International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small-cell lung cancer.

BACKGROUND: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. PATIENTS AND METHODS: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). RESULTS: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. CONCLUSION: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

[Nocardiosis as a Differential Diagnosis of Pulmonary Epitheloid Cell Granulomas]. / Nokardiose als Differenzialdiagnose pulmonaler epitheloidzelliger Granulome.

A 47-year-old man presented with fever, weight loss and pulmonary consolidations and cavitation in the x-ray of the thorax. The comprehensive diagnostics resulted pulmonary epitholoid cell granulomas, therefore an immunosuppressive therapy was applied on suspicion of sarcoidosis. Progressivly the pulmonary infiltration increased and cerebral and abdominal abscesses were determined with microbiological detection of Nocardia farcinica. Despite antibiotic therapy, the patient died in a septic shock with multiple organ failure.Nocardiosis is a rare granulomatous bacterial infectious disease. Risk factors include immunosuppression and structural lung diseases. Characteristic is an abscess formation that can occur in any organ, while pulmonary onset is common.The case demonstrates the importance of considering rare differential diagnoses in the detection of pulmonary epithelioid granulomas.

[CT-guided cutting needle biopsies of thoracic lesions in patients with negative bronchoscopic findings]. / CT-gesteuerte Stanzbiopsien thorakaler Läsionen bei Patienten mit bronchoskopisch negativen Voruntersuchungen.

PURPOSE: The usefulness and the complication rate of CT-guided core biopsies for obtaining specimens for histopathological examinations in patients with uncertain thoracic lesions were evaluated. MATERIALS AND METHODS: Under local anesthesia CT-guided core biopsies were performed in 121 patients using tru-cut systems (14-18 gauge). Prior to CT all patients underwent bronchoscopy without obtaining sufficient material for a definite histopathological diagnosis. The following areas were punctured: lungs 84 (69%), pleura, chest-wall, ribs 24 (20%) and mediastinum 13 (11%). The diameter of the punctured lesion averaged 4.3 cm. RESULTS: Using CT-guided puncture techniques specimens could be obtained in 118 (97.5%) out of 121 patients. Of these 118 specimens 3 (2.5%) showed marked artifacts and necrosis, which obscured a definite histopathological opinion. In the end the biopsies from 115 (95.0%) out of 121 patients could be used whereby 84 (73.0%) were classified as malignant and 31 (27.0%) as benign. Due to further operations or bronchoscopic procedures in 35 patients additional material was obtained for histopathological tests. In 3 (8.6%) of those 35 patients newly malignant disease was diagnosed, therefore these specimens showed a relevant discrepancy as compared to the result of the CT-guided biopsy. Obviously the vital central part of the tumor was not biopsied due to poor delineation caused by peritumoral infiltration. A small pneumothorax or haemoptysis was seen in 17 (14.3%) out of 121 patients. CONCLUSIONS: Despite negative bronchoscopic findings CT-guided core biopsies will deliver sufficient specimens for histopathological tests in 95% of patients with uncertain thoracic lesions. Infiltrations surrounding the vital part of the tumor may obscure the correct targeting and lead to false negative results in a few patients. Severe complications were not seen in this study, although they might happen in rare cases according to reports in the literature. Therefore CT-guided core biopsies represent an efficient and safe procedure in patients with thoracic lesions.

[Current status of erlotinib and gefitinib in palliative therapy for NSCLC--does the EGF-R mutation state have any significance?]. / Aktueller Stellenwert von Erlotinib und Gefitinib in der palliativen Therapie des NSCLC--welche Bedeutung hat der EGF-R-Mutationsstatus?

In spite of intensive research and a huge amount of chemotherapy trials, the prognosis of metastastic non-small cell lung cancer (NSCLC) is still poor. Erlotinib and Gefitinb are tyrosine kinase inhibitors (TKIs) which act against the EGF receptor (EGF-R). Activation of mutations in the tyrosine kinase domain leads to an increase in effectiveness. What is the clinical impact of EGF-R mutation screening? What value do TKIs in 1st, 2nd and 3rd line have in therapy for metastatic NSCLC? Which treatment options exist after failure of TKI in the 1st line? These and other clinically relevant questions in the context of TKIs are discussed in the present comprehensive review.

