The predictive and prognostic role of single nucleotide gene variants of PD-1 and PD-L1 in patients with advanced melanoma treated with PD-1 inhibitors.

Background: Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis. Methods: We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS. Results: A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P = 0.028) in the homozygous model. Conclusions: Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results.

Evaluation of plasma antioxidant levels during different phases of illness in adult patients with bipolar disorder.

The aim of the present study is to evaluate role of plasma antioxidants (albumin, bilirubin and uric acid) in patients suffering from type I Bipolar Disorder (BD-I) during different phases of illness: acute mania, euthymia and bipolar depression. Medical records of consecutive 110 BD-I patients (38 patients with acute mania, 35 in euthymic state, full remission, and 37 in depressive phase) were reviewed to evaluate plasma antioxidant levels. Laboratory data of 40 healthy controls were also obtained. The scores of Young Mania Rating Scale (YMRS), Bech-Rafaelsen Manic Rating Scale (BRMRS) and Hamilton Rating Scale for Depression (HAM-D) were evaluated. Serum uric acid levels were higher in acute mania than other patient subgroups and healthy controls. Serum uric acid levels directly correlated with BRMRS and YMRS scores. No differences were found between clinical groups during different phases and healthy controls concerning albumin and bilirubin. In conclusion, the results of the present study support the notion that serum uric acid levels may be higher in patients with BP-I (especially during manic phases) which may suggest a dysregulation of the purinergic system. However, limitations should be considered and further studies are needed.

Evaluation of C-reactive protein and total serum cholesterol in adult patients with bipolar disorder.

The aim of the present study is to evaluate the role of CRP and Total Cholesterol (TC) in patients suffering from type I Bipolar Disorder (BD-I). Moreover, the goal is to elucidate possible CRP and TC differences in different phases of BD-I: acute mania, euthymia and bipolar depression. Medical records of 90 BD-I patients (30 patients with acute mania, 30 in euthymic state, full remission, and 30 in depressive phase) were reviewed to evaluate serum CRP and TC levels. Laboratory data of 30 healthy controls were also obtained. The scores of Young Mania Rating Scale (YMRS), Bech-Rafaelsen Manic Rating Scale (BRMRS) and Hamilton Rating Scale for Depression (HAM-D) were evaluated. CRP levels were higher in acute mania and depressive phase subgroups when compared to healthy controls. CRP was positively associated with BRMRS and YMRS scores in acute mania and with HAM-D in depressive phase subgroups. TC levels were lower in all clinical groups compared to controls. TC levels were negatively correlated to BRMRS, YMRS and HAM-D. In conclusion, the results of the present study support the notion that CRP and TC may be altered in patients with BP-I.

The role of C-reactive protein in mood disorders.

Recently, a possible relationship between C-Reactive Protein (CRP), a marker of underlying low-grade inflammation, and mood disorders has been proposed by some researchers. The aim of this review is to elucidate the current facts and views about CRP in mood disorders such as Depressive and Bipolar Disorders. Several studies have examined the relationship between affective disorders and CRP, but the majority of the studies in literature have been limited by retrospective, case-controlled study design, and very few studies have examined the relationship between depression and CRP in large study samples. In conclusion, the role of CRP in mood disorders is, to date, intriguing but somewhat unclear. Further prospective studies are needed to introduce the CRP in clinical settings as a marker of affective states and suicidability.

Diagnostic accuracy of portal-phase CT and MRI with mangafodipir trisodium in detecting liver metastases from colorectal carcinoma.

