Large intersubject variability in the neurobiologie LBH589 effects of aging has been noted by several investigators.44,45 These reports, individually limited by small sample sizes, suggest, that aging effects on brain function are likely highly variable, affected by structural brain changes and systemic factors, and may differ between “successful aging” and individuals with substantial medical burden. Alterations in neurotransmitter systems The functional integrity of several neurotransmitter systems is

altered by the aging process. Characterizing the profile of normal aging changes in neurotransmittcrmediated synaptic processes is the foundation upon Inhibitors,research,lifescience,medical which we will come to decipher the biological basis of behavioral and mood alterations accompanying aging. Further, the potential interaction between age effects and neurochemical

disturbances associated with neuropsychiatrie disease states may influence the susceptibility of the elderly to certain neurobehavioral disorders. Our knowledge of the effect of age on neuroreceptor function is primarily Inhibitors,research,lifescience,medical inferred by postmortem studies, with limited and variable regional sampling of the brain, and by animal models, which may not Inhibitors,research,lifescience,medical appropriately represent, human brain aging. In contrast to studies of pathological changes in aging, there are many problems associated with the biochemical study of neurotransmission in humans. These include the effects of postmortem delay, hypoxia, and drug treatment, as well as the fundamental point that the material is removed most often removed following a terminal illness, which may itself influence neurotransmission regardless of the age at which the patient died. Inhibitors,research,lifescience,medical ‘ITtic reader is referred to a comprehensive review

of the subject, Inhibitors,research,lifescience,medical by DeKosky and Palmer.46 With the development of highly selective radioligands for neuroreceptors, transporters, and other markers of neuronal function, it is possible to study the effects of aging and disease on brain neurotransmitter systems in vivo with PET. This approach permits whole-brain quantitative imaging in well-characterized subjects, with the potential for obtaining longitudinal measures. Such work has demonstrated specific aging reductions in dopamine and serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes (Figure 1).47-50 Interestingly, there is evidence that some neuroreceptors Bay 11-7085 actually increase in density with age, a finding of note in the opiate system.51 PET techniques are desirable relative to neuroendocrine challenge studies, which lack spatial localizing information and physiologic specificity. However, the combination of PET with neuropharmacologic probes is a powerful technique for localizing and quantifying neurotransmitter-mediated function in aging and disease. Figure 1. [18F]Altanserin positron emission tomography (PET) imaging of the 5-hydroxytryptamine (serotonin) type-2A receptor (5-HT2A). Left.

The frequency of the occurrence of movement disorder has especially decreased with the use of second-generation antipsychotics. The second-generation antipsychotics are generally effective in treating the positive as well as negative symptoms of schizophrenia, influencing the serotonergic and dopaminergic system receptors [Tajima et al. 2009; Blanc et al. 2010]. The mechanisms of many side effects

of the antipsychotics are described as receptor blockage. For example, the extrapyramidal symptoms (EPSs) similar to Parkinson’s disease appear to be dependent on decreased dopamine activity through dopamine Inhibitors,research,lifescience,medical receptor blockage in the nigrostriatal pathway; however, dopamine blockage in the hypothalamic and pituitary systems has resulted in hyperprolactinemia [Pramyothin and Khaodhiar, 2010]. Most second-generation antipsychotics do not cause a sustained elevation in prolactin levels, whereas Inhibitors,research,lifescience,medical antipsychotic-induced hyperprolactinemia is almost universal with first-generation antipsychotics agents. The reason for the use of the second-generation antipsychotics has been reduced EPSs and also endocrinological side Inhibitors,research,lifescience,medical effects, due to their influence on the positive and negative symptoms of schizophrenia [Newcomer, 2005; Coccurello and Moles, 2010; Kurt et al. 2008]. A typical drug is risperidone, a derivative of benzoxazole that shows

