Molecular characterization of circulating tumor cells in breast cancer: challenges and promises for individualized cancer treatment

Blood testing using Circulating Tumor Cells (CTCs) has emerged as one of the hottest fields in cancer diagnosis. Research on CTCs present nowadays a challenge, as these cells are well defined targets for understanding tumour biology and improving cancer treatment. The presence of tumor cells in patient’s bone marrow or peripheral blood is an early indicator of metastasis and may signal tumor spread sooner than clinical symptoms appear and imaging results confirm a poor prognosis. CTC enumeration can serve as a “liquid biopsy” and an early marker to assess response to systemic therapy. Definition of biomarkers based on comprehensive characterization of CTCs has a strong potential to be translated to individualized targeted treatments and spare breast cancer patients unnecessary and ineffective therapies but also to reduce the costs for the health system and to downsize the extent and length of clinical studies. In this review, we briefly summarize recent studies on the molecular characterization of circulating tumor cells in breast cancer and discuss challenges and promises of CTCs for individualized cancer treatment.     

Prognostic utility of angiogenesis and hypoxia effectors in patients with operable squamous cell cancer of the larynx

Angiogenesis is active in localised laryngeal squamous cell carcinoma. We assessed relative messenger RNA (mRNA) and immunohistochemical (IHC) expression of Vascular Endothelial Growth Factors (VEGF) A, B, C, their receptors VEGFR1, 2, 3, Neuropilins 1, 2 (NRP1, 2) and Hypoxia-Inducible Factor 1A (HIF1A) in paraffin-embedded localised laryngeal carcinomas. In 289 patients with T3-4 (77.8%), node-negative (84.1%) tumours of the larynx, high VEGFA and VEGFR1 mRNA correlated with advanced T stage, while low VEGFB and VEGFC mRNA with alcohol abuse and supraglottic primary, respectively (p<0.05). Age <55 was associated with high IHC expression of VEGFA, C and poor tumour differentiation with high IHC VEGFA. At a median follow-up of 74.5months, patients with VEGFR1-high tumours had significantly poorer disease-free survival (Hazard Ratio [HR] 1.93, p=0.008) and shorter overall survival (OS, HR 1.71, p=0.041). An association with dismal OS was seen for high VEGFR3 tumoural mRNA expression (HR 1.76, p=0.02). IHC expression of VEGF family proteins in the tumour was not prognostic and had poor concordance with mRNA expression (kappa<0.1, p=NS). In multivariate analysis, node-positive status, non-supraglottic localization, high VEGFR1 mRNA and high IHC VEGFA expression were significantly associated with relapse, while node-positive status, high VEGFR1 and VEGFC mRNA expression in the tumour with risk of death. In laryngeal cancer, upregulated mRNA expression of VEGFR1 and VEGFC is associated with poor patient outcome.     

Chronic nicotine administration improves attention while nicotine withdrawal induces performance deficits in the 5-choice serial reaction time task in rats

Nicotine appears to enhance attention, while nicotine withdrawal leads to attentional deficits in humans that are ameliorated with nicotine administration. However, there has been much debate as to whether nicotine improves performance under baseline conditions, or only ameliorates attentional deficits. Thus, we studied the effects of acute and chronic nicotine administration and nicotine withdrawal on attentional performance in the 5-choice serial reaction time task (5-CSRTT) in Wistar and Sprague Dawley (SD) rats under baseline conditions. Wistar rats performed with higher accuracy compared to SD rats. Acute nicotine administration induced small increases in accuracy and correct responses, impulsivity and speed of responding, and decreases in omission errors. These effects were more pronounced in less accurate rats or after task modifications were implemented to disrupt the rats' performance. Chronic nicotine administration via minipumps consistently increased accuracy during days 4-6 of nicotine infusion after the effect of nicotine on impulsivity during days 1-3 dissipated. By contrast, nicotine withdrawal induced decreases in correct responses, and increases in omissions and latencies to respond, but had no effect on accuracy. These results provide evidence that chronic, but not acute, nicotine administration induced accuracy improvement under baseline conditions, while nicotine withdrawal produced some limited performance deficits.     

The role of metabotropic glutamate receptors in drug reward, motivation and dependence

Addiction to drugs of abuse is a disorder that involves dysfunctions in motivational processes. Both the primary rewarding effects of drugs, as well as the acquired motivational properties of stimuli associated with drug-seeking and -taking, contribute to the perpetuation of dependence on drugs of abuse. Metabotropic glutamate (mGlu) receptors, which mediate slow glutamate neurotransmission, are located throughout limbic and cortical brain sites implicated in drug addiction. Preclinical evidence suggests that mGlu receptors play a crucial role in regulating behavioral effects of drugs of abuse relevant to drug addiction. Specifically, antagonists at excitatory postsynaptic mGlu5 receptors decrease drug self-administration without affecting motor behaviors, cognition or the reward value of natural rewards, while agonists at inhibitory presynaptic mGlu2/3 receptor agonists prevent reinstatement to drug-seeking and -taking after a period of abstinence. These findings have increased our understanding of the neuropathological processes associated with aspects of dependence on drugs of abuse and have provided new targets for pharmacological approaches to the treatment of dysfunctions in motivational processes characterizing the various phases of drug addiction.     

