FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.

BACKGROUND: Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. METHODS: In this open-label, randomised, phase 3 trial, we recruited patients aged 18-75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. FINDINGS: Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2-67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1-63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85-1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8-10·8) in the cetuximab group and 10·3 months (9·8-11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88-1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0-36·6) in the cetuximab group compared with 25·0 months (22·7-27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62-0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). INTERPRETATION: Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. FUNDING: Merck KGaA.

Atrial septal defect in adults: cardiopulmonary exercise capacity before and 4 months and 10 years after defect closure.

OBJECTIVES: The purpose of the study was to evaluate the cardiopulmonary exercise capacity and ventilatory function in adults with atrial septal defect (ASD) preoperatively and 4 months and 10 years postoperatively. BACKGROUND: Only few data are available on cardiopulmonary exercise tolerance after ASD closure, but detailed knowledge might be helpful for indication for defect closure in certain patients. METHODS: The study was performed in adult patients (mean [+/-SD] age at operation 39.9 +/- 11.5 years; left-right shunt 9.6 +/- 5.6 liters/min; pulmonary/systemic flow ratio 2.8 +/- 1.2; mean pulmonary artery pressure 18.2 +/- 6.2 mm Hg). Cardiopulmonary exercise testing was performed with a bicycle ergometer. We determined peak oxygen uptake, anaerobic threshold, performance at anaerobic threshold and maximal performance in relation to these variables in a normal group. Ventilatory function at rest was expressed by vital capacity, maximal voluntary ventilation and forced expiratory volume in 1 s. RESULTS: Preoperatively, ventilatory function at rest was only moderately reduced to approximately 75% to 85%. Four months postoperatively we found no significant improvement, but 10 years postoperatively ventilatory function at rest was normalized. Preoperative cardiopulmonary exercise capacity was markedly reduced to 50% to 60%; early postoperatively it was only slightly higher, but late postoperatively exercise capacity significantly improved and was completely normalized. CONCLUSIONS: Although preoperative cardiopulmonary capacity in adult patients with nonrestrictive ASD was significantly decreased, some improvement was seen at 4 months postoperatively, with complete restitution to normal at 10 years after shunt closure.

Heart transplantation for restrictive cardiomyopathy: development of cardiac amyloidosis in preexisting monoclonal gammopathy.

A 54-year-old woman died 6 months after heart transplantation for treatment of restrictive cardiomyopathy. A monoclonal gammopathy without other signs of malignant disease was present preoperatively, and up to 6 weeks before transplantation no evidence of amyloidosis was established in the rectal, bone marrow, and cardiac specimens. At autopsy there was amyloidosis type AL in the kidneys, bone marrow, liver, spleen, recipient atrium, and donor heart. Retrospectively, the explanted heart also revealed amyloidosis. We conclude that in patients undergoing heart transplantation for treatment of restrictive cardiomyopathy with a preexisting monoclonal gammopathy, a thorough evaluation, including multiorgan biopsy for amyloidosis with electron microscopic workup, should be performed.

[10 years of dental care of hemophiliacs]. / 10 Jahre stomatologische Betreuung Hämophiler.

Increased consciousness of oral hygiene, improvement of sanitation degree and decrease of the number tooth extractions have been proved a success and an expression of high compliance within the scope of long-term interdisciplinary care of haemophilic patients. At the same time both patients registration and concentration at an out-patient department facilitate cooperation with the paediatricians and internal specialists being in charge of them, in addition a change-over from children to adult dispensary care is ensured. Haemophilic patients suffering from hepatitis B or HTLV-III/HIV antibodies carrier may be registered immediately. All patients undergoing dispensary care are subject to preventive test obligations.

[Epidemiology of Hodgkin's disease from the pathophysiologic viewpoint--review]. / Die Epidemiologie des Morbus Hodgkin aus pathophysiologischer Sicht--Ubersicht.

The aetiology of Hodgkin's disease remains unclear, however epidemiological characteristics have led to directive conceptions. The description of the rare familiar appearance of lymphogranulomatosis among other things by two cases of our own population and the presentation of milieu factors influencing incidence and prevalence rates give a extensive basis of discussion to develop pathophysiological ideas and to prove it by clinical, pathological, genetical and immunological knowledge. Genetical determination by an autosomal-dominant allele, with incomplete penetrance, predisposing insufficiency of immune suppression and disease inducing virus infection seems less to be three competing aetiologic systems; they rather form a causing trinity, which internal connexions we are at present not able to understand.

