tbuckley/cabot-search huggingface dataset:
Imbalance between Platelet Vascular Endothelial Growth Factor and Platelet-derived Growth Factor in Pulmonary Hypertension
Authors: SAADIA EDDAHIBI, MARC HUMBERT, SAID SEDIAME, CHRISTOS CHOUAID, CHOHREH PARTOVIAN, BERNARD MAÎTRE, EMMANUEL TEIGER, DOMINIQUE RIDEAU, GERALD SIMONNEAU, OLIVIER SITBON, SERGE ADNOT
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Focal vascular injury and impaired endothelial function are features of pulmonary hypertension (PH) that lead to enhanced platelet endothelial cell interactions. Vascular endothelial growth factor (VEGF) is contained in platelets and released at sites of vascular injury to promote endothelial repair and wound healing in combination with platelet-derived nonspecific mitogens such as platelet-derived growth factor (PDGF). The overall balance between platelet VEGF and PDGF was investigated in 21 patients with primary PH, 8 with secondary PH, and 27 with chronic hypoxemic lung disease (CHLD), as well as in 29 control subjects. Platelet VEGF content was increased in patients with primary and secondary PH as compared with control subjects (518 ± 89, 675 ± 156, and 166 ± 29 fg/105 platelets, respectively; p < 0.01), whereas platelet PDGF content was similar in the three groups (31 ± 2, 36 ± 4, and 33 ± 3 pg/105 platelets, respectively; NS). Patients treated with a continuous prostacyclin infusion had a higher platelet VEGF but a similar platelet PDGF content as compared with untreated patients. Moderate increases in platelet VEGF and PDGF contents were observed in the CHLD patients. We conclude that patients with primary or secondary PH have an increase in platelet VEGF content, but not in platelet PDGF content, and that their platelet VEGF content increases further in response to prostacyclin infusion. We suggest that imbalance between platelet VEGF and PDGF is beneficial to patients with PH.
Up-Front Window Trial of Topotecan in Previously Untreated Children and Adolescents With Metastatic Rhabdomyosarcoma: An Intergroup Rhabdomyosarcoma Study
Authors: Alberto S. Pappo, Elizabeth Lyden, John Breneman, Eugene Wiener, Lisa Teot, Jane Meza, William Crist, Teresa Vietti
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To investigate the antitumor activity and toxicity of topotecan, used alone and in combination with conventional therapy, in patients with metastatic rhabdomyosarcoma (RMS). PATIENTS AND METHODS: Forty-eight patients younger than 21 years of age with newly diagnosed metastatic RMS received 2.0 to 2.4 mg/m 2 of topotecan intravenously daily for 5 days every 21 days before standard therapy. Two courses were given in the absence of progressive disease or excessive toxicity and response was assessed. Patients with at least a partial response (PR) to topotecan proceeded to therapy with alternating courses of vincristine 1.5 mg/m 2 , dactinomycin 1.5 mg/m 2 , and cyclophosphamide 2.2 g/m 2 (VAC) and vincristine 1.5 mg/m 2 , topotecan 0.75 mg/m 2 daily × 5, and cyclophosphamide 250 mg/m 2 daily × 5. Patients who did not respond to topotecan received continuation therapy with VAC alone. RESULTS: The overall response rate to topotecan was 46% (complete response, 4%; partial response 42%). Unexpectedly, patients with alveolar RMS had a higher rate of response (65%) than those with embryonal RMS (28%; P = .08). The most common grade 3 or 4 toxicities were neutropenia (67%), anemia (33%), thrombocytopenia (25%), and infection (21%). Two-year failure-free survival and survival estimates were 24% and 46%, respectively. Response to window therapy did not correlate with survival. CONCLUSION: The high response rate and acceptable toxicity profile of topotecan in children with advanced RMS support further evaluation of this agent in phase III trials. The superior responses in alveolar RMS are of interest.
Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer.
Authors: T R Buroker, M J O'Connell, H S Wieand, J E Krook, J B Gerstner, J A Mailliard, P L Schaefer, R Levitt, C G Kardinal, D H Gesme
Journal: Journal of Clinical Oncology (1994)

