Pegfilgrastim +/- ciprofloxacin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPARTRIO study.

BACKGROUND: TAC (docetaxel/doxorubicin/cyclophosphamide) is associated with high incidences of grade 4 neutropenia and febrile neutropenia (FN). This analysis compared the efficacies of four regimens for primary prophylaxis of FN and related toxic effects in breast cancer patients receiving neoadjuvant TAC. PATIENTS AND METHODS: Patients with stage T2-T4 primary breast cancer were scheduled to receive 6-8 cycles of TAC. Primary prophylaxis was: ciprofloxacin 500 mg orally twice daily on days 5-14 (n = 253 patients; 1478 cycles), daily granulocyte colony-stimulating factor (G-CSF) (filgrastim 5 microg/kg/day or lenograstim 150 microg/m(2)/day) on days 5-10 (n = 377; 2400 cycles), pegfilgrastim 6 mg on day 2 (n = 305; 1930 cycles), or pegfilgrastim plus ciprofloxacin (n = 321; 1890 cycles). RESULTS: Pegfilgrastim with/without ciprofloxacin was significantly more effective than daily G-CSF or ciprofloxacin in preventing FN (5% and 7% versus 18% and 22% of patients; all P < 0.001), grade 4 neutropenia, and leukopenia. Pegfilgrastim plus ciprofloxacin completely prevented first cycle FN (P < 0.01 versus pegfilgrastim alone) and fatal neutropenic events. CONCLUSION: Ciprofloxacin alone, or daily G-CSF from day 5-10 (as in common practice), provided suboptimal protection against FN and related toxic effects in patients receiving TAC. Pegfilgrastim was significantly more effective in this setting, especially if given with ciprofloxacin.

Management of venous port systems in oncology: a review of current evidence.

BACKGROUND: Over the last decades, many changes have occurred in oncology with new chemotherapy combinations and more complex application schemes becoming available. Central venous catheters and implantable venous port systems have become widely used and have facilitated the problem of vascular access. However, important complications are associated with permanent central venous catheters. MATERIAL AND METHODS: This review summarizes evidence on venous port system use published in Medline up to February 2007. Moreover, recent guidelines for the prevention and management of catheter-related infections issued by the Infectious Diseases Society of America, the American College of Critical Care Medicine, the Society for Healthcare Epidemiology of America, the Center for Disease Control and Prevention, Atlanta, and the Infectious Diseases Working Party of the German Society of Hematology and Oncology are included. RESULTS: Sterile precautions are essential when implanting and accessing port systems. Infections must be treated with adequate antimicrobial therapy. Catheter-related thromboembolic complications were found at a rate of 12-64% in retrospective studies. Five current clinical trials investigated the effect of prophylactic anticoagulation with either low molecular weight heparin or warfarin in cancer patients with central venous devices. On the basis of these results, routine anticoagulation cannot be recommended. CONCLUSIONS: This article reviews the current literature on long-term complications of venous port systems, focusing on infection and thrombosis. In addition, it summarizes the evidence regarding routine maintenance of port systems in follow-up care.

Trains of sleep sequences are indices of learning capacity in rats.

In previous work dealing with the identification of four sleep sequences (SS-->W, SS-->PS, SS-->TS-->W and SS-->TS-->PS) in the baseline session of adult male Wistar rats [Mandile P, Vescia S, Montagnese P, Romano F, Giuditta A. Characterization of transition sleep episodes in baseline EEG recordings of adults rats, Physiol Behav 1996;60:1435-1439], we have shown that those containing an intervening episode of transition sleep (TS) strongly correlate with the number of avoidances scored the following day [Vescia S, Mandile P, Montagnese P, Romano F, Cataldo G, Cotugno M, Giuditta A. Baseline transition sleep and associated sleep episodes are related to the learning ability of rats, Physiol Behav 1996;60:1513-152]. More recently, clusters of sleep sequences (trains) separated by waking intervals longer than 60 s have been identified in the baseline session of the same rats [Piscopo S, Mandile P, Montagnese P, Cotugno M, Giuditta A, Vescia S. Identification of trains of sleep sequences in adult rats, Behav Brain Res, this volume], and distinguished in homogeneous or mixed trains according to the presence of a single sleep sequence or more than one sequence. Mixed trains have been further separated into trains containing the SS-->TS-->W sequence (+TSW trains) and trains lacking it (-TSW trains). Analysis of the distribution of variables of baseline trains (and of their sleep sequences and components) among fast learning (FL), slow learning (SL), or non-learning (NL) rats, indicates that variables of +TSW trains prevail in FL rats, while variables of -TSW trains prevail in NL rats. In addition, variables of +TSW trains correlate with the number of avoidances of the training session, while variables of -TSW trains do not significantly correlate, or show inverse correlations. Interestingly, sleep sequences such as SS-->W or SS-->TS-->W show direct or inverse correlations with avoidances depending on whether they are included in +TSW trains or in -TSW trains. The data are interpreted to suggest that the outcome of brain operations performed during a sleep sequence may selectively condition the appearance of later sequences within a time interval shorter than a given threshold. An analogous mechanism may be responsible for the aggregation of sleep components in sleep sequences.

