Association between KLF6 rs3750861 polymorphism and plasma ceramide concentrations in post-menopausal women with type 2 diabetes.

BACKGROUND AND AIM: Based on the emerging role of Kruppel-like factor 6 (KLF6) in lipid metabolism, we examined whether there is a relationship between the KLF6 rs3750861 genetic variant and plasma ceramide levels in people with type 2 diabetes mellitus (T2DM). METHODS AND RESULT: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] amongst 101 Caucasian post-menopausal women with T2DM, who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramides were measured by targeted liquid chromatography-tandem mass spectrometry assay. Genotyping of the KLF6 rs3750861 polymorphism was performed by TaqMan-Based RT-PCR system. Overall, 87 (86.1%) patients had KLF6 rs3750861 C/C genotype and 14 (13.9%) had C/T or T/T genotypes. After adjustment for age, diabetes-related variables, use of lipid-lowering drugs and other potential confounders, patients with C/T or T/T genotypes had higher plasma Cer(d18:1/18:0) (0.159 ± 0.05 vs. 0.120 ± 0.04 µmol/L, p = 0.012), Cer(d18:1/20:0) (0.129 ± 0.04 vs. 0.098 ± 0.03 µmol/L, p = 0.008), and Cer(d18:1/24:1) (1.236 ± 0.38 vs. 0.978 ± 0.36 µmol/L, p = 0.032) compared with those with C/C genotype. CONCLUSIONS: The C/T or T/T genotypes of rs3750861 in the KLF6 gene were closely associated with higher levels of specific plasma ceramides in post-menopausal women with T2DM.

Role of Ulcerative Colitis Endoscopic Index of Severity (UCEIS) versus Mayo Endoscopic Subscore (MES) in Predicting Patients' Response to Biological Therapy and the Need for Colectomy.

BACKGROUND: The main goal in the treatment of ulcerative colitis (UC) is to achieve mucosal healing. Despite being unvalidated, the most widely used scoring system is the Mayo endoscopic subscore (MES). However, the recently established and validated Ulcerative Colitis Endoscopic Index of Severity (UCEIS) represents an interesting alternative method in assessing endoscopic disease activity. OBJECTIVE: Due to a lack of reliable prognostic factors, the aim of this study was to investigate the diagnostic accuracy of the UCEIS and the MES, in predicting response to biological therapy and the need for colectomy. METHODS: We conducted a retrospective, uncontrolled, single-center study on UC patients with endoscopically active disease even with concomitant conventional and/or biological therapy, who had already started or had been changed a biological treatment. RESULTS: Sixty-one UC patients were enrolled. At baseline, 71% were naive to biological therapies and 41% had an extensive colitis. At control time (median time of 11.5 months), MES and UCEIS scores significantly decreased from those at baseline (from 2.6 to 1.8 and 5 to 3.2, respectively, p < 0.001). UCEIS, but not MES, was found to be significantly associated with unresponsiveness to therapy (p = 0.040). Moreover, when UCEIS was ≥7, all patients underwent colectomy after a median time of 5 months (p < 0.001). CONCLUSION: UCEIS may be superior to MES because of its accuracy and predictive role. Therefore, UCEIS should be considered for use in daily clinical practice.

A Seroprevalence Study of Anti-SARS-CoV-2 Antibodies in Patients with Inflammatory Bowel Disease during the Second Wave of the COVID-19 Pandemic in Italy.

