Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Clinicaltrials.gov identifier: NCT01466660.

Prevalence and co-infection of Toxoplasma gondii and Neospora caninum in Apodemus sylvaticus in an area relatively free of cats.

The protozoan parasite Toxoplasma gondii is prevalent worldwide and can infect a remarkably wide range of hosts despite felids being the only definitive host. As cats play a major role in transmission to secondary mammalian hosts, the interaction between cats and these hosts should be a major factor determining final prevalence in the secondary host. This study investigates the prevalence of T. gondii in a natural population of Apodemus sylvaticus collected from an area with low cat density (<2·5 cats/km2). A surprisingly high prevalence of 40·78% (95% CI: 34·07%-47·79%) was observed despite this. A comparable level of prevalence was observed in a previously published study using the same approaches where a prevalence of 59% (95% CI: 50·13%-67·87%) was observed in a natural population of Mus domesticus from an area with high cat density (>500 cats/km2). Detection of infected foetuses from pregnant dams in both populations suggests that congenital transmission may enable persistence of infection in the absence of cats. The prevalences of the related parasite, Neospora caninum were found to be low in both populations (A. sylvaticus: 3·39% (95% CI: 0·12%-6·66%); M. domesticus: 3·08% (95% CI: 0·11%-6·05%)). These results suggest that cat density may have a lower than expected effect on final prevalence in these ecosystems.

Guidelines for the diagnosis and management of hereditary spherocytosis.

Hereditary spherocytosis (HS) is a heterogeneous group of disorders with regard to clinical severity, protein defects and mode of inheritance. It is relatively common in Caucasian populations; most affected individuals have mild or only moderate haemolysis. There is usually a family history, and a typical clinical and laboratory picture so that the diagnosis is often easily made without additional laboratory tests. Atypical cases may require measurement of erythrocyte membrane proteins to clarify the nature of the membrane disorder and in the absence of a family history, occasionally molecular genetic analysis will help to determine whether inheritance is recessive or non-dominant. It is particularly important to rule out stomatocytosis where splenectomy is contraindicated because of the thrombotic risk. Mild HS can be managed without folate supplements and does not require splenectomy. Moderately and severely affected individuals are likely to benefit from splenectomy, which should be performed after the age of 6 years and with appropriate counselling about the infection risk. In all cases careful dialogue between doctor, patient and the family is essential. Laparoscopic surgery, when performed by experienced surgeons, can result in a shorter hospital stay and less pain.

Carers' perceptions of pain in people with dementia: a grounded theory approach.

The purpose of this Grounded Theory based study was to add to the limited understanding about the perception and observation of pain by the formal and informal carers of people with dementia. Thirty-one carers talked about how they know when their person with dementia has pain. Findings showed there is no one set of signs or behaviours that indicate pain in all people with dementia. However, a common pain assessment process amongst carers involved being able to detect deviation from normal behaviours based upon their intimate knowledge of what is normal for their person. A central hypothesis was thus generated from the data that considered that effective pain assessment for people with dementia is dependent on carers having an intimate knowledge of the individual's normal state of being with dementia. Implications for nursing practice are discussed.

The implementation of reproductive health programs: experiences, achievements and challenges.

As a fundamental element of population strategies for international development, reproductive health has received much recognition since the International Conference on Population and Development held in Cairo in 1994. Nevertheless, much remains to be done to improve the understanding of the concept of reproductive health, support reproductive rights, operationalize reproductive healthcare within basic health services and promote a more conducive social, cultural and economic environment, especially for women and girls, to enable the attainment of reproductive health. Collaboration between governments and non-governmental organizations will be crucial and obstetrician-gynecologists have a unique role, through service provision, review of regulatory frameworks, education and advocacy, for the promotion of reproductive health.

Ethanol-induced free radicals and hepatic DNA strand breaks are prevented in vivo by antioxidants: effects of acute and chronic ethanol exposure.

