordant results in all cases, including discordance in potentially clinically relevant amplifications: HER2, NOTCH1, FLT3, and AURKA. Overall concordance rate for mutations on the 46/50-gene panel was 78%, but varied substantially by gene. APC, TP53, NRAS, and BRAF demonstrated concordance similar to KRAS (89% concordance), while PIK3CA demonstrated a 6.8-fold higher odds of discordance between primary and metastatic site (95% CI of odds ratio (OR) of 2.1 to 22.6, P<0.001). Genes with low prevalence (<10%) such as FGFR3, STK11, and FBXW7 likewise had high levels of discordance (OR 4.4, 95% CI: 1.4 to 14.1, P=0.008). Intervening chemotherapy treatment was associated with a 3.5 fold higher odds of discordance across all genes compared to patients that did not receive therapy between resection of primary and metastatic tumors (95% CI 1.26 to 10.4, P=0.008), including KRAS, TP53, and PIK3CA(OR of 5.2, 3.5, and 3.3 respectively). Conclusions: Rates of discordance between primary and metastases mutations vary substantially by gene and prior treatment in mCRC. Prospective efforts to enrich for biomarkers need to account for tumor site and treatment variability on a gene-by-gene basis.
Final results from cohort 1 of a phase II study of volociximab, an anti-α5β1 integrin antibody, in combination with gemcitabine (GEM) in patients (pts) with metastatic pancreatic cancer (MPC)
Authors: T. Evans, R. K. Ramanathan, S. Yazji, R. Glynne-Jones, A. Anthoney, J. Berlin, J. W. Valle
Journal: Journal of Clinical Oncology (2007)

4549 Background: A critical survival step for proliferating endothelial cells is the ligation of fibronectin in the extracellular matrix to integrin a5β1. Volociximab, a chimeric monoclonal antibody, blocks fibronectin binding to a5β1, and induces apoptosis of proliferating endothelial cells. Volociximab activity is independent of growth factor stimuli, suggesting that a5β1 signalling occurs downstream of growth factor signalling, and is possibly a final common pathway for the development of neovasculature. The efficacy and safety of volociximab in combination with GEM was determined in pts with MPC. Methods: This is a multi-center, open-label, 2-cohort, single-arm Phase II study. Eligible pts had confirmed MPC, no prior chemotherapy for MPC, adequate hematologic, renal and hepatic function, and had measurable disease. Pts received volociximab 10mg/kg iv every 2 weeks (days 1 and 15) with GEM (1,000 mg/m 2 iv) on days 1, 8, 15 of a 4- week cycle until disease progression (PD). Radiologic assessments of measurable disease were performed every 8 weeks. The primary endpoint was objective tumor response (RECIST criteria). Sample size was 20 pts per cohort. At least 1 confirmed response at 4 months (mo) or SD ≥ 4 mo was necessary in cohort 1 (n=20) before expansion to the second cohort. Results: 20 pts (male=11, female=9), median age = 59.8 years (range 34–74), were treated in cohort 1 and were evaluable for safety and efficacy. PS (ECOG) was 0–1 (n=19; 95%) or 2 (n=1; 5%). Pts received a median of 8 weeks’ (range 2–58) treatment. Most frequent toxicities included nausea in 14 (70%) pts, vomiting (12; 60%) and constipation (10; 50%). Overall response included 1 confirmed PR (5%), and stable disease in 10 (50%) pts. Median time to progression was 4.3 mo; 41% had not progressed at 6 mo. Overall survival was 5.4 mo, and at 6 and 8 mo was 45%, and 37% at 12 mo. 12 pts died in the study due to PD (10 pts), GI perforation (1), pulmonary embolism (1). Conclusions: Volociximab is well tolerated at 10mg/kg 2-weekly with GEM. Cohort 2 is currently recruiting at a higher dose of volociximab (15 mg/kg) administered weekly. [Table: see text]
Combination nanotherapy penetrates atherosclerosis
Authors: Willem J. M. Mulder
Journal: Cardiovascular Research (2015)

This editorial refers to ‘Nanotherapeutics for inhibition of atherogenesis and modulation of inflammation in atherosclerotic plaques’ by D.R. Lewis et al. , pp. 283–293. 

