bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of vasopressin secretion when dehydrated rats drink water
Authors: Stricker Edward M. , Hoffmann Myriam L.
Published: July 2005

The present study determined whether vasopressin (VP) secretion is inhibited by an oropharyngeal signal associated with swallowing fluids when dehydrated rats drink water, as it is when dehydrated dogs are used as experimental subjects (Thrasher, TN, Keil LC, and Ramsay DJ. Am J Physiol Regul Integr Comp Physiol 253: R509–R515, 1987). VP levels in systemic plasma (pVP) fell rapidly when rats drank water after overnight water deprivation. Systemic plasma Na+ concentration (pNa) also fell, but that change likely contributed little to the early inhibition of VP secretion. In contrast, consumption of water by dehydrated rats with an open gastric fistula had no effect on pVP, nor did consumption of isotonic saline by dehydrated rats; in neither case was pNa affected by fluid consumption. These findings provide no evidence that the act of drinking inhibits VP secretion in dehydrated rats. Thus some postgastric effect of the ingested water seems to be responsible for the inhibitory signal. These results are consistent with previous suggestions that an early inhibitory stimulus for VP secretion in rats is provided by postgastric visceral osmo- or Na+ receptors that sense the composition of the ingested fluid.
Role of Ca2+/calmodulin-dependent kinases in skeletal muscle plasticity
Authors: Chin Eva R.
Published: July 2005

In skeletal muscle, the increase in intracellular Ca2+resulting from motor activation plays a key role in both contractile activity-dependent and fiber type-specific gene expression. These motor activation-dependent signals are linked to the amplitude and duration of the Ca2+transients that are decoded downstream by Ca2+-dependent transcriptional pathways. Evidence is mounting that the Ca2+/calmodulin-dependent kinases (CaMKs) such as CaMKII play an important role in regulating oxidative enzyme expression, mitochondrial biogenesis, and expression of fiber type-specific myofibrillar proteins. CaMKIV has been shown to promote mitochondrial biogenesis and a mild fast-to-slow fiber type transition but has recently been shown to not be required for activity-dependent changes in muscle phenotype. CaMKII is known to decode frequency-dependent information and is activated during hypertrophic growth and endurance adaptations and also is upregulated during muscle atrophy. CaMKII has also been shown to remain active in a Ca2+-independent manner after acute and prolonged exercise, and, therefore, is implicated as a mechanism for muscle memory. This mechanism can sense altered functional demands and trigger activation of an adaptational response that is dose dependently related to the activation level. This class of enzymes may therefore be the ideal decoders of information encoded by the intensity, frequency, and duty cycle of muscle activation and thus translate level of muscle activation into phenotypic adaptations through regulation of important muscle genes.
Fat as an endocrine organ: influence of exercise
Authors: Berggren Jason R. , Hulver Matthew W. , Houmard Joseph A.
Published: July 2005

The prevalence of diabetes and obesity continues to increase. It is therefore important to identify the pathophysiology underlying these disorders. An inability of insulin to stimulate glucose uptake, i.e., insulin resistance, appears to be a common link between diabetes and obesity. The identification of various adipocyte-secreted cytokines (adipocytokines) that influence satiety, energy balance, and insulin sensitivity provide a novel target for the treatment of these disorders. Adipocytokines are differentially expressed with obesity and diabetes, making them a strong candidate for linking insulin resistance to these pathological conditions. This review explores the role of adipocytokines in insulin action and examines the effect of exercise training on adipocytokine content.
The physiological challenges of the 1952 Copenhagen poliomyelitis epidemic and a renaissance in clinical respiratory physiology
Authors: West John B.
Published: July 2005

The 1952 Copenhagen poliomyelitis epidemic provided extraordinary challenges in applied physiology. Over 300 patients developed respiratory paralysis within a few weeks, and the ventilator facilities at the infectious disease hospital were completely overwhelmed. The heroic solution was to call upon 200 medical students to provide round-the-clock manual ventilation using a rubber bag attached to a tracheostomy tube. Some patients were ventilated in this way for several weeks. A second challenge was to understand the gas exchange and acid-base status of these patients. At the onset of the epidemic, the only measurement routinely available in the hospital was the carbon dioxide concentration in the blood, and the high values were initially misinterpreted as a mysterious “alkalosis.” However, pH measurements were quickly instituted, the Pco2was shown to be high, and modern clinical respiratory acid-base physiology was born. Taking a broader view, the problems highlighted by the epidemic underscored the gap between recent advances made by physiologists and their application to the clinical environment. However, the 1950s ushered in a renaissance in clinical respiratory physiology. In 1950 the coverage of respiratory physiology in textbooks was often woefully inadequate, but the decade saw major advances in topics such as mechanics and gas exchange. An important development was the translation of the new knowledge from departments of physiology to the clinical setting. In many respects, this period was therefore the beginning of modern clinical respiratory physiology.
Sleep Restriction Suppresses Neurogenesis Induced by Hippocampus-Dependent Learning
Authors: Hairston Ilana S. , Little Milton T. M. , Scanlon Michael D. , Barakat Monique T. , Palmer Theo D. , Sapolsky Robert M. , Heller H. Craig
Published: July 2005