Identification of trains of sleep sequences in adult rats.

In previous studies based on high resolution EEG analyses of the 7 h baseline session of 18 adult male Wistar rats [6,14], we have identified four sleep sequences initiating with slow wave sleep (SS) and terminating with waking (W) or paradoxical sleep (PS). Two of these sequences contained an intervening episode of transition sleep (TS). Several variables of these sequences (SS-->W, SS-->TS-->W, SS-->TS-->PS, and SS-->PS) were selectively correlated with the capacity of rats to learn a two-way active avoidance task the following day, and were differently distributed in fast learning, slow learning and non learning rats [21]. The temporal organization of different sleep components in sequences suggested that a comparable temporal organization might concern the different sleep sequences, albeit on a longer time scale. We have now used waking periods longer than 60 s to separate clusters of baseline sleep sequences (trains) in the same rats. Trains containing the same sleep sequence (homogeneous trains) have been distinguished from trains containing different sleep sequences (mixed trains). In addition, mixed trains including the SS-->TS-->W sequence (+TSW trains) have been separated from mixed trains lacking that sequence (-TSW trains). Mixed trains of the +TSW type were longest and most numerous, while homogeneous trains were shortest and least abundant. Mixed trains of the -TSW type displayed intermediate values. Several variables of sleep sequences and sleep components differed within mixed trains and among mixed and homogeneous trains. The data indicate that baseline sleep sequences aggregate in relatively long strings in a non random fashion. The mechanism of this association is discussed.

Post-trial sleep sequences including transition sleep are involved in avoidance learning of adult rats.

High resolution computerized EEG analyses, and behavioral observations were used to identify slow wave sleep (SS), paradoxical sleep (PS) and transition sleep (TS) in adult male Wistar rats exposed to a session of two-way active avoidance training. Of the four sleep sequences that could be identified, two included TS (SS-->TS-->W and SS-->TS-->PS), while the other two did not (SS-->W and SS-->PS). Comparison of post-trial sleep variables between fast learning rats (FL, reaching criterion in the training session), slow learning rats (SL, reaching criterion in the retention session the following day), and non learning rats (NL, failing to reach criterion) indicated that the total amounts of SS, TS and PS of the SS-->TS-->PS sequence was markedly higher in FL rats than in SL rats. In addition, in comparison with the corresponding baseline period, the average duration and total amount of SS and TS episodes of the SS-->TS-->PS sequence increased in FL rats, while the number of SS-->TS-->W sequences decreased. On the other hand, the average duration of SS episodes increased in the SS-->TS-->W and SS-->W sequences of SL rats, and in the SS-->W and SS-->TS-->PS sequences of NL rats. Correlative analyses between number of avoidances and post-trial sleep variables demonstrated that avoidances were directly correlated with the duration of SS episodes of the SS-->TS-->PS sequence and with the duration of TS episodes of the SS-->TS-->W sequence, but inversely correlated with the number and amount of SS episodes of the SS-->W sequence and with the duration and amount of SS episodes of the SS-->PS sequence. On the whole, the data supported the view that TS-containing sleep sequences are involved in long-term storage of novel adaptive behavior, while sleep sequences lacking TS are involved in the maintenance of innate behavioral responses.

Characterization of transition sleep episodes in baseline EEG recordings of adult rats.

By scoring 5-s EEG epochs and calculating spectral power of consecutive EEG segments as short as 1-s, transition sleep (TS) episodes were identified in baseline recordings of adult rats. TS episodes were characterized by the abrupt appearance of theta and alpha waves within an ongoing period of slow-wave sleep (SS). They were followed by paradoxical sleep (PS) or, somewhat more frequently, by a period of wakefulness (W) that often led to an additional SS. Statistical values of the main variables of TS-->(W) and TS-->(PS) episodes are presented, together with comparable data concerning previous SS and following W or PS episodes. On the whole, TS episodes were more numerous than PS episodes, and less numerous than SS episodes. Their average duration was considerably shorter. As a consequence of the identification of TS and of brief W or PS epochs intervening within SS, the number of SS episodes was estimated to be considerably higher than previously assessed, and their average duration considerably shorter.

