S-1 maintenance therapy in Caucasian patients with metastatic esophagogastric adenocarcinoma-final results of the randomized AIO MATEO phase II trial.

PURPOSE: Platinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established. DESIGN: MATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints. RESULTS: From 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P = 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P = 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy ≥grade 2 (9.4% versus 36.7%). CONCLUSIONS: S-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.

Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the 'burden of therapy' method.

BACKGROUND: Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non-small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. RESULTS: One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). CONCLUSION: The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).

Fever may be the only clinical symptom at the onset of infection in neutropenic cancer patients undergoing myelosuppressive chemotherapy. A prompt and evidence-based diagnostic and therapeutic approach is mandatory. A systematic search of current literature was conducted, including only full papers and excluding allogeneic hematopoietic stem cell transplant recipients. Recommendations for diagnosis and therapy were developed by an expert panel and approved after plenary discussion by the AGIHO. Randomized clinical trials were mainly available for therapeutic decisions, and new diagnostic procedures have been introduced into clinical practice in the past decade. Stratification into a high-risk versus low-risk patient population is recommended. In high-risk patients, initial empirical antimicrobial therapy should be active against pathogens most commonly involved in microbiologically documented and most threatening infections, including Pseudomonas aeruginosa, but excluding coagulase-negative staphylococci. In patients whose expected duration of neutropenia is more than 7 days and who do not respond to first-line antibacterial treatment, specifically in the absence of mold-active antifungal prophylaxis, further therapy should be directed also against fungi, in particular Aspergillus species. With regard to antimicrobial stewardship, treatment duration after defervescence in persistently neutropenic patients must be critically reconsidered and the choice of anti-infective agents adjusted to local epidemiology. This guideline updates recommendations for diagnosis and empirical therapy of fever of unknown origin in adult neutropenic cancer patients in light of the challenges of antimicrobial stewardship.

Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV.

Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.

Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie.

BACKGROUND: The combination of docetaxel (Taxotere), cisplatin, and fluorouracil improved efficacy in gastric cancer, but was associated with substantial toxicity. This study was designed to incorporate docetaxel into a tolerable biweekly (once every 2 weeks) oxaliplatin-based chemotherapy regimen. PATIENTS AND METHODS: Patients with measurable, metastatic adenocarcinoma of the stomach or esophagogastric junction and no prior chemotherapy received oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 2600 mg/m(2) as a 24-h infusion in combination with docetaxel 50 mg/m(2) (FLOT) on day 1 every 2 weeks. Prophylactic growth factors were not administered. RESULTS: Fifty-nine patients were enrolled; 54 received treatment. Patients had a median age of 60 years (range 29-76) and most (93%) of them had metastatic disease. Objective responses were observed in 57.7% of patients with a median time to treatment response of 1.54 months. Median progression-free survival (PFS) and overall survival were 5.2 and 11.1 months, respectively. Twenty-five percent of patients experienced prolonged (>12 months) PFS. Frequent (>10%) grade 3 or 4 toxic effects included neutropenia in 26 (48.1%), leukopenia in 15 (27.8%), diarrhea in 8 (14.8%), and fatigue in 6 (11.1%) patients. Complicated neutropenia was observed in two (3.8%) patients, only. CONCLUSIONS: Biweekly FLOT is active and has a favorable safety profile.

Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer.

BACKGROUND: To compare the efficacy and safety of three different chemotherapy doublets in the treatment of advanced pancreatic cancer (PC). PATIENTS AND METHODS: At total of 190 patients were randomly assigned to receive capecitabine 1000 mg/m(2) twice daily on days 1-14 plus oxaliplatin 130 mg/m(2) on day 1 (CapOx), capecitabine 825 mg/m(2) twice daily on days 1-14 plus gemcitabine 1000 mg/m(2) on days 1 and 8 (CapGem) or gemcitabine 1000 mg/m(2) on days 1 and 8 plus oxaliplatin 130 mg/m(2) on day 8 (mGemOx). Treatment cycles were repeated every three weeks. The primary end point was progression-free survival (PFS) rate at 3 months; secondary end points included objective response rate, carbohydrate antigen 19-9 response, clinical benefit response, overall survival and toxicity. RESULTS: The PFS rate after 3 months was 51% in the CapOx arm, 64% in the CapGem arm and 60% in the mGemOx arm. Median PFS was estimated with 4.2 months, 5.7 months and 3.9 months, respectively (P = 0.67). Corresponding median survival times were: 8.1 months (CapOx), 9.0 months (CapGem) and 6.9 months (mGemOx) (P = 0.56). Grade 3/4 hematological toxicities were more frequent in the two Gem-containing arms; grade 3/4 non-hematological toxicity rates did not exceed 15% in any arm. CONCLUSION: CapOx, CapGem and mGemOx have similar clinical efficacy in advanced PC. Each regimen has a distinct but manageable tolerability profile.

