Clonal evolution in diffuse large B-cell lymphoma with central nervous system recurrence.

BACKGROUND: The prognosis of patients with secondary central nervous system lymphoma (SCNSL) is poor and despite massive advances in understanding the mutational landscape of primary diffuse large B-cell lymphoma (DLBCL), the genetic comparison to SCNSL is still lacking. We therefore collected paired samples from six patients with DLBCL with available biopsies from a lymph node (LN) at primary diagnosis and the central nervous system (CNS) at recurrence. PATIENTS AND METHODS: A targeted, massively parallel sequencing approach was used to analyze 216 genes recurrently mutated in DLBCL. Healthy tissue from each patient was also sequenced in order to exclude germline mutations. The results of the primary biopsies were compared with those of the CNS recurrences to depict the genetic background of SCNSL and evaluate clonal evolution. RESULTS: Sequencing was successful in five patients, all of whom had at least one discordant mutation that was not detected in one of their samples. Four patients had mutations that were found in the CNS but not in the primary LN. Discordant mutations were found in genes known to be important in lymphoma biology such as MYC, CARD11, EP300 and CCND3. Two patients had a Jaccard similarity coefficient below 0.5 indicating substantial genetic differences between the primary LN and the CNS recurrence. CONCLUSIONS: This analysis gives an insight into the genetic landscape of SCNSL and confirms the results of our previous study on patients with systemic recurrence of DLBCL with evidence of substantial clonal diversification at relapse in some patients, which might be one of the mechanisms of treatment resistance.

Correction: The influence of FCGR2A and FCGR3A polymorphisms on the survival of patients with recurrent or metastatic squamous cell head and neck cancer treated with cetuximab.

In the abstract and in other parts of the manuscript the authors wrote that the mutation rs396991 causes a valine (V) to phenylalanine (F) substitution at position 157. However, the correct codon number is 158. These errors have not been fixed in the original Article.

Retroperitoneal Liposarcoma: A Concern in Inguinal Hernia Repair.

BACKGROUND AND OBJECTIVES: The goal of the study was to evaluate retroperitoneal sarcomas with continuous growth into the scrotum through the inguinal canal with regard to diagnostic approach, surgical treatment, and outcome. The analysis is based on a comprehensively documented case and a complete systematic review of published literature. Potential pitfalls are highlighted. METHODS: We describe the case of a 57-year-old male Caucasian who presented with a swelling in the right groin. Suspecting a scrotal hernia, transabdominal preperitoneal plasty surgery was planned but intraoperatively a large retroperitoneal mass was revealed. After computed tomography scan and magnetic resonance imaging, a complete resection of the tumor was performed. Ten previously published cases describing the same pathology were retrieved from the PubMed database and analyzed systematically in a complete literature review. RESULTS: Histology showed a well-differentiated liposarcoma with tumor-free resection margins. Twenty-two months postoperatively, the patient is in complete clinical remission. CONCLUSION: Preoperative clinical suspicion of retroperitoneal involvement is paramount for developing of a surgical strategy and in unclear cases demands extended preoperative diagnostic workup. Following the appropriate patient management is crucial to prognosis.

The influence of FCGR2A and FCGR3A polymorphisms on the survival of patients with recurrent or metastatic squamous cell head and neck cancer treated with cetuximab.

FCGR2A-H131R and FCGR3A-V157F are single-nucleotide polymorphisms known to influence the outcome of patients treated with rituximab, cetuximab and trastuzumab. We investigated the impact of these polymorphisms on the clinical outcome of 103 patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with a platinum compound, fluorouracil and cetuximab as palliative first-line therapy. The survival of patients with FCGR2A-131H/H and/or FCGR3A-157V/V genotypes was significantly longer compared with patients carrying 131R and 157F alleles (median progression-free survival (PFS): 5.5 vs 4.1 months, P=0.02; median overall survival: 10.2 vs 7.2 months, P=0.04). In multivariate analysis, the FCGR2A and 3A genotypes as well as the time between initial diagnosis and relapse of disease not amenable to curative therapy remained the only independent prognostic factors for PFS. The results are in line with previous reports in colorectal cancer patients and confirm the possible value of genetic polymorphisms of immunocompetent cells for the success of cetuximab treatment.