Sleep deprivation impairs hippocampal-dependent learning, which, in turn, is associated with increased survival of newborn cells in the hippocampus. We tested whether the deleterious effects of sleep restriction on hippocampus-dependent memory were associated with reduced cell survival in the hippocampus. We show that sleep restriction impaired hippocampus-dependent learning and abolished learning-induced neurogenesis. Animals were trained in a water maze on either a spatial learning (hippocampus-dependent) task or a nonspatial (hippocampus-independent) task for 4 days. Sleep-restricted animals were kept awake for one-half of their rest phase on each of the training days. Consistent with previous reports, animals trained on the hippocampus-dependent task expressed increased survival of newborn cells in comparison with animals trained on the hippocampus-independent task. This increase was abolished by sleep restriction that caused overall reduced cell survival in all animals. Sleep restriction also selectively impaired spatial learning while performance in the nonspatial task was, surprisingly, improved. Further analysis showed that in both training groups fully rested animals applied a spatial strategy irrespective of task requirements; this strategy interfered with performance in the nonspatial task. Conversely, in sleep-restricted animals, this preferred spatial strategy was eliminated, favoring the use of nonspatial information, and hence improving performance in the nonspatial task. These findings suggest that sleep loss altered behavioral strategies to those that do not depend on the hippocampus, concomitantly reversing the neurogenic effects of hippocampus-dependent learning.
Cortical Representations of Temporal Structure in Sound
Authors: Hall Deborah A. , Barrett Doug J. K. , Akeroyd Michael A. , Summerfield A. Quentin
Published: July 2005

Pitch and spatial width are two sound attributes that can be coded by temporal acoustic structure. In this study, periodicity pitch was created by temporal iteration in a regular-interval noise, whereas spatial width was determined by the degree of interaural correlation. Previous results suggest that nonprimary auditory cortex, particularly lateral Heschl's gyrus (HG), plays an important role in the analysis of both acoustic properties. It has been argued that this role might reflect a common computational process. One proposed candidate is that of integrating the temporal pattern information across frequency channels. This paper reports the results of a systematic test for whether different classes of temporal structure do indeed engage a common neural architecture in the human auditory cortex by presenting both classes of sound stimuli to a single group of listeners. Activations related to the pitch and spatial width of the sound were partly co-localized in two distinct cortical regions: close to lateral HG and in planum temporale (PT). Lateral HG was more responsive to temporal pitch than to spatial width. This difference plus the variability across listeners for spatial width dispute the claim that the activity in lateral HG reflects a common neural computational step that encodes the temporal patterns associated with pitch and spatial width. Rather, the activity patterns are consistent with a role for lateral HG in perceptual analysis as opposed to temporal acoustic structure. In PT, the superadditive relationship between pitch and spatial width is also consistent with the concept that the auditory cortex plays an important role in integrating different classes of sound information to form auditory objects.
Spinal Source for the Synchronous Fluctuations of Bilateral Monosynaptic Reflexes in Cats
Authors: Manjarrez E. , Hernández-Paxtián Z. , Kohn A. F.
Published: July 2005

Successive stimuli of constant intensity applied to Ia afferents produce spinal monosynaptic reflexes (MSRs) of variable amplitude. We recorded simultaneous MSRs in the left and right L7 (or L6) ventral roots of anesthetized cats. We analyzed the cross-covariance (CCV) between the amplitudes of bilateral MSRs. Long-time series (5 to 8 h) of these bilateral MSRs exhibited transitory changes in their covariations (as measured by the zero-lag peak of their CCV), thus suggesting the existence of certain neural sources contributing to produce these changes. The aim of the present study was to show that spinal centers producing negative spontaneous cord dorsum potentials (nSCDPs) contribute to maintain correlations in the amplitude of bilateral MSRs. After spinal cord transection at the L1 segment, no significant changes were observed in the correlation between the amplitude of bilateral nSCDPs versus the amplitude of bilateral MSRs. However, this correlation, as well as the peak at zero lag in the CCV between bilateral MSRs and the CCV between bilateral nSCDPs, respectively, were abolished after a subsequent longitudinal bisection at the L1–S2 spinal segments. These results suggest that lumbar spinal neurons (bilaterally interconnected) contribute to maintain the synchronous fluctuations of bilateral MSRs.
Saturated Muscle Activation Contributes to Compensatory Reaching Strategies After Stroke
Authors: McCrea Patrick H. , Eng Janice J. , Hodgson Antony J.
Published: July 2005

The control and execution of movement could potentially be altered by the presence of stroke-induced weakness if muscles are incapable of generating sufficient power. The purpose of this study was to identify compensatory strategies during a forward (sagittal) reaching task for 20 persons with chronic stroke and 10 healthy age-matched controls. We hypothesized that the paretic anterior deltoid would be maximally activated (i.e., saturated) during a reaching task and that task completion would require activation of additional muscles, resulting in compensatory movements out of the sagittal plane. For reaching movements by control subjects, joint motion remained largely in the sagittal plane and hand trajectories were smooth and direct. Movement characteristics of the nonparetic arm of stroke subjects were similar to control subjects except for small increases in the abduction angle and the percentage that anterior deltoid was activated. In contrast, reaching movements of the paretic arm of stroke subjects were characterized by increased activation of all muscles, especially the lateral deltoid, in addition to the anterior deltoid, with resulting shoulder abduction power and segmented and indirect hand motion. For the paretic arm of stroke subjects, muscle and kinetic compensations increased with impairment severity and weaker muscles were used at a higher percentage of their available muscle activity. These results suggest that the inability to generate sufficient force with the typical agonists involved during a forward reaching task may necessitate compensatory muscle recruitment strategies to complete the task.
Characterization of Synaptic Conductances and Integrative Properties During Electrically Induced EEG-Activated States in Neocortical Neurons In Vivo
Authors: Rudolph Michael , Pelletier Joe Guillaume , Paré Denis , Destexhe Alain
Published: July 2005