affinity for 5-HT2A serotonin receptors (5-HT2A) and for D2-dopamine receptors (D2), selleck chemicals llc together with H1-histamine (H1) receptor, Inhibitors,research,lifescience,medical alpha -1 and alpha-2 adrenergic receptor blockade. Risperidone is unique among most other ‘atypicals’ in that it has high affinity for the D2 receptor. The affinity of risperidone for 5-HT2A is 10–20 times more than for the D2 receptor. The most common side effects are EPSs, weight gain, hyperprolactinemia, orthostatic hypotension and somnolence [Komossa et al. 2011]. Endocrinological system side effects are not limited to the increase in prolactin and the impaired glucose tolerance test and diabetes mellitus have also been recorded Inhibitors,research,lifescience,medical [Kim et al. 2002]. Many antipsychotics are

known to cause hyperprolactinemia, those which may lead to hypogonadism-induced osteoporosis, galactorrhoea, gynaecomastia (male breast development), irregular menstruation and sexual dysfunction. Risperidone is one of the second-generation antipsychotics most likely to induce hyperprolactinemia, whereas this is infrequently and only transiently associated with other second-generation antipsychotics. Women are more sensitive than men to these effects and risperidone-induced hyperprolactinemia is at least at a similar level to that found with the first-generation antipsychotics [Halbreich et al. 2003]. Acromegaly, a growth hormone (GH)-secreting pituitary adenoma, is due to chronic GH hypersecretion [Melmed et al. 2005]. At diagnosis, about 75% of patients have macroadenomas.

NSC683864 Structural MRI Structural MRI is increasingly accepted as a surrogate for anatomic phenotype in neuroscience research. In many areas, anatomic MRI has replaced the need for analysis of the postmortem brain in order to elucidate relationships between structure and function. It is not hard to find examples in which anatomic MRI has transformed the entire research landscape of a field: cerebrovascular disease, epilepsy, multiple sclerosis, and other inflammatory conditions, cerebral developmental disorders, to some extent psychiatric disorders, and neurodegenerative disorders. Animal model studies at high magnetic fields have made unique contributions to

this development. Morphological images of brain tissue rely largely on proton Inhibitors,research,lifescience,medical density, T1 and T2 differences between tissue types (eg, white matter vs. gray matter, cortex vs. subcortical nuclei etc.). Proton density is clearly a magnetic field independent parameter. However, relaxation times T1 and T2 are field dependent, Inhibitors,research,lifescience,medical generally increasing63,64 and decreasing1,9,65,66 respectively, with higher magnetic fields Inhibitors,research,lifescience,medical (see review in ref 67). It was recently shown that, contrary to expectations, the dispersion in T1 increases

with increasing magnetic fields in the brain, leading to superior T1-weighted structural Images at the higher magnetic fields.68 Lengthening of T1 with increasing magnetic field also holds true Inhibitors,research,lifescience,medical for blood. Blood T1 is virtually insensitive to its oxygenation state. Ex vivo measurements have shown that blood T1 varies linearly with field strength going from 1.5 T to 9.4 T according to T1= 1.226+ 0.134B0.69 This imparts a clear benefit in time-of-flight type vascular imaging, as well as perfusion imaging using spin labeling techniques. Mapping signals in all hemodynamic-based functional imaging

methods, such as fMRI and optical Inhibitors,research,lifescience,medical imaging with intrinsic signals, are mediated through the vasculature. Consequently, vascular components in these methods are of utmost significance in determining the ultimate spatial and temporal accuracy of the neural activity maps produced by these methods. Therefore, it is important to be able to image vasculature in great detail, and ideally together with functional data in order Thymidine kinase to understand more precisely the source of the fMRI signals and their spatial correlation with the volume of altered neuronal activity. Vascular imaging with high resolution is also of paramount importance in other fields of biomedical research such as tumor biology, where angiogenesis is a necessary component of tumor growth. Taking advantage of the gains in SNR and longer T1 values, the feasibility of obtaining high-resolution MR images of intracortlcal vessels was demonstrated in the cat brain.70 This accomplishment relied on a combination of time-of -flight MR angiography and T2*-weighted contrast based on both endogenous BOLD effect and exogenous iron-oxide particles.