AIM: To compare the diagnostic accuracy of single section spiral computed tomography (CT) and magnetic resonance imaging (MRI) with tissue-specific contrast agent mangafodipir trisodium (MnDPDP) in the detection of colorectal liver metastases. MATERIAL AND METHODS: One hundred and twenty-five consecutive patients undergoing surgery for primary and/or metastatic disease were evaluated using CT (5 mm collimation and reconstruction interval, pitch 2), two-dimensional fast spoiled gradient echo (2D FSPGR) T1 and single shot fast-spin echo (SSFSE) T2 weighted breath-hold MRI sequences, performed before and after intravenous administration of MnDPDP. The reference standards were intraoperative ultrasound and histology. RESULTS: The per-patient accuracy of CT was 72.8 versus 78.4% for unenhanced MRI (p = 0.071) and 82.4% for MnDPDP-enhanced MRI (p = 0.005). MnDPDP-enhanced MRI appeared to be more accurate than unenhanced MRI but this was not significant (p = 0.059). The sensitivity of CT was 48.4% versus 58.1% for unenhanced MRI (p = 0.083) and 66.1% for MnDPDP-enhanced MRI (p = 0.004). The difference in specificity between procedures was not significant. The per-lesion sensitivity was 71.7, 74.9 and 82.7% for CT, unenhanced MRI, and MnDPDP-enhanced MRI, respectively; the positive predictive value of the procedures was respectively 84.0, 96.0 and 95.8%. MnDPDP-enhanced MRI provided a high level diagnostic confidence in 92.5% of the cases versus 82.5% for both unenhanced MRI and CT. The kappa value for inter-observer variability was >0.75 for all procedures. CONCLUSIONS: The diagnostic accuracy and sensitivity of MnDPDP-enhanced MRI is significantly higher than single section spiral CT in the detection of colorectal cancer liver metastases; no significant difference in diagnostic accuracy was observed between unenhanced MRI and MnDPDP-enhanced MRI.

Effect of mirtazapine on thyroid hormones in adult patients with major depression.

Hypothalamic pituitary thyroid (HPT) axis abnormalities and alterations in major depression are reported in the literature. The aim of our study was to evaluate the effect of mirtazapine on thyroid hormones after 6 months of therapy in a sample of adult outpatients with Major Depression (MD). 17 adult outpatients (7 men, 10 women) with MD according to DSM-IV criteria, were included in the study. All participants had to have met criteria for a major depressive episode with a score of at least 15 on the Hamilton Depression Rating Scale (HAM-D). Fasting venous blood samples were obtained for determination of serum Thyroid Stimulating Hormone (TSH), Free T3 (FT3) and Free T4 (FT4) concentrations both at baseline and after 6 months of therapy. HAM-D scores decreased significantly from the first day of treatment to the end of the treatment period (P<0.001) and twelve patients (70.6%) were classified as responders. A significant increase in FT3 concentrations was found between baseline and the end of the treatment period (P=0.015), whereas FT4 concentrations decreased (P=0.046). No significant changes were found in TSH levels. Higher FT4 concentrations at baseline predicted higher HAM-D scorers both at baseline and at the end of the treatment period. Furthermore, higher FT3 concentrations at endpoint were found to be predictors of lower HAM-D scores. Long-term treatment with mirtazapine increases FT3 levels and decreases FT4 maybe involving the deiodination process of T4 into T3.

Preserved oral reading in Wernicke's aphasia.

In two patients with Wernicke's aphasia, both oral reading and reading comprehension were relatively preserved despite total destruction of Wernicke's area. The pattern of oral reading suggested an intact ability to derive phonology directly from print; the pattern of reading comprehension implied at least partial ability to interpret syntactic constructions. These features are not readily compatible with current notions of right hemisphere function and may suggest that undamaged left hemisphere structures mediated residual reading in these patients.

Wernicke's and global aphasia without alexia.

It has been proposed that the comprehension of written language requires transcoding from the visual (grapheme) to the auditory (phoneme). It has also been proposed that visual word images can be comprehended without grapheme-phoneme transcoding. We describe three aphasic patients with left hemisphere impairment who had poor speech comprehension but could comprehend written language. One of these patients had a subsequent right hemisphere lesion and lost his ability to read. We propose that the right hemisphere in some individuals may be capable of extracting semantic information from iconic images (ideogram) without phonological processing.