PURPOSE To compare two commonly used schedules of fluorouracil (5FU) and leucovorin in the treatment of patients with advanced metastatic colorectal cancer. Each of these dosage administration schedules has been demonstrated to be superior to single-agent bolus 5FU in previous controlled trials. PATIENTS AND METHODS Three hundred seventy-two ambulatory patients with metastatic colorectal cancer were stratified according to performance status, and presence and location of any measurable indicator lesion(s). They were then randomized to receive chemotherapy with one of the following regimens: (1) intensive-course 5FU plus low-dose leucovorin (5FU 425 mg/m2 plus leucovorin 20 mg/m2 intravenous [IV] push daily for 5 days with courses repeated at 4- to 5-week intervals); (2) weekly 5FU plus high-dose leucovorin (5FU 600 mg/m2 IV push plus leucovorin 500 mg/m2 as a 2-hour infusion weekly for 6 weeks with courses repeated every 8 weeks). RESULTS Three hundred sixty-two of 372 patients randomized (97.3%) were eligible and included in the analysis. Three hundred forty-six patients (95.6%) have died. There were no significant differences in therapeutic efficacy between the two 5FU/leucovorin regimens tested with respect to the following parameters: objective tumor response (35% v 31%), survival (median, 9.3 v 10.7 months), and palliative effects (as assessed by relief of symptoms, improved performance status, and weight gain). There were significant (P &lt; .05) differences in toxicity, with more leukopenia and stomatitis seen with the intensive-course regimen, and more diarrhea and requirement for hospitalization to manage toxicity with the weekly regimen. Financial cost was also higher with the weekly regimen. CONCLUSION Intensive-course 5FU plus low-dose leucovorin appears to have a superior therapeutic index compared with weekly 5FU plus high-dose leucovorin using the dosage administration schedules applied in this study based on similar therapeutic effectiveness, but lower financial cost, and less need for hospitalization to manage chemotherapy toxicity.
PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors.
Authors: S. Kopetz, J. Desai, E. Chan, J. R. Hecht, P. J. O'Dwyer, R. J. Lee, K. B. Nolop, L. Saltz
Journal: Journal of Clinical Oncology (2010)

3534 Background: The BRAF activating mutation is present in up to 10% of metastatic colorectal carcinomas (mCRC) and is associated with unique clinical and pathologic features with a very poor prognosis. PLX4032 (RG7204) is an oral inhibitor of the mutant BRAF kinase, with pronounced activity in BRAF-mutant melanoma patients (pts). Methods: In this phase I study, we treated an extension cohort of mCRC pts whose tumors were positive for mutant BRAF with PLX4032 at the previously determined maximum tolerated dose of 960 mg BID. The BRAF mutation was centrally confirmed by Taqman PCR. Efficacy was evaluated by RECIST every 8 weeks. Results: 21 mCRC pts were enrolled, with a median age of 65 and ECOG performance status of 0 (35%) or 1 (65%). All but one had received prior therapy for metastatic disease. PLX4032 PK values were ∼20% lower than than those previously observed for melanoma. 19 pts were evaluable for response, with 1 confirmed partial response and 4 minor responses (≥ 10% shrinkage). 5 pts showed a mixed response pattern (i.e., with both regressing and progressing lesions). 2 of the 3 pts who underwent repeat FDG-PET imaging achieved a metabolic response, which was concordant with RECIST changes. Median progression-free survival was 3.7 months, with 2 pts still on study. PLX4032 was generally well tolerated. Three pts had dose limiting toxicities of G3 rash and G3 nausea. Other G3 or G4 drug-attributable adverse events in all cycles were seen in 6 pts, and included fatigue, diarrhea, neutropenia, elevated alkaline phosphatase, hyponatremia, hypokalemia, and hyperbilirubinemia. Five pts developed cutaneous squamous cell carcinomas consistent with keratoacanthomas, which were managed by local excision. Conclusions: The clinical activity seen with PLX4032 in previously treated mCRC pts with V600E BRAF mutations is more modest than had been seen in melanoma, but this activity does confirm mutant BRAF as a therapeutic target in this disease. The biology of BRAF activation in pts with CRC is clearly more heterogenous than in melanoma, especially as evidenced in those pts with a mixed response. Subsequent studies are planned to evaluate PLX4032 in combination regimens in an attempt to improve efficacy in this poor prognosis subset of mCRC pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Plexxikon, Roche Roche Plexxikon, Roche Plexxikon, Roche
Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2
Authors: Junko Tanizaki, Dalia Ercan, Marzia Capelletti, Michael Dodge, Chunxiao Xu, Magda Bahcall, Erin M. Tricker, Mohit Butaney, Antonio Calles, Lynette M. Sholl, Peter S. Hammerman, Geoffrey R. Oxnard, Kwok-Kin Wong, Pasi A. Jänne
Journal: Cancer Research (2015)