Baseline transition sleep and associated sleep episodes are related to the learning ability of rats.

The EEGs of 18 adult male Wistar rats were recorded during a baseline session lasting 7 h (day 1). The following day, rats were trained for a 2-way active avoidance task in an automated shuttle-box. A retention test was scheduled on the third day. On the basis of the number of avoidances scored during the training and retention sessions, rats were assigned to a fast-learning group (FL; achieving criterion during the training session), a slow-learning group (SL; achieving criterion in the retention test session), and a nonlearning group (NL; failing to achieve criterion). Vigilance states were determined by analyzing EEG data in 5-s epochs and calculating EEG power spectra of consecutive time intervals as short as 1 s. This high-resolution method led to the identification of transition sleep episodes that followed slow-wave sleep (SS) and were followed by waking (TS-->W) or by paradoxical sleep (TS-->PS). Comparison of the baseline sleep variables of the 3 behavioral groups revealed the presence of several significant differences. These observations were confirmed by the results of correlative analyses between baseline sleep variables and number of avoidances scored during the training and retention sessions. The most reliable indices of the capacity to learn the avoidance task were the amounts of SS preceding the TS-->W or the TS-->PS sequence, and the amounts of either component of the latter sequence. These variables displayed markedly higher values in FL rats. In addition, the amount of SS preceding TS-->W and the amount of TS-->(W) were significantly correlated with the number of avoidances scored during the training session. On the other hand, 1' SS-->(PS) and (SS)-->PS episodes were longer in NL rats than in SL or FL rats, respectively; and 2, the duration of SS-->(PS) episodes was inversely correlated with the number of avoidances of the first training period. The data are interpreted to suggest that TS and associated sleep episodes may predict the acquisition of the avoidance task, and the episodes of SS-->PS not associated with TS may predict the retention of innate responses, such as freezings or escapes.

The sequential hypothesis of the function of sleep.

In addition to modulatory roles concerning bodily functions, sleep is assumed to play a main processing role with regard to newly acquired neural information. Elaboration of memory traces acquired during the waking period is assumed to require two sequential steps taking place during slow wave sleep (SWS) and eventually during paradoxical sleep (PS). This view is suggested by several considerations, not the least of which concerns the natural sequence of appearance of SWS and PS in the adult animal. While the involvement of PS in memory processing is well documented, the involvement of SWS is supported by the results of baseline and post-trial EEG analyses carried out in rats trained for a two-way active avoidance task or a spatial habituation task. Together with control analyses, these data indicate that the marked increase in the average duration of post-trial SWS episodes does not reflect the outcome of non-specific contingent factors, such as sleep loss or stress, but is related to memory processing events. Several considerations have furthermore led to the proposal that, during SWS, after a preliminary selection step, the first processing operation consists in the weakening of non-adaptative memory traces. The remaining memory traces would then be stored again under a better configuration during the ensuing PS episode. This view is in agreement with several relevant features of sleep, including the EEG waveforms prevailing during SWS and PS, as well as the ontogenetic sequence of appearance of SWS and PS. Some theoretical considerations on the role of sleep are also in agreement with the sequential hypothesis. More recent data indicate that the learning capacity of rats is correlated with several baseline EEG features of sleep and wakefulness. They include the average duration of PS episodes and of SWS episodes followed by wakefulness (longer in fast learning rats), and the waking EEG power spectrum of fast learning rats whose output is more balanced in the frequency range below 10 Hz than in slow learning and in non-learning rats. Additional EEG data suggest that fast learning rats may accomplish 'on line' processing of newly acquired information according to a sequence of events not dissimilar from the one proposed by the sequential hypothesis.

Different programs of gene expression are associated with different phases of the 24h and sleep-wake cycles.