[Drug therapy for small-cell lung cancer (SCLC)--new molecular strategies for therapy]. / Medikamentöse Therapie des kleinzelligen Bronchialkarzinoms (SCLC)--neue molekulare Therapieansätze.

Small-cell lung cancer accounts for up to 20 % of lung cancer and is the most aggressive type. Although responding to chemotherapy, it often relapses early. In spite of more than thirty years of intensive research, its prognosis has not been improved. Through increasing knowledge about molecular mechanisms and the involved genes, translational research into antibodies, small molecules and even vaccines, might result in interesting new strategies for the near future. After a short introduction about the function of the relevant genes, the diagnostic and prognostic value will be described. In the second part of this review the focus will lie on current studies (mostly phases I and II) for the treatment of SCLC.

[An approach to individualised therapy of non-small cell lung carcinoma (NSCLC)--relevance of molecular predictive and prognostic factors]. / Auf dem Weg zu einer individualisierten Therapie des nicht-kleinzelligen Bronchialkarzinoms (NSCLC)---Stellenwert molekularer Prädiktions- und Prognosefaktoren.

The treatment of patients with non-small cell lung carcinoma (NSCLC) is guided by results from clinical studies. Data about molecular changes in the tumour are not used (up to now) to decide for an individualised, tumour-tailored therapy. High-throughput technologies and modern analytical methods (e. g., microarrays) lead to exponentially increasing knowledge about genetic changes in the cells and the interaction of proteins. This results in the discovery of molecular factors with high predictive (prediction of tumour response) and prognostic (prediction of survival) value in NSCLC. Among these are ERCC1, RRM1 and some receptor tyrosine kinases. Preliminary data of prospective studies have shown promising results for the selection of specific drugs, when these tumour markers were analysed. Therefore, this review focuses on the actual value of molecular markers for decision-making in the adjuvant and palliative setting and their probable future introduction into clinical practice.

[A 56-year-old man with cystic fibrosis and coeliac disease]. / 56-jähriger Patient mit zystischer Fibrose und Sprue.

Although it has been reported that cystic fibrosis and coeliac disease can coexist, a clear relationship between the two diseases has never been firmly established. Our case concerns a 56-year-old man with cystic fibrosis (delta F508/N1303J). Over the last two years he had been complaining about diarrhoea and meteorism. The serum level of tissue transglutaminase was elevated. Duodenoscopy showed a typical pattern for coeliac disease. This was confirmed by the biopsy. After three months on a gluten-free diet the symptoms had disappeared. In the literature there are some hypotheses to explain the coexistence of cystic fibrosis and coeliac disease. Due to pancreatic insufficiency in patients with cystic fibrosis the mucosa of the bowel may have more contact with the complete gluten protein. In addition, malnutrition might contribute to some additional mucosal damage. Both mechanisms might induce an inappropriate immune response to dietary gluten. In the literature all cystic fibrosis patients with coeliac disease were diagnosed with both diseases in childhood with a maximum latency between both diseases of 26 months. It seems unlikely that manifest coeliac disease remained undiagnosed in our patient since childhood. The long time gap between the diagnosis of cystic fibrosis and the first symptoms of the celiac disease in our patient could support the above-mentioned pathophysiological hypotheses.

[Pulmonary and cardiac recurrence of sarcoidosis in a heart transplant recipient]. / Pulmonales und kardiales Rezidiv einer Sarkoidose nach Herztransplantation.