The activation of the electroencephalogram (EEG) is paralleled with an increase in the firing rate of cortical neurons, but little is known concerning the conductance state of their membrane and its impact on their integrative properties. Here, we combined in vivo intracellular recordings with computational models to investigate EEG-activated states induced by stimulation of the brain stem ascending arousal system. Electrical stimulation of the pedonculopontine tegmental (PPT) nucleus produced long-lasting (≈20 s) periods of desynchronized EEG activity similar to the EEG of awake animals. Intracellularly, PPT stimulation locked the membrane into a depolarized state, similar to the up-states seen during deep anesthesia. During these EEG-activated states, however, the input resistance was higher than that during up-states. Conductance measurements were performed using different methods, which all indicate that EEG-activated states were associated with a synaptic activity dominated by inhibitory conductances. These results were confirmed by computational models of reconstructed pyramidal neurons constrained by the corresponding intracellular recordings. These models indicate that, during EEG-activated states, neocortical neurons are in a high-conductance state consistent with a stochastic integrative mode. The amplitude and timing of somatic excitatory postsynaptic potentials were nearly independent of the position of the synapses in dendrites, suggesting that EEG-activated states are compatible with coding paradigms involving the precise timing of synaptic events.
Association of Amino Acid Substitution Pattern in Core Protein of Hepatitis C Virus Genotype 1b High Viral Load and Non-Virological Response to Interferon-Ribavirin Combination Therapy
Authors: Akuta Norio , Suzuki Fumitaka , Sezaki Hitomi , Suzuki Yoshiyuki , Hosaka Tetsuya , Someya Takashi , Kobayashi Masahiro , Saitoh Satoshi , Watahiki Sachiyo , Sato Junko , Matsuda Marie , Kobayashi Mariko , Arase Yasuji , Ikeda Kenji , Kumada Hiromitsu
Published: July 2005

Objective: Patients with high titer (≧100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs. Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1–191 of the core region and amino acids 2209–2248 of NS5A, and early viral kinetics. Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions. Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.
Regulation of Epithelial Sodium Channel in Puromycin Aminonucleoside-Induced Unilateral Experimental Nephrotic Syndrome in Normal and Analbuminemic Nagase Rats
Authors: Yu Zhenrong , Schumacher Martin , Frey Brigitte M. , Frey Felix J. , Vogt Bruno
Published: July 2005

Background: Nephrotic syndrome (NS) is characterized by renal sodium retention and edema formation. In nephrotic rats the site of enhanced sodium retention has been localized in the cortical collecting duct (CCD). The epithelial sodium channel (ENaC) is the rate-limiting constituent of sodium transport in CCD. Amiloride, an ENaC-blocking drug, corrects the abnormal rate of sodium transport in isolated perfused CCD from puromycin aminonucleoside (PAN)-treated rats. Therefore, we hypothesized that ENaC functional expression is increased in NS. Methods: Unilateral NS was induced by PAN in Wistar rats and analbuminemic Nagase rats (NAR). Urinary protein excretion, renal abundance of mRNA and protein of ENaC subunits, as well as the ENaC regulatory serum glucocorticoid-inducible kinase (Sgk1) and Nedd4-2, were assessed. Results: Proteinuria appeared at day 2 in the Wistar rats and NAR. Surprisingly a downregulation rather than the expected upregulation of α-, β- and γ-ENaC mRNA abundance was observed in both Wistar rats and NAR, when the treated kidney was compared with the untreated kidney. The amount of protein of α-, β- and γ-ENaC was not affected by the NS. Sgk1 mRNA expression did not change and Nedd4-2 protein expression was only decreased at days 1 and 2 in Wistar rats. Conclusion: ENaC mRNA and protein expression are not increased in the early phase of unilateral PAN-induced NS. Sgk1, Nedd4-2 and analbuminemia are not important regulatory factors of ENaC protein expression in experimental NS.
Is Hypertension a Disorder of Volume Control? What Is the Evidence?
Authors: Mindel Graeme , Morrison Aubrey R.
Published: July 2005