2011). ERK1/2 phosphorylation constitutes a selective cell HKI-272 in vitro marker which occurs in response to noxious stimulus (Ji et al. 1999) and not to nonnoxious stimulus such as light touch. This study first aimed at determining whether nigrostriatal

dopamine depletion could induce trigeminal DMA in the rat. We used an animal model for PD (Paillé et al. 2007; Zengin-Toktas et al. 2013). In this model, lesions within the substantia nigra compacta (SNc) and ventral tegmental area (VTA) were obtained by injecting the 6-OHDA into the medial forebrain bundle. Second, Inhibitors,research,lifescience,medical we asked whether a local segmental mechanism is implicated in this type of allodynia. Finally, we investigated whether the action of bromocriptine, a dopamine 2 receptor (D2R) agonist drug, has analgesic effects in this animal model of PD. Inhibitors,research,lifescience,medical Materials and Methods Ethical statement The experiments conformed to the ethical guidelines of the International Association for the Study of Pain, the European Community Council directive of 24 November 1986 (86/609/EEC) and the Animal Ethics Committee of the University of Auvergne (CE08-11). All surgery was performed under anesthesia, and every effort

was made to minimize animal suffering Inhibitors,research,lifescience,medical and number. The rats were kept in specified pathogen-free conditions, and all the procedures performed were approved by the Auvergne University ethics committee. Surgery Eighty-two adult male Sprague–Dawley rats (275–325 g) from Charles River (L’Arbresle, France) were obtained and maintained in a controlled

environment (lights on 07:00–19:00, 22°C) with Inhibitors,research,lifescience,medical ad libitum access to food and water. They were housed three to four per cage. The experiment was performed as described previously (Paillé et al. 2007; Zengin-Toktas et al. 2013). Anesthesia was given with ketamine 60 mg/kg, i.p. and Rompun® (Bayer, France) (xylazine, 10 mg/kg, i.p.). The animals were placed in a stereotaxic frame Inhibitors,research,lifescience,medical (David Kopf Instrument, Tujunga, CA). Eighty-two rats were injected bilaterally in the substantia nigra compacta (SNc) with 6-OHDA (6-hydroxy dopamine, 0.5 μL/min) after dissolution in a vehicle solution (0.02% ascorbate saline) at a concentration of 3 μg/μL Rolziracetam (Sigma-Aldrich, Saint-Quentin, France) in two deposits (2.25 and 2.85 μg, respectively) at the following coordinates (in mm relative to bregma and the surface of the dura mater): posterior (P) −4.0; lateral (L) ± 0.8; ventral (V) −8.0; tooth bar at +3.4 and A −4.4; L ± 1.2; V −7.8; tooth bar at −2.4. In order to preserve adrenergic neurons from 6-OHDA toxicity, the animals received desipramine (25 mg/kg, i.p., Sigma-Aldrich) 30 min prior to the toxin injection; sham-lesioned rats received only the vehicle at the same coordinates. Drugs The following drugs were used: bromocriptine (Sigma-Aldrich) dissolved in 0.9% saline, and sulpiride (Sigma-Aldrich) dissolved in 2.5% HCL, 7.5% dimethyl sulfoxide (DMSO), 90% saline (0.9%). Fresh solutions were prepared just prior to use. In line with our previous study (Zengin-Toktas et al.

