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Proteolysis-Targeting Chimeras (PROTACs) have recently emerged as a promising technology in the drug discovery landscape. Large interest in the degradation of the androgen receptor (AR) as a new anti-prostatic cancer strategy has resulted in several papers focusing on PROTACs against AR. This study explores the potential of a few in silico tools to extract drug design information from AR degradation data in the format often reported in the literature. After setting up a dataset of 92 PROTACs with consistent AR degradation values, we employed the Bemis–Murcko method for their classification. The resulting clusters were not informative in terms of structure–degradation relationship. Subsequently, we performed Degradation Cliff analysis and identified some key aspects conferring a positive contribution to activity, as well as some methodological limits when applying this approach to PROTACs. Linker structure degradation relationships were also investigated. Then, we built and characterized ternary complexes to validate previous results. Finally, we implemented machine learning classification models and showed that AR degradation for VHL-based but not CRBN-based PROTACs can be predicted from simple permeability-related 2D molecular descriptors. [ABSTRACT FROM AUTHOR]

Potential intrinsic resistance mechanisms to regorafenib were explored after short exposure (3 days) on five CRC cell lines (HCT-116, SW1116, LS-1034, SW480, Caco-2). The observation of senescence-like features led to the investigation of a drug-initiated phenotype switch. Following long-term exposure (12 months) of HCT-116 and SW480 cell lines to regorafenib, we developed resistant models to explore acquired resistance. SW480 cells demonstrated senescent-like properties, including a cell arrest in the late G2/prophase cell cycle stage and a statistically significant decrease in the expression of G1 Cyclin-Dependent Kinase inhibitors and key cell cycle regulators. A specific senescence-associated secretome was also observed. In contrast, HCT-116 treated cells presented early senescent features and developed acquired resistance triggering EMT and a more aggressive phenotype over time. The gained migration and invasion ability by long-exposed cells was associated with the increased expression level of key cellular and extracellular EMT-related factors. The PI3K/AKT pathway was a significant player in the acquired resistance of HCT-116 cells, possibly related to a PI3KCA mutation in this cell line. Our findings provide new insights into the phenotypic plasticity of CRC cells able, under treatment pressure, to acquire a stable TIS or to use an early senescence state to undergo EMT. [ABSTRACT FROM AUTHOR]

RENAL score has been validated on predicting adverse events and relapses in percutaneous treatments of renal lesions. To better fit interventional issues a modified score (mRENAL) has been introduced, but the only difference from the RENAL score is on the dimensional parameter. However, it remains of surgical derivation while a specific interventional score is missing. This study aims to obtain a specific score (ABLATE) to better quantify the risk of complications and relapses in percutaneous kidney ablation procedures compared to the existing surgical scores. Taking inspiration from previous papers, a score was built to quantify the real difficulties faced in percutaneous treatment of renal lesions. The ABLATE score was used on 71 cryoablations to evaluate its predictivity of complications and relapses. Logistic regression was used to predict complication incidence; Cox-regression was used for relapses; ROC analysis was used to evaluate the accuracy of the different scores. Between January 2014 and November 2019, 71 lesions in 68 patients were treated. Overall, malignant histology was found in 62 lesions (87.3%). Mean and median RENAL, mRENAL, and ABLATE scores were 7.04 and 7, 7.19 and 7, and 5.11 and 4, respectively. Out of 71 treatments, we experienced 3 bleeding with anemia (4.2%), only 2 of which needed further treatment (2.82%). The mean and median RENAL, mRENAL, and ABLATE scores in those with complications were 7.66 and 7.01 (p = 0.69), 8.0 and 7.1 (p = 0.54), and 6.6 and 5.0 (p = 0.38), respectively. Out of 62 malignant lesions, we experienced 2 persistent and 6 recurrent lesions (3.2% and 8.4%, respectively). At Cox-regression analyses, mABLATE score outperformed both RENAL and mRENAL scores in predicting recurrences (HR 1.48; p < 0.001 vs. 1.41; p = 0.1 vs. 1.38: p = 0.07, respectively). The ABLATE score showed to be a better predictor of relapses than RENAL and mRENAL. The small number of complications conditioned a lack of statistic power on complications for all the scores. At the moment to quantify the risks in percutaneous kidney ablation procedures, surgical scores are used. A specific score better performs this task. [ABSTRACT FROM AUTHOR]

