Modifying the ICE regimen for better prognosis small cell lung cancer--an update.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
J M Brown
Publications and source records attributed to J M Brown.
Effects of chronic anterior cruciate ligament deficiency on muscle activation patterns during an abrupt deceleration task.
OBJECTIVE: This study examined the influence of chronic anterior cruciate ligament deficiency on muscle activation patterns displayed during abrupt deceleration, relative to timing of tibiofemoral shear forces (Fs) generated during the task. DESIGN: Experimental data were collected for both limbs of 11 chronic functional anterior cruciate ligament deficient subjects and 11 matched controls. METHODS: Electromyographic, high speed film and ground reaction force data were sampled as subjects landed in single-limb stance on a force platform after receiving a chest level pass and decelerating abruptly. Temporal characteristics of each muscle burst relative to initial foot-ground contact were derived and Fs were calculated from net joint reaction forces and the patellar tendon force occasioned by the net moments and inertial forces predicted about the knee. RESULTS: Compared to controls, anterior cruciate ligament deficient subjects displayed a delay in hamstring activation so that peak hamstring activity was more synchronous with initial contact and with the high Fs which occurred after initial contact. CONCLUSIONS: It was concluded the delayed hamstring activation was an adaptation developed to enable peak muscle activity to better coincide with the high anterior Fs, thereby stabilizing the injured limb against a giving-way episode via increased joint compression and posterior tibial drawer.
Adult↗
Contrast-enhanced ultrasound for guidance of local tumor ablation.
The objective was to assess the efficacy of sonography with and without contrast medium enhancement in guiding and monitoring percutaneous ethanol ablation of tumors in an animal model. VX-2 carcinoma was implanted into the thighs of New Zealand white rabbits and examined by grey-scale ultrasound, color, power, and pulse Doppler, before and after injection of 95% ethanol into the tumors. Injections of ethanol were guided by ultrasound to sites of tumor vascularity, until all tumor vascularity had been obliterated. Microbubble contrast medium or saline was injected i.v. prior to each of the ultrasonic interrogations. Arteriography was performed before and after ablation. Selected tumor samples were submitted for histologic examination. Contrast enhanced tumor vascularity over saline controls in all cases. In some, incompletely ablated foci of tumor could only be identified with contrast medium enhancement. Arteriography showed complete ablation of all but 1 tumor. We conclude that ultrasound enhanced by contrast better shows the presence or absence of tumor vascularity. Ultrasound enhanced by contrast might offer an accurate means of guiding and monitoring percutaneous ethanol injection for tumor ablation.
Albumins↗
Cisplatin anti-tumour potentiation by tirapazamine results from a hypoxia-dependent cellular sensitization to cisplatin.
Tirapazamine (TPZ) is a new anticancer drug that is activated specifically at the low oxygen level typically found in solid tumours. It exhibits preferential cytotoxicity towards hypoxic cells and has been shown in preclinical studies with transplanted tumours and in phase II and III clinical trials to potentiate the anti-tumour efficacy of cisplatin without increasing its systemic toxicity. At present, the mechanism for this potentiation is unknown. Here we show that there is a schedule-dependent enhancement of cisplatin cytotoxicity by TPZ for cells in vitro that is similar to that seen with transplanted murine tumours. This cisplatin potentiation depends on the TPZ exposure being at oxygen concentrations below 1%, which are typical of many cells in tumours but not in normal tissues. Also, the interaction between TPZ and cisplatin does not occur in cells mutant in ERCC4, a protein essential for repair of DNA interstrand cross-links. Incubation of the cells with TPZ under hypoxia prior to cisplatin treatment increases cisplatin-induced DNA interstrand cross-links with kinetics suggesting that TPZ inhibits or delays repair of the DNA cross-links. In conclusion, we show that the tumour-specific potentiation of cisplatin cytotoxicity is likely the result of an interaction between TPZ and cisplatin at the cellular level that requires the low oxygen levels typical of those in solid tumours. The mechanism of the interaction appears to be through a potentiation of cisplatin-induced DNA interstrand cross-links, possibly as a result of a diminished or delayed repair of these lesions
3T3 Cells↗
DNA damage measured by the comet assay in head and neck cancer patients treated with tirapazamine.