In the paper’s Abstract, it was better to mention in detail the family members who

participated in the study. Also a description should have been provided on the type of the intervention. For example, it had to be made clear wether the intervention was done on individual subjects or was performed on a group on subjects. In Materials and Methods section, the type of the study, which was a one-group semi-experimental pretest/post-test design,2 was not mentioned. Moreover, in the Acknowledgements section, instead of using “investigation”, Inhibitors,research,lifescience,medical or “study”, the word “survey” was used, which is a different type of study by itself. No description was provided on the method of counseling. It is not known if the counseling were conducted for single individuals or for a group of individuals. The theoretical basis of intervention, which should have been thoroughly explained in introduction section as well as time, number Inhibitors,research,lifescience,medical and frequency of sessions were not clear as well. Moreover, it was not clear if the counseling sessions for children, mothers, fathers, siblings and spouse were the same. Reliability coefficients for Inhibitors,research,lifescience,medical subscales of the questionnaire were not

mentioned. Also, the paper could have used more accurate ways to validate the questionnaire rather than using face and content validity. As it can be seen in the attitude section of the Inhibitors,research,lifescience,medical questionnaire (table 2), instead of evaluating the families’ attitudes toward their patients, items number 2, 3, and 4 evaluated the participant’s attitude

toward the show that was presented at Behavioral Counseling Center. It would have been better if the attitude dimension of the questionnaire had been measured by rating scales using appropriate scoring system such as the Likert scale. The age range of the participants was 27-53 years; therefore, children as the patients’ family members could not have been included in the study as participants. In the results section, the frequency and percentage of spouses, which were a sizeable portion of the participants, were not mentioned. Inhibitors,research,lifescience,medical Since there are no appropriate non-parametric tests for analyzing most of the findings in behavioral sciences research, it is recommended to use parametric tests with strong statistical power, even when the data are discrete (items 8 and 9 in table 1) and do not meet the criteria of why normality of distribution and homogeneity of variance. 3 In the section of discussion, there was no an explanation as to why the study was better than similar click here studies, which had used more accurate designs. Moreover, it was not possible to conclude from the study that counseling had an explanatory role, although such a role had been confirmed in many controlled randomized trials. The paper indicated that family members were assumed as one individual in the processes.

These tumours rarely cause perforation, obstruction, intussusception, acute appendicitis or symptoms mimicking prostatism (20). What confounded the diagnosis in this case was the finding on clinical examination of an intra-abdominal lump with very limited mobility and the subsequent core needle biopsy report of liposarcoma. The provisional diagnosis of a retroperitoneal lipoSelleckchem Sirtuin inhibitor sarcoma was at odds with the contrast enhanced CT finding of a multilobulated heterogeneously enhancing soft tissue attenuation lesion in the left lumbar region with mesenteric vessels posterior to the lesion. CT and MRI are indispensible for determining the tissue characteristics,

size and invasion of adjacent Inhibitors,research,lifescience,medical organs (5). The reported characteristics of liposarcoma on CT images are (I) inhomogeneity, (II) infiltration or poor margination, (III) CT numbers greater than normal fat, and (IV) contrast enhancement (19). The enhancement on CT changes according to the degree of histological grade (21). Well-differentiated liposarcomas Inhibitors,research,lifescience,medical are hyperintense on T2-weighted MRI with minimal or no enhancement (22). In the present case the bowel loops were displaced anteriorly and this has been described Inhibitors,research,lifescience,medical as the ‘Straddling sign’ (15). The necrotic

component and mass effect pointed towards the radiological diagnoses of either a GIST or sarcoma. As regards the role of gastrointestinal angiography, Hirakoba et al. have stated that Inhibitors,research,lifescience,medical it may be useful for preoperative planning (12).

Liposarcomas are usually avascular to moderately vascular, and cause displacement of the major vessels. Moderately hypervascular liposarcoma may show irregular, fine tumor vessels and areas of tumor stain with early venous filling. Among all the histological subtypes the myxoid variety is the most common, found in approximately 50% of cases. Inhibitors,research,lifescience,medical The well-differentiated type is further subdivided histologically into the inflammatory, lipoma-like, sclerosing and de-differentiated types (5) and the recently proposed ‘lymphocyte-rich’ type (6). Evans in 1979 reported that the median survival of patients with the well-differentiated, myxoid, dedifferentiated and pleomorphic types was 119, 113, 59 and 24 months, respectively. Thus, Calpain there was a definite correlation of the histology with the prognosis (23). Intracytoplasmic fat droplets (Oil Red O positive) are a non-specific finding and even S-100 staining may be negative in highly undifferentiated tumours. S-100 positivity has an important role in distinguishing this tumour type from malignant fibrous histiocytoma (24). An entity known as mesenteric lipodystrophy should be kept in mind as one of the differential diagnosis of mesenteric tumour. These tumours may also present as cystic masses on imaging (14).

