Low-molecular-weight heparin adherence and effects on survival within a randomised phase III lung cancer trial (RASTEN).

BACKGROUND: Coagulation activation is a hallmark of cancer, and anticoagulants have shown tumour-inhibiting properties. However, recent trials have failed to demonstrate improved survival with low-molecular-weight heparin (LMWH) in cancer populations. This has raised the question of suboptimal adherence as a possible explanation for the lack of benefit. Still, there is no standardised method to directly monitor LMWH in patient plasma. Here, we directly determine LMWH levels in patients using the Heparin Red assay to objectively assess adherence and how this associates with the patient outcome in the RASTEN trial. METHODS: RASTEN is a multicentre, randomised phase III trial investigating if the addition of LMWH to standard therapy can improve survival in small-cell lung cancer. LMWH was measured in plasma (N = 258) by the Heparin Red assay and compared with the anti-factor Xa (anti-FXa) activity assay. RESULTS: Both methods could differentiate patients in the LMWH arm from the control arm and patients receiving therapeutic LMWH owing to thrombosis. Receiver Operating Characteristic (ROC) analysis yielded adherence rates of 85% for anti-FXa and 68% for Heparin Red. No survival benefits were found in the adherent subgroup compared with the control arm (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 0.95-1.67; P = 0.105 and HR: 1.19; 95% CI: 0.89-1.60; P = 0.248 for anti-FXa and Heparin Red, respectively). Heparin Red could define patients with high probability of adherence to LMWH treatment, which warrants prospective studies for further validation. Our finding that the LMWH-adherent subpopulation did not show improved survival excludes that the negative outcome of RASTEN was due to poor adherence.

Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: A sub-study of RASTEN - A randomized trial with low molecular weight heparin.

Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04-1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness.

Gestational surrogacy. Medical, psychological and legal aspects: 9 years of experience in Mexico.

STUDY QUESTION: What are the medical, psychological and legal aspects involved in running a gestational surrogacy (GS) program in Mexico? SUMMARY ANSWER: The correct and complete implementation of a medical protocol, adherence to legality and psychological screening are key elements for the success of a GS program. WHAT IS KNOWN ALREADY: To our knowledge, this is the first reported GS case series in Mexico. STUDY DESIGN SIZE DURATION: This was a retrospective, descriptive study of 135 cycles performed between 2007 and 2016 at a fertility center in Villahermosa, Tabasco, Mexico. PARTICIPANTS/MATERIALS SETTING METHOD: We analyzed data from 135 GS cycles, 57 intended parents (IP) and 63 gestational carriers (GC). MAIN RESULTS AND THE ROLE OF CHANCE: GS in Mexico is only allowed in its altruistic mode. The legal requirements for the GCs are age 25-35 years and a complete medical examination that certifies no pregnancy during the last 365 days before embryo transfer and excludes infectious and chronic diseases. The IPs must be aged 25-40 years of age, have Mexican citizenship, and provide life insurance and medical expenses for the GCs. The GC recruitment was carried out by word of mouth. Of the 150+ women that requested information, 89 were identified as possible candidates. In total, 77 underwent the psychological evaluation protocol and nine were rejected owing to behavior and emotional alterations, giving 68 who began the medical selection protocol. Five women were not accepted as they were positive for human papilloma virus, or had experienced endometrial polyposis or recurrent pregnancy loss. Finally, 63 women entered the IVF protocol as GCs. The indications for GS were: hysterectomy 32%, implantation failure 21%, single fathers 14%, maternal medical condition 14%, recurrent pregnancy loss 11%, previous pregnancy complication 5% and uterine pathologies 3%. The mean age of intended mothers was 38.8 years. The average number of embryos transferred per cycle was 1.9, with 22.2% of cycles resulting in pregnancies. The live-birth rate per IP was 33.3%, 18.5% of cycles resulted in live births, with 24% of live births being twins. LIMITATIONS REASONS FOR CAUTION: Owing to the retrospective nature of this study conclusions must be drawn accordingly. WIDER IMPLICATIONS OF THE FINDINGS: As the first article addressing GS in Latin America, it may serve as a reference for future practice and publications. The results demonstrate the importance of having an assisted reproduction program in the form of GS. STUDY FUNDING/COMPETING INTERESTS: There was no external funding used and there are no conflicts to report.

Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial.