Chronic nicotine improves cognitive performance in a test of attention but does not attenuate cognitive disruption induced by repeated phencyclidine administration

Rationale

Nicotine-induced cognitive enhancement may be a factor maintaining tobacco smoking, particularly in psychiatric populations suffering from cognitive deficits. Schizophrenia patients exhibit higher smoking rates compared with the general population, suggesting that attempts to self-medicate cognitive schizophrenia deficits may underlie these high smoking levels.

Objectives

The present study explored pro-cognitive effects of nicotine in a model of schizophrenia-like cognitive dysfunction to test this self-medication hypothesis.

Materials and methods

We investigated whether chronic nicotine (3.16 mg/kg/day, base) would attenuate the performance disruption in the five-choice serial reaction time task (5-CSRTT, a task assessing various cognitive modalities, including attention) induced by repeated administration of phencyclidine (PCP), an N-methyl-d-aspartate receptor antagonist that induces cognitive deficits relevant to schizophrenia.

Results

Chronic nicotine administration shortened 5-CSRTT response latencies under baseline conditions. Nicotine-treated rats also made more correct responses and fewer omissions than vehicle-treated rats. Replicating previous studies, repeated PCP administration (2 mg/kg, 30 min before behavioral testing for two consecutive days followed 2 weeks later by five consecutive days of PCP administration) decreased accuracy and increased response latencies, premature responding, and timeout responding. Chronic nicotine did not attenuate these PCP-induced disruptions.

Conclusions

Chronic nicotine had pro-cognitive effects by itself, supporting the hypothesis that cognitive enhancement may contribute to tobacco smoking. At the doses of nicotine and PCP used, however, no support was found for the hypothesis that the beneficial effects of nicotine on cognitive deficits induced by repeated PCP administration, assessed in the 5-CSRTT, are larger than nicotine effects in the absence of PCP.     

Percutaneous removal of residual intrahepatic stones

In the Orient there is a high frequency of residual intrahepatic stones after biliary tract surgery. Percutaneous removal of residual intrahepatic stones was attempted in a group of 74 patients. Stones were exclusively intrahepatic in 57 patients, whereas 17 patients also had stones in the common bile duct. Biliary strictures were present in 60 cases (81%). A combination of techniques was used, including preshaped angulated catheters, irrigation-suction, balloon dilation of strictures, and crushing of large stones. In 36 cases all stones were removed and in 14 cases most stones were removed, for a success rate of 67.6%. Biliary stricture was the factor most often responsible for failure.     

The Selective Serotonin Reuptake Inhibitor Paroxetine, but not Fluvoxamine, Decreases Methamphetamine Conditioned Place Preference in Mice

Monoamine transporters are the main targets of methamphetamine (METH). Recently, we showed that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), decreased METH conditioned place preference (CPP), suggesting that serotonin transporter (SERT) inhibition reduces the rewarding effects of METH. To further test this hypothesis, in the present study we investigated the effects of additional SSRIs, paroxetine and fluvoxamine, on METH CPP in C57BL/6J mice. In the CPP test, pretreatment with 20 mg/kg paroxetine abolished the CPP for METH, whereas pretreatment with 100 mg/kg fluvoxamine prior to administration of METH failed to inhibit METH CPP. These results suggest that paroxetine, a medication widely used to treat depression, may be a useful tool for treating METH dependence. Further, these data suggest that molecules other than the SERT [such as G protein-activated inwardly rectifying K+ (GIRK) channels] whose activities are modulated by paroxetine and fluoxetine, but not by fluvoxamine, are involved in reducing METH CPP by paroxetine and fluoxetine.     

Extended access to methamphetamine self-administration affects sensorimotor gating in rats

Disturbed information processing observed in neuropsychiatric disorders is reflected by deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). Long-term, higher dose methamphetamine (METH) abuse patterns are associated with cognitive impairments, mania and/or schizophrenia-like psychosis. The present study investigated in rats METH-induced impairment of sensorimotor gating using an intravenous self-administration (IVSA) escalating dose procedure. In this procedure, rats escalated drug intake during weekly extended access periods to METH IVSA (1, 3, and 6h), where PPI was assessed after each access period and thus at various times of drug exposure. Despite increased drug intake over the course of extended access to METH, disruption of sensorimotor gating was only seen after the access period of 6h. The data suggest that METH-induced impairment of sensorimotor gating in IVSA-tasks is rather attributed to continuous and higher dose exposure than to actual amounts of drug present at the time of testing. IVSA procedures, comprising stepwise stimulant escalation may serve as a useful translational model in rats that approximate important aspects of human abuse pattern in the context of stimulant-induced cognitive and behavioral deficits.