Ethanol was given to male Wistar rats as an acute dose (5 g/kg) or continuously at 5% (w/v) in a liquid diet to provide 36% of the caloric requirement. Free radicals generated in the liver were collected as a stable adduct in bile following the in vivo administration of the spin trapping agent alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN; 700 mg/kg). [1-(13)C]ethanol was used to confirm the formation of the 1-hydroxyethyl radical and to demonstrate that this was ethanol-derived in the case of the single-dose treatment. Free radical production increased up to 1h after the acute dose and then plateaued over the next 30 min. During chronic exposure to ethanol, free radical generation increased significantly after 1 week and then declined again to remain at a low level over the next 2 weeks; this transient increase corresponded closely with the induction of cytochrome P-450 2E1 (CYP 2E1) in response to ethanol feeding. Single-cell electrophoresis was used to investigate effects on DNA. After an acute dose of ethanol, the frequency of single-strand breaks increased from 1 h to peak at 6 h but then declined again to control values by 12 h. During the chronic exposure, an increase in the frequency of DNA breaks was seen at 3 days, reached a peak at 1 week and then decreased slowly over the next 5 weeks. The effects of antioxidants on these parameters was investigated after an acute dose of ethanol. Pre-treatment with vitamin C (400 mg/kg, i.p., daily for 5 days) or vitamin E (100 mg/kg, i.p., for 5 days) prior to the administration of ethanol (5 g/kg) inhibited generation of the 1-hydroxyethyl-POBN adduct by 30 and 50%, respectively, and both agents prevented the increased frequency of DNA single-strand breaks caused by ethanol. The significance of the temporal coincidence of changes in the above parameters in response to ethanol is discussed.

Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials.

The long-term consequences of adenovirus-mediated conditional cytotoxic gene therapy for gliomas remain uncharacterized. We report here detection of active brain inflammation 3 months after successful inhibition of syngeneic glioma growth. The inflammatory infiltrate consisted of activated macrophages/microglia and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and included secondary demyelination. We detected strong widespread herpes simplex virus 1 thymidine kinase immunoreactivity and vector genomes throughout large areas of the brain. Thus, patient evaluation and the design of clinical trials in ongoing and future gene therapy for brain glioblastoma must address not only tumor-killing efficiency, but also long-term active brain inflammation, loss of myelin fibers and persistent transgene expression.

Feasibility of imaging photodynamic injury to tumours by high-resolution positron emission tomography.

One early effect of the treatment of tumours by the new modality photodynamic therapy (PDT) is a reduction in tumour glucose levels. We have employed the widely used positron-emitting glucose analogue flurorine-18 fluoro-2-deoxy-D-glucose ([18F]-FDG), to determine whether, in principle, PDT-induced injury might be delineated non-invasively and quantitatively by positron emission tomography (PET). The scanner was of the high-density avalanche-chamber (HIDAC) type with a resolution of 2.6 mm. Subcutaneous T50/80 mouse mammary tumours, sensitised by haematoporphyrin ester, were illuminated by graded doses of interstitial 630 nm light. Thirty hours later, any remaining viable tumour was detected (a) by region-of-interest analysis of the PET images and (b) by gamma counting the excised tumour. PET measurements of % uptake of [18F]-FDG into tumour correlated closely with ex vivo gamma counting (slope=0.976, r2=0. 995), validating the in situ method. Uptake into untreated, control tumours was 3.8%+/-1.1% of the injected activity. Uptake of [18F]-FDG into treated tumours decreased by 0.7% for every 100 mm3 reduction in remaining viable histological volume. Outcome was further compared with that measured by (a) T2-weighted proton imaging on a 4.7-T magnetic resonance imaging (MRI) system and (b) histological analysis of subsequently sectioned tumours. PET using [18F]-FDG described the absolute volume of surviving tumour histological mass to the same degree as high-resolution MRI. The conclusion of these initial studies is that PET with [18F]-FDG, although non-specific, quantitatively described at early times the extent of tumour destruction by PDT.

Prediction of pathological stage and clinical outcome in prostate cancer: an improved pre-operative model incorporating biopsy-determined intraductal carcinoma.