The discovery of oncogenic driver mutations and the subsequent developments in targeted therapies have led to improved outcomes for subsets of lung cancer patients. The identification of additional oncogenic and drug-sensitive alterations may similarly lead to new therapeutic approaches for lung cancer. We identify and characterize novel FGFR2 extracellular domain insertion mutations and demonstrate that they are both oncogenic and sensitive to inhibition by FGFR kinase inhibitors. We demonstrate that the mechanism of FGFR2 activation and subsequent transformation is mediated by ligand-independent dimerization and activation of FGFR2 kinase activity. Both FGFR2-mutant forms are predominantly located in the endoplasmic reticulum and Golgi but nevertheless can activate downstream signaling pathways through their interactions with fibroblast growth factor receptor substrate 2 (FRS2). Our findings provide a rationale for therapeutically targeting this unique subset of FGFR2-mutant cancers as well as insight into their oncogenic mechanisms.
Imatinib mesylate in soft tissue and bone sarcomas: Interim results of a Sarcoma Alliance for Research thru Collaboration (SARC) phase II trial
Authors: R. Chugh, D. Thomas, K. Wathen, P. F. Thall, R. S. Benjamin, R. S. Maki, B. L. Samuels, M. L. Keohan, D. A. Priebat, L. H. Baker
Journal: Journal of Clinical Oncology (2004)

9001 Background: The success of imatinib (Gleevec) in gastrointestinal stromal tumor (GIST) is proof that a small oncogene targeted molecule can have significant benefit in a solid tumor. Sarcomas, other than GIST, also overexpress one or more of the tyrosine kinases inhibited by imatinib. We are performing a multi-institutional study to evaluate imatinib activity in nine different sarcoma subtypes and desmoid tumors. Methods: Patients ≥10 years old with a sarcoma subtype not curable by multidisciplinary management were eligible. Imatinib was prescribed at 300 mg BID (BSA≥1.5m2), 200 mg BID (BSA=1.0–1.49m2), or 100 mg BID (BSA<1.0m2). Responses at two and four months were collected. Rules for early termination within each disease type were based on a hierarchical Bayesian probability model accounting for correlation of the responses of the 10 disease types. Tissue specimens were analyzed by immunohistochemistry for c-kit, PDGFRα, PDGFR****223'3f NEEDS TO BE ADDED TO TIMES NEW ROMAN GREEK FONT****, AKT, PTEN, FKHR, and by allelic PCR analysis for PDGFRα exon 18. Results: 181 patients have been enrolled; 161 currently evaluable. Patients received prior chemotherapy and all had progressive disease. Four month progression-free survival (PFS) rates follow: all sarcoma subtypes 18% (27/147), angiosarcoma 10% (1/10), Ewing sarcoma 0% (0/13), fibrosarcoma 29% (2/7), liposarcoma 32% (9/28), leiomyosarcoma (LMS) 20% (6/30), malignant fibrous histiocytoma 1/15 (7%), osteosarcoma 18% (3/17), peripheral nerve sheath tumor 20% (1/5), rhabdomyosarcoma 0% (0/2), synovial sarcoma 20% (4/20). Among patients with LMS, one had a complete remission for 11 months while four others had PFS greater than one year. Conclusions: Further investigation of imatinib in the therapy of liposarcoma, LMS, and fibrosarcoma is warranted. Imatinib is less likely to be active in the other sarcoma subtypes. The postulated mechanism of action is through inhibition of polymorphisms of PDGFR and/or downstream effectors. The hierarchical Bayesian probability model is an effective method for studying rare diseases and their subtypes, when it is reasonable to assume that their response rates are exchangeable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis
Untying the Gordian knot: unravelling what influences quality of life in asthma patients
Authors: Ralph R. Turner, Christopher Landon
Journal: European Respiratory Journal (2015)