Background and Objectives: Studies have shown a lower prevalence of anti-SARS-CoV-2 antibodies in patients with inflammatory bowel disease (IBD), including amongst those receiving biological therapy. Aims were to determine the seroprevalence of anti-SARS-CoV-2 antibodies in IBD patients and to assess any association between seropositivity and IBD characteristics. Materials and Methods: Serum from adult IBD patients was prospectively collected between December 2020 and January 2021 and analyzed for anti-SARS-CoV-2 antibodies. Information about IBD characteristics and SARS-CoV-2 exposure risk factors was collected and analyzed. Serum from non-IBD healthcare workers formed the control group. Results: 311 IBD patients on biologics and 75 on mesalazine were enrolled. Ulcerative colitis (UC) extension (p < 0.001), Crohn's disease (CD) phenotype (p = 0.009) and use of concomitant corticosteroids (p < 0.001) were significantly different between the two IBD groups. Overall seroprevalence among IBD patients was 10.4%. The control group showed a prevalence of 13.0%, not significantly different to that of IBD patients (p = 0.145). Only a close contact with SARS-CoV-2 positive individuals and the use of non-FFP2 masks were independently associated with a higher likelihood of seropositivity amongst IBD patients. Conclusion: In IBD patients, the prevalence of anti-SARS-CoV-2 antibodies is not determined by their ongoing treatment. Disease-related characteristics are not associated with a greater risk of antibody seropositivity.

Oral anticancer therapy project: Clinical utility of a specific home care nursing programme on behalf of Italian Association of Medical Oncology (AIOM).

AIMS AND OBJECTIVES: To assess the effectiveness of a specific home care nursing programme in addition to standard care in patients (pts) receiving oral anticancer treatments. BACKGROUND: Oral anticancer therapy present challenges for pts since treatment is a home-based therapy. This study evaluates the potentiality of a home care nursing programme in decreasing hospital accesses for not severe toxicity. METHODS: This is an open-label, multicentre, randomised trial including pts who were receiving an anticancer oral drug. The study complies with the CONSORT checklist published in 2010. Concomitant use of radiation therapy, intravenous or metronomic therapies, or the intake of previous oral drugs was not allowed. Pts were randomly assigned to home care nursing programme (A) or standard care (B). In arm A, dedicated nurses provided information to pts, a daily record on which pts would take note of drugs and dosages and a telephone monitoring during the first two cycles of therapy. The primary outcome was the reduction in improper hospital accesses for grade 1-2 toxicity according to CTCAE v4.0. RESULTS: Out of 432 randomised pts, 378 were analysed (184 pts in arm A and 194 in arm B). Hospital accesses were observed in 41 pts in arm A and in 42 pts in arm B (22.3% vs. 21.6%, respectively). No difference was detected in proportion of improper accesses between arm A and arm B (29.3% vs. 23.8%, respectively). CONCLUSIONS: Our experience failed to support the role of a specific home care nursing programme for pts taking oral chemotherapy. An improved attention to specific educational practice and information offered to pts can explain these results. RELEVANCE TO CLINICAL PRACTICE: Our results underline the role of nurse educational practice and information offered to patients. A careful nurse information of patients about drugs is essential to reduce toxicities avoiding the opportunity of a specific home monitoring.

Association of Plasma Ceramides With Myocardial Perfusion in Patients With Coronary Artery Disease Undergoing Stress Myocardial Perfusion Scintigraphy.

Objective- It is known that specific plasma ceramides are associated with stress-induced reversible myocardial perfusion defects in patients with established or suspected coronary artery disease undergoing myocardial perfusion scintigraphy (MPS). However, it is currently uncertain whether plasma ceramides are also associated with reduced poststress myocardial perfusion in these patients. Approach and Results- We measured 6 previously identified high-risk plasma ceramide species (ceramide [d18:1/16:0], ceramide [d18:1/18:0], ceramide [d18:1/20:0], ceramide [d18:1/22:0], ceramide [d18:1/24:0], and ceramide [d18:1/24:1]) in 167 consecutive patients with established or suspected coronary artery disease undergoing stress MPS for clinical indications. Plasma ceramides were measured by a targeted liquid chromatography-tandem mass spectrometry assay both at baseline and after MPS. Multivariable linear regression analysis was undertaken to examine the associations (standardized B coefficients) between plasma ceramides and the percentage of poststress myocardial perfusion after adjustment for multiple cardiovascular risk factors. Seventy-eight patients had stress-induced myocardial ischemia on MPS (mainly located in the anteroapical wall). Of the 6 measured plasma ceramides, higher levels of basal ceramide (d18:1/18:0; B=-0.182; P=0.019), ceramide (d18:1/20:0; B=-0.224; P=0.004), ceramide (d18:1/22:0; B=-0.163; P=0.035), and ceramide (d18:1/24:1; B=-0.20; P=0.010) were associated with lower poststress anteroapical wall perfusion. Notably, these significant associations persisted even after adjustment for conventional cardiovascular risk factors, previous coronary artery disease, electrocardiographic left bundle branch block, left ventricular ejection fraction and type of stress testing. Similar results were observed for poststress plasma ceramides. Conclusions- Higher circulating levels of specific ceramides, both at baseline and after stress, were independently associated with lower poststress anteroapical wall perfusion in patients with suspected or established coronary artery disease referred for clinically indicated MPS.