Figure 4 STS (steroid sulfatase) and SULT1E1 (estrogen sulfotransferase 1E1) in high-grade serous ovarian carcinoma. Immunoreactivity of STS and SULT1E1 is demonstrated in paraffin-embedded tissue sections from ovarian carcinoma. Sections were probed with an antibody … Further studies in estrogen receptor alpha-expressing OVCAR-3 cells showed that STS is inhibited by the STS inhibitor STX64. As STS expression is highly variable and found at high levels in tumors of nearly all patients, blocking

the sulfatase pathway may be of values for these DNA-PK inhibitor clinical trial patients [75]. Also the aromatase pathway to convert the androgens to estrogen is active in ovarian cancer cells and will lead via the Inhibitors,research,lifescience,medical conversion of dehydroepiandrostenedione to androstenedione Inhibitors,research,lifescience,medical to the production of E2. Therefore, a combined inhibitor for both, STS and aromatase, might be suitable for these patients [76]. 4.4. Colorectal Cancer Estimated new cases and deaths from colon and rectal cancer in the USA, in 2012, were 103.170 new cases of colon cancer and 40.290 cases of rectal cancer. 51.690 deaths were from colorectal cancer [30]. These cancers accounts for approx. 10% of new cancer diagnoses among women worldwide with an incidence of 571.204 cases and a

mortality of 288.654 worldwide [31]. Colorectal cancer is the third leading cause of cancer for women after lung and breast cancer. Screening Inhibitors,research,lifescience,medical programmes for colorectal cancer in man and woman over the age of 50, now widely applied in many industrialized countries, are leading to a reduction in the incidence and mortality of colorectal cancer (similar to data shown for the USA) [77]. Estrogens were found to play a role in the pathogenesis of colorectal Inhibitors,research,lifescience,medical carcinomas and may have a protective role [78]. Many epidemiological studies have found a reduction in the risk of colon cancer associated with use of estrogen/progesterone-based regimens of HRT. Inhibitors,research,lifescience,medical Although overall diagnoses were decreased, a larger proportion of poor prognosis tumors was detected among these patients [79]. In the estrogen-alone group, there was no reduction in the risk of colorectal cancer. Therefore, a recent evaluation

of the outcome of various studies on HRT led to the conclusion that application of Carnitine palmitoyltransferase II any HRT regimen to prevent colorectal cancer is not recommended [80]. In many colon carcinoma specimens and colon cancer cell lines, ERbeta [81], aromatase, STS, SULT1E1 [82], and 17βHSDs [83] are expressed. It was also demonstrated that concentrations of estrogens in the cancer tissue were twice of those in normal colonic mucosa [82]. Moreover, higher intratumoral concentrations of total estrogens were significantly associated with poorer survival. Thereby, the ratio between STS and SULT1E1 will determine the intratumoral concentration of total estrogens and determine the clinical outcome of the patients. However, these findings are not fully supported by epidemiological data on the application of estrogens to prevent colon cancer (see above).