OBJECTIVE: To relate the predictive value of serum prostate specific antigen (PSA) levels, histological grade and intraductal carcinoma (IDC-P, a possible marker of poor prognosis) to pathological stage and subsequent clinical outcome, and thus derive an improved predictive model to aid the decision to initiate potentially curative therapy in localized prostate cancer. MATERIALS AND METHODS: Fifty-nine radical prostatectomy specimens were histologically graded, allocated a pathological stage and the tumour volume determined by image analysis. Pre-operative (needle biopsy) tumour grade, the presence or absence of IDC-P, and serum PSA levels were correlated with the pathological stage. This was used to define the sequence and values that would be incorporated into a predictive model for pathological stage and clinical outcome. RESULTS: There were close correlations between cancer volume and tumour grade (P = 0.004) and between cancer volume and serum PSA level (P = 0.003). However, in tumours with IDC-P, serum PSA level did not correlate with tumour volume of IDC-P (P > 0.9). IDC-P was an independent variable that significantly improved the prediction of pathological stage and tumour volume, and furthermore, was closely related to (r = 0.53, P = 0.001) and accurately predicted treatment failure. CONCLUSION: The model which best predicted pathological stage and clinical outcome involved first identifying those cancers with IDC-P as having the poorest outcome. Cancers without IDC-P were then separated into low- and high-risk groups on the basis of serum PSA levels below and above 10 ng/mL, and those in the high-risk group further stratified using Gleason grading. Furthermore, the use of a sequential consideration of pre-operative variables including IDC-P allowed cases to be grouped which, after radical surgery, closely correlated with clinical outcome.

Electric current density imaging of mice tumors.

The use of electric current density imaging (CDI) to map spatial distribution of electric currents through tumors is presented. Specifically, a method previously tested on phantoms was implemented in vivo and in vitro for mapping electric current pulses of the same order of magnitude (j approximately 2500 A/m2) as in electrochemotherapy through T50/80 mammary carcinomas, B-16 melanomas and SA-1 sarcomas. A technically simplified method of electric current density imaging is discussed as well. Three geometries of electrodes (flat-flat, point-point, point-flat) indicate altered electric current distribution for the same tumor. This indicates that the method can be used for monitoring the effects of electrochemotherapy as a function of electrode geometry.

Singlet oxygen and superoxide characteristics of a series of novel asymmetric photosensitizers.

The singlet oxygen quantum yields and superoxide quantum yields for a series of novel compounds based on an asymmetrical protoporphyrin molecule have been examined. Electron spin resonance was used to measure superoxide yield and time resolved luminescence for singlet oxygen. A comparison between these results and previously published cell survival data was carried out. A broad association was found between singlet oxygen quantum yield and clonogenic cell kill.

Graft dysfunction following liver transplantation: role of free radicals.

BACKGROUND/AIMS: Following orthotopic liver transplantation primary graft non-function occurs in about 10% of patients, and survival depends on early retransplantation. The aetiology has yet to be defined, but reperfusion injury as a result of free radical production has been considered as a possible mechanism. In this study we looked for evidence of free radical generation intraoperatively and assessed the relationship between free radical production and graft function. METHODS/RESULTS: Twenty-one patients (M:F 10:11, mean age; 53 +/- 3.8 years) who underwent liver transplantation for end-stage liver disease were studied. Free radical activity increased significantly following reperfusion, as shown by: (i) the diene conjugated method, where the percentage molar ratio increased from a baseline of 10.87 +/- 0.78% to 24.42 +/- 7.8% (p < 0.01), and (ii) by electron paramagnetic resonance, where a more than a twofold rise in radical concentration was detected (p < 0.05). The increase in free radical activity detected by the diene conjugated method was significantly higher in patients with poor outcome as compared with those who had uneventful recovery (p < 0.01). CONCLUSION: Free radical activity is increased following reperfusion of liver graft during transplantation, and the magnitude of the rise is related to the severity of graft dysfunction.

Impact of selective iron and/or iodine interventions on iron and iodine status of adolescents.

