Second-Line Treatment for Advanced Pancreatic Adenocarcinoma: Is There a Role for Gemcitabine?

PURPOSE: Advanced pancreatic adenocarcinoma (PA) is an aggressive disease that has poor prognosis and frequently interferes with patient's quality of life. There has been progress in first-line regimens; however, there is no standard second-line regimen. The aim of this study is to analyze second-line gemcitabine after first-line fluorouracil (FU) + leucovorin (LV) + irinotecan + oxaliplatin (FOLFIRINOX) regimen. METHODS: This study included consecutive patients with advanced PA treated at Hospital Sirio-Libanês from 2011 to 2016. The patients received FOLFIRINOX as first-line treatment and upon progression, received gemcitabine alone. Survival analysis was performed using the Kaplan-Meier method. RESULTS: A total of 54 patients were evaluated. Most patients were male (61.1%) and most had an ECOG performance status of 0 or 1 prior to the beginning of second-line treatment (66.6%). The mean number of gemcitabine cycles was 3.4. Most patients had disease progression as the best response to treatment (75.9%), 11.1% had stable disease, and 9.3% experienced a partial response. The median progression-free survival was 1.7 months, and the median overall survival was 6.8 months. CONCLUSIONS: Gemcitabine alone did not show meaningful clinical benefit as second-line treatment after FOLFIRINOX.

Thyroid nodules with indeterminate cytology: prospective comparison between 18F-FDG-PET/CT, multiparametric neck ultrasonography, 99mTc-MIBI scintigraphy and histology.

PURPOSE: To evaluate the role of (18)F-flurodeoxiglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) in predicting malignancy of thyroid nodules with indeterminate cytology. PATIENTS AND METHODS: We analysed 87 patients who have been scheduled to undergo surgery for thyroid nodule with indeterminate cytology. All patients underwent (18)F-FDG-PET/CT, multiparametric neck ultrasonography (MPUS), and (99m)Tc-methoxyisobutylisonitrile scintigraphy ((99m)Tc-MIBI-scan). Histopathology was the standard of reference. We compared the sensitivity (SE), specificity (SP), accuracy (AC), positive (PPV) and negative predictive (NPV) values of (18)F-FDG-PET/CT with those of (99m)Tc-MIBI-scan and MPUS in detecting cancer. Univariate and multivariate analyses evaluated the association between each diagnostic tool and histopathology. RESULTS: On histopathology, 69 out of 87 nodules were found to be benign and 18 to be malignant. The SE, SP, AC, PPV and NPV of (18)F-FDG-PET/CT were 94, 58, 66, 37 and 98% respectively. The SE, AC and NPV of (18)F-FDG-PET/CT were significantly higher than those of MPUS and (99m)Tc-MIBI-scan. The association of both positive (18)F-FDG-PET/CT and MPUS (FDG+/MPUS+) showed significantly lower SE (61% vs 94%) and NPV (88% vs 98%) than (18)F-FDG-PET/CT alone, but significantly higher SP (77% vs 58%). On univariate analysis, (18)F-FDG-PET/CT and the combination of FDG+/MPUS+ and of FDG+/MIBI- were all significantly associated with histopathology. On multivariate analysis, only FDG+/MIBI- was significantly associated with histopathology. CONCLUSION: The AC of (18)F-FDG-PET /CT in detecting thyroid malignancy is higher than that of (99m)Tc-MIBI-scan and MPUS. A negative (18)F-FDG-PET/CT correctly predicts benign findings on histopathology. The association of FDG+/MPS+ is significantly more specific than (18)F-FDG-PET/CT alone in identifying differentiated thyroid cancer. A positive (18)F-FDG-PET/CT is significantly associated with malignancy when qualitative (99m)Tc-MIBI-scan is rated as negative.

Intracerebroventricular capsaicin influences the body weight increasing of rats.

Adult rats were treated for ten days with capsaicin or with NaCl 0.9% directly injected into the lateral cerebral ventricles through a surgically implanted cannula. A third group of rats was implanted with the same cannula but did not receive any treatment. The food intake and the body weight were recorded for at least six weeks after stopping the treatment. The animals were always kept at constant ambient temperature of 22 °C. The body weight of the capsaicin-treated group was reduced by the treatment, and showed a regular but lower degree of recovery trend than the control groups after the treatment period. In fact the capsaicin treated animals never reached the body weight of the controls. Nevertheless, food intake did not significantly vary after the capsaicin treatment. On the basis of these and previous findings, we can assume that capsaicin injected into the cerebral ventricles to rats kept at constant ambient temperature can acts on hypothalamic neurons, but a permanent action on metabolic pathways can not be excluded.