The etiological factors responsible for the hypertensive phenotype are complex and several experimental and clinical observations point to a major role of the kidney as being responsible. Genetic studies of uncommon diseases which express monogenetic inheritance all have in common a dysregulation of Na+ balance and volume expansion. Furthermore, epidemiological data suggest an increased incidence of hypertension in communities with high excretory rates of Na+. Experimental data also suggest that low birth weight is associated with an increase in the frequency of hypertension later in life and raises the possibility that intrauterine imprinting may contribute to the expression of the phenotype. Upregulation of the Na+/K+/2Cl– and thiazide-sensitive transporters in low birth weight animals may provide the physiological basis for these observations. In addition, low birth weight is associated with a decrease in nephron number. Therefore, low nephron number may induce adaptive changes in utero which influence volume homeostasis later in life and subtle gain of function mutations in one or more of these transporters may unmask defects in volume homeostasis with increasing salt intake. Finally, the high prevalence of hypertension in functionally anephric patience seems to respond to sustained maintenance of ‘dry weight’ through ultrafiltration.
Myocilin Gene Expression in the Trabecular Meshwork of Rats in a Steroid-Induced Ocular Hypertension Model
Authors: Sawaguchi Keiko , Nakamura Yoshimi , Nakamura Yuko , Sakai Hiroshi , Sawaguchi Shoichi
Published: July 2005

Purpose: To investigate the expression pattern of myocilin in the trabecular meshwork of normal and dexamethasone-induced ocular hypertensive rat eyes. Materials and Methods: An ocular hypertension model was generated by application of topical dexamethasone to rat eyes 4 times daily for 1, 2, and 4 weeks. Age-matched untreated eyes served as controls. The intraocular pressure (IOP) was monitored by electronic Tono-pen under anesthesia. The protein and mRNA levels of myocilin in the trabecular meshwork and endothelial lining of Schlemm’s canal were investigated by immunohistochemistry and in situ hybridization, respectively. For semiquantitative evaluation, areas with positive staining were analyzed by a computer-assisted image-processing system with NIH software. Results: The IOP in rat eyes was elevated after 2 weeks of topical dexamethasone treatment. Despite the IOP elevation, the protein and mRNA levels of myocilin in the trabecular meshwork and around Schlemm’s canal in the steroid-treated eyes were not different from those of controls. Conclusion: No discernible changes in myocilin expression in the chamber angle indicate that myocilin may not be directly linked to ocular hypertension, at least not in rat eyes after relatively short-term steroid application.
HER2/neu Oncoprotein Overexpression in Epithelial Ovarian Cancer: Evaluation of its Prevalence and Prognostic Significance
Authors: Verri Elena , Guglielmini Pamela , Puntoni Matteo , Perdelli Luisa , Papadia Andrea , Lorenzi Paola , Rubagotti Alessandra , Ragni Nicola , Boccardo Francesco
Published: July 2005

Introduction: The HER2/neu proto-oncogene encodes a transmembrane receptor protein involved in the development and progression of the majority of cancers. Prior studies have shown that HER2/neu oncogene is overexpressed in approximately 15–30% of ovarian carcinomas. However findings regarding the overexpression and prognosis are still conflicting. Methods: Our retrospective study was performed on 194 ovarian carcinoma tissues obtained at the time of first surgery. The staining procedure for HER2/neu overexpression was performed using a polyclonal antibody. Results: HER2/neu overexpression was found in 53 out of 194 (27.3%) investigated cases of which 26 (13.4%) carcinomas were weakly positive (score 1+) and 27 (13.9%) moderately (score 2+) to intensely positive (score 3+). No significant relationship was found between HER2/neu score and main clinical and pathological features. Significant difference in overall survival was evident between negative women (0/1+) and positive women (2+/3+): 48 and 29 months, respectively (p = 0.04). In multivariate analysis HER2/neu overexpression appeared to be the only variable significantly correlated with progression and death. CA125 normalization at 3 and 6 months appeared a strong predictor of progression and survival. Conclusion: In this study HER2/neu overexpression was associated with an increased risk of progression and death, especially among women with FIGO Stage I and II ovarian carcinoma.
Effect of Clomiphene Citrate on Ovarian, Endometrial, and Cervical Histologies in a Rat Model
Authors: Ozdemir Ismail , Ustundag Nil , Guven Aysel , Duran Bulent , Demirci Fuat
Published: July 2005

Objective: To examine the effect of clomiphene citrate (CC) on the ovarian, endometrial, and cervical histologies in a rat model. Methods: The rats (n = 40) were randomly assigned to 4 treatment groups: CC 50 (repetitive doses of 0.2 mg CC); CC 100 (repetitive doses of 0.4 mg CC); CC 200 (repetitive doses of 0.8 mg CC), and control (repetitive doses of normal saline). Each study group received its CC dose intraperitoneally in 2 ml saline for 5 days and the controls received 2 ml saline only. Each treatment cycle was repeated six times. Six months later the rats were euthanized. Their ovaries, uterine horns, and cervices were removed and examined for histologic changes. Results: We found no significant difference in the number of follicles and corpora lutea of the study groups (p > 0.05). The numbers of granulosa, theca, and luteal cells of the CC 100 and CC 200 groups were significantly higher than those of the CC 50 group and controls (p < 0.05). There was no important finding related to pre-malign and malign changes in ovarian, endometrial and cervical samples of the control and CC 50 groups. Focal atypia and atypical mitoses were noted in 2 cases of granulosa cells in the CC 100 and CC 200 groups. Conclusion: We did not find an association between the use of CC and ovarian, endometrial, and cervical neoplasms; nevertheless, we noticed an increase in granulosa, theca and luteal cells with high doses of CC, which may be a risk factor for granulosa, theca, and luteal cell tumors.
Effects of Resveratrol, Raloxifene, Tibolone and Conjugated Equine Estrogen on Vaginal Squamous Cell Maturation of Ovariectomized Rats
Authors: Hascalik Seyma , Celik Onder , Tamser Mustafa , Mizrak Bulent
Published: July 2005

