[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.

[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.

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.

In vivo efficacy of two heated humidifiers used during CPAP-therapy for obstructive sleep apnea under various environmental conditions.

STUDY OBJECTIVES: To investigate the humidification performance-defined as the maximum achievable absolute humidity in the CPAP tube-of two heated humidifier systems (HH) offered as CPAP accessories, as a function of ambient air conditions. DESIGN: In 48 patients undergoing CPAP treatment, temperature (T) and relative humidity (RH) in the distal CPAP tube system were measured, with and without either of the two heated humidifiers A (HH-A, n=23), or B (HH-B, n=25), until a steady state was achieved. At the same time, ambient T and RH in the examination room were recorded. T and RH were used to calculate the absolute humidity (AH). SETTING: University Hospital, Erlangen, Germany. PATICIPANTS: 48 patients with obstructive sleep apnea undergoing CPAP therapy. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Conditions in the examination room during measurement with the HH-A, T = 22.5+2.1 (16.4-26.0) degrees C and AH = 9.3+2.4 (5.3-13.9) g/m3 did not differ significantly from those prevailing during measurements with the HH-B, T = 22.9+1.9 (18.9-26.3) degrees C and AH = 9.9+2.8 (6.2-16.4) g/m3. The mean humidification performance (steady state AH with HH within the CPAP tube) of the HH-A was 23.5+2.9 (19.1-29.9) g/m3, that of the HH-B 26.8+3.9 (21.0-34.4) g/m3. CONCLUSIONS: Under the ambient conditions of humidity and temperature, commonly found in European and North American bedrooms, both HH demonstrate a high humidification performance that even falls within the range recommended for intubated patients. The difference between the two HH is small, and probably not clinical relevant. Thus, it would appear that both HH are suitable for the treatment of dry upper airways under CPAP therapy.

Evaluation of a portable recording device (Somnocheck) for use in patients with suspected obstructive sleep apnoea.

BACKGROUND: Portable recording devices for the diagnosis of obstructive sleep apnoea (OSA) should be carefully evaluated before being used on a routine basis in out-patients. OBJECTIVE: This study was designed to evaluate the diagnostic accuracy of the new portable recording device, Somnocheck (SC). METHODS: Nocturnal polysomnographies (PSG) and SC recordings were performed simultaneously in the sleep laboratory in 51 patients with suspected OSA, and were analysed manually by a blinded investigator. RESULTS: The apnoea/hypopnoea index (AHI) obtained by manual SC analysis correlated closely with that obtained by PSG (r = 0.98), but the correlation with AHI obtained by automatic SC analysis was markedly lower (r = 0.83). When an AHI > or =10 was defined as indicative of OSA, the sensitivity of manual SC analysis was 0.97 and its specificity 1.00. The sensitivity of automatic analysis was 0.83 and its specificity 0.95. CONCLUSIONS: In this experimental setting, the SC showed a very high diagnostic accuracy for the diagnosis of OSA and was able to define its severity precisely. The diagnostic accuracy of manual analysis was found to be superior to that of automatic analysis. Considering the results of this technical evaluation, the SC may also be expected to work reliably when it is used in an ambulatory setting.

Reproducibility of a standardized titration procedure for the initiation of continuous positive airway pressure therapy in patients with obstructive sleep apnoea.