Tirapazamine (TPZ) [3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233, WIN 59075, and Tirazone] is a novel anticancer drug that is selectively activated by the low oxygen environment in solid tumors. By killing the radioresistant hypoxic cells, TPZ potentiates the antitumor efficacy of fractionated irradiation of transplanted tumors in mice. As this cell kill is closely correlated with TPZ-induced DNA damage, we investigated whether human head and neck cancers would show DNA damage similar to that seen in mouse tumors following TPZ administration. TPZ-induced DNA damage in both transplanted tumors in mice and in neck nodes of 13 patients with head and neck cancer was assessed using the alkaline comet assay on cells obtained from fine-needle aspirates. The oxygen levels of the patients' tumors were also measured using a polarographic oxygen electrode. Cells from the patients' tumors showed DNA damage immediately following TPZ administration that was comparable to, or greater than, that seen with transplanted mouse tumors. The heterogeneity of DNA damage in the patients' tumors was greater than that of individual mouse tumors and correlated with tumor hypoxia. The similarity of TPZ-induced DNA damage in human and rodent tumors suggests that tirapazamine should be effective when added to radiotherapy or to cisplatin-based chemotherapy in head and neck cancers.
Animals↗
Development of an EORTC questionnaire module to be used in health-related quality-of-life assessment for patients with multiple myeloma. European Organization for Research and Treatment of Cancer Study Group on Quality of Life.
A multiple myeloma-specific quality-of-life questionnaire module has been designed in collaboration with the EORTC Quality-of-Life Study Group to be used in clinical trials with the EORTC QLQ-C30, a general cancer questionnaire. Strict methodology was employed to ensure thorough and appropriate development of the module. An extensive literature review was performed to identify health-related quality-of-life issues relevant to patients with multiple myeloma. Semi-structured interviews were then carried out in several European countries with health-care providers experienced in the treatment of patients with multiple myeloma, and with a group of patients with multiple myeloma, to identify the issues which were most important to patients. A questionnaire was devised from the list of issues, using a 1-week time-frame and response categories consistent with the EORTC QLQ-C30. The provisional questionnaire and the EORTC QLQ-C30 were administered to patients with multiple myeloma in each participating country with further semi-structured interviews to refine the content and design of the questionnaire. A review of the results obtained in each stage of development resulted in a 24-item myeloma-specific module, the EORTC QLQ-MY24, which assesses disease-specific symptoms and their impact on everyday life, treatment side-effects, social support, and future perspective. The module is currently undergoing further international field-testing to assess its psychometric properties.
Adult↗
A pseudoepidemic of postoperative scleritis due to misdiagnosis.
OBJECTIVE: To describe a pseudoepidemic of infectious scleritis following eye surgery. METHODS: Retrospective cohort study with selected procedural and laboratory investigations. RESULTS: Twenty-one patients with postoperative scleritis were identified during a 2-month outbreak. Neither an infectious etiology nor a causative pre-, intra-, or postoperative exposure was found. The clinical findings, when carefully reviewed, were consistent with poor surgical-wound closure. CONCLUSIONS: The art of clinical diagnosis involves the subjective interpretation of clinical history, physical findings, and laboratory results. A repeated error in the interpretation of clinical findings can simulate an outbreak of disease. Clinicians may be reluctant to concede misdiagnosis.
Adult↗
Kinesin-II is preferentially targeted to assembling cilia and is required for ciliogenesis and normal cytokinesis in Tetrahymena.
