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.

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.

Selective loss of vergence control secondary to bilateral paramedian thalamic infarction.

The supranuclear pathways for vergence eye movements are poorly understood. The authors report a 57-year-old patient who presented with selective loss of vergence control and dissociation of light and near reaction. MRI showed a symmetric paramedian thalamic infarction without midbrain lesion. The findings suggest that this syndrome is due to an interruption of supranuclear fibers to midbrain vergence neurons.

Abolished tilt suppression of the vestibulo-ocular reflex caused by a selective uvulo-nodular lesion.

Within the cerebellum several structures are considered to modulate the function of the vestibulo-ocular reflex (VOR). The nodulus and uvula have been implicated with the low-frequency components of the VOR, which are mediated by the velocity storage system. We report a patient with a selective lesion of the nodulus and ventral uvula. The findings suggest that nodulus and uvula normally exert an inhibitory effect on the velocity storage mechanism.

Are snoring medical students at risk of failing their exams?

STUDY OBJECTIVES: To compare the examination results of self-reported snoring and nonsnoring medical students DESIGN: We studied the examination scores obtained by medical students answering a multiple-choice test forming part of their final examinations. The students were asked to classify themselves as "nonsnorers," "occasional snorers," or "frequent snorers," and to state their age, sex, height and weight. SETTING: University Hospital, Erlangen, Germany PARTICIPANTS: 201 medical students (61% males/39% females; mean age 24.6 +/- 2.1 years; BMI 22.4 +/- 2.5 kg/m2) taking their final examinations in internal medicine. MEASUREMENTS AND RESULTS: Seventy-eight students (38.8%) claimed to be nonsnorers, 99 (49.3%) occasional snorers and 24 (11.9%) frequent snorers. The mean examination scores (adjusted for age, sex, and BMI) were 69.6 +/- 9.9% for the nonsnorers, 65.3 +/- 10.0% for the occasional snorers and 62.0 +/- 8.2% for the frequent snorers (p < 0.0001). 12.8% of the nonsnorers failed the exam, compared with 22.2% of the occasional snorers and 41.7% of the frequent snorers (p < 0.001). Logistic regression analysis showed an association between failing the exam and snoring (p = 0.013), but not between failure and age, BMI, or sex (relative risk for snorers adjusted for age, sex and BMI: 1.26; 95%--CI 1.01-1.57). CONCLUSIONS: In medical students, snoring seems to be associated with an increased risk of failing exams in a dose-response manner, even after controlling for age, sex and BMI. For the present, the mechanisms underlying this association must remain a matter of speculation. Snoring-related sleep fragmentation ("upper airway resistance syndrome") might be a causal factor.

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.

Effects of nifedipine and moxonidine on cardiac structure in spontaneously hypertensive rats. Stereological studies on myocytes, capillaries, arteries, and cardiac interstitium.

Light and electron microscopic stereological studies were performed on the myocardium of spontaneously hypertensive rats (SHR-SP) before and after treatment with nifedipine (27 mg/kg body weight/day) and the antisympathotonic agent moxonidine (8 mg/kg body weight/day). The treated groups were compared with nontreated SHR-SP and normotensive WKY (n = 10 in each group). At the beginning of therapy (when the male SHR-SP were 6 months old), blood pressure was increased and left ventricular hypertrophy had developed whereas pathologic changes of myocardial structure were not observed. After 3 months, the nontreated hypertensive rats showed cardiac fibrosis, activation and proliferation of interstitial cells, wall thickening of intramyocardial arteries, reduced capillarization as well as focal degeneration of myocytes at the ultrastructural level. Both treatments showed similar effects on blood pressure, degree of hypertrophy, and cardiac structure. Blood pressure as well as the degree of hypertrophy were significantly reduced. As far as myocardial fibrosis, capillarization, and regressive changes of myocytes are concerned a complete normalization was observed. Furthermore, nifedipine enhanced capillary supply beyond the normal level by induction of capillary neoformation. Microarteriopathy and activation of nonvascular interstitial cells (first step in development of interstitial myocardial fibrosis) were significantly suppressed by therapy, but the level of the normotensive control could not be maintained. Additional experiments with a low dose combination therapy of nifedipine and moxonidine that did not reduce blood pressure provided evidence that hypertension is an important determinant of the alterations of intramyocardial arteries, but not of cardiac interstitial fibrosis.