This applied to patients with psychotic and nonpsychotic depression. The relation between PSDEP and NE was particularly present in patients with PSDEP and melancholia. Correlation between plasma norepinephrine and vasopressin in psychotic depression Figure 1 shows the click here uncorrected positive correlations between plasma NE and lnAVP in PSDEP and non-PSDEP. Partial

correlations between NE and lnAVP were analysed in the subgroups of PSDEP (n = 9) and non-PSDEP (n = 69), and in the subgroups of melancholic PSDEP (N = 7) and all other patients (N = 71), controlling for the Inhibitors,research,lifescience,medical effects of smoking habit, tricyclic treatment and antipsychotic drug dosage. These analyses showed positive correlations Inhibitors,research,lifescience,medical in both psychotic groups (r = 0.729 and r = 0.718 respectively), and the absence of a correlation in the two patient control groups (r = 0.050 and r = 0.049). Fisher’s z test showed that these correlations differed significantly in both comparisons (z = 4.11, p < 0.01; z = 3.32; p < 0.01). Figure 1. Relations between plasma norepinephrine and vasopressin (lnAVP). Discussion Increased noradrenergic activation in psychotic depression This study confirmed the hypothesis that PSDEP is characterized by an increased concentration of plasma NE, and reconfirmed the correlation between plasma NE and AVP concentrations [Goekoop et al. 2011] while Inhibitors,research,lifescience,medical using a more complete set of confounders in the analyses. The correlation between central and

plasma NE [Esler et al. 1995; Kelly and Cooper, 1997; Ziegler et al. 1977] suggests that in PSDEP a high central noradrenergic activation may induce a high noradrenergic–vasopressinergic activation. The role of NE and AVP in the activation of the HPA axis [Al-Damluji, Inhibitors,research,lifescience,medical 1993] suggests that an increased noradrenergic–vasopressinergic mechanism combined with the increased vasopressinergic activation of the HPA axis common to all depressive disorders [Goekoop et al. 2010] could explain the very high rate of dexamethasone nonsuppression that characterizes PSDEP [Nelson and Davis, 1997]. This hypothesis should be tested Inhibitors,research,lifescience,medical in future studies. The role of confounders The search for potential confounders appeared to be very useful in this study.

As far as the subcategories of depression are concerned, neither melancholia according to the DSM-IV-TR nor the better validated HAR and ANA subcategories appeared to be significantly related to PSDEP, and only the HAR subcategory was (negatively) related to plasma NE. In contrast, all three GBA3 global dimensions of the CPRS [Goekoop et al. 1992] selected for the study eventually appeared to be related to NE. The dimension of Emotional Dysregulation was negatively related, and the dimensions of Retardation and Anxiety positively related, as has been found previously [Roy et al. 1985b]. In separate analyses PSDEP appeared to be related to the dimension of (psychomotor) Retardation, evidence of which has also been found previously [Parker et al.

12 AASs such as ND affect the structure and function of the reproductive system via impacting the secretion of FSH and LH through a negative feedback mechanism.5,13 The hormonal assay of the present study showed a rise in the level of androgens and a drop in the levels of FSH, LH, estrogen, and progesterone in the blood circulation as well as the total and cortical volumes Inhibitors,research,lifescience,medical of the ovary and the number of the ovarian primordial follicles of the ND-treated rats. This result is in agreement with those obtained by Attardi et al.14Gao et al.15 and Karbalay-Doust et al.13These authors showed that androgen reduces gonadotropin release via

a negative feedback mechanism and decreases estrogen secretion in rats and mice. Synthetic steroids such as Estradiol Valerate suppress the serum levels of LH, FSH, and sex hormones and lead to a decrease in the number of the primordial follicles in rats.16,17ND may break up the function of the neuroendocrine axis, thus modifying the ovarian function and reducing the Inhibitors,research,lifescience,medical release of gonadotropins.18 Such a decline in the levels of estrogen and progesterone in the blood may induce structural GW3965 cost changes such as a decrease in the number of the preantral and antral Inhibitors,research,lifescience,medical follicles in female rats and mice. Therefore, a reduction in the number of primordial follicles may be attributed to a reduction in the female