Readers of the European Respiratory Journal are well aware that asthma is an important healthcare concern. Current treatments include glucocorticoids, leukotriene antagonists, long-acting bronchodilators, monoclonal antibodies directed at interleukin (IL)5, IgE, and IL13, and a degree of chemotherapy in cost and degree of complexity becoming close kin to individualised treatment for cancer, and yet hospitalisation and emergency care with substantial impact on quality of life continues. Alexander has yet to winter at Gordium, unsheathe his sword and slice the knot. In this issue of the European Respiratory Journal, Stucky et al. [1] present work that disentangles major contributors to asthma-specific quality of life that often have been confounded in patient measures reported in previous research [2]. By doing so, the authors have clarified how asthma symptoms, asthma control and general health-related quality of life, uniquely and in the aggregate, influence asthma-specific quality of life. This work points the way for more focussed and precise measures which will, in turn, help inform the discussion about treatment options and healthcare services delivery. A new study reports that non-symptom aspects of asthma control and generic QOL best predict asthma-specific QOL <http://ow.ly/PWNMB>
Abstract 19656: What is the Prevalence of Familial Hypercholesterolemia in the US?
Authors: Sarah D de Ferranti, Angie M Rodday, Michael Mendelson, John B Wong, Laurel K Leslie, R. C Sheldrick
Journal: Circulation (2014)

Background: The prevalence of Familial Hypercholesterolemia (FH) ranges from 1 in 500, as commonly cited, to 1 in 200 in a population-based Danish study. The prevalence of FH in the US, particularly in those of non-European background, remains unknown. Methods: To estimate the US prevalence of FH in National Health and Nutrition Examination Survey (NHANES) 2001-2012 datasets (n = 59,423), we used the Dutch Lipid Clinic (DLC) criteria (Benn et al 2012), which classifies individuals as definite or probable FH based on personal history of premature coronary artery disease (CAD), family history in a first-degree relative of known premature CAD or vascular disease, LDL level, and genetic criteria. Genetic testing is not available in NHANES and therefore was not included. For persons reporting statin use, we multiplied by 1.43 to estimate untreated LDL levels. Results: The overall US prevalence of probable/definite FH in NHANES was 0.33% (95% CI 0.19-0.48) or 1 in 299 (1 in 210-519). The prevalence of FH was similar in males and females (0.34%; 1 in 293 vs. 0.33%; 1 in 305) and in blacks and whites (0.35%; 1 in 283 vs. 0.37%; 1 in 270), but lower in Mexican Americans (0.16%; 1 in 620) and other races (0.08%, 1 in 1235) and higher in other Hispanics (0.40%; 1 in 252). FH prevalence was lowest in 30-39 year olds (0.15%, Figure ), and highest in 50-59 year olds (0.60%), and higher with obesity (0.49%; 1 in 204) than non-obesity (0.26%; 1 in 387), likely reflecting the impact of increasing age and weight on LDL when using DLC criteria. Summary: Our analysis of NHANES data suggests a US prevalence of FH of 1 in 299, which is higher than the commonly cited estimate of 1 in 500 and is likely an underestimate due to the absence of genetic testing in NHANES. Higher prevalence with obesity and in middle-age highlights the influence of increasing age- and weight-related effects on LDL in FH prevalence estimates. Consideration should be given to incorporating genetic testing into future studies of US FH prevalence.
Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity.
Authors: K Sorensen, G Levitt, C Bull, J Chessells, I Sullivan
Journal: Journal of Clinical Oncology (1997)