Purpose: Endovascular repair of true visceral artery aneurysms (VAAs) and pseudoaneurysms (VAPAs) with stent-grafting (SG) can simultaneously allow aneurysm exclusion and vessel preservation, minimizing the risk of ischemic complications. Our aim was to report a single-center experience on SG of visceral aneurysms, focusing on technical aspects, clinical outcome and mid-term patency.Materials and Methods: Consecutive patients affected by VAAs-VAPAs and submitted to endovascular treatment were retrospectively reviewed, and SG cases with the self-expandable peripheral Viabahn stent-graft were analyzed (2003-2017). Aneurysm type, patient number, SG clinical setting, procedural data, peri-procedural complications, technical success, 30-day clinical success, 30-day mortality and follow-up period (aneurysm exclusion, stent-graft patency, ischemic complications) were analyzed.Results: SG was performed in 40 patients (24 VAPAs/16 VAAs) and in 44 procedures (25 in emergency, 19 in elective treatments), via transfemoral in 37 cases (transaxillary in 7 cases). One peri-procedural complication was recorded (a splenic artery dissection successfully converted to transcatheter embolization). The overall technical and clinical success rates were, respectively, 96 and 84%, with excellent trend in elective treatments (both 100%). Overall 30-day mortality was 12.5% (septic shock after pancreatic surgery). Stent-graft thrombosis occurred in 2 patients within 3 months, with aneurysm exclusion and without ischemic complications. Stent-graft patency and aneurysm exclusion were confirmed at 6, 12 and 36 months in 18, 12 and 7 patients, respectively.Conclusion: SG of VAAs and VAPAs was safe and effective, particularly in elective treatments. The Viabahn stent-graft, flexible and without shape memory, is suitable for endovascular repair of tortuous visceral arteries. [ABSTRACT FROM AUTHOR]

Purpose: To retrospectively report a large single-center experience of visceral artery aneurysms (VAAs) and pseudoaneurysms (VAPAs) treated with covered stenting (CS) as the first therapeutic option vs transcatheter embolization (TE).Methods: One hundred patients (mean age 59±14 years; 58 men) underwent 59 elective and 41 emergent endovascular procedures to treat 51 VAAs and 49 VAPAs. Seventy patients had TE and 30 received CS (27 Viabahn and 3 coronary stent grafts). Both TE and CS were performed in 10 cases.Results: Technical success was 96% (97% CS, 96% TE), and 30-day clinical success was 83% (87% CS, 81.4% TE). Four major complications occurred; 30-day mortality was 7%, mainly due to septic shock following pancreatic surgery. The midterm follow-up was 20.8 months in the total population and 32.8 months in the CS group. More than 6 months after CS all aneurysms remained excluded; stent patency was achieved in 88%. Twelve CS patients with >3 years' follow-up had maintained stent patency.Conclusion: In endovascular treatment of visceral aneurysms, covered stenting was feasible in 30%. CS showed a slightly better efficacy than TE and good midterm patency. The Viabahn covered stent seems to be suitable for endovascular repair of tortuous visceral arteries affected by true or false aneurysms. [ABSTRACT FROM AUTHOR]

Objective: The aim of our preliminary study was to compare the efficacy of drug-eluting beads preloaded with irinotecan (DEBIRI) vs drug-eluting beads preloaded with doxorubicin (DEBDOX) as second-line treatment of unresectable liver metastases from cholangiocarcinoma (CCA). Methods: In 2013, 10 patients affected by multiple liver metastases from CCA, resistant to the first-line chemotherapy regimen, were enrolled: 5 patients were submitted to lobar/segmental transarterial chemoembolization (TACE) with DEBIRI (100-mg irinotecan/1 vial) and 5 patients with DEBDOX (50-mg doxorubicin/1 vial), performed every 3 weeks. Patients treated with DEBIRI received antipain premedication consisting of 30-mg of morphine and 3–4 ml of intra-arterial lidocaine. Complications and efficacy were assessed (response evaluation criteria in solid tumour 1.1). Results: A total of 32 TACE were performed (mean: 3.2 TACE/patient), all well tolerated, with only 1 case of asymptomatic cholecystitis spontaneously recovered. Response rates of patients treated with DEBDOX and DEBIRI were: 4/5 progressive disease and 1/5 partial response vs 2/5 partial response, 2/5 stable disease and 1/5 progressive disease, respectively, with the appearance of variable necrosis percentage. Progression-free survival from the first procedure and progressive disease were 12.67 weeks for DEBIRI and 15.78 weeks for DEBDOX, respectively. Overall survival from time of primary diagnosis was 176 weeks for DEBIRI and 125 weeks for DEBDOX, respectively. Conclusion: In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment for hepatic metastases from CCA. Antipain drug administration and the use of the microcatheter led to a good treatment tolerability and a low complication rate. Advances in knowledge: In our preliminary experience, DEBIRI was more effective than DEBDOX as a second-line treatment of hepatic metastases from CCA; further studies involving a larger cohort of patients are needed. [ABSTRACT FROM AUTHOR]

