Identification of 2-aminopyrimidine derivatives as inhibitors of the canonical Wnt signaling pathway.

The canonical Wnt signaling pathway plays a fundamental role in embryonic as well as in adult development. Consequently, dysregulation of the pathway has been linked to a wide spectrum of pathological conditions. In a program aimed at the identification of small molecule inhibitors of the canonical Wnt pathway we identified a series of 2-aminopyrimidine derivatives which specifically inhibited the pathway with minimal or no sign of cellular toxicity. The hit molecules 1 and 2 showed promising inhibitory activity with IC50 values of approximately 10 µM, but low solubility and metabolic stability. During the early stage of the hit series exploration, the pyrimidine core was variously decorated to obtain active compounds with a better physico-chemical profile. In particular, compound 13 showed Wnt inhibition activity comparable to hit molecules 1 and 2, with improved physico-chemical properties. Therefore, this series of compounds may be considered a promising starting point for the design of novel small molecule inhibitors of the canonical Wnt pathway.

The Deterioration of Sarcopenia Post-Transarterial Radioembolization with Holmium-166 Serves as a Predictor for Disease Progression at 3 Months in Patients with Advanced Hepatocellular Carcinoma: A Pilot Study.

PURPOSE: The aim of this pilot study is to explore the relationship between changes in sarcopenia before and after one to three months of Transarterial Radioembolization (TARE) treatment with Holmium-166 (166Ho) and its effect on the rate of local response. Our primary objective is to assess whether the worsening of sarcopenia can function as an early indicator of a subgroup of patients at increased risk of disease progression in cases of hepatocellular carcinoma (HCC). METHODS: A single-center retrospective analysis was performed on 25 patients with HCC who underwent 166Ho-TARE. Sarcopenia status was defined according to the measurement of the psoas muscle index (PMI) at baseline, one month, and three months after TARE. Radiological response according to mRECIST criteria was assessed and patients were grouped into responders and non-responders. The loco-regional response rate was evaluated for all patients before and after treatment, and was compared with sarcopenia status to identify any potential correlation. RESULTS: A total of 20 patients were analyzed. According to the sarcopenia status at 1 month and 3 months, two groups were defined as follows: patients in which the deltaPMI was stable or increased (No-Sarcopenia group; n = 12) vs. patients in which the deltaPMI decreased (Sarcopenia group; n = 8). Three months after TARE, a significant difference in sarcopenia status was noted (p = 0.041) between the responders and non-responders, with the non-responder group showing a decrease in the sarcopenia values with a median deltaPMI of -0.57, compared to a median deltaPMI of 0.12 in the responder group. Therefore, deltaPMI measured three months post-TARE can be considered as a predictive biomarker for the local response rate (p = 0.028). Lastly, a minor deltaPMI variation (>-0.293) was found to be indicative of positive treatment outcomes (p = 0.0001). CONCLUSION: The decline in sarcopenia three months post-TARE with Holmium-166 is a reliable predictor of worse loco-regional response rate, as evaluated radiologically, in patients with HCC. Sarcopenia measurement has the potential to be a valuable assessment tool in the management of HCC patients undergoing TARE. However, further prospective and randomized studies involving larger cohorts are necessary to confirm and validate these findings.

Fluorescence-guided lung nodule identification during minimally invasive lung resections.

In the last few years, minimally invasive surgery has become the standard routine practice to manage lung nodules. Particularly in the case of robotic thoracic surgery, the identification of the lung nodules that do not surface on the visceral pleura could be challenging. Therefore, together with the evolution of surgical instruments to provide the best option in terms of invasiveness, lung nodule localization techniques should be improved to achieve the best outcomes in terms of safety and sensibility. In this review, we aim to overview all principal techniques used to detect the lung nodules that do not present the visceral pleura retraction. We investigate the accuracy of fluorescence guided thoracic surgery in nodule detection and the differences among the most common tracers used.

In Vivo Comparison of Micro-Balloon Interventions (MBI) Advantage: A Retrospective Cohort Study of DEB-TACE Versus b-TACE and of SIRT Versus b-SIRT.

PURPOSE: The purpose of this study was to evaluate in vivo the role of the micro-balloon by comparing trans-arterial chemoembolization (DEB-TACE) and selective internal radiotherapy (SIRT) procedures performed with and without balloon micro-catheter (b-DEB-TACE and DEB-TACE/SIRT and b-SIRT) for the treatment of hepatocellular carcinoma (HCC). METHODS: The impact of a balloon micro-catheter on trans-arterial loco-regional treatment was analyzed using non-enhanced post-procedural cone-beam CT (Ne-CBCT) by comparing the attenuation values in the embolized area and the surrounding liver tissue before and after DEB-TACE versus b-DEB-TACE and by comparing 2D/3D dosimetry in single-photon emission computed tomography after SIRT versus b-SIRT, and by comparing the histological count of the beads following orthotopic liver transplantation in the DEB-TACE versus b-DEB-TACE subgroup. RESULTS: We treated 84 HCC patients using trans-arterial loco-regional therapy. Fifty-three patients (26 DEB-TACE and 27 b-DEB-TACE) were analyzed in the TACE group. Contrast, signal-to-noise ratio, and contrast-to-noise ratio were all significantly higher in b-DEB-TACE subgroup than DEB-TACE (182.33 HU [CI95% 160.3-273.5] vs. 124 HU [CI95% 80.6-163.6]; 8.3 [CI95% 5.7-10.1] vs. 4.5 [CI95% 3.7-6.0]; 6.9 [CI95% 4.3-7.8] vs. 3.1 [CI95% 2.2-5.0] p < 0.05). Thirty-one patients (24 SIRT and 7 b-SIRT) were analyzed in the SIRT group. 2D dosimetry profile evaluation showed an activity intensity peak significantly higher in the b-SIRT than in the SIRT subgroup (987.5 ± 393.8 vs. 567.7 ± 302.2, p = 0.005). Regarding 3D dose analysis, the mean dose administered to the treated lesions was significantly higher in the b-SIRT than in the SIRT group (151.6 Gy ± 53.2 vs. 100.1 Gy ± 43.4, p = 0.01). In histological explanted liver analysis, there was a trend for higher intra-tumoral localization of embolic microspheres for b-DEB-TACE in comparison with DEB-TACE. CONCLUSIONS: Due to the use of three different methods, the results of this study demonstrate in vivo, a better embolization profile of oncological intra-arterial interventions performed with balloon micro-catheter regardless of the embolic agent employed.