The impact of iron and iodised salt supplementation and iron with iodised salt supplementation for a period of six months was studied in relation to non-supplemented controls, on selected indicators of iron and iodine status among goitrous and non goitrous adolescents. A significant reduction in total goitre rate (TGR) and visible goitre rate (VGR) was observed in the group given iodised salt alone or with iron supplements. No change was observed in TGR in the group receiving iron supplements though VGR decreased. An increase in urinary iodine excretion (UIE) was observed among goitrous and non goitrous subjects receiving iodised salt alone or iron supplements alone. The goitrous control subjects in contrast showed a significant decrease in their UIE (-10.9 mcg/dL p < 0.05). Iodised salt supplementation caused an increase in T4 (thyroxine) in goitrous and non goitrous subjects and a decrease in TSH (thyroid stimulating hormone) in goitrous subjects. However, iron supplementation had an adverse effect on T3 (triidothyronine) and T4 in non goitrous subjects. Dual supplementation caused a significant decline in T3 (among goitrous subjects) and T4 concentrations (among non goitrous subjects). Haemoglobin (Hb) and serum ferritin (sf) concentrations improved with iodised salt among both the goitrous and non goitrous subjects, but for goitrous subjects, not with iron alone. This study suggests that if a subject is both iron and iodine deficient, iodine deficiency may be corrected in part by iron or iodine supplementation, although their co-administration may not be synergistic. The metabolic relationship between iron and iodine deficiency needs further investigation. However, goitre prevalence is clearly ameliorated with combined micronutrient supplementation to a greater extent than with iodised salt alone and not at all with iron alone.

Use of ESR for the detection of irradiated dates (Phoenix dactylifera L.).

One variety (Aple) of Libyan dry dates (Phoenix dactylifera L.) was irradiated in a 60Co source to absorbed doses of 0.8, 1.0, 1.5 and 2.0 kGy. Unirradiated date stone contains a radical with a single line g = 2.0045, feature A. Irradiation to a dose of 2.0 kGy (the recommended dose for fruits in U.K.) induces the formation of additional radicals with signals g = 1.9895 and 2.0159, feature C. The single line having g = 2.0045 decays in both unirradiated and irradiated samples whereas the additional signals g = 1.9895 and 2.0159 remain almost unchanged over a period of time 15 months stored at room temperature and 4 degrees C.

Evidence for free radical generation after primary percutaneous transluminal coronary angioplasty recanalization in acute myocardial infarction.

In animal models, oxygen-derived free radicals have been found to be important mediators of reperfusion injury to ischemic but viable myocardium. However, in humans, there is no direct evidence of free radical production after the restoration of coronary artery patency in acute myocardial infarction. The purpose of this study was to quantitate and assess the time course of free radical production in coronary venous outflow in patients with acute myocardial infarction undergoing successful recanalization of the infarct-related artery by primary percutaneous transluminal coronary angioplasty (PTCA). Primary PTCA was performed in 17 patients with acute myocardial infarction of < 6 hours duration. Direct free radical production was assessed by coronary venous effluent blood sampling before PTCA and at timed intervals up to 24 hours (or 48 hours in 6 patients) after recanalization. All samples were added to the spin trapping agent alpha-phenyl N-tert butyl nitrone and analyzed by electron paramagnetic resonance spectroscopy. Vessel patency resulted in a sharp increase in free radical signal. Relative to the level before PTCA, the changes reached statistical significance after only 15 minutes (p < 0.05). Peak signals were observed between 1 1/2 and 3 1/2 hours (p < 0.001), then declined up to 5 hours. A second increase in signal level was detected between 18 and 24 hours despite no angiographic evidence of reocclusion. A gradual decline was observed after 24 hours. These findings provide the first direct and quantitative evidence of free radical production in the immediate postrecanalization phase after thrombotic occlusion of a major coronary artery in humans.

Low-level direct electrical current therapy for hepatic metastases. I. Preclinical studies on normal liver.

Low-level direct electrical current has shown promise as a potential therapeutic modality (direct current therapy; DCT) in the treatment of malignant disease, including metastases, but to date much experimental work has been empirical and has added little to our knowledge of the mechanisms involved. As a prerequisite to a clinical trial for metastases in the liver, we have employed an in vivo liver model to examine the quantitative and qualitative relationships between electrode polarity, charge and tissue necrosis. Two distinct regions of necrosis were induced, distinguishable histologically and by magnetic resonance imaging: (i) a cylindrical region of primary necrosis centred on the electrode, its volume directly proportional to the charge passed, but greater at the anode than cathode; and (ii) a wedge-shaped infarct, apex at the electrode and base extending to the liver edge. The extent of this infarct was again greater at the anode than the cathode, but showed a sigmoidal relationship with charge. Results indicate pH changes at the electrodes as likely mediators of tissue injury, but show also that significant distant ischaemic injury can occur as a consequence of primary damage. These findings should be considered when selecting tumours for possible direct current therapy and when determining the sites of electrode placement.