Prospective randomized controlled trial for patch augmentation in rotator cuff repair: 24-month outcomes.

BACKGROUND: To evaluate the anatomic integrity of rotator cuff repair performed by medialized single row and augmented by a porcine dermal patch, in comparison with a nonaugmented group. METHODS: We conducted a single-center, prospective, double-blinded, randomized controlled trial. The sample size was predefined, and patients were divided into a study group and a control group, assessed preoperatively and at 1, 3, 6, 12, and 24 months. The EuroQol-visual analog scale; Constant-Murley questionnaire; Disabilities of the Arm, Shoulder and Hand Score; and Simple Shoulder Test were administered. The humeral-acromial distance was calculated on radiographs. Tendon thickness, tear extension, and tendon signal intensity were all measured on magnetic resonance images (MRIs) along with an evaluation of footprint extension and a classification into one of 4 healing grades-healed, thinned, partially healed, not healed. RESULTS: The study population consisted of 92 patients who were equally randomized into 2 homogenous groups. Sixty-nine patients completed the 24-month follow-up. The study group showed a healing rate of 97.6% compared with 59.5% for the standard repair group. The study group showed better results in terms of repaired tendon thickness and footprint coverage, with a P value < .05, although the tendon density was comparable. The study group showed better strength recovery and functionality with the outcome scores submitted. During the entire study, only 2 patients reported complications, calling for a biopsy during revision surgery. CONCLUSIONS: Rotator cuff repairs augmented with a porcine dermal patch resulted in excellent clinical outcomes with a higher healing rate and close-to-normal MRI findings. The technique is safe and effective; in addition, it is reproducible and allows for better outcomes compared with those of standard medialized single-row repairs.

Neuroendocrine differentiation in breast carcinoma: clinicopathological features and outcome.

AIMS: Primary neuroendocrine (NE) breast carcinoma (BC) is an entity with a wide range of prevalence and poorly defined clinical behaviour. We evaluated the prevalence, clinicopathological features and clinical outcome of NEBC. METHODS AND RESULTS: Immunohistochemical staining for synaptophysin and chromogranin A was performed on whole sections from 1232 consecutive cases of invasive BC. We divided NEBC into focal (10-49% positive cells) and diffuse (≥50% positive cells) and compared the outcome of patients with NEBC with strictly matched non-NEBC. A total of 128 BC showed NE differentiation (10.4%): 84 diffuse (6.8%) and 44 focal (3.6%). NE differentiation showed a significant association with T4 stage (P = 0.001), solid-papillary and mucinous histotype (P < 0.0001), G2 grading (P = 0.002), positive oestrogen receptor (ER) (P = 0.003) and progesterone receptor (PR) (P = 0.002). Almost 90% of NEBC were ER(+) /HER2(-) and more than half ER(+) /HER2(-) /Ki67≥14%. Kaplan-Meier analysis revealed that patients with NEBC showed worse disease-free survival (DFS) (P = 0.04) compared to matched non-NEBC. We did not find significant differences regarding clinicopathological features, DFS and CSS between diffuse and focal neuroendocrine BC. CONCLUSIONS: This study demonstrates that NEBC represents 7-10% of invasive BC and that NE differentiation does not affect the prognosis of BC in terms of CSS.