Lung function changes after allogenic bone marrow transplantation.

The lung function of 21 patients with leukaemia (11 with acute myeloid leukaemia, six with acute lymphatic leukaemia, four with chronic myeloid leukaemia) and of five with severe aplastic anaemia was tested before and after allogenic bone marrow transplantation. Vital capacity (VC) was lowered in patients with leukaemia before transplantation. VC and FEV1 fell significantly after transplantation. Residual volume (RV) and RV as a percentage of total lung capacity (RV % TLC) were already increased and rose significantly after transplantation. Patients with severe aplastic anaemia had noticeably increased RV and RV % TLC, values that did not change after transplantation. In contrast to the patients with aplastic anaemia, the patients with leukaemia had significantly reduced VC, RV, RV % TLC, and FEV1 before and after transplantation. The specific airway resistance (sRaw) was raised significantly before and after transplantation in the leukaemic patients. In addition, transfer coefficient (Kco) fell significantly more after transplantation in the patients with leukaemia than in those with severe aplastic anaemia. In three patients with histologically established obstructive bronchiolitis in conjunction with chronic graft versus host disease after transplantation, VC, FEV1 and FEV1 % VC fell, while RV, RV % TLC, and sRaw rose; Kco was far below normal. On the basis of these findings it is concluded that in patients with leukaemia obstructive disorders of ventilation develop or, if they are already present, worsen. In patients with severe aplastic anaemia lung function was not impaired in the early phase after transplantation. These differences are probably due to the more intensive immunosuppressive and cytotoxic preparatory regimen before transplantation in the leukaemic patients. Obstructive bronchiolitis, a complication of graft versus host disease, first manifests itself in a typical rise in specific airway resistance and must be treated early.

Lung diseases after bone marrow transplantation. Results of a clinical, radiological, histological, immunological and lung function study.

The case histories of 72 subsequently treated patients - 44 with acute leukemia, 10 with chronic myeloid leukemia, 16 with severe aplastic anemia and 2 with neuroblastoma - were analyzed after bone marrow transplantation (BMT) with respect to pulmonary diseases. Thirty-eight patients suffered from a total of 51 pulmonary complications, which led to death in 20. Of 13 patients, 3 died of bacterial pneumonia, all of them during granulocytopenia; 2 of 6 patients died of fungal pneumonia and 2 out of 3 of a mixed bacterial-mycotic infection. Adult respiratory distress syndrome (ARDS) led to death in 2 patients. A granulocyte count under 500/microliter correlated significantly (P less than 0.002) with the fatal outcome of bacterial, fungal and ARDS pneumonia as well as with bronchitis. Viral pneumonia led to death in 8 of 9 patients; in each there was a significant correlation (P less than 0.05) with graft-versus-host disease (GvHD). Patients with repeated episodes of pulmonary illness had significantly more chronic GvHD (P less than 0.05); several of these patients displayed a reduction in helper T cells and an increase in suppressor T cells in the peripheral blood. The natural killer (NK) cells were reduced and the percentage of activated NK cell level lay between 6% and 69%. B-cells were absent or deficient. These findings explain in part the absence of specific antibody reactivity. Five of these patients also contracted GvHD-associated obstructive bronchiolitis, which did not respond to therapy. Pulmonary infiltrates of unknown origin (including idiopathic interstitial pneumonia) occurred in 8 of the patients (11.1%), with a fatal outcome in 3 patients. Significant changes (P less than 0.05) in lung function after BMT appeared in the form of reduced vital capacity (VC) increased residual volume (RV) and an increase in RV expressed as the percentage of total lung capacity. Pulmonary diseases were the most common complication and cause of death in our patients after BMT.

Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive.