PURPOSE Late abnormalities of left ventricular (LV) performance occur in most survivors of childhood acute lymphoblastic leukemia (ALL) treated with moderate anthracycline doses. We studied the prevalence of late cardiotoxicity in patients treated with lower anthracycline doses and related this to survival. PATIENTS AND METHODS Echocardiograms were performed in 50 normal children and 120 relapse-free ALL survivors 6.2 +/- 2.0 years after the end of cumulative daunorubicin doses of 90 mg/m2 (n = 40), 180 mg/m2 (n = 40), or 270 mg/m2 (n = 40) on UKALL X pilot (1982 to 1984) or UKALL X (1985 to 1989) protocols. Age at treatment onset was 4.7 +/- 2.8 years. Cardiac abnormalities were reviewed in light of the UKALL X 5-year disease-free survival rates of 57% (95% confidence interval [CI], 51% to 63%), 61% to 62% (95% CI, 56% to 68%), and 71% (95% CI, 66% to 76%) for the groups that received 90, 180, and 270 mg/m2 of daunorubicin, respectively. RESULTS ALL survivors had reduced LV fractional shortening (FS) compared with normal (32.3% +/- 4.4% v 35.9% +/- 4.2%, P &lt; .005), which was accounted for by increased LV end-systolic stress (49.4 +/- 13.5 v 42.2 +/- 9.1 g/cm2, P &lt; .001), whereas LV contractility independent of loading conditions was normal for the group as a whole. Of 27 patients (23%) with cardiac abnormalities, 25 (21%) had increased end-systolic stress, whereas only two (2%) had reduced contractility. The proportion with cardiac abnormality was similar in the three dose groups. Anthracycline dose, age at treatment, sex, follow-up duration, growth hormone, pubertal status, hemoglobin level, and total WBC count at presentation were not predictive of increased LV end-systolic stress. CONCLUSION There was a reduced incidence and severity of cardiac abnormalities with the lower anthracycline dose protocols (90 to 270 mg/m2) studied compared with previous reports in which subjects had received moderate anthracycline doses (approximately 300 to 550 mg/m2). Cumulative anthracycline dose within the range 90 to 270 mg/m2 did not relate to cardiac abnormalities. This suggests that there may be no safe anthracycline dose to avoid late cardiotoxicity, but reinforces the use of the protocol that affords best survival within the dose range studied.
Every hour of daily screen time knocks two grades off teenagers’ exam scores, study shows
Authors: Nigel Hawkes
Journal: BMJ (2015)

Every hour spent each day by teenagers watching television, browsing the internet, or playing computer games knocks the equivalent of two grades off their performance at GCSE, a study has found.1 It also showed that extra hours of homework had a positive effect on GCSE performance unless they became excessive.

