tbuckley/cabot-search huggingface dataset:
Rare incidence of congestive heart failure (CHF) in gastrointestinal stromal tumor (GIST) and other sarcoma patients (pts) receiving imatinib mesylate (IM) therapy
Authors: A. Y. Khakoo, D. M. Steinert, S. R. Patel, J. C. Plana, J. Ludwig, R. S. Benjamin, J. C. Trent
Journal: Journal of Clinical Oncology (2007)

10026 Background: Potential IM cardiotoxicity has not been evaluated in patients with GIST or other sarcomas. CHF has been reported in leukemia pts on IM. Objectives: To determine the incidence of CHF in GIST and other sarcoma pts receiving IM. Methods: From our clinical trial database we reviewed all Grade III/IV potential cardiac adverse events (PCAEs) including dyspnea, dyspnea on exertion, chest pain, edema, pleural effusion, ascites, cardiac ischemia, and arrhythmia. Results: 219 pts were enrolled on clinical trials with IM from Dec 27, 2000 to May 11, 2006. 18 pts (8.22%) were identified as having PCAEs. The median age was 65.5 yrs (range, 21 to 88 yrs) and 7 were women. Their diagnoses were advanced GIST (13 of 125 pts, 10.40 %), primary GIST (4 of 48 pts, 8.33 %), or osteosarcoma (1 of 46 sarcoma pts, 2.17%). The osteosarcoma pt had received prior anthracycline therapy. The median time from start of IM to a PCAE was 173.5 days (11 to 1,568 days). IM dose at the time of the PCAE was 400 mg/d in 10 pts, 600 mg/d in 4 pts, and 800 mg/d in 4 pts. 13 pts had a past medical history of risk factors for coronary artery disease (CAD) or established heart disease: diabetes (4 pts, 22.22%), hypertension (9 pts, 50%), CAD (2 pts, 11.11%), hypertrophic obstructive cardiomyopathy (1 pt, 5.56%), peripheral vascular disease (2 pts, 11.11%), hyperlipidemia (3 pts, 16.67%) or arrhythmia (1 pts, 5.56%). None of these patients had evidence of pulmonary vascular congestion by chest film. 8 pts had an ECHO or MUGA scan at the time of the PCAE, and 1 of them had documented low ejection fraction; in only 2 of these 8 pts was there an ECHO prior to IM (LVEF &gt;50% in both). The single pt with LVEF&lt;50% at the time of the PCAE had prior a history of hypertension, multi-vessel CAD and coronary artery bypass grafting 12 years prior to the PCAE. All of the pts continued IM therapy with dose adjustments and toxicity-specific management with no further complications. Conclusions: Pts who develop PCAEs on IM should be treated with diuretics, ACE-inhibitors, and beta-blockers with continuation of IM as clinically indicated. CHF in sarcoma patients treated with IM is rare and was observed in only one elderly patient with known prior cardiac disease. No significant financial relationships to disclose.
Health benefits of a multidimensional exercise program for cancer patients undergoing chemotherapy
Authors: M. Rorth, C. Andersen, M. Quist, A. G. Tveterås, L. Knutsen, J. Midtgaard, T. Møller, L. Adamsen
Journal: Journal of Clinical Oncology (2005)

8010 Background: Cancer patients frequently experience considerable loss of physical capacity and well-being when diagnosed and treated for the disease. This study aims at evaluating the health benefits of a multidimensional exercise program for cancer patients who are undergoing chemotherapy. Methods: The program includes high and low intensity activities (physical exercise, relaxation, massage and body-awareness training) carried out in groups of 7–9 patients 9 hours weekly for 6 weeks. Ninetythree patients with different cancer diagnosis were included, 82 completed the program of these 39 received adjuvant chemotherapy (2/3 breast cancer patients) while 43 were treated for advanced disease. Maximal oxygen uptake (VO2Max) and repetition maximum strength (RM) were compared prior to and after completion of the program. Psychosocial well being and side effects were evaluated using questionnaires (EORTC, QLQ-36, SF-36,HAD) interviews and patient diaries. Results: VO2 max improved 16%, RM 40% (p<.001). Fatique, insomnia, constipation, diarrhoe and pain improved significantly. All 9 indicators of general well-being (SF-36) improved significantly including physical role (p<.0001) and emotional role (p<.0007), the latter in particular among elderly patients. Conclusions: Cancer patients undergoing chemotherapy can significantly increase muscular strength, physical fitness and physical activity level, actively reduce treatment related side-effects and improve their quality of life by participating in a multidimensional exercise program. No significant financial relationships to disclose.
Abstract 15058: Disruption of Extracellular Cytotoxic Chromatin by Acute DNase1 Administration Improves Left Ventricular Remodeling after Myocardial Infarction
Authors: Benjamin Vogel, Hisahito Shinagawa, Ullrich Hofmann, Georg Ertl, Stefan Frantz
Journal: Circulation (2014)

