Determination of the target population in early benefit assessments in Germany: challenges for non-small-cell lung cancer.

OBJECTIVES: Dossiers submitted for early benefit assessments in Germany also provide information on the precise determination of the target population (patients eligible for a drug). The situation is complex for non-small-cell lung cancer (NSCLC) due to highly specific therapeutic indications. Our aim was to compare the different methodological steps applied to determine the target population in dossiers on drugs for NSCLC. METHODS: We analysed NSCLC dossiers assessed by the German Institute for Quality and Efficiency in Health Care (IQWiG) between 01.01.2011 and 31.12.2017. Methodological details regarding the determination of the target population were extracted and compared. RESULTS: We analysed 23 NSCLC dossiers. In all dossiers, the target population was determined using the number of all patients with lung cancer as the basis for calculations. This patient population was further reduced in several successive steps by assuming proportions of patients with a specific characteristic (e.g. disease stage). The most important calculation steps were patients with NSCLC (n = 23 dossiers), with a specific disease stage (n = 23), with a specific tumour mutation (n = 14), with a specific tumour histology (n = 7), without prior treatment (n = 15), with pretreatment in second or further treatment lines (n = 17), and/or with specific pretreatments (n = 9). The proportions of patients determined within the same calculation step varied considerably between dossiers. DISCUSSION: The calculation methods applied and the target population sizes reported in NSCLC dossiers vary considerably. A consensus with regard to the databases and calculation methods used to determine the target population in NSCLC would be helpful to reduce variations.

Reviewing asthma and anxiety.

The main characteristic of asthma is sudden and unexpected attacks of impaired breathing. Both the attacks themselves and the prospect of attacks generate much anxiety amongst patients. Several different forms of anxiety can be identified which vary in intensity and the situations in which they appear. Anxiety disorders are more common in asthmatics and have a considerable influence on asthma management because they influence symptom perception. Excessive anxiety about asthma symptoms can affect the patient's response to an asthma attack; anxiety related to asthma triggers can reduce the patient's quality of life and anxiety related to medical treatment can influence compliance. The extent of this influence depends upon an individual's ability to cope. Behavioural therapeutic programmes for patient education offer an opportunity to reduce anxiety and to improve asthma self-management. Physicians should look carefully for anxiety when taking the patient's history, and should support the patient's participation in asthma education programs.

Perception of dyspnea during histamine- and methacholine-induced bronchoconstriction.

BACKGROUND: Perception of dyspnea is poorly related to bronchoconstriction and may be influenced by distinct psychophysiologic stimuli. OBJECTIVE: This study compared the perceived psychophysiologic changes during histamine- and methacholine-induced bronchoconstriction using verbal as well as nonverbal assessment techniques. METHODS: Perception of dyspnea was studied during induced bronchoconstriction in 40 atopic subjects randomly ascribed to either histamine (n = 20) or methacholine (n = 20) bronchial challenge. A 100% increase in specific airway resistance (sR(aw)) indicated airway hyperresponsiveness (AHR). Dyspnea was verbally assessed by the Borg Scale (BS) and the Asthma Symptom Checklist (ASL). A hand dynamometer (HD) served for nonverbal assessment. Both challenge groups did not differ significantly with respect to age, anthropometric data, smoking and lung function before challenge. RESULTS: AHR did not differ between groups but groups differed significantly with respect to the number of symptoms and to symptom intensity reported after challenge. Subjects who underwent the histamine challenge scored significantly higher on both measures derived from the ASL. BS ratings and HD scores correlated significantly but were not significantly related to the degree of AHR. Accurate and poor perceivers could be discriminated by analysis of the relationship between BS and sR(aw). CONCLUSIONS: These findings suggest that perception of induced dyspnea differs between histamine and methacholine when assessed by a symptom report.

Creation of new bone by an osteopromotive membrane technique: an experimental study in rats.