Background: Coagulation activation and venous thromboembolism (VTE) are hallmarks of malignant disease and represent a major cause of morbidity and mortality in cancer. Coagulation inhibition with low-molecular-weight heparin (LMWH) may improve survival specifically in small-cell lung cancer (SCLC) patients by preventing VTE and tumor progression; however, randomized trials with well-defined patient populations are needed to obtain conclusive data. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a homogenous population of SCLC patients. Patients and methods: We carried out a randomized, multicenter, open-label trial to investigate the addition of enoxaparin at a supraprophylactic dose (1 mg/kg) to standard treatment in patients with newly diagnosed SCLC. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), incidence of VTE and hemorrhagic events. Results: In RASTEN, 390 patients were randomized over an 8-year period (2008-2016), of whom 186 and 191 were included in the final analysis in the LMWH and control arm, respectively. We found no evidence of a difference in OS or PFS by the addition of enoxaparin [hazard ratio (HR), 1.11; 95% confidence interval (CI) 0.89-1.38; P = 0.36 and HR, 1.18; 95% CI 0.95-1.46; P = 0.14, respectively]. Subgroup analysis of patients with limited and extensive disease did not show reduced mortality by enoxaparin. The incidence of VTE was significantly reduced in the LMWH arm (HR, 0.31; 95% CI 0.11-0.84; P = 0.02). Hemorrhagic events were more frequent in the LMWH-treated group but fatal bleedings occurred in both arms. Conclusion: LMWH enoxaparin in addition to standard therapy did not improve OS in SCLC patients despite being administered at a supraprophylactic dose and despite resulting in a significant reduction in VTE incidence. Addition of LMWH cannot be generally recommended in the management of SCLC patients, and predictive biomarkers of VTE and LMWH-associated bleeding in cancer patients are warranted.

Endogenous gas gangrene after laparoscopic cholecystectomy / Gangrena Gaseosa endógena tras la colecistectomía laparoscópica

Clostridial gas gangrene of the abdominal wall is rare, and it is usually associated with organ perforation, immunosuppression or gastrointestinal malignancies. In this paper, we present a case of fulminant, endogenous gas gangrene in a 58-year old diabetic female with arterial hypertension and atherosclerosis, following uneventful laparoscopic cholecystectomy. She developed gas gangrene of the abdominal wall 12-hours after cholecystectomy and died 24-hours after the onset of the first symptoms, in spite oftreatment.

La gangrena gaseosa clostridial de la pared abdominal es rara, y normalmente se halla asociada con la perforación de órganos, inmunosupresión o malignidades gastrointestinales. En este trabajo, se presenta un caso de gangrena gaseosa endógena fulminante en una mujer diabética de 58 años con hipertensión arterial y ateroesclerosis, tras una colecistectomía laparoscópica sin incidentes. Doce horas después de la colecistectomía, la mujer desarrolló una gangrena gaseosa de la pared abdominal, y murió 24 horas después del comienzo de los primeros síntomas, a pesar del tratamiento.

Treatment with paclitaxel 1-h infusion and carboplatin of patients with advanced non-small-cell lung cancer: a phase II multicentre trial. Joint Lung Cancer Study Group.

The primary aim of this phase II study was to determine the response rate of a combination of paclitaxel and carboplatin in advanced non-small cell lung cancer (NSCLC) in a multicentre setting. The secondary aim was to determine time to progression (TTP), 1-year survival rate and toxicity. 65 patients were treated and all of them were included in the follow up for survival and toxicity. 60 patients were followed for response rate and time to progression. 55% were stage IV patients and 45% stage IIIB patients. The treatment consisted of paclitaxel 200 mg/m2 given as a 1-h i.v. infusion and carboplatin given as a 30 min i.v. infusion and the latter was dosed by using the Calvert formula at an area under the concentration time curve (AUC) of 5. The glomerular filtration rate (GFR) was determined by iohexol clearance and was not calculated from the serum creatinine level. The chemotherapy courses were given every third week with a maximum number of six or eight courses for patients who responded late. As premedication we used 8 mg betamethasone 40 min prior to infusion and then 10 min later clemastin and cimetidine. One complete response and 18 partial responses were seen giving a response rate of 29%. 40% of the patients progressed during the treatment and 28% had stable disease. The median TTP was 22 weeks. At a minimum follow up of 1 year, the 1-year survival rate was 38% and the median survival rate was 41 weeks. Haematological toxicity was mild with no grade 4 leucopenia and only seven patients (11%) had grade 3 leucopenia. There was no grade 4 toxicity. Grade 3 toxicity was seen as myalgia 5%, allergic reaction 3% and peripheral neuropathy 6%. 15% of the patients had a dose reduction due to neurotoxicity. The haematological toxicity was much milder than we expected, probably because of more exact determination of the GFR. This trial confirms the results of earlier reported trials of the efficacy and the ease of the regimen as an out-patient treatment option in advanced NSCLC. The main problem with this treatment is peripheral neuropathy.

