GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

Intraventricular injection of 6-hydroxydopamine results in an increased number of tyrosine hydroxylase immune-positive cells in the rat cortex.

Previously we have demonstrated that intraventricular injection of 6-hydroxydopamine (6-OHDA) results in increased proliferation and de-differentiation of rat cortical astrocytes into progenitor-like cells 4 days after lesion (Wachter et al., 2010). To find out if these cells express tyrosine hydroxylase (TH), the rate-limiting enzyme in the catecholamine synthesis pathway, we performed immunohistochemistry in the rat cortex following intraventricular injection of 6-OHDA. Four days after injection we demonstrated a strong emergence of TH-positive (TH(+)) somata in the cortices of 6-OHDA-lesioned animals. The number of TH(+) cells in the cortex of 6-OHDA-lesioned animals was 15 times higher than in sham-operated animals, where virtually no TH(+) somata occurred. Combining TH immunohistochemistry with classical Nissl stain yielded complete congruency, and ∼45% of the TH(+) cells co-expressed calretinin, which indicates an interneuron affiliation. There was no co-staining of TH with other interneuron markers or with glial markers such as glial fibrillary acidic protein (GFAP) or the neural stem/progenitor marker Nestin, nor could we find co-localization with the proliferation marker Ki67. However, we found a co-localization of TH with glial progenitor cell markers (Sox2 and S100ß) and with polysialylated-neural cell adhesion molecule (PSA-NCAM), which has been shown to be expressed in immature, but not recently generated cortical neurons. Taken together, this study seems to confirm our previous findings with respect to a 6-OHDA-induced expression of neuronal precursor markers in cells of the rat cortex, although the TH(+) cells found in this study are not identical with the potentially de-differentiated astrocytes described recently (Wachter et al., 2010). The detection of cortical cells expressing the catecholaminergic key enzyme TH might indicate a possible compensatory role of these cells in a dopamine-(DA)-depleted system. Future studies are needed to determine whether the TH(+) cells are capable of DA synthesis to confirm this hypothesis.

Characterisation and validation of an enzyme-immunoassay for the non-invasive assessment of faecal glucocorticoid metabolites in cheetahs (Acinonyx jubatus).

The non-invasive measurement of adrenocortical function in cheetahs is an important tool to assess stress in captive and free-ranging individuals, because stress has been suggested to be one of the causes of poor reproductive performance of captive cheetahs. We tested four enzyme immunoassays (EIA) in two captive cheetahs in Germany using adrenocorticotropic hormone (ACTH) challenges and identified the corticosterone-3-CMO EIA to be most sensitive to the increase in faecal glucocorticoid metabolite (fGCM) concentrations after the ACTH challenge. This EIA performed also well in five captive cheetahs in South Africa. The fGCM concentrations across all seven cheetahs increased within 24h by 681% compared to the baseline levels prior to ACTH. Storage of faecal samples at 0-4°C did not strongly affect fGCM concentrations within 24h, simplifying sample collection when immediate storage at -20°C is not feasible. The two cheetahs in Germany also received an injection of [(3)H]cortisol to characterise fGCMs in faecal extracts using high-performance liquid chromatography (HPLC) immunograms. HPLC fractions were measured for their radioactivity and immunoreactive fGCM concentrations with the corticosterone-3-CMO EIA, respectively. The results revealed a polar peak of radiolabelled cortisol metabolites co-eluting with the major peak of immunoreactive fGCMs. Thus, our EIA measured substantial amounts of fGCMs corresponding to the radioactive peaks. The peaks were of higher polarity than native cortisol and corticosterone, suggesting that the metabolites were conjugated, which was confirmed by solvolysis of the HPLC fractions. Our results show that the corticosterone-3-CMO EIA is a reliable tool to assess fGCMs in cheetahs.

Natural History of Innate Host Defense Peptides.