One-year prevalence and socio-cultural aspects of chronic headache in Turkish immigrants and German natives.

The aim of this research was to study the prevalence of chronic headache (CH) and associated socio-cultural factors in Turkish immigrants and native Germans. Five hundred and twenty-three Turkish and German company employees were screened using a standard questionnaire. Those who suffered from headaches were also examined by a neurologist. Complete data were available for 471 (90%) subjects. Thirty-four participants (7.2%) had CH. Two independent factors for association with CH could be identified: overuse of acute headache medication (OR = 72.5; 95% CI 25.9-202.9), and being a first-generation Turkish immigrant compared with native Germans (OR = 4.4; 95% CI 1.4-13.7). In contrast, the factor associated with chronic headache was not increased in second-generation Turkish immigrants. Medication overuse was significantly more frequent in first-generation Turkish immigrants (21.6%) compared with second-generation Turkish immigrants (3.3%) and native Germans (3.6%; chi(2) = 38.0, P < 0.001). First-generation Turkish immigrants did not contact headache specialists at all, compared with 2.8% of second-generation Turkish immigrants and 8.8% of native Germans (chi(2) = 118.4, P < 0.001). Likewise no first-generation Turkish immigrant suffering from CH received headache preventive treatment, compared with 6.6% of native Germans (chi(2) = 19.1, P = 0.014). The data from this cross-sectional study reveal a high prevalence of chronic headache as well as a very low utilization of adequate medical care in first-generation Turkish immigrants in Germany.

A functional-structural model to understand cardiac autonomic nervous system (ANS) dysregulation in affective illness and to elucidate the ANS effects of antidepressive treatment.

Numerous studies provide evidence that major depression (MD) is associated with certain disorders of cardiac autonomic nervous system (ANS) function, in particular, with an autonomic neurocardiac imbalance characterized by a low cardiovagal modulation, a raised sympathetic nerve activity and a high resting heart rate. We assume that such MD-associated cardiac ANS disorders are mainly caused by functional-structural abnormalities within the central autonomic network (CAN), in particular, by well-defined abnormalities of hypothalamic structures in MD. In view of the well-known association between an autonomic neurocardiac imbalance and the risk for cardiac arrhythmias, we assume that MD-associated cardiac ANS disorders are at least partly responsible for the high cardiovascular mortality risk in MD. It is, however, still unclear whether antidepressive treatment will lower the risk for cardiovascular complications in MD. There is convincing evidence that a successful antidepressive treatment with electroconvulsive therapy, cognitive behavioral therapy, or pharmacotherapy with primarily non-antimuscarinergic antidepressants can improve an initially disturbed cardiac ANS function in MD. These studies correspond well to our findings that treatment with both, nefazodone or reboxetine, can induce a reduction of central sympathetic nerve activity and an increase of the initially lowered cardiovagal modulation depending on the improvement of depressive symptoms after treatment. Since both effects occured obviously independent from the primarily serotonergic or noradrenergic action of the antidepressants, our findings suggest the existence of a generally supraordinate and uniform mechanism underlying the ANS effects of antidepressive treatment with drugs inhibiting serotonin- or noradrenaline reuptake.

[Does acupuncture influence the cardiac autonomic nervous system in patients with minor depression or anxiety disorders?]. / Beeinflusst Akupunktur die autonom kardiale Regulation bei Patienten mit leichten depressiven Episoden oder Angststörungen? Eine randomisierte, plazebokontrollierte Verlaufsstudie.