Objective: Islet allotransplantation is a less invasive alternative to surgical pancreas transplantation for Type 1 diabetes, while percutaneous intraportal islet autotransplantation (PIPIAT) is usually performed after pancreatic surgery to prevent diabetes. Our aim was to assess the feasibility, radiological aspects, complications and clinical outcome of PIPIAT following pancreatic surgery for not only chronic pancreatitis but also benign and malignant nodules. Methods: From 2008 to 2012, 41 patients were enrolled for PIPIAT 12-48 h after pancreatic surgery (extended pancreatic surgery for chronic pancreatitis and benign/malignant neoplasms). PIPIAT was performed using a combined ultrasonography and fluoroscopy-guided technique (4-F catheter). PIPIAT feasibility, median follow-up and metabolic (insulin independence rate, graft function based on C-peptide levels) and oncologic outcomes were recorded. Results: PIPIAT was not performed in 7/41 patients (4 cases for an inadequate islet mass, 2 cases for haemodynamic instability and 1 case for islet culture contamination), while it was successfully performed in 34/34 patients. Procedure-related major complications occurred in four patients: two bleedings requiring transfusions, one patient with left portal vein thrombosis and one patient with sepsis. Median follow-up duration was 546 days. Insulin independence was achieved in 15/34 (44%) patients, partial graft function in 16/34 (47%) patients and no function in 3/34 (9%) patients. None of the 17 patients with malignant nodules developed liver metastases during follow-up. Conclusion: PIPIAT, performed under ultrasound and fluoroscopy combined guidance and not requiring immunosuppression, is feasible, with a relatively low complication rate and a better metabolic outcome than allotransplantation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of orbital color Doppler ultrasound (OCDUS) in the diagnosis of carotid-cavernous fistula (CCF) with anterior drainage and particularly whether a negative OCDUS could avoid an invasive diagnostic cerebral angiography (DSA). Materials and methods: Twenty-two consecutive patients with ophthalmic signs suspecting CCF were submitted to ophthalmologic examination, OCDUS and DSA. CCF diagnosis with OCDUS was based on the finding of a reversed, arterialized and low-resistive-index (RI <0.5) blood flow in the superior ophthalmic vein (SOV). Sensibility, specificity, PPV, NPV, and accuracy of OCDUS were calculated considering both patients and eyes, using DSA as gold standard. Results: DSA demonstrated 20 CCFs in 18 patients. Considering the patients, in 18/22 CCF diagnosis was positive at OCDUS and DSA while 4/22 were negative at both. Considering the eyes, in 24/43 CCF diagnosis was positive at both DSA and OCDUS (total eyes = 43, due to one case of SOV thrombosis). In 19/43 eyes diagnosis was negative at both OCDUS and DSA. So sensitivity, specificity, PPV, NPV, and accuracy of OCDUS in the patients and eyes analysis were all 100 %. Conclusions: OCDUS is a reliable, noninvasive tool in the diagnosis of CCF; a negative OCDUS could avoid an invasive DSA in patients suspected for anterior-draining CCF. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose Our aim was to prospectively analyze the use of contrast-enhanced ultrasound (CEUS) in the quantitative assessment of the response of uveal melanoma (UM) to gamma-knife radiosurgery (GKR), investigating whether changes in tumor vascularization precede thickness reduction, which on average occurs at 12 months after GKR. Methods Ten patients with UM treated with GKR underwent sonography (US) and CEUS at baseline and at 3, 6, and 12 months after GKR. The transverse diameter, thickness, and quantitative parameters of the UM (ie, area under the curve in the wash-in phase, wash-in perfusion index, peak enhancement, and wash-in rate) were calculated by using dedicated software and compared by using Wilcoxon's signed-rank test. Results The mean tumor thickness on US was significantly less at both 6 (6.6 mm) and 12 months after GKR (5.8 mm) than it was at baseline (8.3 mm; p < 0.05, both comparisons). Compared with baseline data, the median flow quantitative parameters on CEUS were significantly changed as follows: the peak enhancement (in arbitrary units [au]) at baseline was 5 × 106; 6 months after GKR, it was 2 × 101 ( p < 0.05), and 12 months after GKR, it was 4 × 101 ( p < 0.05). The wash-in rate (in au) at baseline was 1 × 106; 6 months after GKR, it was 2.1 ( p < 0.05), and 12 months after GKR, it was 9.3 ( p < 0.05). The wash-in perfusion index (in au) at baseline was 2 × 107; 6 months after GKR, it was 7 × 101 ( p < 0.05), and 12 months after GKR, it was 1 × 102 ( p < 0.05). The area under the curve during the wash-in phase (in au) at baseline was 1 × 108; 12 months after GKR, it was reduced to 6 × 102 ( p < 0.05). Conclusions At 6 months after GKR, a reduction of tumor thickness, as detected on US, occurred in 6 of the 10 patients, whereas a reduction in all the quantitative parameters measured on CEUS occurred in all 10 patients. However, a larger population is needed to investigate whether CEUS could become the first-choice technique for monitoring the response of UM to GKR. © 2015 Wiley Periodicals, Inc. J Clin Ultrasound 43:421-430, 2015 [ABSTRACT FROM AUTHOR]