Domes, 5 and 8 mm in diameter, were made of expanded polytetrafluorethylene membrane with different degrees of stiffness and internodal distance. The domes were placed on denuded calvarial bones of rats and covered by the skin and periosteal flaps. Histologic evaluation 9 to 16 weeks after surgery showed the formation of various amounts of new bone on the calvarial bone surface inside the domes. The amount of bone neogenesis was dependent on membrane qualities, such as stiffness and porosity, and the length of the healing period. In the most successful experiments, about 80% of the dome volume was filled with newly formed bone, whereas in other experiments considerable amounts of connective tissue were present. Using bioabsorbable membrane domes proved less successful in that they did not maintain their shape and thus did not provide space for bone formation. This study showed that it is possible to obtain bone neogenesis by an osteopromotive membrane technique. This possibility may eventually be of great significance for reconstructive surgery.

Repair of complete atrioventricular canal. 15 year's experience.

Corrective surgery for complete atrioventricular canal was performed over a 15-year period on 72 patients, 49 of whom had Down's syndrome: 46 were without major associated cardiac anomalies and 15 had previously undergone pulmonary artery banding. The pressures in the right and left ventricles equilibrated in 77% of the patients. The early mortality rate was 18% and the late mortality 7%. At follow-up 4% of the patients had severe mitral incompetence and 6% had severe tricuspid incompetence. The mean reduction of pulmonary artery pressure was 40 mmHg. The mean peak systolic pressure ratio between pulmonary artery and aorta was 0.73 before repair and had fallen to 0.38 at follow-up catheterization, when 88% of the patients were asymptomatic. Early repair in the first year of life is nowadays preferred in order to avoid progressive pulmonary vascular disease. Although the alternative of first-stage pulmonary artery banding gave lower (13%) mortality at the corrective operation, it cannot be recommended if atrioventricular valvular incompetence is significant.

Effect of metabolic control and duration on exercise-induced albuminuria in diabetic teen-agers.

Nineteen type I diabetic teen-agers without clinical signs of nephropathy with a duration of diabetes varying from 3 to 16.8 years were examined by a standardized exercise test for analysis of urinary excretion of albumin and beta 2-microglobulin. The patients were studied both in poor and improved (but not perfect), metabolic control as defined by HbA1c and blood glucose profiles, and the values were compared to those of 14 age-matched healthy controls. The controls showed no increase in albumin excretion rate during exercise as was found in diabetic patients. The albumin excretion rate during exercise was significantly correlated (p less than 0.05) to systolic blood pressure in the diabetic patients. Blood pressure in the diabetic patients was, however, similar to that of controls both at rest and during exercise. Urinary beta 2-microglobulin did not change during exercise. The urinary albumin excretion during exercise decreased significantly with improved metabolic control in diabetic patients, but the albumin excretion rate was not correlated with either blood or urinary glucose or diuresis during the exercise test. When metabolic control was improved there was a significant correlation between the increase in albumin excretion rate during exercise and the duration of diabetes, indicating that part of the exercise-induced albumin excretion might reflect irreversible morphological changes in the diabetic kidney. This test might therefore have a predictive value for diabetic nephropathy if performed during strict metabolic control.

Ventilation-perfusion relationships in children.

Ventilation-perfusion relationships (Va/Q) were studied in nine lung-healthy children, 7-15 years old, in whom a diagnostic heart catheterization was performed. VA/Q was assessed by a multiple inert-gas elimination technique. In subjects above 10 years of age, single, narrow modes of ventilation and perfusion were seen centred upon a VA/Q ratio of one. In three of the four youngest children, 10 years old or less, additional; 'high' VA/Q regions were observed. Neither shunt, nor 'low' VA/Q regions were seen in any child. Arterial PO2 was above 12 kPa in all except one and no age dependence was observed.

Skeletal muscle fibre types and sizes in anorexia nervosa patients.