Rationale: Myocardial infarction (MI) leads to necrosis of multinucleated and polyploid myocytes. This causes uncontrolled release of cellular content like chromatin to the infarct area. Chromatin is mainly comprised of histones which are essential for controlling and packing of DNA but paradoxically are also known to be cytotoxic. This makes free chromatin a toxic DNA polymer creating local high concentrations of hazardous histones. Objective: We hypothesized that chromatin from necrotic cells accumulates in ischemic myocardium, creates local high concentrations of cytotoxic histones, and thereby potentiates ischemic damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion and could decrease local histone concentrations and cytotoxicity. Methods and Results: After permanent coronary artery ligation in mice we found extracellular histones accumulated within the infarcted myocardium. Histone cytotoxicity towards isolated myocytes was confirmed in vitro. To reduce histone related cytotoxicity in vivo DNase1 was injected within the first 6 hours after induction of MI. DNase1 accumulated in the infarcted region of the heart, effectively disrupted extracellular cytotoxic chromatin and thereby reduced high local histone concentration. Animals acutely treated with DNase1 revealed significantly improved left ventricular remodeling as measured by serial echocardiography up to 28 days after MI (e.g. NaCl vs DNase1, papillary end diastolic area [mm 2 ]: 23.26 ± 2.06 vs 18.90 ± 1.24, n=9 vs 10, p&lt;0,05). Treatment did not influence mortality, infarct size or inflammatory parameters as determined by neutrophil infiltration and RTQ-PCR analysis of characteristic cytokines. However improved myocyte survival was discovered within the infarct region which might account for the protective effects in DNase1 treated animals (NaCl vs DNase1: 3.0 ± 0.7% vs 8.3 ± 2.3%; p&lt;0.05; n=7 vs 8). Conclusions: Targeting extracellular cytotoxic chromatin within the infarcted heart by DNase1 is a promising approach to preserve myocytes from histone induced cell death and to conserve left ventricular function after MI. The efficacy of other chromatin degrading agents is now under investigation.
A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumours
Authors: H. Shaw, R. Plummer, L. Vidal, R. Perrett, M. Pilkington, G. Temple, P. Fong, A. Amelsberg, H. Calvert, J. De Bono
Journal: Journal of Clinical Oncology (2006)