Alectinib's activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series.

In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS.

Failure of dihydroartemisinin-piperaquine treatment of uncomplicated Plasmodium falciparum malaria in a traveller coming from Ethiopia.

BACKGROUND: Artemisinin combination therapy (ACT) is used worldwide as the first-line treatment against uncomplicated Plasmodium falciparum malaria. Despite the success of ACT in reducing the global burden of malaria, the emerging of resistance to artemisinin threatens its use. CASE REPORT: This report describes the first case of failure of dihydroartemisinin-piperaquine (DHA-PPQ) for the treatment of P. falciparum malaria diagnosed in Europe. It occurred in an Italian tourist returned from Ethiopia. She completely recovered after the DHA-PPQ treatment but 32 days after the end of therapy she had a recrudescence. The retrospective analysis indicated a correct DHA-PPQ absorption and genotyping demonstrated that the same P. falciparum strain was responsible for the both episodes. CONCLUSION: In consideration of the growing number of cases of resistance to ACT, it is important to consider a possible recrudescence, that can manifest also several weeks after treatment.

Analysis of in vitro ADCC and clinical response to trastuzumab: possible relevance of FcγRIIIA/FcγRIIA gene polymorphisms and HER-2 expression levels on breast cancer cell lines.

BACKGROUND: Trastuzumab is a humanized monoclonal antibody (mAb) currently used for the treatment of breast cancer (BC) patients with HER-2 overexpressing tumor subtype. Previous data reported the involvement of FcγRIIIA/IIA gene polymorphisms and/or antibody-dependent cellular cytotoxicity (ADCC) in the therapeutic efficacy of trastuzumab, although results on these issues are still controversial. This study was aimed to evaluate in vitro the functional relationships among FcγRIIIA/IIA polymorphisms, ADCC intensity and HER-2 expression on tumor target cells and to correlate them with response to trastuzumab. PATIENTS AND METHODS: Twenty-five patients with HER-2 overexpressing BC, receiving trastuzumab in a neoadjuvant (NEO) or metastatic (MTS) setting, were genotyped for the FcγRIIIA 158V>F and FcγRIIA 131H>R polymorphisms by a newly developed pyrosequencing assay and by multiplex Tetra-primer-ARMS PCR, respectively. Trastuzumab-mediated ADCC of patients' peripheral blood mononuclear cells (PBMCs) was evaluated prior to therapy and measured by (51)Chromium release using as targets three human BC cell lines showing different levels of reactivity with trastuzumab. RESULTS: We found that the FcγRIIIA 158F and/or the FcγRIIA 131R variants, commonly reported as unfavorable in BC, may actually behave as ADCC favorable genotypes, in both the NEO (P ranging from 0.009 to 0.039 and from 0.007 to 0.047, respectively) and MTS (P ranging from 0.009 to 0.032 and P = 0.034, respectively) patients. The ADCC intensity was affected by different levels of trastuzumab reactivity with BC target cells. In this context, the MCF-7 cell line, showing the lowest reactivity with trastuzumab, resulted the most suitable cell line for evaluating ADCC and response to trastuzumab. Indeed, we found a statistically significant correlation between an increased frequency of patients showing ADCC of MCF-7 and complete response to trastuzumab in the NEO setting (P = 0.006). CONCLUSIONS: Although this study was performed in a limited number of patients, it would indicate a correlation of FcγR gene polymorphisms to the ADCC extent in combination with the HER-2 expression levels on tumor target cells in BC patients. However, to confirm our findings further experimental evidences obtained from a larger cohort of BC patients are mandatory.

P16 but not retinoblastoma expression is related to clinical outcome in no-special-type triple-negative breast carcinomas.