Fibre type composition and fibre areas in skeletal muscle of anorexia patients were studied on biopsies from the m. quadriceps femoris in five male and five females, whose body weight was 2-3.5 SDs less than expected from the normal weight/height relationship. In two of the males, the muscles studies were also made after rehabilitation. A higher than normal percentage of type I fibres was found in the patients (male, 62 +/- 12, female, 69 +/- 7) whereas the percentage of type IIA fibres did not differ from normal individuals (male, 38 +/- 12, female 24 +/- 15). Of note was the observation that no type IIB fibres were found and some patients had an increased occurrence of the normally rare type IIC fibres. All muscle fibres were markedly atrophied with the mean cross-sectional area of type IIA fibres being significantly smaller (male, 26.1 +/- 3.7, female, 21 +/- 10.3, micrometers2 x 10(-2)) than the mean area of type I fibres (male, 34.1 +/- 4.7, female, 35.3 +/- 7.4), micrometers2 x 10(-2)). In the two males studied after rehabilitation (body weight increased 12 and 19 kg), mean fibre area increased by 40%. Our results suggested that a predominant part of the reduction in body weight and lean body mass, seen in adolescent children suffering from anorexia nervosa, could be accounted for by a loss of skeletal muscle mass. In the six subjects where marker enzymes of glycolytic (TPDH, LDH) and mitochondrial pathways (CS, HAD) were assayed, the former were 50% and the latter 10-20% below sedentary controls. Maximal oxygen uptake was only 35 (males) and 29 (females) ml/kg min-1; this contrasted with the physical activity pattern of these patients, yet was in line with their small muscle mass with its low oxidative potential.

New ways of treating children with congenital heart disease.

The rapid development of new methods of diagnosis and treatment of children with congenital heart disease is revealed. Because of decreasing death risk open heart surgery is now available already in infancy. Early corrective surgery has advantages to two-step repair. As an example of new ways of treatment a reconstructive method for tricuspid atresia is presented and the follow-up results of 41 total repairs of complete AV canal are reviewed. Double-outlet right ventricle and truncus communis are two other malformations that are accessible for successful reconstructive surgery.

Prolonged exercise in adolescent boys with juvenile diabetes mellitus. Circulatory and metabolic responses in relation to perceived exertion.

Seven well-trained adolescent boys with juvenile diabetes mellitus were studied. They were non-ketotic and performed a 60 min exercise in the afternoon at an average intensity of 58% of maximal working capacity. Blood glucose, blood lactate, plasma levels of insulin, C-peptide and 3-hydroxybutyrate, oxygen uptake and respiratory quotient were determined. The perception of exertion was scored as rate of perceived exertion. Healthy athletes of the same age were controls. Blood glucose, monitored continuously, decreased successively after 10-15 min of exercise with a significant correlation to the pre-exercise glucose value. Blood glucose decreased during exercise to the same level or below that of controls. Despite hypoglycemia with values of 2-3 mmol/l, the exercise continued. Plasma insulin was unchanged. The 3-hydroxybutyrate level was significantly higher in the diabetics, increased somewhat during exercise and still more during the recovery period. The diabetic subjects had significantly higher systolic blood pressure and heart rate during exercise despite a relatively equal work intensity and lower absolute workload. The rate of perceived exertion increased normally during exercise without interference of decreasing blood glucose.

Exercise testing with special reference to children with diabetes mellitus.

The purpose of exercise testing in diabetes mellitus is to examine physical fitness and to motivate the patient to perform physical activity as a valuable part of the treatment. Different types of tests and ergometry are presented. The stepwise increase of workload at submaximal levels is recommended for diabetics as an annual test. Maximal exercise is of value in determining the maximal oxygen uptake (VO2 max) = the aerobic capacity, maximal heart rate and systolic blood pressure.

Right atrial-right ventricular anastomosis for correction of tricuspid atresia.