We cloned two genes, KIN1 and KIN2, encoding kinesin-II homologues from the ciliate Tetrahymena thermophila and constructed strains lacking either KIN1 or KIN2 or both genes. Cells with a single disruption of either gene showed partly overlapping sets of defects in cell growth, motility, ciliary assembly, and thermoresistance. Deletion of both genes resulted in loss of cilia and arrests in cytokinesis. Mutant cells were unable to assemble new cilia or to maintain preexisting cilia. Double knockout cells were not viable on a standard medium but could be grown on a modified medium on which growth does not depend on phagocytosis. Double knockout cells could be rescued by transformation with a gene encoding an epitope-tagged Kin1p. In growing cells, epitope-tagged Kin1p preferentially accumulated in cilia undergoing active assembly. Kin1p was also detected in the cell body but did not show any association with the cleavage furrow. The cell division arrests observed in kinesin-II knockout cells appear to be induced by the loss of cilia and resulting cell paralysis.
Animals↗
Tirapazamine: a new drug producing tumor specific enhancement of platinum-based chemotherapy in non-small-cell lung cancer.
BACKGROUND: Tirapazamine (TPZ), a new anti-cancer drug activated to a toxic free radical under hypoxic conditions, produces a tumor specific potentiation of cell kill by cisplatin. In the present study we discuss the mechanism and clinical potential of this effect, as well as investigate the influence of p53 mutations on the activity of TPZ. MATERIALS AND METHODS: For in vitro experiments we have used mouse SCCVII tumor cells, minimally transformed mouse embryo fibroblasts (MEFs) from wild-type and p53 knockout mice, and several human NSCLC cell lines. For in vivo experiments we have used RIF-1 tumors implanted subcutaneously into C3H mice. RESULTS: Prior injection of TPZ into tumor-bearing mice markedly potentiated tumor cell kill by cisplatin, but produced no effect on systemic toxicity. The maximum potentiation occurred when TPZ was injected two to three hours prior to cisplatin administration. Experiments performed with cells in vitro showed a similar synergistic interaction between the two drugs when cells were exposed to TPZ under hypoxic conditions prior to exposure to cisplatin. Experiments with MEFs from either p53 wild-type or p53-knockout mice showed no influence of p53 on the sensitivity of cells to killing by TPZ under hypoxia. A similar lack of influence of p53 on the toxicity to TPZ was obtained for a panel of NSCLC cell lines. CONCLUSIONS: TPZ is a novel anticancer drug that produces tumor selective potentiation of cisplatin and carboplatin in both pre-clinical and clinical studies. The fact that the drug produces no potentiation of the systemic side effects of these drugs, or of other anticancer drugs used in combination with platinum in NSCLC, suggests that TPZ could become a useful agent in the treatment of lung cancer.
Animals↗
Reduction of infarct size in the rat heart by LPS preconditioning is associated with expression of angiogenic growth factors and increased capillary density.
Inflammation induces the expression of angiogenic growth factors in tissues, which leads to microvascular growth. Bacterial lipopolysaccharide (LPS) provokes a transient inflammatory response in the heart and induces delayed cardiac resistance to post-ischemic contractile dysfunction. In this study, we examined: 1) the effects of LPS on myocardial expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), 2) whether an increase in the density of myocardial microvessels follows the expression of angiogenic growth factors, and 3) the effect of LPS on myocardial resistance to infarction and its relationship with microvascular growth. Rats were treated with LPS (from Salmonella typhimurium, 0.5 mg/kg i.p.). The expression of bFGF and VEGF in the myocardium was examined at 6 and 12 h after LPS treatment by immunofluorescent staining. Myocardial capillary and arteriole densities were determined 3 days after LPS treatment by morphometry, using immunofluorescent staining of von Willebrand factor (a marker protein of endothelial cells) and alpha-smooth muscle actin (a marker protein of smooth muscle cells). To examine cardiac resistance to infarction, hearts were subjected to 40 min of regional ischemia and 2 h of reperfusion by reversible occlusion of left coronary artery at 3 days after LPS treatment. LPS induced cardiac bFGF and VEGF at 6 and 12 h after treatment. The expression of these growth factors was followed by an increase in myocardial capillary density (2032 +/- 78/mm2 vs. 1617 +/- 47/mm2 in saline control, P < 0.05), but not arteriole density, at 3 days. Meanwhile, infarct size was significantly reduced by LPS preconditioning (infarct/left ventricle 12.3 +/- 1.04% vs. 21.7 +/- 1.65% in saline control, 43% reduction, P < 0.05). These results suggest that LPS preconditioning induces cardiac bFGF and VEGF, and an increase in myocardial capillary density. This increased myocardial capillary density is associated with a reduced infarct size after in vivo regional ischemia-reperfusion.