Rats desensitized by capsaicin alter their food intake regulation especially at cold ambient temperature.

Adult rats were treated subcutaneously for 10 days with capsaicin, and their food intake and body weight were recorded for almost 6 weeks after stopping the treatment. The animals were exposed to different ambient temperatures: Ta (22, 32, 35, 10 and 22 degrees C). In the capsaicin-treated group a persistent increase in food intake and a reduction of body weight were observed when the animals were exposed to the lowest Ta of 10 degrees C. Starting from this temperature, food intake remained significantly higher than in controls until the end of the experiment at a Ta of 22 degrees C. The discrepancy between body weight increase and food intake especially at low temperature (10 degrees C) suggests that capsaicin could prevent suppression of food intake through the mediation of capsaicin-sensitive vagal afferent fibers by activation of cold-temperature-sensitive receptors.

Hyperalgesic effect of intrathecally administered interleukin-1 in rats.

The present study demonstrates that intrathecal injection of interleukin-1 (IL-1) in rats at a dose of 50 pg or 500 pg induced a significant hyperalgesic effect in the hot-plate test. The hyperalgesia or the altered nociceptive responses were not considered to be the result of sensitization to the hot plate, since the nociceptive alteration caused by intrathecal administration of IL-1 stopped after 20 min. The results suggest that IL-1 can affect pain responsiveness in a dose-dependent manner and that it is able to modulate neuronal functions. Taken together, our findings and the data from the literature suggest that IL-1-induced hyperalgesia is related not only to the route of administration but also to the algesia testing method used.

Intracerebroventricular capsaicin and food intake in the rat.

To investigate whether capsaicin affected food intake and body weight and/or interfered with the mechanisms regulating the body temperature, capsaicin was administered intracerebroventricularly to rats at a daily dose of 25 micrograms of 5 microliters of vehicle for 10 consecutive days. The vehicle consisted of 5% ethanol plus 5% Tween 80 in isotonic saline. The ambient temperature (Ta) was 22 degrees C. Two control groups were used: the first group was treated with the vehicle but its concentration was lowered 10 times in order to avoid the wellknown brain toxicity of Tween 80; the second group was injected with NaCl 0.9% alone. The subsequent observation period lasted 38 days and the rats were exposed to a Ta of 22, 32, 35, 10 and 22 degrees C for different times. Food intake and body weight showed a remarkable decrease during the treatment period in both the capsaicin- and vehicle-treated groups. During the observation period, food intake behavior and body weight evolution were different among the three groups of treated rats. The influence of Ta was most apparent in the capsaicin-treated rats that showed a long-lasting deficit in their body weight and a clear inability to regulate their body temperature (Tb) in a warm environment (Ta 35 degrees C). However, the capsaicin-treated rats began to recover from the weight loss when they were finally housed at Ta 22 degrees C. Tween 80-treated rats began to recover from the weight loss earlier, the pretreatment body weight having been reached during Ta 32 degrees C exposure, i.e., 12 days after the end of the treatment. Since capsaicin did not reduce food intake for a long time during the recovery process, the effect of capsaicin on Ta and body weight seems to be related to metabolic processes. Under the conditions of the present study, neither capsaicin nor Tween 80 seem to have permanently impaired the animals' energy balance regulation.

Food and water intake suppression by intracerebroventricular administration of substance P in food- and water-deprived rats.

The purpose of this present experiment was to determine the effect of substance P (SP) on the feeding and drinking behavior. This was investigated in male rats totally food and water deprived for a period of 24 h. The intracerebroventricular (i.c.v.) administration of SP (20 microg 10 microl-1 rat-1) suppressed food and water intakes during the 8 h following administration. At 24 h after i.c.v. injection of SP, the rats were not recovered 10.5% of their feeding and 24.9% of their drinking behavior. However, contrary to what happened with SP, i.c.v. injection of the vehicle of SP did not suppress feeding and drinking behavior, as was observed also in the rats (second control) cannulated i.c.v. but which did not receive any injection. At 48 h after SP injection, no alteration of food and water intakes was observed. These results indicated that SP may function as an endogenous anorexigenic peptide.

Interleukin-1 and nociception in the rat.