Previously reported methods for the correction of tricuspid atresia involve the use of conduits and/or valves. Since many of the younger patients will outgrow their conduits and the long-term durability of the valve prostheses is open to question, we have devised an operation in which the right atrial (RA) appendage is anastomosed to the right ventricle (RV) with the aid of a pericardial patch. The RV, if not too hypoplastic, is used as a pumping chamber and the pulmonary valve is in its normal position. Three patients, 8, 9, and 12 years of age, were operated on with good clinical and hemodynamic results. Postoperatively, all three were acyanotic and had improved physical capacity compared with their preoperative status. The RA pressure in the first two patients 1 year after operation was 12 mm. Hg and at angiocardiography the RA-RV anastomosis was widely patent. In one of the patients, the RV was too hypoplastic to function. It should be possible to perform this operation even in younger patients and it may eliminate the need for palliative procedures and reoperations.

Long-term effect of previous swimtraining in girls. A 10-year follow-up of the "girl swimmers".

Thirty girls, studied in 1961 after 2.5 years of intensive swimtraining, were the subject of a follow-up for ten years. When last examined, seven and ten years after the original study, all the girls had given up swimtraining. The increased values for vital capacity observed in 1961 remained unchanged, but residual volume, functional residual capacity and total lung capacity showed small increases even after corrections for body growth. Such increases are, however, normal in these years. Heart volume which was high originally, was found to be lower ten years later, although mean values were still higher than normal. The decreases seen from 1961 to 1971 could mainly be ascirbed to a decrease in the subjects with the larges hearts originally. Both total hemoglobin and blood volume decreased to normal values in relation to body size. Maximal oxygen uptake, though, fell from 2.80 l/min (51. 4 ml/kg X min) to 2.18 l/min (36.4 ml/kg X min) ten years later. It is suggested that the functional capacity of the cardiovascular system declined more markedly than its dimensions.

Limb circulation in anorexia nervosa.

Blood flow, skin temperature and blood pressure of the lower limbs and the effect of indirect, radiant heat on calf blood flow and leg skin temperature was determined in sixteen children with anorexia nervosa (group A) and fourteen healthy children (group H) of the same age and body height. Calf blood flow as measured by venous occlusion plethysmography. Arm blood pressure was obtained by tourniquet and toe pressure and digital plethysmograms by a strain-gauge. Skin temperature was measured with a thermocouple. In group A calf blood flow was about 50--60% lower than the mean values observed in group H and a marked difference was maintained after the heat load. Skin temperature of the knees and toes were higher in group H. Systolic arm blood pressure and toe pressure were on the average 20 mmHg and 13 mmHg lower in group A. It is suggested that there is a heat-conserving, selective peripheral vasoconstriction in the anorexic patients.

Total body potassium fat free weight and maximal aerobic power in children with anorexia nervosa.

Body composition and aerobic work performance have been studied in 5 boys and 10 girls suffering from anorexia nervosa. The average ages of the two groups of children were 15.4 (boys) and 15.2 (girls) years respectively. Measurements of body composition included height, weight (W), body potassium (40K), skinfold thickness (SFT) at triceps and subscapularis, blood volume (BV) and femoral condylar and radioulnar breadths. From these measurements estimates of fat free weight (FFW), skeletal weight (S) and lean body mass (LBM) were made. Work performance was assessed by measurement of the maximal aerobic power (VO2 max). The patients had lost on average 26% of their former body weight. The boys had on average greater than 7% of their body weight as fat compared with greater than 9% in the girls. However, the loss of weight was not solely due to loss of body fat, but could also be ascribed to a decrease in soft fatfree tissue. LBM or FFW could be estimated as well from SFT as from 40k. vo2 max averaged 1.43 1/min (35.1 ml/kg/min) in the anorexic boys and 1.24 l/min (33.2 ml/kg/min) in the girls and was associated with FFW and LBM. However, VO2 max was lower in relation to LBM than in healthy children of the same age. Thus it was suggested that the emaciation in anorexia is directly attributable to loss of both fat and muscle and accounts in part for the reduction of aerobic power observed. However, an important factor may be the debilitating effect of starvation on the patient, particularly in its advanced and later stages, which reduces his/her level of habitual physical activity.