Sarcopenia Worsening One Month after Transarterial Radioembolization Predicts Progressive Disease in Patients with Advanced Hepatocellular Carcinoma.

(1) Background: To demonstrate correlation between skeletal muscle depletion measured before and after one month of TARE treatment and its induced local response rate. (2) Material and methods: For this retrospective, single center study, we evaluated 86 patients with HCC treated with TARE. Sarcopenia status was measured using the psoas muscle index (PMI). The PMI was calculated according to the formula: PMI [mm/m2]: [(minor diameter of left psoas + major diameter of left psoas + minor diameter of right psoas + major diameter of right psoas)/4]/height in m2. Population was divided in two groups according to the delta value of PMI measured at the time of TARE and one month after TARE, a group in which the delta PMI was stable or increased (No-Sarcopenia group; n = 42) vs. a group in which the delta-PMI decreased (Sarcopenia group; n = 44). Patient response was evaluated at 1, 3 and 6 months after TARE treatment with CT/MRI. (3) Results: When the radiological response of the tumor was evaluated according to the mRECIST criteria, the two groups were similar in terms of rates of complete response (p = 0.42), partial response (p = 0.26) and stable disease (p = 0.59). Progressive disease (PD) was more commonly observed in the Sarcopenia group (38.6% vs. 11.9%; p = 0.006). (4) Conclusions: Worsening of sarcopenia status measured one month after TARE is able to predict patients who will undergo disease progression.

Yttrium-90 Radioembolization in Unresectable Intrahepatic Cholangiocarcinoma: Results of a Multicenter Retrospective Study.

BACKGROUND: Y90 transarterial radioembolization (Y90-RE) may improve clinical outcomes of unresectable intrahepatic cholangiocarcinoma (ICC); however, the optimal timing for Y90-RE is still debated. The purpose of this multicenter study was to retrospectively evaluate clinical outcomes of RE in patients with unresectable ICC, comparing three different settings: chemotherapy naïve patients (group A), patients with disease control after first-line chemotherapy (group B) and patients with progression after first-line chemotherapy (group C). MATERIALS AND METHODS: The study included 81 consecutive patients (49 male, mean age 62.4 ± 11.8 years): 35 (43.2%) patients were in group A, 19 (23.5%) in group B, and 27 (33.3%) in group C. Preprocedural clinical variables, tumour response according to RECIST 1.1 and overall survival (OS) were analysed and compared. RESULTS: Baseline demographic and clinical features did not differ significantly among groups, with the exception of prior surgical procedures that were significantly higher in group C patients, and macrovascular invasion that was more frequent in group B. Radiological response was available in 79 patients; objective response and disease control rates were 41.8% and 83.6%, respectively, without significant differences among groups. Median OS was 14.5 months (95% CI: 11.1-16.9) and was not significantly different among treatment groups. At multivariate analysis, tumour burden > 50%, neutrophil-to-lymphocyte (N/L) ratio ≥ 3 and radiological progression as best response resulted to be significant (P < 0.05) independent factors, negatively associated with OS. CONCLUSION: Y90-RE is a valuable treatment option in unresectable ICC, irrespectively from the timing of treatment. Tumour extension, N/L ratio and radiological response affect post-treatment survival.

Structure-activity relationship and properties optimization of a series of quinazoline-2,4-diones as inhibitors of the canonical Wnt pathway.

Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.

A homogeneous HTRF assay for the identification of inhibitors of the TWEAK-Fn14 protein interaction.

The TWEAK-Fn14 pathway is upregulated in models of inflammation, autoimmune diseases, and cancer. Both TWEAK and Fn14 show increased expression also in the CNS in response to different stimuli, particularly astrocytes, microglia, and neurons, leading to activation of NF-κB and release of proinflammatory cytokines. Although neutralizing antibodies against these proteins have been shown to have therapeutic efficacy in animal models of inflammation, no small-molecule therapeutics are yet available. Here, we describe the development of a novel homogeneous time-resolved fluorescence (HTRF)-based screening assay together with several counterassays for the identification of small-molecule inhibitors of this protein-protein interaction. Recombinant HIS-TWEAK and Fn14-Fc proteins as well as FLAG-TWEAK and Fn14-FLAG proteins and an anti-Fn14 antibody were used to establish and validate these assays and to screen a library of 60 000 compounds. Two HTRF counterassays with unrelated proteins in the same assay format, an antiaggregation assay and a redox assay, were applied to filter out potential false-positive compounds. The novel assay and associated screening cascade should be useful for the discovery of small-molecule inhibitors of the TWEAK-Fn14 protein interaction.