Host defense peptides act on the forefront of innate immunity, thus playing a central role in the survival of animals and plants. Despite vast morphological changes in species through evolutionary history, all animals examined to date share common features in their innate immune defense strategies, hereunder expression of host defense peptides (HDPs). Most studies on HDPs have focused on humans, domestic and laboratory animals. More than a thousand different sequences have been identified, yet data on HDPs in wild-living animals are sparse. The biological functions of HDPs include broad-spectrum antimicrobial activity and immunomodulation. Natural selection and coevolutionary host-pathogen arms race theory suggest that the extent and specificity of the microbial load influences the spectrum and potency of HDPs in different species. Individuals of extant species-that have lived for an extended period in evolutionary history amid populations with intact processes of natural selection-likely possess the most powerful and well-adapted "natural antibiotics". Research on the evolutionary history of the innate defense system and the host in context of the consequences of challenges as well as the efficacy of the innate immune system under natural conditions is therefore of immediate interest. This review focuses on evolutionary aspects of immunophysiology, with emphasis on innate effector molecules. Studies on host defense in wild-living animals may significantly enhance our understanding of inborn immune mechanisms, and help identify molecules that may assist us to cope better with the increasing microbial challenges that likely follow from the continuous amplification of biodiversity levels on Earth.

Female mate-choice drives the evolution of male-biased dispersal in a social mammal.

Dispersal has a significant impact on lifetime reproductive success, and is often more prevalent in one sex than the other. In group-living mammals, dispersal is normally male-biased and in theory this sexual bias could be a response by males to female mate preferences, competition for access to females or resources, or the result of males avoiding inbreeding. There is a lack of studies on social mammals that simultaneously assess these factors and measure the fitness consequences of male dispersal decisions. Here we show that male-biased dispersal in the spotted hyaena (Crocuta crocuta) most probably results from an adaptive response by males to simple female mate-choice rules that have evolved to avoid inbreeding. Microsatellite profiling revealed that females preferred sires that were born into or immigrated into the female's group after the female was born. Furthermore, young females preferred short-tenured sires and older females preferred longer-tenured sires. Males responded to these female mate preferences by initiating their reproductive careers in groups containing the highest number of young females. As a consequence, 11% of males started their reproductive career in their natal group and 89% of males dispersed. Males that started reproduction in groups containing the highest number of young females had a higher long-term reproductive success than males that did not. The female mate-choice rules ensured that females effectively avoided inbreeding without the need to discriminate directly against close kin or males born in their own group, or to favour immigrant males. The extent of male dispersal as a response to such female mate preferences depends on the demographic structure of breeding groups, rather than the genetic relatedness between females and males.

Thermal physiology of the common eelpout (Zoarces viviparus).

We investigated the temperature dependence of some physiological parameters of common eelpout (Zoarces viviparus) from different locations (North Sea, Baltic Sea and Norwegian Sea) on acclimation temperature (3 degrees C and 12 degrees C) and acute temperature variation. The lethal limit of 12 degrees C-acclimated eelpout was determined as the critical thermal maximum [loss of equilibrium (LE) and onset of muscular spasms (OS)] and it was found to be 26.6 degrees C for LE and 28.8 degrees C for OS for all populations. However, these parameters do not have any relevant ecological interpretation. We therefore investigated the effect of gradually increased water temperature on standard metabolic rate (measured as resting oxygen consumption Mo2) and critical oxygen concentration ([O2]c) of eelpouts. Acclimation to low temperature (3 degrees C) resulted in partial compensation of Mo2, paralleled by a decrease of activation energy for Mo2 (from 82 kJ mol(-1) at 12 degrees C to about 50 kJ mol(-1) at 3 degrees C) in North Sea and Baltic Sea eelpouts. At the same time, Norwegian eelpout showed no acclimation of oxygen demand to warm temperature (12 degrees C) at all. The scope for eelpout aerobic metabolism shrank considerably with increased acclimation temperature, as [O2]c approached water oxygen concentrations. At 22.5+/-1 degrees C the [O2]c reached air saturation, which is equivalent to the upper critical temperature (TcII) and at this temperature the aerobic scope for the metabolism completely disappeared. In line with previous insight, the comparative analysis of the temperature dependence of Mo2 of Z. viviparus from different populations suggests that a pejus (sub-critical) temperature for this species is about 13-15 degrees C. In conclusion, the capacity to adjust aerobic metabolism relates to thermal tolerance and the bio-geographical distribution of the species. Global warming would thus be likely to cause a shift in the distribution of this species to the North.