BACKGROUND: Manual titration of continuous positive airway pressure (CPAP) under polysomnographic control is the method most commonly employed to establish the minimal effective pressure (P(eff)) for the treatment of the obstructive sleep apnoea syndrome (OSA). To date, however, the reproducibility of P(eff) titrated in this way has not been investigated in any detail. OBJECTIVES: The present study aims to establish the reproducibility of P(eff) determined by manual titrations of CPAP under polysomnographic control in the sleep lab. METHODS: In a group of 50 patients (5 women), with a mean (SD) apnoea-hypopnoea index of 39.3 (21.8), apnoea index of 28.1 (20.9) and oxygen desaturation index of 39.3 (22.6), with newly diagnosed OSA, manual titration of CPAP was performed on two consecutive nights using the following standard titration protocol: starting at 4 mbar, CPAP was increased by steps of 1 mbar at intervals of at least 5 min, until no signs of airway obstruction could be seen, and arousals were no longer elicited. When no airway obstruction was detected over a period of 30 min, the pressure was lowered once during the night in steps of 1 mbar at intervals of at least 10 min, until obstructive events reappeared, whereupon the pressure was again increased as described above, until, once more, no signs of airway obstruction and no arousals occurred. The second titration was carried out in a blind manner, that is the lab technician did not know the results of the first pressure titration. RESULTS: The mean (SD) P(eff) for all titrations was 8.1 mbar (2.9). A high level of correlation was found between the P(eff) titrated on the first night and that titrated on the second night (Spearman correlation coefficient = 0.89). In a few individual cases, however, differences of up to 3 mbar were found between P(eff) on the first night and P(eff) on the second night. On average, the P(eff) measured on the second night was 0.5 mbar (SD = 1.3, range: -2.0 to 3.0 mbar) higher than that of the first night. CONCLUSIONS: With standardization of the manual titration of CPAP, P(eff) is readily reproducible. In individual cases, however, a difference of as much as 3.0 mbar between the two titrations is possible.

[A humidification system for CPAP therapy in obstructive sleep apnea--evaluation of the effectiveness in changing climatic environmental conditions]. / Ein Befeuchtersystem für die CPAP-Therapie bei obstruktiver Schlafapnoe--Evaluierung der Leistungsfähigkeit bei wechselnden klimatischen Umgebungsbedingungen.

OBJECTIVE: Upper airway dryness is a frequent side-effect of nasal continuous positive airway pressure (nCPAP) therapy in obstructive sleep apnoea syndrome (OSA). In this situation, heated humidification is often used. Therefore, the present study aimed to investigate the humidification performance--defined as the maximum achievable humidity in the tube system of the CPAP device--of a heated humidifier (HH) offered as CPAP accessories, as a function of ambient air conditions (humidity and temperature). PATIENTS AND METHODS: In 30 patients (22 male, 8 female, mean age 56.4 +/- 11.7 years) with OSA undergoing CPAP treatment, temperature (T) and relative humidity (RH) in the CPAP tube system were measured, with and without the HH Somnowave, until a steady state was achieved. At the same time, ambient T and RH in the examination room were recorded. T and RH were used to calculate the absolute humidity (AH). RESULTS: The conditions of the examination room during the examination nights were as follows: T = 21.9 +/- 2.8 degrees C (15.2-26.9), RH 46.5 +/- 11.9% (21.7-69.1) and AH 9.2 +/- 3.2 g/m3 (3.7-16.7). The steady state AH without HH was 9.6 +/- 3.0 g/m3 (4.1-15.4), that with HH (humidification performance) 23.2 +/- 2.8 g/m3 (19.1-29.9) (p < 0.001). CONCLUSION: Under the ambient conditions of humidity and temperature, commonly found in European bedrooms, the HH demonstrate a high humidification performance. Thus, it would appear that the HH is suitable for the treatment of dry upper airways under nCPAP therapy.

Sensitivity of a simplified forced oscillation technique for detection of upper airway obstruction.

The sensitivity of a simplified variant of forced oscillation technique (FOT) was studied for assessment of dynamic upper airway obstruction during nasal continuous positive airway pressure (nCPAP) therapy for obstructive sleep apnoea (OSA). The airway impedance P[FOT] was measured by FOT and the oesophageal pressure (P(oes)) was recorded during stable stage II sleep in 11 patients with OSA. The CPAP level was initially set high enough to completely abolish upper airway obstruction. To induce gradually increasing upper airway re-obstruction, the CPAP pressure was then lowered stepwise. Thirty six such manoeuvres were analysed, blind, to define the first inspiration at which upper airway re-obstruction was detectable by analysis of P[FOT](t(FOT)) and by P(oes)(t(oes)), respectively. On seven occasions t(FOT) and t(oes) occurred together, in the remaining 29 cases t(FOT) preceded t(oes) with a mean latency of 6.0+/-7.7 (0-32) breath cycles. In no case did t(oes) preceed t(FOT). FOT is a highly sensitive tool for the assessment of incipient upper airway obstruction during nCPAP therapy.