Animals↗
Sexual activity questionnaires in clinical trials: acceptability to patients with gynaecological disorders.
OBJECTIVE: To assess the feasibility and acceptability of including sexual activity questionnaires in gynaecological clinical trials. DESIGN: A longitudinal quality of life study during the Maintenance Interferon Trial and the EVALUATE Hysterectomy Trial. SETTING: Gynaecology clinics and women's homes. SAMPLE: Ninety-six women with advanced ovarian cancer participating in the Maintenance Interferon Trial and 542 women undergoing a hysterectomy in the EVALUATE Hysterectomy Trial. METHODS: Quality of life questionnaires, including the sexual activity questionnaire, were completed by women prior to randomisation and periodically after randomisation. MAIN OUTCOME MEASURES: Compliance rates of the sexual activity questionnaire, both overall and with respect to the level of sexual functioning and age of the women. Attitudes of the women towards completing the questionnaire, and suitability of using the sexual activity questionnaire in clinical trials. RESULTS: Compliance rates of over 80% were achieved in both trials, both overall and for each questionnaire completed. The age of the woman did not appear to influence the completion of the questionnaire, nor did her level of sexual functioning. Women were supportive of the research and did not find the questionnaire intrusive. CONCLUSIONS: It is feasible to include sexual activity questionnaires in gynaecological clinical trials requiring repeated assessment of quality of life over a long period of time. The sexual activity questionnaire is an appropriate tool to carry out investigations of sexual functioning and is worth considering for use in future clinical trials.
Adult↗
Central line sepsis in a child due to a previously unidentified mycobacterium.
A rapidly growing mycobacterium similar to strains in the present Mycobacterium fortuitum complex (M. fortuitum, M. peregrinum, and M. fortuitum third biovariant complex [sorbitol positive and sorbitol negative]) was isolated from a surgically placed central venous catheter tip and three cultures of blood from a 2-year-old child diagnosed with metastatic hepatoblastoma. The organism's unique phenotypic profile and ribotype patterns differed from those of the type and reference strains of the M. fortuitum complex and indicate that this organism may represent a new pathogenic taxon.
Bacteremia↗
An intervention to reduce playground equipment hazards.
OBJECTIVES: A community intervention trial was carried out to evaluate the relative effectiveness of two methods of reducing playground hazards in schools. The study hypotheses were: (1) a health promotion programme addressing barriers to implementing the New Zealand Playground Safety Standard will reduce playground hazards and (2) the intervention programme will be more successful than providing information alone. METHODS: Twenty four schools in Wellington, New Zealand were randomly allocated into two groups of 12 and their playgrounds audited for hazards. After the audit, the intervention group received a health promotion programme consisting of information about the hazards, an engineer's report, regular contact and encouragement to act on the report, and assistance in obtaining funding. The control group only received information about hazards in their playground. RESULTS: After 19 months, there was a significant fall in hazards in the intervention schools compared with the control schools (Mann-Whitney U test, p = 0.027). No intervention schools had increased hazards and eight out of 12 had reduced them by at least three. In contrast, only two of the control schools had reduced their hazards by this amount, with three others increasing their hazards in that time. CONCLUSIONS: It is concluded that working intensively with schools to overcome barriers to upgrading playground equipment can lead to a reduction in hazards, and that this form of intensive intervention is more effective than providing information alone.
Accident Prevention↗
Applications of impulsive stimulated scattering in the Earth and planetary sciences.