Social, state-dependent and environmental modulation of faecal corticosteroid levels in free-ranging female spotted hyenas.

Little is known about to what extent the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis may be state dependent and vary in the same species between environments. Here we tested whether the faecal corticosteroid concentrations of matrilineal adult female spotted hyenas are influenced by social and reproductive status in adjacent ecosystems and whether they vary between periods with and without social stress. Females in the Serengeti National Park frequently become socially subordinate intruders in other hyena territories by undertaking long-distance foraging trips to migratory herds, whereas in the Ngorongoro Crater they usually forage inside their own small territories on resident prey. The faecal corticosteroid concentrations in Serengeti females were significantly higher than in Ngorongoro females. Energy expenditure by lactation is exceptionally high in spotted hyenas and this may be reflected in their corticosteroid levels. The faecal corticosteroid levels in both populations were higher in lactating than in non-lactating females. During periods of social stability, faecal corticosteroid concentrations increased in non-lactating females but not in lactating females as social status declined. Lactating Serengeti females had significantly higher faecal corticosteroid concentrations during periods with acute severe social stress than during periods without, indicating that the HPA axis is sensitive to social stimuli even in lactating females. So far few studies have used non-invasive monitoring methods for assessing social stress in freeranging animals. This study demonstrates for the first time, to the authors' knowledge, that corticosteroid concentrations may differ between periods with and without social stress for a free-ranging female mammal and that the modulating effect of social status may depend on reproductive status.

Extracranial lower cranial nerve sheath tumors.

OBJECTIVE: The purpose of this article is to review the clinicoradiographic features of lower cranial nerve sheath tumors and to outline surgical approaches that allow the safe and complete resection of these lesions. METHODS: Thirteen patients with lower cranial nerve sheath tumors of the infratemporal fossa were surgically treated between 7/88 and 10/99. A retrospective chart analysis provided details pertaining to clinical manifestations, radiographic assessment, intraoperative findings, tumor histology, and postoperative results. RESULTS: The most common presenting symptoms were neck pressure and voice change while submucosal palatal fullness and vocal cord paralysis were the most common presenting signs. All tumors were removed via lateral skull base approaches and the most common postoperative sequelae was dysphasia. CONCLUSION: Lower cranial nerve sheath tumors of the infratemporal fossa usually reach considerable size before diagnosis because of a naturally slow growth rate in this relatively silent location. The safe surgical removal of these tumors, based on superior control of the internal carotid artery, can be achieved through the use of contemporary lateral skull base techniques.

Preoperative differences between male and female patients with sleep apnea.

OBJECTIVES/HYPOTHESIS: To evaluate the differences between female and male patients with obstructive sleep apnea syndrome (OSAS) in the preoperative period. STUDY DESIGN: Nonrandomized cross-sectional study. METHODS: An analysis of 686 patients (111 women and 575 men) with OSAS was completed. Multivariate modeling techniques were employed to correlate gender with the preoperative respiratory disturbance index (RDI), apnea index (AI), hypopnea index (HI), body mass index (BMI), age, and initial symptoms. RESULTS: At presentation, the male patients were significantly younger and had a lower BMI and a higher RDI and AI than the female patients. For the entire OSAS population studied, the RDI increased as the BMI increased (correlation coefficient [r] = 0.35, P = <.001). For the female patients there was a weaker correlation (r = 0.21, P =.034), and in male patients there was a stronger correlation (r = 0.40, P <.001). For the entire population there was a negative correlation between age and RDI (r = -0.15, P <.001). In female patients there was a nonsignificant correlation (r = -0.09, P =.35), and in male patients the correlation was significant (r = -0.16, P <.001). There was no difference in the reporting of the number of symptoms based on gender (P =.355). Female patients noted headaches on awakening more commonly than male patients (P =.001), and male patients noted snoring (P =.014) and stopping breathing during sleep (P =.001) more often than female patients. CONCLUSIONS: The analysis demonstrated that within a surgical population sample, gender differences exist. The findings of this series were as follows: 1) Apnea severity in women was less weight-dependent than in men; (2) in men there was a significant negative correlation between age and apnea severity; and (3) female and male patients reported the same number of signs or symptoms on presentation, although certain signs and symptoms were more commonly reported based on gender. Current clinical evaluation practices must take into account this gender disparity.