HISTORY: A 38-year-old man underwent heart transplantation for end-stage heart failure as a result of sarcoid cardiomyopathy. Routine post-transplantation endomyocardial biopsies demonstrated no graft rejection. However, six months post-transplantation, while on immunosuppressive medication, the patient noted a dry cough. INVESTIGATIONS: Cardiovascular magnetic resonance imaging (MRI) showed recurrent sarcoidosis in the transplanted heart, and bronchoscopy revealed granulomas consistent with pulmonary sarcoidosis. The chest radiograph revealed bilateral perihilar interstitial nodular infiltration. Whole blood analysis, coagulation and electrolyte parameters as well as inflammatory and enzyme values were within the normal range. TREATMENT AND COURSE: The patient was treated with an increased dosage of prednisone. Furthermore, the immunosuppression with cyclosporin and everolimus was replaced by cyclosporin and azathioprine. Regular pulmonary function tests were done in addition to the routine biopsy controls and the laboratory tests as well as electrocardiography, echocardiography and radiography. The patient has remained well at eighteen months after transplantation. CONCLUSIONS: For those patients who develop end-stage cardiomyopathy from sarcoidosis, heart transplantation is still the therapy of choice. The recurrence of sarcoidosis in a transplanted heart has been only very rarely reported in the literature. Once recurrence is diagnosed patients should be treated with an increased dosage of steroid in addition to standard immunosuppressives.

Arthropathy and cutaneous manifestations in a 28-year-old patient with cystic fibrosis.

We report on a 28-year-old man with known cystic fibrosis who presented with pain and cutaneous nodules in the elbow joints. His symptoms had appeared episodically in the previous months, they were always self-limiting, and independent of pulmonary exacerbations. A radiograph of the joints was unremarkable. These findings fit well with a special form of CF-related arthritis. As in the case of classical CF arthritis, the treatment to be considered is, in particular, symptomatic administration of non-steroidal anti-inflammatory drugs and possibly glucocorticoids. Also under discussion as a further possibility is the use of antibiotics. Our patient has always refused medication. The condition again proved to be self-limiting. In contrast to the classical form of CF arthritis, the special form is not associated with either joint swelling or local warmth. In the presence of arthritic symptoms in CF patients, consideration must always be given to a hypertrophic pulmonary osteoarthropathy. The latter, however, shows typical radiological changes and is exacerbated by lung infections. The presence of arthritic pathologies in a patient with CF further underscores the fact that CF is a multiorgan morbid condition.

[Fire-eater's lung. Two cases and review of the literature]. / Feuerspuckerlunge. Zwei Kasuistiken und Literaturübersicht.

HISTORY AND ADMISSION FINDINGS: Two men were hospitalized (three years apart) after aspirating petroleum on their fist attempt at "fire-eating". Pt.1 (aged 25 years) complained of chest pain, dyspnea and dizziness. The other (Pt. 2; aged 29 years) had a hemoptysis. Pt. 1 had a normal body temperature, but the breath sounds were decreased over the left base. The breath sounds in Pt. 2 were normal, but he had a fever of 38.8 degrees C. Routine physical examination was unremarkable. INVESTIGATIONS: Laboratory tests in both patients revealed increased inflammatory parameters. Chest radiographs showed that Pt. 1 had a left basal alveolar infiltrate, while Pt. 2 had an infiltrate in the right middle and upper lobe, which on computed tomography after a few days showed signs of cavitation in the left infrahilar region and the middle lobe, respectively. Pneumococci were found in the sputum of Pt. 2. TREATMENT AND COURSE: Both patients were given antibiotics, Pt. 1 also had salbutamol inhalation treatment. The patients were discharged symptom-free after 8 and 10 days, respectively. A follow-up chest radiograph four weeks later in Pt. 1 merely showed streaky-fibrotic residues. CONCLUSION: These two case reports and detailed literature search indicate that immediate administration of antibiotics is important, while routine steroid treatment is not necessary.

[Alpha 1-proteinase inhibitor deficiency and isolated liver cirrhosis without pulmonary emphysema in a 53-year-old female patient]. / Alpha 1-Proteinaseninhibitormangel und isolierte Leberzirrhose ohne Lungenemphysem bei einer 53-jährigen Patientin.