Pinch grafting of leg ulcers. A retrospective study of 412 treated ulcers in 146 patients.

In a retrospective study of 412 leg ulcers in 146 patients treated with pinch grafting, with a mean duration of follow-up of 32 months (range 2-84), the overall healing rate was 38%. The healing rate was best in the vasculitic ulcers (56%), followed by venous ulcers (38%), arteriosclerotic ulcers (33%), mixed ulcers (33%) and "other ulcers" (20%). In the series as a whole, the mean duration of ulcer problems was 8 years, and that of the 412 ulcers treated 2.5 years; the mean recurrence rate was 28%, and the mean remission time 12.5 months. In the ulcers that were still healed at close of the study (comprising 27% (112/412) of the series), the remission time was > or = 26.6 months. Thus we consider pinch grafting to be a successful complement to conservative therapy in most types of ulcers.

Behçet's disease: a review and a report of 12 cases from Sweden.

In a retrospective study of 12 patients with Behçet's disease, more than half were found to originate from the Near East, where the prevalence of the disease is known to be high. The immigrant patients were all males, whereas 3 of the 5 patients with Swedish ancestry were females. Certain differences emerged between the two groups, including different sex ratio and absence of HLA B5 association and pathergy skin reaction among the Swedish patients. Moreover, serious neurological and ocular symptoms showing no tendency to recede with age afflicted all the Swedish female patients. Urogenital symptoms were, besides ulcers, common in both groups, including prostatitis, urethritis, orchitis, chronic sterile cystitis and relapsing salpingitis. Although the maternal does not allow statistical inferences, the estimated prevalence was higher than expected among both Swedish and immigrant patients. Recent studies, including the diagnostic criteria proposed by the "International Study Group for Behçet's disease", are discussed in relation to previously used criteria as well as present findings. The sensitivity and specificity of the first mentioned criteria and the ones proposed by Mason & Barnes seemed equal.

Prediction of behavior-management problems in 3-year-old children.

The aim was to determine power of nondental background factors to predict behavior-management problems at the first dental visits of 3-yr-old children. A total of 273 children from three kinds of residential area--city, town, and rural area--in Sweden took part. The parents were interviewed before the child's dental visit. The behavior of the child was rated by registering the degree of acceptance according to the method of HOLST & CROSSNER. The following steps were rated: entering the dental treatment room, mirror in mouth, probe on fingernail and tooth, air-blower on hand and in mouth, sitting in the dental chair, and examination. The behavior was then analyzed in relation to the answers of the interviews, and a logistic regression model was used to calculate the power of the variables, separately or combined, to predict behavior-management problems. Seventy-six percent of the children cooperated well at the dental examination; 13% reacted reluctantly, and 11% reacted negatively. Two interview variables had statistically significant predictive power: the parent's expectation of a negative reaction from the child in the dental situation and the child's anxiety when meeting unfamiliar people. Sixty-nine percent of child patients accepted the examination while sitting alone in the chair. Sitting alone used as a predictor for cooperation showed sensitivity 0.80, specificity 0.71, predictive value for positive test 0.44, and predictive value for negative test 0.94.

Dry powder inhalation of budesonide in allergic rhinitis.