The study, published in the International Journal of Behavioral Nutrition and Physical Activity ,1 included 845 children from 18 secondary schools in Cambridgeshire and measured daily activity and sedentary behaviour at an average age of 14.5, comparing this with their GCSE results a year later. All of the points the children scored at GCSE were added up …
Dose-dense neoadjuvant treatment of women with breast cancer utilizing docetaxel, vinorelbine and trastuzumab with growth factor support
Authors: M. Jahanzeb, A. Brufsky, J. Erban, D. Lewis, S. Limentani
Journal: Journal of Clinical Oncology (2005)

591 Background: The NSABP has confirmed the role of neoadjuvant chemotherapy for the treatment of women with breast cancer. NSABP B18 has demonstrated a relationship between complete pathological response (pCR) and a better survival. Recently Buzdar and colleagues reported a 65% pCR rate with six months of neoadjuvant chemotherapy plus trastuzumab in 23 women with breast cancer. Methods: We report the results of a trial in which women with stage IIB-IIIB and locoregional stage IV (LCRSIV) breast cancer with HER2 overexpression (by fluorescence in situ hybridization) were treated with docetaxel (D) 60 mg/m2 and vinorelbine (V) 45 mg/m2 administered every two weeks with weekly trastuzumab (12 weeks only), G-CSF and quinolone prophylaxis for six cycles prior to surgery. Results: Accrual has been completed and 31 patients (pts) have been enrolled. Age range 27–65. Stage II-12, Stage III-18, LCRSIV-1. Sixty-eight percent of pts had T3 or T4 tumors. Ninety percent of patients had clinically palpable lymph nodes. The average tumor size was 6.6 cm. All patients have completed their preoperative therapy and are evaluable for both clinical and pathological response. Grade 3/4 toxicity has included neutropenic fever 7/31 (23%). There has been no dominant grade 3/4 non-hematologic toxicity. Eight patients have required dose reduction (26%). There were 26 (84%) complete responses (cCr) and 3 (10%) partial responses (PR), one patient with stable disease (3%) and one pt has progressed in the breast only (3%). Pathological data demonstrates a pathologic complete response (pCR) in 14 pts (45%) by NSABP criteria (T0, Tis, NX) and in 12 pts (39%) by other criteria (T0, Tis, N0), 6 additional pts had residual T1a tumors at the time of surgery (65%). Conclusions: The overall clinical response rate is 88% with a cCR rate of 65%. The pCR rate of 45% with 65% of patients having a residual T1a or T0 lesion is among the highest response rates reported with preoperative chemotherapy. This supports the findings of Buzdar and colleagues considering that they treated patients with smaller tumors and utilized six months of therapy including an anthracycline. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, sanofi-aventis Genentech, GlaxoSmithKline, Pierre Fabre, sanofi-aventis Genentech, GlaxoSmithKline, sanofi-aventis
Rapid Induction of Carcinomas and γ-Glutamyl Transpeptidase-Rich Clones in &lt;italic&gt;N&lt;/italic&gt;-Methyl-&lt;italic&gt;N&lt;/italic&gt;-benzylnitrosamine-Treated Hamster Buccal Pouch&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Dennis B. Solt, Lilian Calderon Solt, Tetsuyo Odajima
Journal: JNCI Journal of the National Cancer Institute (1985)

Topical application of N-methyl-N-benzylnitrosamine [(MBN) CAS: 937-40-6] to Syrian hamster buccal pouch epithelia resulted within 4 days in the induction of epithelial cell foci with histochemical gamma-glutamyl transpeptidase (GGTase) activity. Approximately 94% of the foci consisted of individual cells or nests of 8 cells or less, as visualized in wholemounts of GGTase-stained pouch epithelia. During a regimen of twice weekly MBN applications, the GGTase-stained foci increased in size to a maximum diameter of approximately 0.4 mm by the third week. In histologic sections, the enlarging foci were similar morphologically to those of the adjacent GGTase-negative epithelium. Groups of animals treated with MBN for 2, 4, and 8 weeks developed a buccal pouch tumor incidence of 43, 86, and 100%, respectively, within 39 weeks or less. Of the 138 papillomas and carcinomas examined, 11 contained patchy GGTase activity.