Objective: The effects of estrogen replacement therapy, selective estrogen receptor modulators, or tibolone on vaginal squamous cell maturation in postmenopausal women are not well established. Resveratrol (3,5,4′-trans-trihydroxystilbene) has been shown to bind the estrogen receptor in rat uteri. The aim of this study was to cytologically evaluate vaginal smears from ovariectomized rats treated with resveratrol, raloxifene, tibolone and conjugated equine estrogen, and to compare each drug with regard to vaginal epithelial maturation. Material and Methods: Forty-two bilaterally ovariectomized Wistar albino rats were equally randomized into 6 groups: (1) control sham-operated rats; (2) ovariectomized rats administered 0.1% ethanol; (3) ovariectomized rats administered resveratrol at a dose of 5 mg/kg/day p.o.; (4) ovariectomized rats administered conjugated equine estrogen (CEE) at a dose of 0.1 mg/kg/day p.o.; (5) ovariectomized rats administered tibolone at a dose of 0.25 mg/kg/day p.o., and (6) ovariectomized rats administered raloxifen at a dose of 1 mg/kg/day p.o. Administration of drugs started 5 days after bilateral ovariectomy and continued for 35 days. After 35 days of treatment a vaginal smear was obtained from each rat. Smears were stained with the usual Papanicolaou method, and observed with a light microscope by an experienced cytopathologist. Cytological grading was made according to the extent of parabasal, intermediate, superficial and anuclear squamous cells. Results: Ovariectomized rats had lower scores for superficial and anuclear cells when compared to sham-operated rats (p < 0.05). The CEE group had higher scores for superficial and anuclear cells than those of the ovariectomized, raloxifene and tibolone groups (p < 0.05). The resveratrol-treated rats had higher scores for superficial cells but lower scores for parabasal cells than ovariectomized rats (p < 0.05). The raloxifene and tibolone groups had the same scores for intermediate, superficial and anuclear cells but lower scores for parabasal cells compared to ovariectomized rats. Conclusion: The results of our study suggest that resveratrol offsets the reduction in vaginal stratification generally observed after oophorectomy.
Current Concepts of Treatment Strategies in Advanced or Recurrent Ovarian Cancer
Authors: Salzberg Marc , Thürlimann Beat , Bonnefois Hervé , Fink Daniel , Rochlitz Christoph , von Moos Roger , Senn Hansjörg
Published: July 2005

Ovarian cancer is the fifth most common cause of death from cancer in women. The standard first-line treatment for advanced ovarian cancer is a combination of paclitaxel and carboplatin or carboplatin alone. Sequential single-agent therapy is of particular interest in patients with symptom-free disease progression. Age, performance status and treatment preferences of the respective patient are further decisive factors which should be taken into account when selecting single or combination therapy. Second-line treatment depends, for instance, on the duration of response to first-line platinum therapy, previous treatment regimens used, tolerability, the patient’s performance status and preference of a particular treatment, and cost-effectiveness. If tumor recurrence occurs within 6 months following platinum-based therapy, other agents such as paclitaxel, pegylated liposomal doxorubicin, topotecan or gemcitabine should be used. If the tumor recurs after 6 months, a combination therapy of platinum and paclitaxel has proven to be the most effective. Reasonable options in progressive disease are treatment with platinum, either alone or combined with other agents, especially investigational compounds.
Prospective, Double-Blind, Placebo-Controlled, Multicenter, Randomized Phase III Study with Orally Administered Budesonide for Prevention of Irinotecan (CPT-11)-Induced Diarrhea in Patients with Advanced Colorectal Cancer
Authors: Karthaus M. , Ballo Harald , Abenhardt Wolgang , Steinmetz Tilmann , Geer Thomas , Schimke Jörg , Braumann Dietrich , Behrens Rüdiger , Behringer Dirk , Kindler Manfred , Messmann Helmut , Boeck Hans-Peter , Greinwald Roland , Kleeberg Ulrich
Published: July 2005

Background: Unpredictable and severe diarrhea (NCI grade ≧3) remains a life-threatening adverse event in patients treated with irinotecan (CPT-11). The aim of this study was to evaluate the efficacy and safety of orally administered budesonide for prevention of CPT-11-induced delayed diarrhea in patients with advanced colorectal cancer. Patients and Methods: A total of 56 patients with advanced colorectal cancer receiving CPT-11 therapy (125 mg/m2 once weekly) were enrolled in this multicenter trial. Patients were randomly treated with 3 mg budesonide orally 3 times daily versus placebo. Detailed assessment of diarrhea by monitoring stool frequency, stool consistency and loperamide rescue medication was made by keeping a diary. Results: Diarrhea, defined as number of stools >4 occurring on a single day during the study period, could be prevented in 58.3% of the budesonide-treated patients compared to 38.5% of the patients under placebo. Patients in the budesonide group had less episodes (0.7 vs. 2.2 episodes) and a considerably shorter total duration of diarrhea (1.8 vs. 4.2 days) episodes than patients in the placebo group. Loperamide use was more frequent in the placebo than in the budesonide arm (55.6 vs. 41.7%). Also, exposure to rescue medication of loperamide was higher for placebo (36.2 capsules) than for budesonide (24.9 capsules). A superior prevention of diarrhea was observed for budesonide compared to placebo in the first cycle (14 vs. 10; p = 0.257), with more failures observed in the placebo group (16 vs. 10). Conclusion: This double-blind randomized trial failed to show that budesonide has a significant benefit in preventing CPT-11-induced diarrhea. While a trend exists, further trials are warranted.
Serum Protein S-100 Predicts Clinical Outcome in Patients with Melanoma Treated with Adjuvant Interferon – Comparison with Tyrosinase RT-PCR
Authors: Domingo-Domènech J. , Molina R. , Castel T. , Montagut C. , Puig S. , Conill C. , Martí R. , Vera M. , Auge J.M. , Malvehy J. , Grau J.J. , Gascón P. , Mellado B.
Published: July 2005