Morphological and metabolic changes in common carp, Cyprinus carpio, during short-term copper exposure: interactions between Cu2+ and plasma cortisol elevation.

The effects of increased endogenous cortisol levels were compared with those of sublethal copper exposure in the freshwater common carp, Cyprinus carpio. Fish were exposed to either increased levels of endogenous cortisol (200 ng/ml) or sublethal copper (1.9 microM) alone or were pretreated by elevating plasma cortisol levels prior to copper exposure to assess whether interactions between both treatments occurred. Effects induced by increased cortisol levels included increased Na+/K(+)-adenosine triphosphate (ATPase) activity and increased plasma Na+ and plasma osmolarity, while copper exposure induced anaerobic metabolism, gill damage, decreasing Na+/K(+)-ATPase activity, decreasing plasma ion levels, and blood thickening. Pretreatment of copper-exposed fish with cortisol partially protected these fish by reducing the copper-induced decrease in Na+/K(+)-ATPase activity. Overall, the results obtained in this study argue against a major role for cortisol as an intermediate for the toxic effects of copper.

Dynamics of (Cd,Zn)-metallothioneins in gills, liver and kidney of common carp Cyprinus carpio during cadmium exposure.

Cadmium concentrations, (Cd,Zn)-metallothionein (MT) concentrations, MT synthesis and the relative amounts of cadmium bound to (Cd,Zn)-MTs were determined in gills, liver and kidney of common carp Cyprinus carpio exposed to 0, 0.5 microM (0.06 mg.l(-1)), 2.5 microM (0.28 mg.l(-1)) and 7 microM (0.79 mg.l(-1)) Cd for up to 29 days. Cadmium accumulation was in the order kidney > liver > gills. Control levels of hepatic (Cd,Zn)-MT were four times higher compared to those of gills and kidney. No increases in (Cd,Zn)-MT concentrations were observed in liver during the exposure period. In comparison with control carp, (Cd,Zn)-MT concentrations increased up to 4.5 times in kidney and two times in gills. In both these organs, (Cd,Zn)-MT concentrations were linearly related with cadmium tissue levels and with the de novo synthesis of MTs. Hepatic cadmium was almost completely bound to (Cd,Zn)-MT, while percentages of non-MT-bound cadmium were at least 40% in gills and 25% in kidney. This corresponded with a total saturation of (Cd,Zn)-MT by cadmium in kidney and a saturation of approximately 50 and 60% in gills and liver, respectively. The final order of non-MT-bound cadmium was kidney > gills > liver. Our results indicate that cadmium exposure causes toxic effects, which cannot be correlated with the accumulated levels of the metal in tissues. Although cadmium clearly leads to the de novo synthesis of MT and higher (Cd,Zn)-MT concentrations, the role of this protein in the detoxification process is clearly organ-specific and its synthesis does not keep track with cadmium accumulation.

Effect of salinity on the swimming velocity of the water flea Daphnia magna.