Triple-negative breast carcinomas represent a tumor group of pivotal clinical importance given the lack of target therapies. The prognostic significance of triple-negative breast carcinomas remains unclear because of their histological and molecular heterogeneity. Currently, neither prognostic nor predictive factors are available for these tumors. Retinoblastoma (Rb) pathway loss has been linked to clinical outcome in various cancer types, including breast cancer. We investigated the association between Rb and p16 protein expression and clinical outcome in no-special-type triple-negative breast carcinomas. Immunohistochemical staining for Rb, p16, p53 and CK5 was carried out on a section from archival specimens of 117 no-special-type triple-negative breast carcinomas. Immunopositive p16 (p16+) and immunonegative Rb (Rb-) staining were seen in 49.5% and in 24.8% of tumors, respectively. There was an inverse correlation between p16+ and Rb- (P<0.001). P16+ was correlated with G3 grade (P<0.001), high Ki-67 (P=0.03), p53 overexpression (P<0.001) and CK5 immunopositivity (P=0.01). Rb- was not associated with any clinicopathologic variable. Follow-up and therapy data were available in 95 patients. In 20 patients treated with surgery only, neither p16+ nor Rb- immunostaining were associated with disease-free survival and overall survival. In 75 patients treated with adjuvant chemotherapy, p16+ was associated with good response to therapy with significant increased disease-free survival (P=0.001) and showed a trend towards a statistical significance for increased overall survival (P=0.056); Rb- were not associated with disease-free survival and overall survival. In multivariate analysis, p16+ was independently associated with disease-free and overall survival, with a hazard ratio of 0.18 (95% CI: 0.06-0.51; P=0.001) and 0.21 (95% CI: 0.06-0.74; P=0.015), respectively. In patients with no-special-type triple-negative breast carcinomas, p16+ is related to good response to adjuvant chemotherapy and can be considered the best surrogate marker for Rb pathway loss.

Trastuzumab quantification in serum: a new, rapid, robust ELISA assay based on a mimetic peptide that specifically recognizes trastuzumab.

Trastuzumab, a humanized monoclonal antibody directed against the epidermal growth factor receptor 2 (HER2), is a milestone in the treatment of HER2-overexpressing breast cancer patients. An enzyme-linked immunosorbent assay (ELISA) for trastuzumab has been developed for routine use in the laboratory to support clinical and pharmacokinetic studies to optimize therapy. The method relies on an antigen peptide linked to a 96-well plate via the streptavidin/biotin system. The peptide sequence mimics the extracellular portion of the HER2 receptor that is recognized by trastuzumab. The calibration range of the assay is 10 to 360 ng/mL per well, corresponding to a trastuzumab serum concentration from 5 to 180 µg/mL with a lower limit of quantification of 10 µg/mL. Validation results demonstrate that trastuzumab can be accurately and precisely quantified in human serum using this assay. The procedure was also tested in sera obtained from breast cancer patients to evaluate trastuzumab serum levels, confirming the applicability of method that could be a valid assay to use in daily laboratory practice.

Repotrectinib's Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer.

In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier.

Failure of malaria chemoprophylaxis with mefloquine in an oversize traveller to Mozambique.

A case of failure of mefloquine prophylaxis in an oversize traveller, who correctly took the drug. This case seems to be attributed to mefloquine resistance, however it is suggested that mefloquine dosage should be modulated by body weight, as is already indicated by some authorities.

SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials.

PURPOSE: In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. EXPERIMENTAL DESIGN: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. RESULTS: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04-2.94)], rs749292 [sHR 2.11, (1.12-3.94)], and rs727479 [sHR 2.62, (1.17-5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026). CONCLUSIONS: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

A predictive model of polymetastatic disease from a multicenter large retrospectIve database on colorectal lung metastases treated with stereotactic ablative radiotherapy: The RED LaIT-SABR study.