Actigraphy in agitated patients with dementia. Monitoring treatment outcomes.

Especially in pharmacotherapeutic research, a variety of methods to monitor behavioural and psychological symptoms of dementia (BPSD) are currently being discussed. To date, the most frequently used of these are clinical scales, which, however, are subjective and highly dependent on personnel resources. In our study, we tested the usefulness of actigraphy as a more direct and objective way to measure day-night rhythm disturbances and agitated behaviour. After a baseline assessment, 24 patients with probable dementia of the Alzheimer type (NINCDS-ADRDA) and agitated behaviour received either 3 mg melatonin (n=7), 2.5 mg dronabinol (n=7), or placebo (n=10) for two weeks. In addition, 10 young and 10 elderly healthy subjects were examined as a control group. Motor activity levels were assessed using an actigraph worn continuously on the wrist of the non-dominant hand. At the beginning and the end of the study, patients' Neuropsychiatric Inventory (NPI) scores were also assessed. In the verum group, actigraphic nocturnal activity (P=0.001), NPI total score (P=0.043), and NPI agitation subscale score (P=0.032) showed significant reductions compared to baseline. The treatment-baseline ratio of nocturnal activity (P=0.021) and treatment-baseline difference of the nocturnal portion of 24 h activity (P=0.012) were reduced. Patients' baseline activity levels were similar to those seen in healthy elderly subjects. Younger healthy subjects exhibited higher motor activity even at night. There was no correlation between actigraphy and NPI. Both actigraphic measures and the gold standard clinical scale were able to distinguish between the verum and placebo groups. However, because they did not correlate with each other, they clearly represent different aspects of BPSD, each of which reacts differently to therapy. As a result, actigraphy may well come to play an important role in monitoring treatment success in BPSD.

Pegfilgrastim supports delivery of FEC-100 chemotherapy in elderly patients with high risk breast cancer: a randomized phase 2 trial.

This randomized phase 2 study explored the feasibility of delivering four to six cycles of the dose-intensified regimen FEC-100 (5-fluorouracil, epirubicin, and cyclophosphamide) to elderly patients with stage II-III breast cancer, using pegfilgrastim for neutrophil support. Sixty patients aged 65-77 years received single 6mg doses of pegfilgrastim on day 2 of FEC-100, either as primary prophylaxis (all cycles: PP), or as secondary prophylaxis (all cycles following a neutropenic event: SP). Neutropenic events (a composite endpoint that included grade 3 neutropenia+fever, grade 4 neutropenia, infectious complication requiring systemic anti-infectives and chemotherapy dose delay/reduction) occurred in 24/30 (80%) of the PP and 21/29 (72%) of the SP group in the first cycle. Most patients received all chemotherapy cycles at full dose on schedule (26/30 [87%] PP; 20/29 [69%] SP). These data indicate that delivery of FEC-100 is feasible with pegfilgrastim support in elderly breast cancer patients.

Computed tomography of the human pineal gland for study of the sleep-wake rhythm: reproducibility of a semi-quantitative approach.

PURPOSE: To propose a semi-quantitative computed tomography (CT) protocol for determining uncalcified pineal tissue (UCPT), and to evaluate its reproducibility in modification of studies showing that the degree of calcification is a potential marker of deficient melatonin production and may prove an instability marker of circadian rhythm. MATERIAL AND METHODS: Twenty-two pineal gland autopsy specimens were scanned in a skull phantom with different slice thickness twice and the uncalcified tissue visually assessed using a four-point scale. The maximum gland density was measured and its inverse graded on a non-linear four-point scale. The sum of both scores was multiplied by the gland volume to yield the UCPT. The within-subject variance of UCPT was determined and compared between scans of different slice thickness. RESULTS: The UCPT of the first measurement, in arbitrary units, was 39+/-52.5 for 1 mm slice thickness, 44+/-51.1 for 2 mm, 45+/-34.8 for 4 mm, and 84+/-58.0 for 8 mm. Significant differences of within-subject variance of UCPT were found between 1 and 4 mm, 1 and 8 mm, and 2 and 8 mm slice thicknesses (P<0.05). CONCLUSION: A superior reproducibility of the semi-quantitative CT determination of UCPT was found using 1 and 2 mm slice thicknesses. These data support the use of thin slices of 1 and 2 mm. The benefit in reproducibility from thin slices has to be carefully weighted against their considerably higher radiation exposure.

Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia.

There is substantial need to improve the outcome of patients with high-risk acute myeloid leukemia (AML). The clinical trial reported here investigated a new approach of up-front allogeneic hematopoietic stem cell transplantation (HSCT), provided a median of 40 days (range 22-74) after diagnosis, in twenty-six consecutive patients with newly-diagnosed high-risk AML characterized by poor-risk cytogenetics (n = 19) or inadequate blast clearance by induction chemotherapy (IC, n = 7). The median age was 49 years (range 17-68). During IC-induced aplasia after the 1st (n = 11) or 2nd (n = 15) cycle, patients received allogeneic peripheral blood stem cells (PBSC) from related (n = 11) or unrelated (n = 15) donors following a fludarabine-based reduced-intensity regimen. Seventeen patients were not in remission before HSCT with a median marrow blast count of 34% (range 6-70). All patients achieved rapid engraftment and went into remission with complete myeloid and lymphatic chimerism. Grades II to IV acute GvHD occurred in 14 (56%) and extensive chronic GvHD was documented in 8 (35%) patients. The probability of disease-free survival was 61% with only three patients relapsing 5, 6 and 7 months after transplantation, respectively. Up-front allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in high-risk AML patients and warrants further investigation.

[Erectile dysfunction in depression and under treatment with antidepressants -- current treatment options]. / Erektile Dysfunktion bei Depressionen und antidepressiver Therapie -- derzeitige Therapieoptionen.

Erectile dysfunction (ED) is a common problem in the general population, but also a symptom of both treated and untreated depression. As a side effect of antidepressant medication, erectile dysfunction appears to be one of the principal reasons for discontinuing antidepressant treatment. Avoiding or switching antidepressants is problematic, as this may lead to an increase in depressive symptoms. Our review shows that oral phosphodiesterase inhibitors are an option in treating both ED resulting from depression and from antidepressant medication.

Serotonergic effects of smoking are independent from the human serotonin transporter gene promoter polymorphism: evidence from auditory cortical stimulus processing.

BACKGROUND: Cigarette smoking has been associated with mood enhancing properties and modulating effects on serotonin activity. The loudness dependence (LD) of the auditory-evoked N1/P2-component has been related to serotonergic neurotransmission, i. e. the allelic variants in the promoter of the 5-hydroxytryptamine-transporter (5-HTT) gene (SCL6A4). Moreover, smoking behavior has been associated to the 5-HTT-genotype. It was hypothesized that cigarette smoking modulates the LD and this effect was expected to interact with the 5-HTT-genotype. METHODS: 5-HTT-genotype and LD were determined in 63 healthy smokers and 114 nonsmokers. RESULTS: LD was significantly affected by smoking status (p = 0.008) and 5-HTT-genotype (p = 0.045) but not by smoking*genotype-interaction or daily cigarette consumption. Current smokers exhibited a significantly weaker LD compared to nonsmokers. 5-HTT-genotype showed no significant effect on smoking behavior. DISCUSSION: The results indicate a higher serotonergic activity in smokers as compared to nonsmokers independent of 5-HTT-genotype. Since former smokers and never smokers showed similar LDs, the serotonin enhancing effect of smoking seems to be a characteristic state, which may contribute to the maintenance of smoking behavior.

Antimicrobial therapy of unexplained fever in neutropenic patients--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society).