It has recently become accepted that several cytokines may affect peripheral and central nervous system functions. Consistently with these findings, accumulating evidence points toward an important role for interleukin- in the modulation of nociceptive information. Here we review the observations collected after the administration of this cytokine by intracerebroventricular, intrathecal or peripheral route in rats. Taken together, these data suggest that IL-1 can differently affect pain responsivity depending on the dose and the site of action, and clearly demonstrate that this immune factor is deeply involved in the modulation of neuronal functions.

Intracerebroventricular injection of capsaicin or substance P provokes the micturition reflex in the rat.

Acute intracerebroventricular injection of 25 micrograms capsaicin or 40 micrograms substance P in isotonic saline elicited approximately similar effects on the micturition reflex, but capsaicin had twice as much effect as substance P. This effect is specific, since acute intracerebroventricular injection of isotonic saline did not produce the micturition reflex. It can be hypothesized that capsaicin and substance P may act on the brain micturition centers directly or by mediation of neuropeptides such as tachykinins, but other hypotheses are also made.

Intracerebroventricular self-injection of beta-endorphin by rats in response to intermittent electrical shocks.

Rats were taught to self-administer beta-endorphin (0.1 microgram or 0.5 microgram/microliter) or NaCl 9% by pressing a lever that activated a pump connected with a cannula implanted in the lateral cerebral ventricle (icv). The pump delivered 1 microliter at each lever pressing. After a training period of 2 weeks, the self-injection behaviour was studied before, during and after nociceptive stimulation. In response to a nociceptive stimulation, 4 rats increased their self-injection of beta-endorphin at 0.5 microgram/microliter per injection. This effect is specific for beta-endorphin since under identical conditions 6 rats did not increase the injection of isotonic NaCl saline solution. Another 6 rats did not increase their self-injection during nociceptive electrical stimulation and the post-nociceptive period when the dose of beta-endorphin was 0.1 microgram/microliter per injection. However these animals self-administered significantly higher levels of beta-endorphin during the pre-control period. Also studied were the acute effects of 10 micrograms of icv beta-endorphin on tail-flick latency in sec. The acute administration of 10 micrograms of beta-endorphin induced a long-lasting analgesia. The results show that the rats increased beta-endorphin self-administration during the pre-control period when the dose was 0.1 microgram/microliter and during the nociceptive stimulation period when the dose was 0.5 microgram/microliter. In the former case the self-administration had the profile of a voluntary doping drug intake, in the latter case the profile was that of an antalgic self-medication.

Convulsions and death induced in rats by Tween 80 are prevented by capsaicin.

Two or three minutes after intracerebroventricular (i.c.v.) injection of Tween 80 plus ethanol as vehicles for capsaicin, strong convulsive movements occurred in the treated rats; they twisted and turned, dashed themselves against their cage and all died. Tween 80 in saline without ethanol also produced convulsions and death in all the rats treated. Capsaicin dissolved in the vehicle seemed to furnish protection against such death. Moreover, when capsaicin in Tween 80 was administered i.c.v. 10 min before the Tween vehicle it prevented the death which would have been caused by the i.c.v. vehicle. Thus a new effect is added to those already discovered in the numerous pharmacological studies on capsaicin.

New technique for cannulae implantation into the dorsal raphe nucleus using layer 5 of cerebellum reference in rat stereotaxic surgery.

A new surgical method for needle or electrode implantation using layer 5 of the cerebellum (C5) as anatomical reference in rat stereotaxic surgery was developed. The coordinates of the new technique for electrode or needle implantation into dorsal raphe nucleus (DRN) are: PA: 3.20-340 mm, V: 6.00-6.40 mm, and L: 0.00 mm. The success of the new surgical procedure was confirmed by histological control of the lesion impact of the electrode into NRD. This lesion impact was well positioned in 83-86% of implanted rats. The use of this method can be extended to other nuclei than the DRN of the brain for cannula implantation. In addition, it can be used in rats on a larger scale, because it suppresses the limitations due to age and body weight.

Thermogenesis in brown adipose tissue is activated by electrical stimulation of the rat dorsal raphe nucleus.