We undertook this study to evaluate the effects of needle acupuncture on cardiac autonomic nervous system (ANS) function in patients with minor depression or anxiety disorder. Patients (n = 36) were randomly distributed into a verum acupuncture (VA) group (needles were applied at classical acupuncture points, e. g. He7, Pe6, Du20, Bl62, Ex6) or a placebo (PL) group (needles were applied only epidermal at non-acupuncture points). Both groups underwent standardized measurements of the 5-minute resting heart rate variability (HRV), which were performed before the first and after the 9th acupuncture session of an acupuncture series, and also three times (before the start and 5, respectively, 15 minutes after needle application) during the third acupuncture session. Demographic data between the VA and PL group did not differ. Before the start of acupuncture there were also no significant differences in HRV data between these groups. Compared to PL the VA group showed a significant decrease of the mean resting heart rate both, 5 and 15 minutes after needle application, combined with a trend towards an increase of the high frequency (HF; 0.15 - 0.4 Hz) and a decrease of the low frequency (LF; 0.04 - 0.15 Hz) spectral power. The latter effects resulted in an overall significant decrease of the mean LF/HF ratio in VA compared to PL treated patients. This pattern of findings suggests that in patients with minor depression or anxiety only verum acupuncture 1.) leads to a relative increase of cardiovagal modulation of heart rate and 2.) facilitates the physiological regulatory ANS function in response to alterations of external or internal environment. Clinical implications of these findings are discussed.

Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine.

As part of a prospective clinical study investigating the effects of atypical neuroleptics on autonomic neurocardiac function (ANF), serial standardized recordings of conventional electrocardiograms and computer-calculated measurements of 5-minute resting heart rate variability (HRV) were obtained from 51 medication-free inpatients with schizophrenia (DSM-III-R-diagnosed) before and after an average of 14.1 days of treatment with amisulpride 400 mg/day (N = 12), olanzapine 20 mg/day (N = 13), sertindole 12 mg/day (N = 13), or clozapine 100 mg/day (N = 13). Reference values for the HRV data were obtained from a large group of well-matched healthy controls (N = 70). The most important findings were the following: (1) clozapine, olanzapine, and sertindole all prolonged mean frequency-corrected QTc times, which, in the case of sertindole, proved to be significant (Wilcoxon test p <0.05); (2) sertindole and clozapine significantly increased the mean resting heart rate; and (3) only clozapine significantly reduced the parasympathetic resting tone. The results of the HRV studies are discussed considering the in vitro receptor profiles of the atypical neuroleptics under study. Potential implications for the cardiac safety and tolerance of these drugs are also discussed.

Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone.

BACKGROUND: Major depression (MD) is associated with an augmented risk of cardiovascular mortality. One possible explanation for this association is that MD influences autonomic neurocardiac regulation (ANR). However, previous studies on this subject revealed conflicting results. METHODS: Using an autonomic test battery, which consisted of standardised measurements of heart rate variability (HRV) and blood pressure, we (1) compared ANR between 25 patients with DSM-III-R diagnosed MD and 60 healthy controls, and (2) investigated the autonomic effects of antidepressive treatment with nefazodone. RESULTS: Following multivariate analysis of all tests a significant reduction in HRV could only be shown for the Valsalva ratio amongst the depressives compared to controls. There was a significant inverse correlation between the HRV during deep respiration and both the severity of depression and the duration of the depressive episode. Serial HRV recordings revealed that both the mean resting heart rate and systolic blood pressure significantly decreased after 21 days of nefazodone treatment (average dosage 413 mg/day), whereas after 10 days (average dosage 270.8 mg/day) there were no striking changes compared to the pre-treatment values. During nefazodone treatment no significant changes in parasympathetic tone occurred. LIMITATIONS: ANR was not assessed in a randomised, placebo-controlled fashion. CONCLUSIONS: (1) Patients with MD may suffer from functional disturbances in the interaction between the sympathetic and parasympathetic autonomic tree. (2) The pattern of autonomic changes during treatment suggests that nefazodone induced a dose dependent, serotonergically-mediated down-regulation of the sympathetic tone. This mechanism might be responsible for nefazodone's properties of reducing anxiety.

[Acupuncture in patients with minor depressive episodes and generalized anxiety. Results of an experimental study]. / Akupunktur bei leichten bis mittelschweren depressiven Episoden und Angststörungen. Ergebnisse einer experimentellen Untersuchung.