Cytostatic chemotherapy of hematological malignancies is often complicated by neutropenia, which increases the risk of infections, especially if the neutrophil count is below 500/microl. Frequently, fever is the first, and in most patients the only, sign of an infection. Unexplained fever is defined as follows: temperature of >/=38.3 degrees C or >/=38.0 degrees C for at least 1 h, or measured twice within 12 h, if the neutrophil count is <500/microl or <1000/microl with predicted decline to 500/microl. Different risk categories can be identified according to the duration of neutropenia: low risk /=10 days. An empirical mono- or duotherapy with antipseudomonal and antistreptococcal agents should be initiated immediately. In the low risk patient group, oral therapy with cipro-, levo-, or ofloxacin combined with amoxicillin/clavulanic acid is permissible. For standard and high risk patients, monotherapy can be carried out with either ceftazidime, cefepime, piperacillin with tazobactam or a carbapenem. In duotherapy, a single dose of an aminoglycoside is combined with acylaminopenicillin or a cephalosporin of the third or fourth generation. The addition of glycopeptides in empirical therapy should only be considered in the presence of severe mucositis, or if a catheter-associated infection is suspected. If fever persists after 72-96 h of first-line therapy with antibiotics, the regimen should be modified (with the exception of e.g. coagulase-negative staphylococci infections, because these infections take longer to respond). Intermediate risk patients should additionally receive an aminoglycoside after monotherapy (penicillin or a cephalosporin). If a carbapenem was administered for monotherapy, this can be followed by a quinolone and/or a glycopeptide. In the high risk group, the same modifications should be made as in the intermediate risk group but with additional systemic antifungal treatment. In the presence of unexplained fever, fluconazole can be administered at first, but if this fails, amphotericin B (conventional or liposomal), itraconazole, voriconazole or caspofungin should be started. After defervescence to <38 degrees C, treatment should be continued for 7 days if the neutrophil count is <1000/microl, and for 2 days if the neutrophil count is >1000/microl.

Alternative splicing of the p15 cdk inhibitor in glioblastoma multiforme.

Thirty-four to fifty-six percent of malignant gliomas harbor homozygous co-deletions of the INK4a(p16-p14ARF) and INK4b(p15) tumor suppressor genes. Recently, an alternatively spliced form of p15 has been cloned and termed p10 based on the presumed molecular weight of the protein. In this study, we have investigated the role of p10 expression in human glioblastomas. Both, wild-type p15 and p10 were detected in three of nine glioblastoma cell lines. Sixteen of twenty-nine (55%) glioblastoma tumor samples contained INK4b transcripts, but only nine (31%) tumors expressed p15 protein. Three p15 protein-negative tumors expressed only p10 mRNA. Preferential expression of p10 was not due to splice site mutations. Strong suppression of tumorigenicity was seen in four glioblastoma cell lines after transfection with p15 but not with p10. Loss of p15 protein expression was almost always accompanied by loss of p16 expression. p1 6/p15-negative tumors commonly lacked p14ARF expression. These results suggest that differential splicing of the INK4b gene may result in the expression of p10 at the expense of p15, which would lead to loss of p15-mediated growth suppression. This novel mechanism of loss of p15 might complement alterations of the INK4a tumor suppressor gene in some glioblastomas, resulting in combined loss of p16, p15 and p14ARF.

Basic parameters of saccadic eye movements--differences between unmedicated schizophrenia and affective disorder patients.

BACKGROUND: Smooth pursuit eye movement (SPEM) dysfunctions are considered a biological marker for schizophrenia and have been studied widely. In contrast, saccadic eye movements have received less attention, although disturbances have been described previously. Basic neurophysiologic parameters of saccades in schizophrenics, especially in unmedicated patients, have not been studied extensively. METHODS: Saccadic eye movements of 38 unmedicated schizophrenic patients, 32 patients with major depression and 42 non-psychiatric controls were examined using high-resolution infrared oculography. Two large-amplitude saccadic tasks were presented. The groups were compared on peak velocity, reaction time and accuracy. RESULTS: Peak velocity was significantly increased in schizophrenic patients. Depressive patients had a significantly longer reaction time. Both patient groups needed more corrective saccades to reach the target than controls. CONCLUSIONS: Peak velocity distinguishes unmedicated schizophrenic patients from depressive patients and normal controls. This could be explained by deficits of the prefrontal cortex in the inhibitory control of saccades. Our findings suggest that schizophrenia affects not only SPEM but also saccadic eye movements.

Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression.

Dysregulation of cell cycle progression and telomerase activation have been implicated in malignant tumor progression as well as in the evasion of senescence and immortalization. We have investigated expression of the cell cycle control and tumor suppressor genes INK4a(p16-p14ARF), INK4b(p15-p10) and RB, and their relation to telomerase activation during malignant meningioma progression. 7/26 (27%) benign, 3/12 (25%) atypical but 4/7 (57%) anaplastic tumors lacked both, p16 and p15 protein expression. 14/39 (36%) benign and atypical but 5/7 (71%) anaplastic meningiomas contained no p14ARF mRNA. 2/46 (4%) tumors failed to express pRB. We observed frequent differential loss of expression of the alternatively spliced INK4a tumor suppressors p16 and p14ARF. Exclusive expression of the alternative INK4b transcript p10 possibly at the expense of p15 and therefore resulting in loss of p15 tumor suppressor activity was noted in two meningiomas. We have previously described telomerase activity or expression of the telomerase catalytic subunit hTERT in this meningioma series. Telomerase activation was detected in 10/27 (37%) benign, but 18/19 (95%) non-benign meningiomas. We observed no significant overall correlation between loss of INK4a/INK4b expression and telomerase activation. In conclusion, our results suggest a greater role for losses of INK4a/INK4b gene products in meningioma formation and malignant progression than previously thought. Inactivation of p16/p15- and pl4ARF-dependent pathways possibly in conjunction with telomerase activation might be critical steps for a meningioma cell towards escape from senescence, that is, immortalization.