Aim: Stereotactic ablative radiotherapy (SABR) showed increasing survival in oligometastatic patients. Few studies actually depicted oligometastatic disease (OMD) evolution and which patient will remain disease-free and which will rapidly develop a polymetastatic disease (PMD) after SABR. Therefore, apart from the number of active metastases, there are no clues on which proven factor should be considered for prescribing local treatment in OMD. The study aims to identify predictive factors of polymetastatic evolution in lung oligometastatic colorectal cancer patients. Methods: This international Ethical Committee approved trial (Prot. Negrar 2019-ZT) involved 23 Centers and 450 lung oligometastatic patients. Primary end-point was time to the polymetastatic conversion (tPMC). Additionally, oligometastases number and cumulative gross tumor volume (cumGTV) were used as combined predictive factors of tPMC. Oligometastases number was stratified as 1, 2-3, and 4-5; cumGTV was dichotomized to the value of 10 cc. Results: The median tPMC in the overall population was 26 months. Population was classified in the following tPMC risk classes: low-risk (1-3 oligometastases and cumGTV ≤ 10 cc) with median tPMC of 35.1 months; intermediate-risk (1-3 oligometastases and cumGTV > 10 cc), with median tPMC of 13.9 months, and high-risk (4-5 oligometastases, any cumGTV) with median tPMC of 9.4 months (p = 0.000). Conclusion: The present study identified predictive factors of polymetastatic evolution after SABR in lung oligometastatic colorectal cancer. The results demonstrated that the sole metastases number is not sufficient to define the OMD since patients defined oligometastatic from a numerical point of view might rapidly progress to PMD when the cumulative tumor volume is high. A tailored approach in SABR prescription should be pursued considering the expected disease evolution after SABR, with the aim to avoid unnecessary treatment and toxicity in those at high risk of polymetastatic spread, and maximize local treatment in those with a favorable disease evolution.

Tryptophan hydroxylase 2 (TPH2) in a neuronal cell line: modulation by cell differentiation and NRSF/rest activity.

Serotonin (5-HT) is a neurotransmitter involved in many aspects of the neuronal function. The synthesis of 5-HT is initiated by the hydroxylation of tryptophan, catalyzed by tryptophan hydroxylase (TPH). Two isoforms of TPH (TPH1 and TPH2) have been identified, with TPH2 almost exclusively expressed in the brain. Following TPH2 discovery, it was reported that polymorphisms of both gene and non-coding regions are associated with a spectrum of psychiatric disorders. Thus, insights into the mechanisms that specifically regulate TPH2 expression and its modulation by exogenous stimuli may represent a new therapeutic approach to modify serotonergic neurotransmission. To this aim, a CNS-originated cell line expressing TPH2 endogenously represents a valid model system. In this study, we report that TPH2 transcript and protein are modulated by neuronal differentiation in the cell line A1 mes-c-myc (A1). Moreover, we show luciferase activity driven by the human TPH2 promoter region and demonstrate that upon mutation of the NRSF/REST responsive element, the promoter activity strongly increases with cell differentiation. Our data suggest that A1 cells could represent a model system, allowing an insight into the mechanisms of regulation of TPH2 and to identify novel therapeutic targets in the development of drugs for the management of psychiatric disorders.

Association between Higher Circulating Leucine-Rich α-2 Glycoprotein 1 Concentrations and Specific Plasma Ceramides in Postmenopausal Women with Type 2 Diabetes.