Topical steroids are known to be effective in allergic inflammatory airway diseases. However, progress in the treatment of these diseases has also called for the use of unadulterated drugs, without lubricants and preservatives. Rhinocort Turbuhaler, a multi-dose inhaler containing budesonide as a pure powder, is a newly developed device without any carrier gas, preservatives or lubricants. The efficacy and tolerance of this product were evaluated in 60 patients with birch pollen rhinitis. After a run-in period of 1 week the patients received once daily for 4 weeks either budesonide pure powder (400 micrograms) or placebo in a double-blind randomized fashion. Assessment of efficacy was made by comparing scores for different nasal and eye symptoms. The additional use of antihistamine tablets was assessed. In 22 of the patients nasal peak inspiratory flow rate was measured before and after 1 week of treatment. Budesonide was significantly more effective than placebo in controlling the nasal symptoms (P-values ranging from 0.011-0.045). The use of antihistamine tablets was significantly lower in the budesonide group (P = 0.012). The nasal inspiratory flow rate was increased after 1 week of treatment in the budesonide treated group of patients as compared with placebo (P = 0.007). No differences were observed between the groups with regard to eye symptoms or adverse effects. The results show that budesonide delivered from a dry powder inhaler is an effective and well tolerated treatment of seasonal allergic rhinitis.

A double blind comparison of intranasal budesonide 400 micrograms and 800 micrograms in perennial rhinitis.

A randomized double blind placebo controlled cross-over study comparing budesonide 400 micrograms and budesonide 800 micrograms daily in 59 patients is presented. Nasal obstruction was the predominant symptom and was subjectively and objectively improved by both doses of budesonide (P less than 0.001). No significant difference was found between the two treatments. Both patient subgroups with non-allergic, non-eosinophilic rhinitis and perennial allergic rhinitis benefitted from therapy. Basal and stimulated plasma cortisol levels remained unchanged with either dose of budesonide, and no increase in adverse effects occurred with higher dose therapy.

Acute haemodynamic effects of felodipine, verapamil and hydralazine in the anaesthetized dog.

Felodipine, a potent dihydropyridine calcium antagonist with a pronounced vascular selectivity, was given intravenously (0.006-0.025 mumol kg-1) to anaesthetized, open-chest dogs with denervated hearts. The result was a dose-dependent decrease in mean arterial pressure (MAP) and total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and left ventricular end-diastolic pressure remained relatively unchanged. Cardiac tension work (TTI) and oxygen consumption (MVO2) were reduced, probably due to the decrease in afterload. The relative reduction of the coronary vascular resistance (CVR) was greater than that of TPR. The hypotensive effect of verapamil (0.05-0.20 mumol kg-1) was small and MAP decreased mainly via a decrease in HR and SV. Higher doses of verapamil which induced vasodilatation could not be given without the development of complete atrio-ventricular dissociation. Hydralazine (11-45 mumol kg-1) decreased TPR and CVR in parallel but the decrease in MAP was partly counteracted by a powerful increase in HR, SV and cardiac inotropy which was associated with elevated catecholamine levels in plasma. When MAP and HR were maintained constant by means of aortic balloon inflation and atrial pacing, felodipine markedly increased coronary blood flow and coronary sinus oxygen saturation while SV, TTI, inotropy and MVO2 remained relatively unchanged. It is concluded that felodipine markedly dilates peripheral resistance vessels, and in particular those in the coronary vascular bed, without any cardiodepressant effects.

Tachykinins and calcitonin gene-related peptide in oxazolone-induced allergic contact dermatitis in mice.

Neuropeptides in primary afferent neurons have been found to be engaged in the immediate type of hypersensitivity. However, their role in the delayed form of hypersensitivity is not yet established. The hypothesis that substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) are involved in delayed hypersensitivity was tested in oxazolone-induced, murine ear allergic contact dermatitis. Concentrations of immunoreactive SP, NKA, and CGRP were measured in extracts of the eczema ears (n = 26), whereas extracts of the opposite ears were used as controls. The SP, NKA, and CGRP contents in the treated ears were on the average 28% (p = 0.001), 32% (p = 0.004), and 15% (p = 0.016), respectively, lower than in the control ears. Lower peptide concentrations in the eczema ears indicate increased release of the peptides because the peptides are rapidly metabolized locally when released and only replenished by axonal transport from the cell bodies. Our results indicate that peptides released from primary afferent neurons play a role in the delayed type of hypersensitivity reactions.

The duration of Grenz ray-induced suppression of allergic contact dermatitis and its correlation with the density of Langerhans cells in human epidermis.