Changes of vascular architecture independent of blood pressure in experimental uremia.

Striking alterations of the structure of arterial vessels of different caliber are a well-known feature of renal failure, but it is currently unknown to what extent they are a reflection of hypertension or of uremia per se. To address this issue further we studied subtotally nephrectomized rats, sham-operated and pair-fed with matched controls. After uremia of 14 days' duration, stereologic measurements were carried out on perfusion-fixed tissue. To eliminate a potential influence of hypertension, subgroups of animals received furosemide and hydralazine in the drinking fluid to yield daily doses of 15 mg/kg and 20 mg/kg, respectively. At the end of the experiment, systolic blood pressure (tail plethysmography) was 110 +/- 13.3 (mean +/- SD) mm Hg and 99.4 +/- 8.1 mm Hg in untreated and treated controls, respectively, and 132 +/- 20.7 mm Hg and 103 +/- 13.0 mm Hg in untreated and treated uremic animals, respectively (n = 5 to 10 animals per group). The wall:lumen ratio of intramyocardial small arteries was 0.056 +/- 0.011 and 0.052 +/- 0.006 in untreated and treated controls, respectively. In untreated and treated uremic animals, the corresponding values were 0.077 +/- 0.011 and 0.066 +/- 0.007 (P < .01; control v uremia, ANOVA). A similar increase, unaffected by blood pressure treatment, was found for wall thickness of intramyocardial arteries. Analogous changes were also noted in mesenteric arterioles and veins. Finally, aorta media thickness was significantly (P < .005) higher in uremic animals than in controls (138 +/- 29 micrometers v 103 +/- micrometers).(ABSTRACT TRUNCATED AT 250 WORDS)

New tests of vestibular function.

The vestibulo-ocular reflex (VOR) is the only drive for short-latency eye movements stabilizing the retina during externally imposed, sudden, high-head accelerations. New strategies can exploit this unique VOR feature to study it under conditions relevant to the daily lives of patients, and to exclude the contributions from confounding nonvestibular mechanisms. Testing of the yaw vestibulo-ocular reflex (VOR) during random, whole-body rotational transients at < or = 2800 degrees/s2 delivered about centered and eccentric axes enables measurement of gains and millisecond latencies of the canal and otolith VORs in humans. Repeated measurements in acute unilateral deafferentation show sequential recovery of canal and otolith VORs to contralesional rotation, but severe and permanent deficits to ipsilesional rotation. Patients with bilateral loss of caloric responses show severe bilateral loss of VORs to transient rotation, suggesting that the apparent preservation of their VORs during sinusoidal rotations at moderate frequencies may be due instead to somatosensory inputs. Since visual acuity is degraded by retinal image motion, dynamic visual acuity (DVA) measured during imposed head-on-body or whole-body transient motion can correlate closely with VOR performance only if optotypes are presented during directionally and temporally unpredictable, high-acceleration head motion. Prediction and efference copy are relentlessly employed by vestibulopathic patients to enable good DVA during predictable or low-acceleration head motion. The linear VOR to transient lateral acceleration is strongly dependent upon viewing distance. The latency of this otolith VOR is slightly longer and more variable than the canal VOR. Unlike the canal VOR, the otolith VOR does not develop a strong directional asymmetry in unilateral deafferentation. The otolith VOR is bilaterally attenuated in bilateral vestibulopathy, and loses target distance dependence in cerebellar degeneration.

Cortical responses to object-motion and visually-induced self-motion perception.

We investigated the spatiotemporal cortical dynamics during the perception of object-motion and visually-induced self-motion perception in six normal subjects, using a 143-channel neuromagnetometer. Object-motion specific tasks evoked early transient activity over the right temporooccipital cortex, while self-motion perception, or vection, additionally was followed by sustained bilateral activity in the temporoparietal area. The specific signal distributions suggest to represent the different perceptual modes of object-motion and self-motion sensation.

Ocular flutter and truncal ataxia may be associated with enterovirus infection.