The swimming velocity of the water flea Daphnia magna is dependent on its body size. Therefore, environmental factors that influence growth also influence swimming velocity. This study examined whether exposure to increased salinity reduces swimming velocity only through its effect on body size or whether it also reduces size-specific swimming velocity. Initially, size-specific swimming velocity decreased in a salinity-dependent way. Thereafter, swimming velocities gradually returned to their expected values in all treatments. This acclimation coincided with considerable mortality in the highest-salinity treatment, indicating that daphnids in this treatment either acclimated or died. The initial decrease in size-specific swimming velocity could not be explained by decreased uptake of food. Thus, the results indicate that salinity temporarily impaired physiology. The experiment illustrates how size effects can be accounted for in swimming-velocity analysis and how size-specific swimming-velocity analysis can be used as a non-invasive method to detect stress-induced deviations from normal physiology.

Water household of the common carp, Cyprinus carpio, when submitted to an osmotic challenge, as determined by diffusion-weighted magnetic resonance imaging at 7 T.

In vivo diffusion-weighted magnetic resonance imaging (MRI) was used to determine the effects of an osmotic challenge (1% NaCl) to a freshwater fish, the common carp (Cyprinus carpio). The imaged region covered organs such as the swimbladder, the liver, the kidney, the intestine, the spinal cord, and muscle tissue. A striking difference between salt-treated and control fish was found in the liver. The apparent diffusion coefficient value of livers from control fish was (0.39 +/- 0.16) 10(-9) m2/s and of salt-treated fish was (1.23 +/- 0.14) 10(-9) m2/s, which points to an increase in extracellular water content. These results were partially confirmed by a decrease in dry/wet weight ratio of the liver tissue. We also found increased levels of stress proteins in liver tissue. The Q factor of the applied radiofrequency coil dropped dramatically when we performed experiments with salt-exposed fish, indicating an increased conductivity resulting from the increased ion concentration and osmolarity of the fish. The data on plasma osmolarity of salt-exposed fish confirm a significant osmolarity increase upon salt exposure (from 334 to 430 mOsm/kg) and exceeded the osmolarity of the salt water (324 mOsm/kg), indicating that carp tend to cope with an increased salinity by increasing the internal osmolarity (hyperosmotic regulation). These data demonstrate that diffusion-weighted MRI might be a useful and noninvasive tool in the study of osmotic challenges of aquatic organisms.

The anaerobic endproduct lactate has a behavioural and metabolic signalling function in the shore crab

This study presents the first evidence that, in invertebrates, the anaerobic endproduct lactate has an alarm signal function and induces metabolic and behavioural responses as in the anuran Bufo marinus. In support of this function, behavioural hypothermia was demonstrated in the shore crab Carcinus maenas. The animals moved to a cooler environment when exposed to hypoxic conditions. A decrease in preferred temperature of the same magnitude was also found when normoxic animals were injected with an iso-osmotic lactate solution resulting in a haemolymph concentration of approximately 12 mmol l-1. Under normoxic (PO2=>18 kPa) and moderately hypoxic conditions (PO2=12 kPa), injection of this lactate solution also caused a significant increase in the rate of oxygen consumption (100 and 50 % respectively). The increase in the rate of oxygen consumption was smaller and delayed, but lasted longer, under hypoxic conditions compared with normoxic conditions. Low but significant correlations between levels of lactate and levels of adrenaline, octopamine and tryptophan suggest the involvement of biogenic amines in the mediation of the signal.

Combination of 5-fluorouracil, adriamycin, ifosfamide and cisplatin in metastatic adult soft tissue sarcoma: results of a phase II study.