Free radicals and food irradiation.

Ionizing radiation can be used to control insect and microbial infestation of foodstuffs, inhibit sprouting, delay ripening and reduce the dangers from food-poisoning bacteria. Irradiation produces free radicals, most of which decay rapidly, although some are more persistent. These latter radicals can be detected and characterized by electron spin resonance (ESR). In bone and other calcified tissues, the radiation-induced radicals are distinguishable from naturally occurring radicals, and their stability makes them ideal for radiation dosimetry. The radicals induced in plant material, such as seeds and dried spices, are generally indistinguishable from the endogenous radicals and decay over a period of days or weeks. However, in many of these materials, a radiation-specific radical can be detected at low concentration, thereby permitting identification of irradiated samples, although precluding accurate dosimetry. ESR, although not universally applicable, currently provides the most specific method for the detection of irradiated food.

The effects of low-level direct current therapy on a preclinical mammary carcinoma: tumour regression and systemic biochemical sequelae.

Low-level direct electric current has been shown to be capable of destroying tumour tissue. Using an early-passage subcutaneous murine mammary carcinoma, the relationships between the volume of tumour destruction, charge and polarity have been examined. The results revealed a direct correlation between charge passed and absolute volume regression when the intratumoral electrode was made either an anode or a cathode. Tumour destruction for a given charge was significantly greater following anodic than cathodic treatment. A direct correlation was also observed between the percentage volume of prompt treatment-induced regression and the in situ end point of tumour growth delay. During the course of these experiments, a highly reproducible toxic effect was discovered, which has not been previously reported for this modality. An anodic charge greater than 10.6 coulombs or a cathodic charge greater than 21.6 coulombs resulted in 100% mortality at 24-72 h, while lower charges had no influence on mortality. Quantitative assays of a number of blood parameters showed that mortality was associated with serum electrolyte imbalances and appeared to be the result of the metabolic load of tumour breakdown products. These effects are similar to the tumour lysis or surgical crush syndromes and should not constitute a significant problem in clinical practice, where the tumour mass to total body mass ratio will normally be much smaller.

Iodine deficiency in adolescents from Bombay slums.

BACKGROUND: Iodine deficiency may be associated with endemic goitre, lowered levels of circulating thyroid hormone and suboptimal brain function. We studied iodine deficiency, thyroid status and scholastic performance in 866 (416 girls and 450 boys) adolescents from the slums of Bombay. METHODS: We examined 866 adolescents (416 girls and 450 boys) to determine the presence of goitre. Circulating levels of T3 and T4 were estimated by radioimmunoassay and of thyroid stimulating hormone by the immunoradiometric assay technique. Their scholastic performance was assessed by the average marks obtained in the last examination. RESULTS: The prevalence of goitre was 56% in both boys and girls. The visible goitre rate was also similar in boys (9.8%) and girls (10.6%). We found no significant difference in the mean urinary iodine excretion and urinary iodine to creatinine ratio between boys and girls, but the mean serum T3 and T4 levels were lower in girls than in boys, while the thyroid stimulating hormone levels were higher. The mean thyroid hormone levels were consistent with normal thyroid function. With an increase in the size of goitre, there was a decrease in urinary iodine excretion, urinary iodine to creatinine ratio, T3 and T4 levels while the thyroid stimulating hormone levels increased. The scholastic performance of the adolescents with goitre was poor. Forty-eight per cent of them obtained less than 50% marks and their academic grades showed a significant association with thyroid stimulating hormone levels. CONCLUSION: Goitre has a high prevalence among adolescents in the slums of Bombay. This can be attributed partly to the increasing demand for iodine at puberty which cannot be satisfied with the limited amounts available in food. The children also show a poor scholastic performance. Mild iodine deficiency can be easily controlled by encouraging the use of iodized salt in adolescents.