We report on three patients who presented a rare, uniform clinical syndrome consisting of ocular flutter and truncal ataxia. In all patients the symptoms followed an upper respiratory infection and resolved without sequelae within a few weeks. Previous reports have emphasized the apparent relationship of this entity to infectious disease, but the infectious agent remained uncertain. In one patient we could find a significant rise in antibody titres to enterovirus. We are not aware of any other similar documented case.

Mismatch repair deficiency in sporadic synchronous colorectal cancer.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) patients frequently develop synchronous colorectal cancer (SCRC) which also occurs sporadically in other patients. Recent studies on microsatellite instability (MSI) in sporadic SCRC diverge completely in their findings (0%-100%). In the present study MSI and mismatch repair (MMR) proteins were evaluated according to standardised criteria (exclusion of a family history, MSI analysed according to NCI recommendations) METHODS: Paraffin embedded sections of SCRC of 30 patients were evaluated for MSI and the loss of protein expression of hMLH1 and hMSH2. RESULTS: 3 out of 30 (10%) patients exhibited MSI-H which 5 out of 30 (17%) showed MSI-L. Loss of protein expression of either hMLH1 or hMSH2 was found in all cases of MSI-H and none of the MSI-L cancers. CONCLUSION: MSI is found in sporadic cases of SCRC to about the same extent as it is mentioned in the literature on sporadic single colorectal cancers. Immunohistochemistry with mismatch repair proteins could be used as a pre-screening for MMR deficiency in sporadic SCRC.

Ki-67 expression and residual tumour (R) classification are associated with disease-free survival in desmoid tumour patients.

BACKGROUND: In order to evaluate prognostic factors in the long-term survival of desmoid tumour patients, analysis of clinicopathological, immunohistochemical and follow-up data was performed. PATIENTS AND METHODS: Between 1969 and 1998, 54 patients underwent resection of aggressive fibromatosis (desmoid) and 33 of them (10 patients with FAP and 23 sporadic) were followed-up with a median time of 130 months (range 10-355 months). Additionally, immunohistochemical analysis of the desmoid tumours using Ki-67 was performed. RESULTS: In univariate analysis, curative resection (R0) (p<0.001) and low proliferation of Ki-67 (p=0.002) were of significant positive prognostic value concerning disease-free survivaL R0 and absence of Ki-67 staining were significantly associated with each other (p=0.004). CONCLUSION: Ki-67 seems to serve as a predictive marker concerning disease-free survival of desmoid tumour patients. In patients presenting with Ki-67 positive desmoids, which are unlikely to be resected in a curative manner, alternative treatment (e.g. sulindac) may be preferable.

A heated humidifier reduces upper airway dryness during continuous positive airway pressure therapy.

Upper airway dryness is a frequent side-effect of nasal continuous positive airway pressure (nCPAP) therapy in obstructive sleep apnoea (OSA). In this situation, heated humidification is often used. Alternatively, oily nose drops are frequently applied to relieve dryness. The present study aimed to investigate the efficacy of a heated humidifier in comparison with oily nose drops. Twenty-four OSA patients complaining of serious nCPAP-related upper airway dryness were randomized to 6 weeks of treatment either with heated humidification (HC 100, Fischer & Paykel, Inc., Auckland, New Zealand) or oily nose drops (Colda-Stop, Desitin, Inc., Germany). The patients completed questionnaires on the degree and frequency of upper airway dryness, compliance with nCPAP, intention to terminate nCPAP and comfort during the nCPAP therapy. All 12 patients treated with heated humidification improved in terms of the degree and frequency of upper airway dryness, and reported greater comfort when using the nCPAP device. All patients in the heated humidification group intending to terminate nCPAP therapy because of upper airway dryness persisted with nCPAP on addition of humidification. In contrast, only five out of 12 patients (42%) in the oily nose drops group reported their degree of upper airway dryness to be improved (P = 0.003), only three patients (25%) reported an improvement in the frequency of upper airway dryness (P < 0.001), and only five patients (42%) reported greater comfort when using the nCPAP device with oily nose drops (P < 0.001). In the group using oily nose drops none of the three patients who intended to terminate nCPAP therapy persisted with nCPAP. Heated humidification is highly effective and superior to oily nose drops in reducing the symptoms of upper airway dryness during nCPAP.