The Fos and Jun proteins are encoded by proto-oncogenes acting as immediate early genes in that they are rapidly induced by different kinds of stimuli in the nervous system. These two proteins bind to DNA regulating gene transcription, and thus determining the specificity of the neuronal response to the applied stimulation. We investigated whether the expression of these genes undergoes a variation during 24h in the absence of exogenous stimulation. Male Wistar adult (200 gr. body weight) rats, kept under a 12h/12h light-dark cycle, were sacrificed every 4h starting at 0700. The expression of c-fos, c-jun and jun B mRNAs was studied in six different brain areas by means of Northern blot hybridization, c-fos expression was also studied with in situ hybridization and immunohistochemistry. In basal conditions c-fos expression displayed a highly significant spontaneous oscillation, with the highest level during the darkness hours and the lowest during the light hours. Parallel levels of jun B expression were found in the cortex and striatum, whereas c-jun mRNA remained constantly high throughout 24 h. The periodicity of c-fos and jun B oscillation persisted also when the animals were exposed for 6 days to constant (24h/24h) light or darkness. Such oscillation could instead be inverted by manipulating the rest-activity cycle, i.e. keeping the animals awake during the light hours and allowing them to sleep during the dark hours. We then verified whether the expression of fos and jun could be correlated with states of wakefulness (W) and sleep (S), monitored with EEG recording under behavioral control.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term habituation to spatial novelty modifies posttrial synchronized sleep in rats.

To assess the role of posttrial synchronized sleep in the processing of a nonassociative task, adult male Sprague-Dawley rats with chronically implanted cortical electrodes for EEG recording were exposed to a Làt-maze, and horizontal (HA; corner crossing) and vertical (VA; rearings) activities were monitored during two 10-min test trials made at a 3-h (experiment 1) or 24-h (experiment 2) interval. EEG conventional recording was taken during 3 h under baseline conditions (day 1), and following exposure to the maze (day 2), and analyzed as to the amount (a), number (n), and mean duration (d) of synchronized sleep (SS) episodes followed by wakefulness (SS-->W) or by paradoxical sleep (SS-->PS). In both experiments there was a significant intertrial decrement (long-term habituation: LTH) for horizontal activity (LTH-HA), vertical activity (LTH-VA), and emotionality (LTH-E). In experiment 1, in comparison to baseline values, the posttrial SS-->PS(a) increased, mainly for the appearance of SS-->PS episodes in the 1st h. SS-->W(a) also increased in the first h. Correlative analyses among behavioral and sleep parameters showed that SS-->PS(n) and (d) covaried positively with LTH-HA relative to the entire test, and with LTH-VA relative to the second part of the test in the third h. Negative correlations were present between SS-->PS(n) and (d), and LTH-E. In experiment 2, exposed rats showed a lower SS-->PS(n) in the first hour and an increased SS-->PS(d) in the second hour. No change was observed as to SS-->W episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

The antitumor action of seminal ribonuclease tested with the plasmacytoma spleen colonization assay.

The antitumor action of bovine seminal ribonuclease was evaluated with a quantitative assay based on the production of tumor foci in the spleens of mice injected with plasmacytoma cells. The antitumor action depended on the integrity of the catalytic site, and on the dimeric structure of the enzyme. A working hypothesis is proposed, based on these results, and on previous results obtained studying the antitumor action of seminal RNAase in vitro on cell cultures. According to this hypothesis, the antitumor action is based on the ability of seminal RNAase to interact at specific receptor sites on the tumor cell membrane, as well as on its RNA degrading ability.

Endogenous opioids in marine invertebrates.

A study of the presence of opioids in invertebrates was carried out on 11 species of marine organisms, ranging from sponges to tunicates. Delipidized acid-acetone extracts from whole organisms or dissected organs were assayed by receptor binding assays and radioimmuno assays. The extracts from all species tested were found to contain substances capable of competing in both assays with opioid peptides.

Antitumoral action of bovine seminal ribonuclease.

The antitumor action of bovine seminal RNAase is studied as a function of the enzyme concentration and of the number of plated cells. With polyoma transformed hamster kidney cells, a 50% inhibition of cell growth is obtained with a 10 micrograms/ml of enzyme, while at this concentration growth of normal cells is very little affected. On the other hand the higher the number of plated cells, the lesser is the effect. The enzyme is found to be very effective also on tumor cells derived from a spontaneous tumor (neuroblastoma) and on cells derived from a chemically induced tumor (glioma). Amphoterycin B which is known to alter the permeability of eukariotic cells, does not affect the resistance of normal cells to the cytotoxic action of the enzyme.

In vitro studies on selective inhibition of tumor cell growth by seminal ribonuclease.

The effect on cell growth of bovine seminal RNase has been tested on cells cultured in vitro. A selective inhibition of growth has been observed on tumor cells as compared to normal cells using several virus-transformed cell lines and a neuroblastoma line. The different cellular response of virus-transformed cells does not appear to depend on a differential permeability to the protein of transformed cells with respect to nontransformed ones. The selective cytotoxic action of seminal RNase on tumor cell growth was also compared with the action of other structurally related RNases and of various RNase derivatives prepared by specific chemical modifications. The results indicate that the protein dimeric structure and its enzymic activity are essential requirements for its action.