Objective: To study the clinical value of the determination of serum S-100 protein as a single tumor marker or in combination with tyrosinase RT-PCR in patients with melanoma receiving adjuvant interferon. Patients and Methods: Patients were tested for serum S-100 protein luminoimmunometric assay and for blood tyrosinase mRNA (RT-PCR), before starting interferon and every 2–3 months thereafter. Results: One hundred and six patients (stage IIA, 27; IIB, 19; III, 49; and IV, 11) were included in the study. Median follow-up was 51 months (range 2–76). In the univariate analysis, under treatment S-100 ≧0.15 µg/l and a positive RT-PCR correlated with a lower disease-free survival and overall survival (OS). In the multivariate analysis, clinical stage, under therapy positive RT-PCR and S-100 levels ≧0.15 µg/ml, were independent prognostic factors for OS. The hazard ratio for OS was 3.9 (95% CI, 1.67–9.15; p = 0.004) and 2.2 (95% CI, 1.05–4.6; p = 0.016) for S-100 ≧0.15 µg/l and positive RT-PCR, respectively. When both techniques where combined, a positive RT-PCR indicated a poorer clinical outcome only in patients with S-100 <0.15 µg/l. Conclusions: S-100 ≧0.15 µg/l and a positive RT-PCR during adjuvant interferon therapy indicate a high risk of death in resected melanoma patients. S-100 determination has a higher positive predictive value than RT-PCR, while tyrosinase RT-PCR adds prognostic information in patients with S-100 <0.15 µg/l.
Survival Outcome of Inoperable Non-Small Cell Lung Cancer Patients Receiving Conventional Dose Epirubicin and Paclitaxel as First-Line Treatment
Authors: Yang Chih-Hsin , Chen Min-Chun , Cheng Ann-Lii , Hsu Chih-Hung , Yeh Kun-Huei , Yu Yu-Chie , Whang-Peng Jacqueline , Yang Pan-Chyr
Published: July 2005

Objective: High-dose epirubicin was shown to be effective in the treatment of inoperable non-small cell lung cancer (NSCLC). Paclitaxel is synergistic to a conventional dose of anthracyclines in the treatment of advanced cancer. A phase II study was designed to test the effectiveness of combining paclitaxel with a conventional dose of epirubicin in inoperable NSCLC patients. Methods: Eligibility criteria included inoperable stage IIIB or IV NSCLC patients, Eastern Cooperative Oncology Group performance status of 0–2, measurable or evaluable disease and adequate organ function. Epirubicin 70 mg/m2 intravenous infusion for 15 min was given on day 1. Paclitaxel 175 mg/m2 intravenous infusion for 3 h was given on day 2. Cycles were repeated every 21 days. Tumor response was evaluated every two cycles. Patients received treatment until disease progression, unacceptable toxicity or stable disease after cycle 6. Results: Thirty-eight patients received a total of 185 cycles (median 6 cycles). Seventeen patients responded to treatment (response rate 44.7%). Twenty-six (68%) patients received second-line chemotherapy. All patients were followed until their death. Median survival was 11.9 months (95% confidence interval 9.0–14.9 months). Median time-to-treatment-failure was 4.6 months. Conclusion: Conventional dose epirubicin plus paclitaxel is effective as a first-line treatment for inoperable NSCLC patients.
Weekly Docetaxel in Pretreated Metastatic Breast Cancer Patients: A Phase I-II Study
Authors: Nisticò Cecilia , Cognetti Francesco , Frontini Luciano , Barni Sandro , Ferretti Gianluigi , Bria Emilio , Milella Michele , Garufi Carlo , Cuppone Federica , Vanni Barbara , Carlini Paolo , Terzoli Edmondo
Published: July 2005