Background: Although ceramides are involved in the pathophysiology of cardiovascular disease and other inflammation-associated disorders, there is a paucity of data on the association between plasma ceramides and inflammatory biomarkers in type 2 diabetes mellitus (T2DM). Therefore, we explored whether there was an association between plasma leucine-rich α-2 glycoprotein 1 (LRG1) concentrations (i.e., a novel proinflammatory signaling molecule) and specific plasma ceramides in postmenopausal women with T2DM. Methods: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)], amongst 99 Caucasian postmenopausal women with non-insulin-treated T2DM (mean age 72 ± 8 years, mean hemoglobin A1c 6.9 ± 0.7%), who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramide and LRG1 concentrations were measured with a targeted liquid chromatography-tandem mass spectrometry assay and a Milliplex® MAP human cardiovascular disease magnetic bead kit, respectively. Results: In linear regression analyses, higher plasma LRG1 levels (1st tertile vs. 2nd and 3rd tertiles combined) were associated with higher levels of plasma Cer(d18:1/16:0) (standardized ß coefficient: 0.289, p = 0.004), Cer(d18:1/18:0) (standardized ß coefficient: 0.307, p = 0.002), Cer(d18:1/20:0) (standardized ß coefficient: 0.261, p = 0.009) or Cer(d18:1/24:1) (standardized ß coefficient: 0.343, p < 0.001). These associations remained significant even after adjusting for age, body mass index, systolic blood pressure, total cholesterol level, hemoglobin A1c, insulin resistance and statin use. Conclusions: The results of our pilot exploratory study suggest that higher plasma LRG1 concentration was associated with higher levels of specific high-risk plasma ceramide molecules in elderly postmenopausal women with metabolically well-controlled T2DM, even after adjusting for known cardiovascular risk factors and other potential confounding variables.

The predictive and prognostic role of metabolic and volume-based parameters of positron emission tomography/computed tomography as non-invasive dynamic biological markers in early breast cancer treated with preoperative systemic therapy.

Introduction: The role of fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in early breast cancer treated with preoperative systemic therapy (PST) is not yet established in clinical practice. PET parameters have aroused great interest in the recent years, as non-invasive dynamic biological markers for predicting response to PST. Methods: In this retrospective study, we included 141 patients with stage II-III breast cancer who underwent surgery after PST. Using ROC analysis, we set optimal cutoff of FDG-PET/CT parameters predictive for pathological complete response (pCR). We investigated the correlation between FDG-PET/CT parameters and pCR, median disease-free survival (DFS), and median overall survival (mOS). Results: At multivariable analysis, baseline SUVmax (high vs low: OR 9.00, CI 1.85 - 61.9, p=0.012) and Delta SUVmax (high vs low: OR 9.64, CI 1.84, 69.2, p=0.012) were significantly associated with pCR rates. Interestingly, we found that a combined analysis of the metabolic parameter Delta SUVmax with the volume-based parameter Delta MTV, may help to identify patients with pCR, especially in the subgroup of hormone receptor positive breast cancer. Delta SUVmax was also an independent predictive marker for both mDFS (high vs low: HR 0.17, 95%CI 0.05-0.58, p=0.004) and mOS (high vs. low: HR 0.19, 95%CI 0.04-0.95, p=0.029). Discussion: Our results suggest that Delta SUVmax may predict survival of early BC patients treated with PST.

High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial.

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. The aim of this study was to assess the safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. This was a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants were adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection. Exclusion criteria were: pregnant or lactating women; CNS disease; dialysis; severe medical condition with prognosis <6 months; warfarin treatment; and antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned (ratio 1:1:1) according to a randomised permuted block procedure to one of the following arms: placebo (arm A); single-dose ivermectin 600 µg/kg plus placebo for 5 days (arm B); and single-dose ivermectin 1200 µg/kg for 5 days (arm C). Primary outcomes were serious adverse drug reactions (SADRs) and change in viral load at Day 7. From 31 July 2020 to 26 May 2021, 32 participants were randomised to arm A, 29 to arm B and 32 to arm C. Recruitment was stopped on 10 June because of a dramatic drop in cases. The safety analysis included 89 participants and the change in viral load was calculated in 87 participants. No SADRs were registered. Mean (S.D.) log10 viral load reduction was 2.9 (1.6) in arm C, 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (P = 0.099 and 0.122 for C vs. A and B vs. A, respectively). High-dose ivermectin was safe but did not show efficacy to reduce viral load.