3027 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of EGFR and HER2 receptor tyrosine kinases with IC 50 values of 0.5 and 14 nM, respectively. Methods: Patients (pts) with advanced solid malignancies were enrolled. BIBW 2992 was given orally as a continuous once daily dose from 10 mg, doubled in successive cohorts until drug-related toxicity &gt; grade 2, when escalation of no more than 50% was allowed. All pts had pharmacokinetic sampling and pre- and post-treatment skin biopsies. DNA sequencing of tumour cell EGFR and HER2 was performed on pts achieving objective response. Results: Twenty-six pts were treated (14 M/11 F). Median age: 53 (range: 30–68). ECOG PS 0/1: 7/19. 19 pts completing ≥ 28 days were evaluable for adverse events (AEs). Three dose-limiting toxicities (DLT) were seen. One pt with HER2+ breast cancer who had previously received trastuzumab and lapatinib treated at 30 mg of BIBW 2992 developed dyspnoea with radiological interstitial changes, which fully recovered on drug discontinuation. The 2 other DLTs were grade 3 acneiform skin rash, at doses of 40 mg and 50 mg daily. AEs resolved on drug discontinuation and the pts were dose reduced to 30 mg and 40 mg, respectively. The 50 mg dose level is being expanded. One pt treated at 50mg developed grade 3 diarrhoea in cycle 2 and was dose reduced to 40mg with resolution of the AE. Other AEs were mild (CTCAE v3 grade 1 or 2); nausea, diarrhoea, mucositis and fatigue. Two female pts with lung adenocarcinoma treated with 10 mg and 40 mg daily had confirmed partial responses (PR) and remain on study after 14 and 5 months, respectively. The pt with PR at 10mg has a complex heterozygous EGFR mutation in tumour cells, including a deletion and missense mutations of 4-amino acids (WT: KELREATSPKANKEILD; Patient: KEP—-SPRANKEILD) in the kinase domain, but a wildtype HER2 domain. One pt with cervical and one pt with colorectal cancer had stabilization of disease and tumour markers for 6 and 4 months, respectively. Conclusions: BIBW 2992 shows promising activity with skin rash as the main AE. Maintained PR seen in lung adenocarcinoma indicates effective mutated EGFR kinase modulation at the lowest evaluated dose level. Exploration of BIBW 2992 in Phase II is warranted. [Table: see text]
Predictive and prognostic impact of plasma vascular endothelial growth factor levels in non-small-cell lung cancer patients treated with gefitinib
Authors: T. Sone, K. Kasahara, Y. Tanbo, S. Tamori, T. Araya, H. Kimura, A. Yoshimoto, M. Fujimura, S. Nakao, K. Shibata
Journal: Journal of Clinical Oncology (2006)

13030 Background: In non-small cell lung cancer (NSCLC), sensitivity to gefitinib is associated with activating mutations of the epidermal growth factor receptor (EGFR). Tumor samples obtained for diagnosis of NSCLC are limited and often unsuitable for analysis of mutations. Other biomarkers are thus needed. We previously reported that serum vascular endothelial growth factor (VEGF) levels were significantly lower in responders to gefitinib than non-responders. To assess levels of circulating VEGF as a predictive and prognostic marker of gefitinib treatment in NSCLC patients, we examined the associations between plasma VEGF levels before gefitinib treatment and clinical outcome. Methods: Eighty four NSCLC patients treated with gefitinib were enrolled into this investigation. Plasma VEGF levels were measured in blood samples before gefitinib administration. Patients were grouped according to VEGF level around a cut-off of 80.7 pg/ml, based on results from normal controls. Response to gefitinib was judged using RECIST guidelines. Time to progression (TTP) and overall survival (OS) following gefitinib treatment were calculated using Kaplan-Meier methods. Groups were compared using log-rank test. We evaluated the immunohistochemical expression of VEGF and EGFR mutations in tumor samples from 37 patients. Results: Response rate was significantly higher with low VEGF level than with high VEGF level (p = 0.0010). Multivariate analysis for response to gefitinib including sex, histology, smoking status, performance status and plasma VEGF level identified only low VEGF level as predictive of response to gefitinib. Low VEGF level was also correlated with prolonged median TTP (4.1 months vs. 1.1 months, p = 0.0081) and OS (11.1 months vs. 5.4 months, p = 0.0290). Multivariate analysis for survival revealed low VEGF level as associated with prolonged TTP (p = 0.0081) and OS (p = 0.0708). Plasma VEGF level was not associated with either VEGF expression or EGFR mutations of tumor tissue. Conclusions: Our results suggest that plasma VEGF levels before gefitinib treatment are predictive of response to gefitinib and prognostic of patients who receive gefitinib. [Table: see text]
Diagnosis of Mitral Stenosis
Authors: D S MUNROE, C R RALLY
Journal: JAMA (1963)

The diagnosis of classical mitral stenosis is easy, but many pitfalls lead to over-diagnosis or under-diagnosis. These have been considered in detail and variations in symptoms and signs have been illustrated by case histories. Such variations include: (1) Embolism producing the Leriche syndrome; (2) mitral stenosis with insignificant hemodynamic effect; (3) myxoma masquerading as mitral stenosis; (4) mitral stenosis without apical murmurs, and (5) mitral stenosis with a systolic murmur predominant or alone. In cases of combined mitral and aortic stenosis, the history, radiographic configuration, and incidence of hemoptysis, edema, bronchitis, embolism and atrial fibrillation resemble such findings in cases of isolated mitral stenosis, but the auscultatory signs of the latter may be obscured. The degree of aortic stenosis is difficult to determine in cases of combined stenosis. In the diagnosis of re-stenosis the condition of the valve at the first commissurotomy, the precise procedure performed and the degree of regurgitation produced are of prime importance. Congenital mitral stenosis is rare and is associated with a high incidence of other defects.
Light-Dark-Shift Stress, With Special Reference to Spontaneous Tumor Incidence in Female BN Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: W J Kort, P E Zondervan, L O Hulsman, I M Weijma, D L Westbroek
Journal: JNCI Journal of the National Cancer Institute (1986)