Forty patients with chronic liver disease and portal hypertension but without clinical signs of portasystemic encephalopathy (15 patients with nonalcoholic cirrhosis, 15 patients with alcoholic cirrhosis, and 10 patients with minimal EEG changes) and a control group of 12 patients with chronic alcohol pancreatitis were studied using an extensive psychometric program, which, in the same form, is used for expert reports on driving capacity. Of the cirrhotic patients, 60% were considered unfit to drive; in 25% driving capacity was questionable, 15% (only nonalcoholic cirrhotics) were considered fit to drive. In contrast 75% of the patients with alcoholic pancreatitis were considered fit to drive. Major defects were found only in three heavy alcoholics. Patients with alcoholic cirrhosis scored lower than patients with nonalcoholic cirrhosis. This was due to differences in liver function rather than to the effect of alcohol consumption. Patients with minimal EEG changes were practically all considered unfit to drive.

[Spiroergometrical criteria in the non-invasive evaluation of work-induced variation in lactic acid levels and acid-base equilibrium during unsteady-state exercise (author's transl)]. / Spiroergometrische Kriterien in der nichtinvasiven Beurteilung arbeitsinduzierter Anderungen von Laktatspiegel und Säure-Basen-Status während Unsteady-state-Belastung.

During an incremental exercise test the spiroergometric parameters Respiratory Quotient (RQ), Ventilatory Equivalent for oxygen (AEO2 = VE/VO2) and Ventilatory Equivalent for carbondioxide (AECO2 = VE/VCO2) initially decrease. These values then increase continuously at various work load levels until exhaustion. Experiments on 40 healthy untrained men between 20 and 40 years of age using upright bicycle ergometry and computer assisted on-line ergospirometry in which the work load was increased each minute by app. 16.3 watts show that the following 3 performance levels can be used to sufficiently describe the incremental exercise test: 1. Minimum AECO2 (77.9 +/- 22.3 watts approximately 1183 +/- 320.1 ml VO2 approximately 45.1 +/- 9.62% VO2 max), 2. Minimum AECO2 (148.5 +/- 32.7 watts approximately 1883 +/- 388.9 ml VO2 approximately 71.8 +/- 11.43% VO2 max), 3. Maximal power output (220.1 +/- 30.6 watts approximately 2638 +/- 442.3 ml VO2) (mean +/- SD). In addition simultaneous determinations of lactic acid levels and acid base equilibrium from arterialized capillary blood sampled at one minute intervals were carried out on a further 15 persons. It is shown that VO2 at the rise of AEO2 from its minimum is closely correlated with VO2 at the first significant increase of lactic acid levels (r = 0.942). There is less correlation between VO2 at the rise of AECO2 from its minimum and VO2 at the begin of the decompensation of the work induced metabolic acidosis (r = 0.854). The results indicate that through the use of spiroergometric parameters it is possible to obtain further information on the peripheral and cardiopulmonary adaptability of the organism under low submaximal work load conditions avoiding the necessity of invasive measurements.

[Pulmonary fibrosis due to working with hard metals (author's transl)]. / Lungenfibrosen bei der Bearbeitung von Hartmetallen.

Hard metals are worked with in numerous small industries. Thus hard metal fibroses are probably more frequent than has been supposed up to now. Observations on three patients have shown that a dry cough may preceed demonstrable manifestations by several months. As the full picture of the disease is hard to influence therapeutically an immediate change of job should be encouraged as soon as suspicious symptoms occur.

Determination of anaerobic threshold by the ventilation equivalent in normal individuals.

In 131 untrained healthy volunteers, unsteady-state upright bicycle ergometry was carried out by means of computer-assisted on-line ergospirometry. In 11 males and 4 females capillary lactate and blood gas analyses sampled simultaneously at 1-min intervals revealed that it is possible to determine the 'anaerobic threshold' (AT) and a 'threshold of decompensated metabolic acidosis' (TDMA) from the respiratory gas exchange by controlling the ventilation equivalent for oxygen (VEO2 = VE/VO2) and carbon dioxide (VECO2 = VE/VCO2). There is no necessity of invasive measurements. Solely ergospirometrical tests in 66 males and 50 females, aged 20--65 years, showed the expected higher work load levels and VO2 at AT and TDMA in males. There was a significant negative correlation to age. In contrast, there are no differences with regard to sex in AT and TDMA for weight-corrected work rates. In the age group 20--39 years, AT is about 1 W/kg body weight, TDMA at about 2 W/kg body weight. The larger maximum exercise capacity weight corrected for males (3 W/kg) in comparison to females (2.6 W/kg) was dependent on a greater capability in the range of maximum exertion and not on a different level of AT and TDMA.