HISTORY: A 53 year-old woman presented with an elevated serum aminotransferase and cirrhosis of the liver of unknown cause. She reported neither alcohol nor drug abuse and had no previous serious illness. She had smoked about 10 pack years of cigarettes in the past. INVESTIGATIONS: Serological markers were negative for infectious agents, hemochromatosis, Wilson's disease and autoimmune diseases. Serum electrophoresis showed a decrease of the alpha1-globulin fraction (1 %; normal: 1.5 - 4.0); serum alpha1-antitrypsin was very low at 0.25 ng/l (normal: 0.9 - 2.0). The histology revealed liver cirrhosis due to alpha1-proteinase-inhibitor deficiency. Genetic testing proved a PiZZ type of proteinase-inhibitor deficiency. The patient had normal lung functions. Because of the increased risk of hepatocellular carcinoma, future sonographic monitoring and alpha-fetoprotein measurements every 6 months were recommended. TREATMENT AND COURSE: As lung functions were normal there was no indication for administering alpha1-antitrypsin. CONCLUSION: Although proteinase-inhibitor deficiency is a rare cause of liver cirrhosis, especially without any sign of emphysema, it should be considered when other, more common causes of liver cirrhosis are excluded.

[69 year-old patient with opaque hemithorax on the right side]. / 69-jähriger Patient mit weissem Hemithorax rechts.

Liposarcomas are the most common sarcomas in adults. Mediastinal occurrence is very rare. We report on a 69 year-old man with a huge tumor in the right pleural cavity leading to a complete atelectasis of the right lung. The tumor could be completely resected. Histology showed a well-differentiated liposarcoma of the mediastinum. One year after resection there was no evidence for local recurrence or metastatic spread.

[Unspecified gain of weight?]. / Unklare Gewichtszunahme?

In the case of a 49 year old patient, a weight gain of 37 kg occurred during the first weeks of the year 2003, accompanied by a painless increase in the diameter of the upper arms and thighs. This process did spontaneously cease in the summer of 2003, but weight reduction could not be achieved. The diagnosis of multiple symmetrical lipomatosis, also known as Launois-Bensaude syndrome, the first authors to describe the condition in detail in 1898, could be established due to the unique appearance of the patient. Typical features of the disease are the accumulation of multiple lipomata in the shoulder girdle, upper arms, thorax and thighs, whereas the face, the forearms and the shanks are typically excluded. The etiology of the disease is obscure, dietetic intervention is futile, surgical approaches are liposuction or excision of the lipomata. Cessation of alcohol consumption may also be helpful, since the condition is typically associated with present or past alcohol abuse. The disease is usually reported to be rare, but there is reason enough to assume, that it is frequently misdiagnosed as simple truncal obesity.

Vestibular processing in human paramedian precuneus as shown by electrical cortical stimulation.

The authors describe a 16-year-old patient with recurrent episodes of epileptic linear self-motion perception and occasional body tilts. Intracranial seizure monitoring located the seizure onset, caused by a circumscribed ependymoma, in the right paramedian precuneus. Electrical cortical stimulation of this area could reproduce the same vestibular sensations, which ceased after lesionectomy. The findings implicate the paramedian area of the precuneus in the processing of static and dynamic vestibular, probably otolithic, information.

Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment.