As a way to induce mild chronic stress, light-dark (L-D)-shift stress was applied to inbred BN virgin female rats during their whole life-span (group I, 100 animals); the incidences of spontaneous tumor and nontumor processes were recorded. A group of rats (group II, 100 animals) exposed to a standard lighting system served as the control group. Total tumors of 128 in group I and of 154 in group II were found in 74 and 86 animals, respectively. Neither were these differences nor was the pattern of spontaneous tumors statistically significant. Although in earlier studies L-D-shift stress had proved to be effective, especially with regard to its capacity to induce a substantial decrease in cellular immune response, apparently such alterations did not unfavorably affect longevity of BN female rats. Although as a side issue of this study, a strong predisposition for tumor incidence appeared to exist, in particular for the incidence of Langerhans' islet tumors, in fat animals at weaning.
Struan John Tannahill Robertson
Authors: Andrew Senior
Journal: BMJ (2016)

Born into a medical family, Struan John Tannahill Robertson was born at Hartwood, where his father was the assistant medical superintendent in the local psychiatric hospital. After attending school in Melrose and at Glasgow High School, he entered Glasgow University Medical School in 1939. During the war, he served on the Clyde River Patrol and, after house jobs at Glasgow Royal Infirmary, he was called up to the Royal Naval Volunteer Reserve in 1946, serving two years as surgeon lieutenant.

He was demobbed in 1948 and returned to Glasgow Royal Infirmary as a postgraduate student with J A G Burton. It was here that he met Rhoda, whom he married in 1952. He held several assistant GP posts and worked for a brief period as a general practitioner in Eynsham, before becoming a partner in general practice in Glasgow in October 1952.

In December 1965 the …
Phase I-II study of oral vinorelbine (NVBO ) and capecitabine (X) in metastatic breast cancer (MBC): Results of the phase I trial
Authors: A. Anton, A. Lluch, A. Casado, M. Provencio, M. Muñoz, J. Lao, B. Bermejo, A. B. Paules, J. Gayo, M. Martin
Journal: Journal of Clinical Oncology (2008)

1105 Background: Both NVBO and X are active drugs in MBC. We designed a phase I trial of the combination of these two oral drugs in MBC. Methods: Main inclusion criteria were: documented MBC, ECOG PS 0–1, HER2 negative, and adequate major organ function. Patients could have received chemotherapy (CT) for the disease. Four dose levels were established: 1) NVBO 60 mg/m2, X 1,650 mg/m2/day; 2) NVBO 70 mg/m2, X 1,650 mg/m2/day; 3) NVBO 70 mg/m2, X 2,000 mg/m2/day; 4) NVBO 80 mg/m2, X 2,000 mg/m2/day. No further escalation was attempted. NVBO was given on days 1 and 8 and X was given from day 1 to 14. Cycles were repeated every 3 weeks. Results: Eighteen patients (pts) with MBC entered the study. Median age 61 years (range 44–80), 11 pts (61%) received prior (neo)adjuvant CT. 14 pts (78%) received prior hormone therapy, 13 pts (72%) received no prior chemotherapy for advanced disease and 3 pts (16%) were CT-naïve. After including 3 patients on each dose level no dose limiting toxicity (DLT) was found. No additional dose level was explored due to published experience reporting toxicity when NVBO and X are administered at higher doses. Three additional patients were included on dose levels 3 and 4 without any further DLT. Relative dose intensity of NVBO and X was 84.6% and 83.6% at dose level 3 and 88.8% and 93.6% at dose level 4, respectively. A total of 91 cycles (cy) were analyzed. 13 pts received at least 6 cy as per protocol. Grade 3 neutropenia occurred in 5 pts (28%) and 12% of cy, grade 4 in 1 pt (5%) and 1% of cy. One pt developed febrile neutropenia, not requiring hospitalization. Grade 3 anemia occurred in 1 pt (1 cy). Grade 3–4 nonhematologic toxicities were rare with grade 3 hand-foot syndrome observed in 1 pt (1 cy) and grade 4 constipation (described as nonrelated to treatment) in 1 pt (1 cy). 1 complete response, 4 partial responses and 3 disease stabilization were observed among the 11 evaluable patients for response. Conclusions: The combination of NVBO and X can be safely administered in the palliative setting of MBC and appears to be active. The recommended dose is NVBO 80 mg/m² days 1 and 8 and X 2,000 mg/m²/day days 1 to 14, both drugs administered every 3 weeks. A phase II study with this schedule is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pierre Fabre Iberica
Kinetics of Dimethylamine Nitrosation in Relation to Nitrosamine Carcinogenesis&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Sidney S. Mirvish
Journal: JNCI Journal of the National Cancer Institute (1970)