Objective: We conducted a phase I-II study to determine the maximum tolerated dose (MTD), toxicity and activity of weekly docetaxel administration in pretreated metastatic breast cancer patients. Methods: In phase I, cohorts of 3women with pretreated metastatic breast cancer were treated with a 1-hour infusion of docetaxelat 30, 35, 40 mg/m2/week after premedication with two doses of dexamethazone 8 mg 12 h apart. Subsequently, a cohort of 28 women was treated at the MTD for 24 consecutive weeks in a phase II setting and was assessed for toxicity and activity. Results: Three patients were treated at each of the first two dose levels; 9 patients were treated at the 3rd level (40 mg/m2/week). Dose-limiting toxicities (DLTs) were experienced at that level by 2/6 patients of the first two accrued groups and in 2/3 patients of the 3rd (confirmation) group, thus establishing the subsequent phase II dose at 35 mg/m2/week. Two out of 28 evaluable patients (7.1%, 95% CI 0–16.7) showed complete responses, whereas 8 (28.6%, 95% CI 11.8–45.3) showed partialresponses, and an objective response rateof 35.7% (95% confidence interval, CI 18–53.5%). In addition, 8 patients (28.6%) had stable disease. The median time to progression and overall survival were 5 (range 1–15) and 15months (95% CI 7–23), respectively. One patient experienced 1 episode of grade 3 neutropenia. Severe asthenia was the main reason for interruption of chemotherapy (10 patients, 35.5%). Conclusions: In pretreated metastatic breast cancer patients, the sustained weekly administration of docetaxel, even though it demonstrated an activity similar to a 3-weekly schedule could not be maintained for the planned 24 weeks due to the progressive emergence of nonhematological side effects that approached DLTs.
Maintenance Hormone Therapy with Letrozole after First-Line Chemotherapy for Advanced Breast Cancer
Authors: Bertelli Gianfilippo , Garrone Ornella , Bertolotti Laura , Occelli Marcella , Conforti Serafino , Marzano Nicola , Febbraro Antonio , Carlini Paolo , Liossi Christina , Del Mastro Lucia , Leonard Robert C.F.
Published: July 2005

Objectives: Maintenance hormone therapy after first-line chemotherapy is routinely used by many clinicians in advanced breast cancer patients with potentially hormone-sensitive tumors, although there are insufficient evidences in the literature to support this practice. We investigated the effects of the third-generation aromatase inhibitor letrozole as a maintenance therapy in postmenopausal patients who had responded or had stable disease with first-line chemotherapy. Methods: Fifty-eight patients (median age 62 years, range 31–80) were recruited and received letrozole, 2.5 mg/day starting within 8 weeks since the last cycle of chemotherapy. Estrogen and/or progesterone receptor status was positive in 81% of the patients, unknown in 19%; 57% of the patients had visceral disease. First-line chemotherapy included anthracyclines and/or taxanes in 74% of cases. Results: The median time to progression (TTP) from starting letrozole was 18.5 months. A shorter TTP was found in patients with abnormal CA 15-3 levels at the start of maintenance letrozole (median TTP, 9.9 months: p = 0.01), or with levels increasing >25% from baseline during the first 6 months of letrozole therapy (median TTP, 8.2 months: p < 0.0001). Response status improved during letrozole in 15.5% of patients who had obtained less than a complete response to chemotherapy. Maintenance treatment was well tolerated and had no significant impact on quality of life scores. Conclusions: This study provides evidence in support of the common clinical practice of maintenance hormone therapy after chemotherapy in suitably selected patients with advanced breast cancer.
Clinical Outcomes of 54 Pelvic Osteosarcomas Registered by Japanese Musculoskeletal Oncology Group
Authors: Matsuo Toshihiro , Sugita Takashi , Sato Keiji , Hotta Tetsuo , Tsuchiya Hiroyuki , Shimose Shoji , Kubo Tadahiko , Ochi Mitsuo
Published: July 2005

Background: To determine the clinical outcomes in patients with pelvic osteosarcoma, we reviewed the experience with 54 pelvic osteosarcoma patients. Methods: Thirty-five patients underwent surgical treatment with 30 undergoing limb salvage procedures and 5 requiring hemipelvectomies. Results: Oncological outcome was continuously disease free in 12 cases, no evidence of disease in 3, alive with disease in 3, died of disease in 34 and died of other causes in 2. The 5-year survival rate was 29.5%. For the patients who underwent surgery, statistically significant prognostic factors were chemotherapy, surgical margin, tumor location in sacrum, efficacy of chemotherapy, local recurrence, metastasis and treatment for metastases. With univariate analysis, local recurrence, surgical margin and tumors resected from the sacrum were significant prognostic factors for metastasis. Surgical margin, tumor resected from sacrum and metastasis were significant prognostic factors for local recurrence. With regard to postoperative functional mobility, patients with tumors resected from the sacrum exhibited poorer functional mobility when compared with other sites. Conclusions: Patients with tumors located in the sacrum had worse prognosis, and significant prognostic factor for local recurrence and metastasis. Treatment of pelvic osteosarcoma especially located in the sacrum requires new approaches and further improvements in order to ensure successful outcomes.
Changing Quality of Life in Patients with Advanced Head and Neck Cancer after Primary Radiotherapy or Chemoradiation
Authors: Fang Fu-Min , Tsai Wen-Ling , Chien Chih-Yen , Chiu Herng-Chia , Wang Chong-Jong , Chen Hui-Chun , Hsiung Ching-Yeh
Published: July 2005