Brainstem mechanisms involved in the central control of thermogenesis in brown adipose tissue (BAT) were investigated, in urethane-anaesthetized rats, by observing changes in the temperature of interscapular BAT following electrical stimulation of sites in the dorsal raphe nucleus (DRN). Large increases in temperature could be produced by single 30 s stimulation trains. The magnitude of the temperature increase grew as a function of both current and frequency. Non-linear temporal summation was observed when near-threshold trains were delivered in close succession. These results are consistent with the view that ascending projections from the DRN relay thermal information to the basal forebrain and hypothalamus.

Chronic intrathecal cannulation affects hypothalamic opioids depending on the technique employed.

Previous studies have shown that chronic intrathecal cannulation can interfere with the homeostasis of central opioid peptides. These results show that beta-endorphin and Met-enkephalin concentrations did not change in the hypothalamus of rats bearing a chronic cannula inserted between C8-T1 up to L3 and fixed to the processes transversus T1. These results suggest that chronically cannulated rats can be considered as normal when studying hypothalamic beta-endorphin or Met-enkephalin concentrations, and used in physiological studies, depending on the technique employed.

After two weeks habituation to capsaicinized food, rats prefer this to plain food.

In a first series of experiments rats were accustomed for two weeks to eat chow with capsaicin (250 micrograms: 1 g of food). After this habituation period, when free to choose, 3 rats out of 4 preferred eating the piquant chow. In a second series of experiments the rats had access to a choice of chows without any habituation period. In this series, the choice between piquant and nonpiquant chow showed that 4 rats out of 5 preferred to eat the chow without capsaicin. The present experiment shows that the piquant chow eaten by rats produced a fall in rectal temperature 48 h later. The present experiment provides some evidence that rats accustomed to eat piquant food manifested, when free to choose, a preference for an innately unpalatable piquant chow.

Effects of intrathecal capsaicin on autonomic and behavioral heat loss responses in the rat.

Capsaicin and Tween 80 were injected into the lumbar subarachnoid space of rats via a chronic cannula, and the thermoregulatory effects compared. The rats were placed in a climatic chamber at an ambient temperature (Ta) of 20 and 30 degrees C. In the first series of experiments the rats had no access to the fan lever. Intrathecal (IT) capsaicin injection produced a fall in rectal temperature, with a rise in cutaneous temperatures due to vasodilation. On the contrary, IT or the intraperitoneal (IP) Tween 80 injection route had no effect on body temperature. In addition capsaicin-administered IP induced a fall in spinal cord temperature (Tsp). In the second series of experiments the rats had access to a lever activating a fan that drew cool outside air into the climatic chamber. After IT capsaicin injection, the rats increased bar-pressing behavior for fresh air. This was significant at both Ta 20 and 30 degrees C. The results tend to support the hypothesis of capsaicin action somewhere on the thermal afferent pathways. Furthermore, it is possible that the action of capsaicin on thermoregulatory behavior is mediated by the release of substance P from primary afferent terminals.

Thermoregulatory behaviour induced by intrathecal injection of substance P in the rat.

A climatic chamber at an ambient temperature (Ta) of 20 and 30 degrees C was used to examine the effect on thermoregulation in the rat of substance P (SP) injected into the lumbar subarachnoid space via a chronic indwelling catheter. In the first series of experiments, the rats had no access to the lever in the climatic chamber. At Ta of 20 degrees C, intrathecal (IT) injections of SP or saline had no effect on body temperature. In the second series of experiments, the rats had access to the lever which actuated a fan that drew cool outside air into the chamber. At Ta 20 and 30 degrees C, IT injection of SP stimulated the activation of bar-pressing to obtain air for cooling. This behaviour was more evident when Ta was 30 degrees C. Under similar conditions, IT injection of saline did not activate bar-pressing. These findings suggest that spinal cord SP receptors may be involved in the control of body temperature.

Modifications involved in brain glycoconjugate metabolism induced by neonatal capsaicin treatment.

Neonatal capsaicin treatment induces significant changes in rat brain glycoconjugate metabolism. All glycosyltransferase activity involved either in glycoprotein or glycolipid biosynthesis was strongly enhanced. Higher enzymatic activities were obtained when capsaicin-treated rats (T1) had received an additional capsaicin dose (T2). In this case, the fucosyl and galactosyltransferase activities were markedly increased. However, the enhancement of sialyltransferase activity only affects the biosynthesis of glycoproteins and is not correlated with a significant change in ganglioside content. The present results suggest that the modulation of the microsomal glycosyltransferase activity, after capsaicin treatment, could not be stated up through a direct lipid interaction or a change in membrane properties because the phospholipid brain content is not significantly modified.