In a placebo-controlled, randomized, modified double-blind study we investigated the effects of body needle acupuncture (n = 10) in 43 patients with minor depression (ICD 10 F32.0, F32.1) and 13 patients with generalized anxiety disorders (ICD10 F41.1). The severity of the disease was assessed by the Clinical Global Impression Scale (CGI). Treatment response was defined as a significant improvement in CGI. An intent-to-treat analysis was performed to compare treatment responses between verum- and placebo acupuncture. After completing an total of 10 acupuncture sessions the verum acupuncture group (n = 28) showed a significantly larger clinical improvement compared to the placebo group (Mann-Whitney test, p < 0.05). There were significantly more responders in the verum-compared to the placebo group (60.7% vs. 21.4%; chi-square test, p < 0.01). In contrast, no differences in the response rates were evident just after 5 acupuncture sessions. A multivariate analysis with the independent factor acupuncture (verum vs. placebo) and the results of the results of the additional rating scales (total score of HAMA, HAMD, Bf-S, BL) as dependent variables (ANOVA, 1:54 D.F.) revealed a clear trend towards lower HAMA scores in the verum group after completing 10 acupunctures (F3.29, p = 0.075). This corresponds well to the high response rate of 85.7% in patients with generalized anxiety disorders, in whom verum acupuncture was applied. Our results indicate that needle acupuncture (Du.20, Ex.6, He.7, Pe.6, Bl.62) leads to a significant clinical improvement as well as to a remarkable reduction in anxiety symptoms in patients with minor depression or with generalized anxiety disorders. The total sum of acupuncture sessions and the specific location of acupuncture needle insertions might be important factors for bringing about therapeutic success.

Cardiovascular autonomic reactivity in schizophrenics under neuroleptic treatment: A potential predictor of short-term outcome?

In schizophrenics cardiovascular autonomic reactivity (CAR) can be used as an indicator of autonomic arousal. Using a standardized autonomic test battery (modified according to Ewing and Clarke) we prospectively compared the CAR between 46 actually ill schizophrenics (diagnosis according to DSM-III-R) treated with either haloperidol (n = 26) or clozapine (n = 20) and 30 well-matched healthy volunteers. Multivariate analysis demonstrated a significant effect of neuroleptic medication (haloperidol vs. clozapine) on heart rate and diastolic blood pressure under resting conditions as well as on the heart rate variance (30:15 ratio, deep-breathing, Valsalva) and blood pressure tests (sustained handgrip, Schellong). In addition a positive treatment response (using predefined outcome criteria of the Brief Psychiatric Rating Scale) was independently associated with lower resting heart rates and less impaired 30:15 ratios under neuroleptic medication. Our data indicate that clozapine treatment was associated with a substantial impairment of CAR, which can be explained by the drug's anticholinergic properties in combination with an increase in norepinephrine outflow. The greater heart rate variability in responders might be due to an early neuroleptic-induced decrease of sympathetic activity in the autonomic nervous system, which may precede clinical improvement. Our findings are discussed in relation to neuroleptic-induced changes in plasma catecholamine levels suggested to be useful biological markers in predicting treatment outcome.

Sensitivity of carbohydrate-deficient transferrin (CDT) in relation to age and duration of abstinence.

Carbohydrate-deficient transferrin (CDT) serum concentrations were prospectively determined in 162 subjects (alcoholics n=62, controls n=100) using three different methods of detection (IEF, CDTect, Axis%CDT). Repeated testing in alcoholics after 3 and 5 days of abstinence demonstrated a significantly higher sensitivity of CDT in patients above 40 years of age compared to younger patients.

Improved autonomic neurocardial balance in short-term abstinent alcoholics treated with acamprosate.