Recent investigations have shown that Grenz rays can suppress the allergic contact dermatitis reaction completely and that Langerhans cells, identified by OKT6 antibodies and electron microscopy, disappear from the epidermis at the same time. It is not known for how long this suppression lasts. This has been investigated in 28 nickel-sensitive patients who were given Grenz rays (3 Gy) on the back, once a week for 3 weeks. The patients were then divided into four groups and tested with patch tests for nickel at 1, 7, 14 and 21 days after the last Grenz ray treatment. Biopsies were taken from positive patch test sites, and from the corresponding opposite control. They were labelled with OKT6 antibodies to detect Langerhans cells. The patch test reactions were suppressed and the Langerhans cell density was decreased initially. These changes were restored after 3 and 6 weeks, respectively. The results show that the effect of Grenz rays on eczematous reactions extends to a maximum of 3 weeks and imply that Langerhans cells are necessary for the elicitation of the efferent phase of allergic contact dermatitis.

Effect of systematized "behavior shaping" on acceptance of dental treatment in children.

The aim of this study was to compare the acceptance level of children treated by dentists who had participated in a training program of psychologic care and systematized "behavior shaping", with the acceptance level of children treated to a large extent by the same dentists before their training program. The material consisted of 2400 children treated by 149 dentists, to be compared with the material of 2773 children treated by 161 dentists in the "before training" study; 127 dentists took part in both studies. The training program included a video film, a manual, and a case form. Of the children treated before the dentists underwent the training program, 79% showed positive acceptance of all treatment steps encountered during dental visits, 13% reluctant acceptance, and 8% negative or no acceptance. The corresponding figures for children treated after the training program were 92, 6, and 2%. The distributions of overall positive acceptance in the two studies were compared by means of a logistic regression model. The level of overall positive acceptance was significantly increased after the dentists had participated in the training program. The improvement was most pronounced among the youngest children and children in need of restorative treatment or extraction. Of all the background variables studied, age, present need of treatment, and the before/after training variable had the greatest influence. The study shows that dentists can be trained to obtain significantly increased positive acceptance of dental treatment in children, and that the method does not require extra time in the dental chair.

Prediction of behavior management problems in children.

The aim of the present investigation was to study non-dental and dental background variables with a view to estimating their influence on behavior management problems by means of a structured interview and analyzing their separate and combined predictive power. The material consisted of a case group, 101 children aged 3-16 yr, referred for management problems to clinics of specialized pedodontics, and a control group, individually matched with the cases as regards age, sex, residential area, number of tooth surfaces restored, and dentist. The children or their parents were interviewed concerning background variables. Logistic regression was used for the analyses. Three non-dental variables turned out to be statistically significant as predictors (P less than 0.05): problems on visiting a medical doctor, dental fear in the mother or father, and anxiety when meeting unfamiliar people. Management problems might be expected if one of these attributes is found. Four dental variables had significant predictive power: earlier problems on seeing a dentist, dislike of the dentist, not enough time to adjust to the dental situation, and fear of injection. However, none of these dental variables was found to have predictive power in 3-6-yr-olds, and none of them improved the predictive power of the three main non-dental variables.

Cardiac anti-ischemic effect of metoprolol: role of beta-blockade within the ischemic region.

The distribution of metoprolol and atenolol into ischemic and nonischemic myocardium was studied in anesthetized dogs, pigs, and cats. The beta-blockers were administered intravenously after coronary artery occlusion. Metoprolol was found to be significantly more efficiently distributed to the ischemic myocardium than atenolol in all three species. To investigate the functional implications of this difference in tissue distribution, the anti-ischemic effects of the two beta-blockers were studied in the 2-h period following coronary artery occlusion in anesthetized cats, in which heart rate was kept at a constant level. In this model, metoprolol (0.3 mg.kg-1 + 0.15 mg.kg-1.h-1) was found to attenuate or delay the developing ischemic process. This is shown by its significant reduction of (a) the decline of CK activity in ischemic myocardium, (b) the ST elevation in a precordial ECG lead, and (c) the decrease of arterial pressure and cardiac output. In contrast to metoprolol, atenolol (0.3 mg.kg-1 + 0.15 mg.kg-1.h-1) caused no significant anti-ischemic effect in this cat model. The difference in the effectiveness of the two drugs can most probably be explained by their differential distribution in the ischemic heart. Furthermore, the anti-ischemic effect of metoprolol shows that the presence of a beta-blocker in ischemic left ventricular myocardium can favorably affect the early phase of developing infarction.