sex hormones. A decrease in the number of the primordial follicles in the ovary may give rise to a reduction in the volume of the ovarian cortex and, subsequently, the total ovarian volume. The destruction of various follicles following treatment with ND in rats has been demonstrated by Gerez et al.19 Elsewhere, Shirwalkar et al.16 reported that the exposure of adult rats to Estradiol Valerate results in the destruction of folliculogenesis and increase Inhibitors,research,lifescience,medical in apoptosis in the granulosa cells of secondary and antral follicles. This may suggest that the decrease in the volume of the ovary and cortex after ND administration is due to the reduction in the number of ovarian follicles. Inhibitors,research,lifescience,medical Yoshiko et al.20 reported that Ethinyl Estradiol influences the granulosa cells and oocytes

in mice and thus brings about the degeneration of primordial follicles. It seems that the interaction between degenerative follicular cells and oocytes triggers the degeneration Cell press of primordial follicles. The present study revealed that the administration of hMG with a low dose of ND (3 mg/kg) led to an increase in the total volume of the ovary, its cortical region, and the number of the primordial follicles compared with a high dose of ND (10 mg/kg) in rats. Our literature review showed that gonadotropins can be considered a primary factor for the survival and maintenance of ovarian follicles. Wang et al.7 demonstrated that hMG increases the survival of ovarian follicles by the induction of the expression of vascular endothelial growth factor (VEGF) and improves blood supply reconstruction in the ovarian tissue in mice.

Twelve to fourteen percent of GIST patients have primary this website resistance to imatinib while 40-50% develop secondary resistance with progression of disease within 2-3 years (6,7). Resistance to tyrosine kinase inhibitors is of special consideration in exon

17 mutations in both the primary and secondary settings (8). Imatinib has been demonstrated to be more effective in juxtamembrane mutations like KIT exon 11 and Inhibitors,research,lifescience,medical PDGFR exon 12 and less effective in those mutations affecting activation loops like KIT exon 17 and PDGFR exon 18 (8). Exon 17 mutants have also been shown to develop cross-resistance to sunitinib. Sunitinib has been approved as second line treatment following development of resistance or treatment failure with imatinib (9). A 2012 retrospective analysis of sorafenib as third or fourth line therapy Inhibitors,research,lifescience,medical in advanced GIST demonstrated a median overall survival of 13.5 months (10). Sorafenib, with its antagonism of the activation loop in exon 17 mutants, has provided rationale for its use in imatinib-resistant patients (11). Studies have suggested a role for intermittent imatinib in exon 17 mutant GIST (12). Liegl et Inhibitors,research,lifescience,medical al. reported on the heterogeneity of kinase inhibitors resistance mechanism in GIST, in a study of 53 GIST

metastases in 14 patients, 6 out of 14 patients had two to five different secondary mutations in separate metastases. Furthermore, three patients were found to have two secondary KIT mutations within the same metastasis thus potentially raising the question Inhibitors,research,lifescience,medical of a consideration for studies evaluating combining TKI monotherapies if deemed tolerable and beneficial (13). Inhibitors,research,lifescience,medical While our patient developed resistance to

imatinib six months after initiating therapy, he has had quite durable responses to sorafenib plus imatinib lasting more than two years. Recently, regorafenib has been approved for 3rd line treatment of GIST following progression after imatinib and sunitinib. GRID—a randomized phase 3 trial of 133 patients treated with regorafenib 160 mg once daily three out of four Parvulin weeks showed a significantly improved PFS of 4.8 versus 0.9 months in the placebo arm (n=66) (14). Further studies are warranted to understand the role of regorafenib in patients with exon 17 mutations. Acknowledgements Disclosure: The authors declare no conflict of interest.
The liver is the most frequent site of metastasis from colorectal cancer. In patients with resectable colorectal liver metastases (CLM), the efficacy of hepatic resection (HR) has been established. HR is associated with low peri-operative mortality and morbidity (1,2) and 5-year survival rates ranging from 25% to 58% (3-8). Traditionally, only 10-15% of patients with CLM were considered as candidates for HR (9).