Objective: The purpose of this study was to investigate the longitudinal changes in quality of life (QoL) for patients with advanced stage (stage III or IV) head and neck squamous cell carcinoma (HNSCC) following primary radiotherapy (RT) or concomitant chemoradiotherapy. Methods: From January 2001 to January 2003, 149 patients with advanced HNSCC were enrolled. The data pertaining to their QoL were collected using the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) and the EORTC Head and Neck Module (QLQ-H&N35) before and 1 year after RT. Results: Sixty-eight (46%) patients dropped out during the study period. Thirty-nine (57%) of them died of cancer. Those who were older, stage IV, treated by RT alone, or had worse pretreatment EORTC QoL scales were significantly more likely to drop out. For those completing the study, only the problems of swallowing, dry mouth, and sticky saliva were found to become more serious with both statistical (p < 0.05) and clinical (difference >10 points) significance 1 year after RT. Those subjects with cancer at the hypopharynx/larynx had a 3.3-fold higher probability to report an improvement in global QoL (95% confidence interval, CI: 1.11–6.82) than those with cancer at the oral cavity/oropharynx. Those alive without cancer 1 year after RT had a 3.6-fold higher probability to report an improvement in global QoL (95% CI: 1.32–7.13) than those alive with cancer. Conclusion: The study showed a high dropout rate in this longitudinal QoL study for patients with advanced HNSCC. Pretreatment cancer sites and living with cancer or not after treatment significantly affected the change in global QoL 1 year after RT.
Chemoradiotherapy for Locally Advanced Pancreatic Carcinoma in Elderly Patients
Authors: Morizane Chigusa , Okusaka Takuji , Ito Yoshinori , Ueno Hideki , Ikeda Masafumi , Takezako Yoriko , Kagami Yoshikazu , Ikeda Hiroshi
Published: July 2005

Objectives: Chemoradiotherapy, which is one of the standard treatments for locally advanced pancreatic carcinoma, is considered a high-risk procedure in elderly patients. This study investigated the outcome and tolerability of this treatment in elderly patients. Methods: We reviewed our database from November 1993 to March 2003 and retrospectively examined the clinical data of patients with histologically confirmed exocrine pancreatic carcinomas that were nonresectable but confined to the pancreatic region, who were treated with protracted 5-fluorouracil infusion (200 mg/m2/day) and concurrent radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks). We evaluated the outcome of patients ≧70 years and those <70 years. Results: There were 19 patients ≧70 and 39 patients <70. On pretreatment evaluation, the elderly patients showed lower serum albumin levels, lower transaminase levels, better ECOG performance status, more frequent body weight loss and less frequent abdominal and/or back pain with the administration of morphine than the younger patients. There were no significant differences in the frequency of severe toxicity. Neither the response rate nor the incidence of treatment discontinuation differed significantly between the two groups. The median survival time was longer in the elderly patients than in the younger patients (11.3 vs. 9.5 months, p = 0.04). Conclusions: With careful patient selection, chemoradiotherapy can be one of the treatment options for locally advanced pancreatic carcinoma in elderly patients.
Activity of the Hypothalamus-Pituitary-Adrenal System and Oral Glucose Tolerance in Depressed Patients
Authors: Weber-Hamann Bettina , Kopf Daniel , Lederbogen Florian , Gilles Maria , Heuser Isabella , Colla Michael , Deuschle Michael
Published: July 2005

We hypothesized that the activity of the hypothalamus-pituitary-adrenal system in depressed patients is related to oral glucose tolerance. In 70 moderately depressed inpatients, we measured morning saliva cortisol for 6 days and assessed oral glucose tolerance. We found glucose concentrations to be positively associated with mean morning cortisol concentrations (F3,236 = 2.86, p < 0.05). Also, the ISI, a measure of insulin receptor sensitivity, was negatively associated with mean morning cortisol concentrations (r = –0.25, p < 0.04). These findings support the hypothesis that hypercortisolemia may lead to disturbed glucose utilization in depressed patients.
Neocuproine, a Copper (I) Chelator, Potentiates Purinergic Component of Vas Deferens Contractions Elicited by Electrical Field Stimulation
Authors: Göçmen Cemil , Kumcu Eda Karabal , Büyüknacar H. Sinem , Önder Serpil , Singirik Ergin
Published: July 2005

Effects of the specific copper (I) chelator, neocuproine, on the purinergic and adrenergic components of nerve-evoked contractions were investigated in the prostatic rat vas deferens. Electrical field stimulation (EFS; 4 Hz) induced bimodal contractions of vas deferens tissue in the presence of α1-adrenoceptor antagonist prazosin (to isolate the purinergic component) or purinoceptor antagonist suramin (to isolate the adrenergic component). Neocuproine significantly potentiated the purinergic component of the contractile responses to EFS. However, the same agent failed to elicit any significant effect on the adrenergic component of nerve-evoked contractions. The copper (II) chelator cuprizone could not affect the purinergic component of contractions. The potentiating effect of neocuproine which was reversible after washout of the drug, did not occur following the application of the pre-prepared neocuproine-copper (I) complex. A nitric oxide synthase inhibitor, L-nitroarginine; a cyclooxygenase inhibitor, indomethacin or an α2-adrenoceptor antagonist, yohimbine, failed to alter the responses to neocuproine on the purinergic component of the contraction to EFS. Neocuproine did not elicit any significant effect on preparations in which the purinergic receptors were desensitized with α,β-methylene ATP. In conclusion, our results suggest that neocuproine potentiates the purinergic component of rat vas deferens contractions elicited by EFS, presumably by facilitating purinergic neurotransmission and that copper (I)-sensitive mechanisms can modulate purinergic transmission in this tissue.