Nanoparticle therapeutics are increasingly considered for applications beyond oncology. Whereas nanomedicine's indication for the treatment of cancers is clear-cut, its use for atherosclerotic and atherothrombotic complications is not trivial.1 First and foremost, atherosclerosis is a very slowly progressing inflammatory disease. Therefore, injectable nanomedicines need to exhibit significantly elevated therapeutic benefits over existing lipid-lowering therapies, which …
The paradoxical impact of a commitment statute on prediction of dangerousness
Authors: A Beigel, M R Berren, T W Harding
Journal: American Journal of Psychiatry (1984)

Forty psychiatrists in Arizona were asked to rate the dangerousness to self or others of 16 patients described in case histories and to recommend an appropriate course of action. Half the psychiatrists were given the state defining dangerousness to use in responding. Psychiatrists who used the statute summary were less consistent in their predictions of dangerousness than were those who did not use it, especially when the patient had a history of violence. The concept of cognitive dissonance is used to partially explain this paradoxical finding.
Feasibility of hypomethylating therapy in patients with renal insufficiency
Authors: G. Batty, H. Kantarjian, J. J. Issa, G. Garcia-Manero, S. Pierce, S. O'Brien, E. Jabbour, J. Cortes, F. Ravandi
Journal: Journal of Clinical Oncology (2009)

7089 Background: Epigenetic therapy with hypomethylating agents (HA) is the standard of care in patients (pts) with myelodysplastic syndrome (MDS). Although neither 5-azacytidine (5AZA) nor 2'-deoxy azacytidine (decitabine; DAC) are excreted by the kidneys, many studies exclude pts with a serum creatinine level (sCr) ≥ 1.5 mg/dL. Moreover, there are no reports of use of these agents in pts with renal insufficiency (RI) commonly seen in pts with MDS. Methods: We investigated the outcomes of pts with RI and MDS, chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML) receiving therapy with HA. RI was defined by a sCr ≥ 1.5 mg/dL. We examined the compliance, dose adjustments (DA), and complications of treatment with DAC and 5AZA given at standard doses. We used the International Working Group criteria to evaluate the response rates. Data for pts with sCr &gt; 2 mg/dL were compared to pts with sCr ≤ 2 mg/dL (Kantarjian H, et al, Blood. 2007). Results: Forty-two pts with sCr ≥ 1.5 mg/dL (including 17 with MDS, 16 with AML, and 9 with CMML) were treated with DAC or 5AZA alone or in combination with other agents (primarily histone deacetylase inhibitors). 14 (33%) and 28 (67%) of the pts received 5AZA and DAC, respectively. The median number of courses was 4.5 (range 1–19). 9 pts (21%) required treatment delay or discontinuation, and 12 pts (28%) required dose reduction (DR). Overall, 25 (62%) had an objective response (OR), and 4 pts (9%) had complete response (CR). 15 (36%) and 7 (17%) of the pts experienced episodes of therapy-related infections and bleeding, respectively. Among 12 pts who had sCr &gt; 2.0 mg/dL, 7 pts (58%) required DR due to myelosuppression (n = 3) and to worsening of renal function (n = 4). The incidence of complications, DA, and the response rate were not significantly different for pts with sCr &gt; 2.0 mg/dL. Conclusions: The use of HA is well tolerated in pts with MDS and AML and RI who achieved comparable OR rates to those without RI. Dose adjustment might be required in some pts. [Table: see text] [Table: see text]
Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma.
Authors: S Pilotti, F Rilke, C Bartoli, A Grisotti
Journal: Journal of Clinical Oncology (1988)

A study of 50 consecutive cases (22 men, 28 women; age range, 39 to 84 years; mean age, 65 years) of cutaneous neuroendocrine Merkel cell carcinoma (CNC), 39 of whom had a mean follow-up of 34 months, revealed that the prognostic significance of the histopathologic subtyping in trabecular, solid, and diffuse variants of CNC was not as important as the pathologic postsurgical staging in localized, regional, and extraregional disease. The overall mortality was 23.5%. None of the 19 patients with localized disease died of CNC, while 11% of the 24 patients with regional disease and all seven patients with extraregional disease at presentation died of CNC. A second primary malignancy was found to be associated with the CNC in 15% of the cases. The clinical course in patients with localized disease was favorable in spite of the high number of local recurrences. Also, the presence of regional metastases was not related to an unfavorable prognosis. In 68% of the cases the disease involved the lower limbs or girdle. In ten cases the overt exophytic presentation of primary CNC was replaced by the presence of tumor masses infiltrating the inguinal soft tissues with or without nodal involvement.