The nitrosation of dimethylamine in buffered aqueous solutions was studied with the aid of the tritium-labeled amine. At pH 3.4, the rate of dimethylnitrosamine (DMN) formation was proportional to the dimethylamine concentration and to the square of nitrite concentration. The rate of reaction was maximal at about pH 3.4. The relative constancy of the appropriate rate constants under various conditions confirmed the third-order kinetics of the reaction, though discrepancies were apparent at pH 1–2. The rate constants were used to estimate the amount of DMN expected to be formed in the gastric contents after ingestion of food containing various concentrations of dimethylamine and nitrite and during storage of such food. For example, it was estimated that, if a man ate a 300-g meal containing 12 mg dimethylamine hydrochloride and 60 mg sodium nitrite, not more than about 3 μg DMN might be expected to be formed intragastrically.
Comparative study of the pharmacokinetics and toxicity of high-dose epirubicin with or without dexrazoxane in patients with advanced malignancy.
Authors: R L Basser, M M Sobol, G Duggan, J Cebon, M A Rosenthal, G Mihaly, M D Green
Journal: Journal of Clinical Oncology (1994)

PURPOSE We evaluated the toxicity and pharmacokinetics of the combination of dexrazoxane with epirubicin at dexrazoxane/epirubicin dose ratios of 5 to 9:1 in a controlled, crossover phase I study in patients with advanced malignancy. PATIENTS AND METHODS Thirty-eight patients with a variety of malignancies were enrolled. Assessable patients received two cycles of chemotherapy consisting of epirubicin alone and in combination with dexrazoxane. Comparisons were made between the toxicity and pharmacokinetics of epirubicin in the two treatment arms, using each patient as his or her own control. Dexrazoxane and epirubicin were delivered at dose levels of 600/120 mg/m2, 900/120 mg/m2, 900/135 mg/m2, 900/150 mg/m2, and 1,200/135 mg/m2, respectively. Twenty-six patients completed two cycles of chemotherapy and were therefore assessable. RESULTS The maximum-tolerated doses (MTDs) of dexrazoxane/epirubicin were 1,200/135 mg/m2, with the dose-limiting toxicities being neutropenia, infection, and stomatitis. There was no difference in the nadir neutrophil or platelet counts between single-agent and combination treatment at any of the dose levels. Severe vomiting and stomatitis occurred less frequently following administration of epirubicin and dexrazoxane when compared with epirubicin alone (P = .01 and .02, respectively). Prior administration of higher doses (900 mg/m2 and 1,200 mg/m2) of dexrazoxane increased the systemic clearance of epirubicin, resulting in a decrease in the area under the curve (AUC). Elimination half-life, maximum plasma concentration (Cmax), and apparent volume of distribution of epirubicin were not significantly affected by dexrazoxane. Left ventricular ejection fraction (LVEF) decreased by greater than 10% in two patients, but neither developed clinical or radiologic evidence of cardiac failure. CONCLUSION This study demonstrates that dexrazoxane can be safely combined with escalating doses of epirubicin at dose ratios of 5 to 9:1 without having an adverse impact on toxicity. Studies are need to determine the optimal dose ratio for cardioprotection and to explore further the pharmacokinetic interactions of the two drugs at increasing doses of epirubicin supported by hematopoietic growth factors.