Serum leptin and ghrelin levels were investigated in patients with obstructive sleep apnoea (OSA) syndrome before and during continuous positive airways pressure (CPAP) treatment and compared with body mass index (BMI)-matched controls without OSA. Male patients (n=30) with OSA (apnoea/hypopnoea index=58+/-16, BMI=32.6+/-5.3 kg x m(-2)) underwent CPAP treatment. Fasting leptin and ghrelin were measured at baseline and 2 days, and in the case of leptin 2 months after initiation of treatment. Baseline plasma ghrelin levels were significantly higher in OSA patients than in controls. After 2 days of CPAP treatment, plasma ghrelin decreased in almost all OSA patients (n=9) to levels that were only slightly higher than those of controls (n=9). Leptin levels did not change significantly from baseline after 2 days of CPAP treatment, but were higher than in the control group. After 8 weeks, leptin levels decreased significantly, although the BMI of the patients showed no change. The decrease in leptin levels was more pronounced in patients with a BMI <30 kg x m(-2). These data indicate that the elevated leptin and ghrelin levels are not determined by obesity alone, since they rapidly decreased during continuous positive airways pressure therapy.

Auto-CPAP therapy based on the forced oscillation technique.

Autoadjusting CPAP devices (APAP) are designed to continuously adjust the positive pressure to the required levels, and thus increase treatment quality and patient compliance. The results of APAP treatment strongly depend on the control mechanism of the respective APAP device. In agreement with other working groups, we have recently shown that the forced oscillation technique (FOT) is capable of detecting incipient upper airway obstruction prior to physiological reactions such as the onset of increasing esophageal pressure swings or microarousals. Therefore we studied efficacy and acceptance of a novel APAP device controlled exclusively by FOT. 100 consecutive patients with OSAS confirmed by polysomnography (mean AHI 47.9 +/- 22.6) and daytime sleepiness (Epworth sleepiness scale, ESS 12.6 +/- 3.9) were randomized to either APAP treatment (n = 50) or conventional CPAP treatment (n = 50). Polysomnographies were performed at the second treatment night and subjective sleepiness (modified ESS) was established in the morning. The respiratory disturbance was largely normalized in both treatment groups in the second treatment night (AHI 4.7 +/- 5.3 vs. 3.7 +/- 3.4; n.s.). Both groups showed largely improved sleep profiles and had markedly reduced ESS-scores (6.6 +/- 3.6 vs. 7.0 +/- 3.4; n.s.). The mean treatment pressure during APAP was significantly lower than during CPAP treatment (6.0 +/- 2.0 vs. 9.0 +/- 1.8 mbar; p < 0.001). There were no significant differences between APAP and CPAP treatment in any parameter of efficacy or acceptance. APAP treatment with this device controlled exclusively by FOT is well accepted by the patients and permits an adequate treatment of OSAS without the need for invidiual CPAP titration.

Initiation of CPAP therapy for OSA: does prophylactic humidification during CPAP pressure titration improve initial patient acceptance and comfort?

BACKGROUND: Heated humidifiers (HH) enable effective treatment of upper airway dryness during nasal continuous positive airway pressure (nCPAP) therapy for obstructive sleep apnoea (OSA), but the role of prophylactic use of HH during the initiation of nCPAP treatment has not been studied so far. OBJECTIVES: The aim of the present study was to investigate whether prophylactic HH during the initiation of CPAP would result in improved initial patient comfort and acceptance. METHODS: In 44 consecutive, previously untreated OSA patients with no history of upper airway dryness, CPAP titration with and without HH was performed on two consecutive nights in a randomised order. The patients were interviewed after each treatment night in order to establish the comfort of the treatment, and, after the second treatment, they were asked which of the two nights they considered more pleasant, and which treatment they would prefer for long-term use. RESULTS: Following CPAP titration with HH, 32 patients (73%) claimed to have had a better night's sleep than usual (i.e. without CPAP treatment) compared with 33 patients (75%) saying the same following CPAP treatment without HH. For 21 patients (47.7%) treatment with HH was more pleasant, 23 (52.3%) saw no difference or said that treatment without HH was more pleasant. Nineteen patients (43.2%) gave preference to treatment with HH for long-term use, while 25 patients (56.8%) had no preference or said they would prefer treatment without HH. CONCLUSIONS: The use of HH during the initiation phase of CPAP treatment was associated neither with an initial improvement in comfort nor with greater initial treatment acceptance.