Association analysis of GABAAbeta2 and gamma2 gene polymorphisms with event-related prefrontal activity in man.

Gamma-aminobutyric acid (GABA)A-receptors play a crucial role in the generation of electroencephalogram (EEG) oscillations and evoked potentials (ERPs). The present association study was designed to test whether EEG and ERPs are modulated by genetic variations of the human GABAA beta2 (GABRB2) and gamma2 (GABRG2) genes on chromosome 5q33. The genotypes of two nucleotide substitution polymorphisms of the GABRB2 and GABRG2 genes were assessed in 95 psychiatrically healthy subjects of German descent. Neurophysiological phenotyping was performed with four factorized EEG/ERP parameters: EEG activation, anterior and posterior EEG synchronization, and event-related activity (N100/ P200-complex). No genotypic association was found for the GABRB2 nucleotide exchange polymorphism with any electrophysiological parameter. A significant association was found between the genotype of the intronic GABRG2 G-->A nucleotide exchange and the event-related N100/P200 (ANOVA: F=3.81; df=2; P=0.026). A comparison of homozygous subjects carrying either the G/G or A/A genotype of the GABRG2 polymorphism consistently revealed an even stronger difference in the effect-size (ANOVA: F=11.13; df=1; P=0.002). Post hoc analysis of this association with current density analysis in three-dimensional neuroanatomic Talairach space-time showed a reduction in the event-related signal power after 120 ms in the right dorsolateral prefrontal cortex. Taking into account the risk of false-positive association findings attributable to multiple testing, our results encourage further replication studies to examine the phenotype-genotype relationship of GABRG2 gene variants and event-related prefrontal activity.

A new concept for melatonin deficit: on pineal calcification and melatonin excretion.

Even though exogenous melatonin has proven to influence sleep and circadian parameters, low endogenous melatonin is not related to sleep disturbances, nor does it predict response to melatonin replacement therapy. In this manuscript, we present a new concept towards a definition of a melatonin deficit. The purpose of the study was to introduce a marker for an intra-individual decrease in melatonin production. Therefore, we developed a method to quantify the degree of pineal calcification (DOC) using cranial computed tomography. Combining pineal DOC with the organs's size, we estimated the uncalcified pineal gland volume. This estimation was positively and significantly associated with 6-sulfatoxymelatonin (aMT6s), collected over 24 hours in urine, in 26 subjects. Data yielded evidence that the decline in aMT6s excretion with age can be sufficiently explained by an increased pineal calcification. These results suggest that DOC might be useful as an indicator of an intra-individual, decreased capability of the pineal gland to produce melatonin. DOC might prove to be a response-marker for melatonin replacement therapy and a vulnerability marker of the circadian timing system.

The valency state of absorbed iron appearing in the portal blood and ceruloplasmin substitution.

(1) Attempts to determine the redox-state of the absorbed iron, which appeared in the portal blood when the free iron-binding capacity was previously saturated, indicate that about 30-90% of this iron was in the ferrous state. This effect was particularly prominent after luminal administration of ferrous iron, but was also seen when iron was given in the ferric state. (2) Total iron absorption is significantly higher in ceruloplasmin-substituted copper-deficient animals as compared to copper-deficient controls. (3) The appearance rate of absorbed iron in the portal blood of copper-deficient animals increased several times immediately after the intravenous infusion of ceruloplasmin. (5) The distribution of absorbed iron was changed due to the ceruloplasmin substitution: it was increased in the reticulocytes (+66%), plasma (+400%) and the body (+112%), whereas in the liver it was decreased by about 78%. (5) In iron-deficient rats intravenously injected ceruloplasmin did not increase iron absorption. (6) The conclusion was drawn that, as for the entrance into the mucosa from the luminal side, also for the release at the contraluminal side into the portal blood, the ferrous state of iron is favoured and that ceruloplasmin accelerates the release into the portal blood by catalyzing the oxidation of ferrous iron due to its high Fe(II): oxygen oxidoreductase (EC 1.16.3.1) activity.