The elastic, thermodynamic, and transport properties of crystals and fluids at high temperature and pressure play a central role in the earth and planetary sciences as well as in a variety of technologies. These properties also constitute a principal experimental constraint on the description of intermolecular interactions at short distances. Aspects of "impulsive stimulated scattering," when adapted to measurements in the diamond-anvil high-pressure cell, provide an approach to the determination of a subset of equilibrium and dynamic properties at high density.
Journal Article↗
Clinical needs assessment of middle and high school students following the 1995 Oklahoma City bombing.
OBJECTIVE: This clinical assessment was designed to identify middle and high school students in need of formal evaluation for posttraumatic response symptoms following the 1995 bombing of the Alfred P. Murrah Federal Building in Oklahoma City. METHOD: A clinical needs assessment instrument was developed and administered to grade 6 through 12 students 7 weeks after the bombing (N = 3,218). RESULTS: More than 40% of the students reported knowing someone injured, and more than one-third reported knowing someone killed in the blast. Posttraumatic stress symptoms at 7 weeks significantly correlated with gender, exposure through knowing someone injured or killed, and bomb-related television viewing. CONCLUSIONS: This study documents the intensity of community exposure to the bombing and the lingering symptoms of stress. The assessment was used in planning for clinical service delivery, training professional responders, and supporting funding requests.
Adolescent↗
Maude Evelyn Callen, RN (1898-1990).
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History, 20th Century↗
Primary T-cell and activated macrophage response associated with tumor protection using peptide/poly-N-acetyl glucosamine vaccination.
The mode of peptide-based cancer vaccine administration critically affects the ability to achieve a clinically relevant tumor-specific response. We have previously shown (Cole et al., Clin. Cancer Res., 3: 867-873, 1997) that a specific formulation of the polysaccharide poly-N-acetyl glucosamine (p-GlcNAc, designated as F2 gel) is an effective vehicle for sustained cytokine and peptide delivery in vitro. The purpose of this study was to evaluate the efficacy of F2 gel/peptide vaccination in the murine EG.7-OVA tumor model and to elucidate potential mechanisms involved in the observed cell-mediated response. C57BL/6 mice were given injections of 200 microl in the base of tail/footpad using either F2 gel alone or 200 microg of: SIINFEKL minimal peptide (OVA) in PBS, OVA peptide/endoplasmic reticulum insertion signal sequence fusion (ESOVA) in PBS, OVA in F2 gel, or ESOVA in F2 gel. Splenocytes were tested 10 days later for a secondary response using a Cr51 assay as well as a primary CTL response using the lactate dehydrogenase cytotoxicity assay. Splenocytes from immunized mice were harvested at specific time points and assayed for cell surface and intracellular markers. On day 10 postvaccination, animals were challenged with EG.7-OVA murine thymoma cells. Tumor size and appearance were recorded. Vaccination with F2 gel/peptide (either OVA or ESOVA) resulted in a primary T-cell response (up to 25% tumor cell-specific lysis) and no tumor growth in 69% of the mice. By 48 h, the proportion of splenic T cells had increased 4-fold compared with B cells. Presence of an increased Th1 CD4 helper population was demonstrated by IFN-gamma production. CD4 cells were activated at 24 and 48 h as shown by IL-2 receptor alpha chain expression (from 2% basal expression to 15.4% at 48 h). Activated splenic macrophages increased from 3 to 8% within 10 h, and their level of B7-2 expression doubled. Depletion of macrophages before vaccine injection abolished any tumor-specific primary CTL response. F2 gel/peptide tumor vaccine can prime the immune system in an antigen-specific manner by generating a measurable primary T-cell response with minimal peptide; this process involves macrophage presence and activation as well as induction of Th1 CD4 cells. This is the first demonstration of a primary CTL response generated with minimal peptide vaccination using a noninfectious delivery system. These results justify additional studies to better define the mechanisms involved in F2 gel/peptide vaccination in preparation for clinical trials.
Adjuvants, Immunologic↗
Roderick Macdonald, M.D. (1898-1985).
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History, 20th Century↗