Treatment results of advanced soft tissue sarcomas are still suboptimal. To evaluate the clinical effects of a combination therapy (FADIP) with Adriamycin (ADM), ifosfamide (IFO), cisplatin (DDP) plus continuous infusion of 5-fluorouracil (FU) as a synergistic factor for alkylating agents, a phase II study was initiated in patients with advanced soft tissue sarcomas of different histological subtypes. Fifty-six previously untreated patients with advanced soft tissue sarcomas of different histological subtypes (24 females, 31 males, median age 51.3 years, median Karnofsky performance status 80%) were included in this study. Treatment consisted of ADM 50 mg/m2 i.v. on day 1, IFO 4,000 mg/m2 i.v. on day 1, mesna 800 mg/m2 i.v. 3 x with 8-hour intervals on day 1 starting with IFO administration, FU 500 mg/m2 i.v. as 24-hour infusion on days 1 + 2, DDP 100 mg/m2 i.v. on day 2. This regimen was repeated every 4 weeks for at least 2 cycles. Major WHO grade III/IV hematological toxicity was observed in 35/56 patients. One toxic death due to severe neutropenia and fungal pneumonia occurred. Granulocyte colony-stimulating factor was administered in 8/35 neutropenic patients. Time to recovery was significantly reduced and no infectious complication was observed. WHO grade III/IV toxic diarrhea was observed in 8 patients requiring intravenous fluid replacement. WHO grade III/IV nausea occurred in 11 patients, 9/11 responded to symptomatic treatment with ondansetron alone. The overall response rate was 30.3%. The median duration of response (complete/partial response, CR/PR) was 18.1 months, the median progression-free interval was 4.5 months. The median survival time of all patients was 11.8 months, and 18.1 months in responding patients (CR/PR). Tumor-related pain was effectively reduced in 15/31 patients under treatment. FADIP produces comparable response rates to other standard treatment regimens in soft tissue sarcomas. Prolonged duration of response and median survival may be due to the use of continuous infusion of FU as a synergistic factor to alkylating agents. Granulocyte colony-stimulating factor is effective in reducing the otherwise observed high rate of WHO grade III/IV hematological toxicity with severe neutropenia.

Haemolymph flow distribution, cardiac performance and ventilation during moderate walking activity in Cancer magister (Dana) (Decapoda, Crustacea)

Adult male Cancer magister (Dana) were equipped with pulsed-Doppler flowmeters and pressure transducers for simultaneous measurement of heart and ventilation frequencies, haemolymph flow through each of the major arterial systems and cardiac output and for calculation of stroke volume. Each variable was measured at rest and during two consecutive periods of moderate treadmill walking activity and recovery. During activity, haemolymph flow through the sternal and anterolateral arteries increased, while flow through the hepatic arterial system decreased. This resulted in a redistribution of haemolymph flow in which a proportion of cardiac output was shifted from the anterior, posterior and hepatic arterial systems to the sternal arterial system. The relative proportion of the cardiac output flowing through the anterolateral artery remained constant. This indicated that oxygen supply was shifted away from the digestive system to the muscles of the walking legs and the respiratory system. Cardiac output, heart rate and stroke volume all increased in response to activity. The increase in cardiac output is the result of a large increase in stroke volume and a small increase in heart rate. A doubling of ventilation rate also occurred during activity. Both the circulatory and ventilatory systems were restored to pre-activity values by 60 min of recovery.

Comparison of Temperature Effects on Heart Performance of the Dungeness Crab, Cancer magister, in vitro and in vivo.

A large percentage of physiological studies are based on isolated components of complex systems, but the question can always be posed, are the responses the same in isolation as when these components are under the homeostatic controls that exist in vivo? For cardiac performance in Cancer magister, the responses to temperature variation over the range 4° to 20°C are different in semi-isolated hearts than in intact animals. Cardiac performance in semi-isolated hearts was measured with a pressure transducer, a flow transducer, and electromyogram (EMG) electrodes, and in intact animals with pulsed Doppler flow probes. Heart rate increase in semi-isolated hearts was about one-third of that in intact animals. The cardiac output of semi-isolated hearts decreased with increasing temperature, whereas that of intact animals increased. Stroke volume decreased linearly in semi-isolated hearts. In intact animals, stroke volume decreased from 4° to 12°C, but remained relatively stable from 12° to 20°C. The ventricular pressure and the EMG amplitude of semi-isolated hearts both decreased with increasing temperature. Double systolic contractions appeared both in semi-isolated hearts and in intact animals in the temperature range 13° to 20°C; this may represent a compensatory mechanism at extreme temperatures. The difference in cardiac performance between intact crabs and semi-isolated hearts reflects, almost certainly, extrinsic control in intact animals, including modulation by cardioregulatory nerves or neurohormonal modulation of the cardiac ganglion, myocardial contractility or changes in outflow resistance.