Standardized investigations on resting heart rate variability (HRV) should provide more information on acamprosate's human pharmacodynamic properties because acamprosate interacts with several neurotransmitter systems which are also involved in maintaining autonomic neurocardiac balance. We performed HRV measurements prospectively in 69 healthy controls and 19 chronic alcoholics to prove the hypotheses that: (1) compared to healthy controls, chronic alcoholics show disturbances in neurocardiac vagal function; and (2) in alcoholics, acamprosate treatment (6-8 days) should further decrease parasympathetic activity if acamprosate interacts with central gamma-aminobutyric acidA receptors in vivo. Cardiovagal dysfunction was initially present in 21% of the alcoholics. After treatment. however, their neurocardiac sympathetic-parasympathetic balance improved significantly.

Alcoholism, peripheral neuropathy (PNP) and cardiovascular autonomic neuropathy (CAN).

In contrast to diabetic autonomic neuropathy, cardiovascular autonomic neuropathy (CAN) in long-term alcoholics has been studied rarely. Using both standardized bedside tests and computer-assisted analysis of heart rate variability (HRV), we prospectively compared autonomic neurocardial function between 35 strictly selected, detoxified alcoholics (DSM-III-R), and 80 well matched healthy controls. Evidence for a potential CAN was found in 25.7% of all the alcoholics studied and in 41% of those with clinically manifest PNP (n=22). Overall, our results demonstrated a significant association between the presence of a CAN and peripheral neuropathy (PNP) amongst chronic alcoholics (chi-square test P<0.05); there was no evidence of a CAN in any of the alcoholics without a clinically manifest PNP. The CAN was characterized by a dissociated appearance of parasympathetic and sympathetic disorders. Our findings provide reason to suspect that the total lifetime dose of alcohol and the duration of alcohol dependence are the most important factors contributing to the pathogenesis of both PNP and sympathetic dysfunction. As is the case with diabetics, computer-assisted measurements of HRV including spectral analysis appear to be far superior to conventional bedside tests for detecting evidence of cardiovagal dysfunction in long-term alcoholics.

Side effects of low dose neuroleptics and their impact on clinical outcome in generalized anxiety disorder.

1. The present study was designed to determine the impact of neuroleptic side effects on clinical outcome in generalized anxiety disorder. 2. 205 outpatients entered the study. In an open label design fluspirilene 1.5 mg per week was administered for a period of 6 weeks. 3. Consistent with previous studies fluspirilene demonstrated again anxiolytic properties and was in general tolerated well. 4. However, in responders significantly less side effects were observed than in nonresponders. The interaction between tolerability and clinical outcome is the main finding of the present study. 5. In conclusion, the data suggest, that neuroleptic treatment of generalized anxiety disorder should be guided by paying more attention to potential side effects. If under neuroleptic treatment of generalized anxiety disorders side effects are observed, pharmacotherapy should be discontinued, because this fact predicts an unfavourable clinical outcome.

Drug monitoring studies as a method of analyzing response criteria.

Two multicenter drug monitoring studies are presented. Some methodological problems are dealt with and the validity of such studies is discussed in terms of differential indication. In a first study (Lehmann et al., 1993) the results of a 12-week xanthinol niacinate treatment (500 to 3000 mg daily) in a cohort of 10,134 outpatients suffering from cerebrovascular insufficiencies were recorded systematically by nonreactive evaluation methods. The therapy was found to be most successful in patients with the target symptoms vertigo, tiredness, lack of concentration, affective disorder, and disturbances of vigilance and vitality. The most frequent side-effects were flush or heat sensations in 9.1% of the patients and gastrointestinal complaints in 3.3%. In a second study (Klieser et al., 1994) we systematically collected data from 219 patients with Major Depressive Disorder during five weeks of treatment with fluoxetine (20 mg daily). The results showed that depressively inhibited, anxious patients with a depression of minor severity, who showed a relatively marked improvement within the first week of treatment, profited the most from this therapy. The first study was designed to use nonreactive evaluation methods. Correlation analyses helped to identify the types of patient with a good response to treatment. The second study was organized on the model of conventional controlled pharmacological studies with the application of commonly used scales. The differential indication was to be inferred from the uni- and multivariate comparison of responders and nonresponders. In the light of these two studies, the problems of target definition, sample design, target variables, practicability, statistical analysis, and validity are discussed.