Second-line treatment with high-dose 5-fluorouracil and folinic acid in advanced colorectal cancer refractory to standard-dose 5-fluorouracil treatment.

Results with second-line treatment of advanced colorectal cancer are poor. Preliminary phase I/II results suggest encouraging response rates to high-dose 5-fluorouracil (FU) (2,600 mg/m2) combined with folinic acid (FA) in pretreated patients with advanced colorectal cancer. To determine the significance of weekly high-dose FU/FA in colorectal cancer refractory to weekly standard doses of FU/FA, a phase II study was initiated. 69 patients with metastatic colorectal cancer refractory to first-line weekly standard-dose FU/FA were treated with weekly high-dose FU 2,600 mg/m2 combined with FA 500 mg/m2 as a 2-hour infusion prior to FU application. Pretreatment was highly homogenous and consisted of weekly FU 500 mg/m2 combined with FA 500 mg/m2 or FA 20 mg/m2 or the pure stereoisomer of FA (6S-FA) 250 mg/m2. At the time of disease progression under first-line therapy, patients were transferred to high-dose FU/FA within 4 weeks. Treatment was continued until tumor progression under therapy was documented. Of the 69 evaluable patients, 17 (24.6%) achieved partial response (PR), 42 (60.9%) had no change (NC) and 10 (14.5%) had progressive disease under therapy. The median duration of PR was 7 months, the median time to progression of NC was 4 months. Median survival of all patients was 9 months, of patients with PR, 11.5 months. 33/38 patients with tumor-related pain experienced impressive relief under therapy. Prognostic factors for a beneficial outcome were complete response/PR under first-line therapy, a small number of metastatic sites and a good Karnofsky performance status. Moderate toxicity was observed, and the pattern of toxic events and severity did not differ from standard-dose FU regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination 5-fluorouracil (FU), folinic acid (FA), and alpha-interferon 2B in advanced gastric cancer: results of a phase II trial.

BACKGROUND: Based on encouraging treatment results with FU/FA or FU/IFN in gastrointestinal tract cancer, a phase II study was conducted to evaluate the effects and toxicity of combination FU/FA/IFN in patients (pts) with inoperable/metastatic gastric cancer. PATIENTS AND METHODS: IFN 6 M.U. s.c. 1 x/week, FU 500 mg/m2 bolus i.v. 1 x/week and FA 500 mg/m2 1 x/week as a 2-hour infusion. Of 72 treated pts, 72 (22 females, 50 males) are evaluable for response and toxicity. Median age was 55.6 years (28-80), and median Karnofsky performance status was 80% (70-100). Sites of measurable disease were inoperable primary tumors/local recurrence (18), liver metastasis (22), lymph nodes (31) and peritoneum (20). One pt had bone marrow metastasis and another had paraneoplastic hyperfibrinolytic coagulopathy. RESULTS: 10/72 pts had complete response, 20/72 pts partial response, 40/72 pts tumor stabilization and 2/72 pts progressive disease. The median duration of response (CR/PR) was 9 months, the median progression-free interval 6 months, the median survival time was 9 months, and for responding patients (CR/PR) 12.5 months. TOXICITY: 1/72 pts had WHO grade 4 toxicity (diarrhea), 5/72 pts had WHO grade 3 toxicity (nausea 1, diarrhea 4). Except for 1 treatment-limiting grade 4 toxicity, no modifications of dose or schedule due to toxicity were required. Thirty-six of 44 pts experienced a significant reduction in tumor-related pain under treatment. CONCLUSION: Biochemical modulation of FU with FA and IFN is effective in advanced gastric cancer. Moderate toxicity, outpatient treatment setting and high rates of amelioration tumor-related pain contribute to an effective palliation.