Introduction: Abdominal pain in PNH has never been investigated by in-vivo imaging studies. With MRI, we aimed to assess mesenteric vessels flow and small bowel wall perfusion to investigate the ischemic origin of abdominal pain. Materials and Methods: Six PNH patients with (AP) and six without (NOP) abdominal pain underwent MRI. In a blinded fashion, mean flow (MF, quantity of blood moving through a vessel within a second, in mL·s-1) and stroke volume (SV, volume of blood pumped out at each heart contraction, in mL) of Superior Mesenteric Vein (SMV) and Artery (SMA), areas under the curve at 60 (AUC60) and 90 seconds (AUC90) and Ktrans were assessed by two operators. Results: Mean total perfusion and flow parameters were lower in AP than in NOP group. AUC60: 84.81 ± 11.75 vs. 131.73 ± 18.89 (P < 0.001); AUC90: 102.33 ± 14.16 vs. 152.58 ± 22.70 (P < 0.001); Ktrans: 0.0346 min-1 ± 0.0019 vs. 0.0521 ± 0.0015 (P = 0.093 duodenum, 0.009 jejunum/ileum). SMV: MF 4.67 ml/s ± 0.85 vs. 8.32 ± 2.14 (P = 0.002); SV 3.85 ml ± 0.76 vs. 6.55 ± 1.57 (P = 0.02). SMA: MF 6.95 ± 2.61 vs. 11.2 ± 2.32 (P = 0.07); SV 6.52 ± 2.19 vs. 8.78 ± 1.63 (P = 0.07). We found a significant correlation between MF and SV of SMV and AUC60 (MF:ρ = 0.88, P < 0.001; SV: ρ = 0.644, P = 0.024), AUC90 (MF: ρ = 0.874, P < 0.001; SV:ρ = 0.774, P = 0.003) and Ktrans (MF:ρ = 0.734, P = 0.007; SV:ρ = 0.581, P = 0.047). Conclusions: Perfusion and flow MRI findings suggest that the impairment of small bowel blood supply is significantly associated with abdominal pain in PNH. [ABSTRACT FROM AUTHOR]

ABSTRACT Cardiac surgery can have severe neurologic complications. The noninvasive monitoring of intracranial circulation during heart surgery is usually performed with transcranial Doppler ultrasonography. We present the case of a 66-year-old man who underwent elective cardiac surgery for aortic valve replacement and coronary artery bypass graft, in whom monitoring was performed by simultaneously assessing blood flow velocity in the central retinal artery and vein. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound 42:112-115, 2014 [ABSTRACT FROM AUTHOR]

Objectives: To assess changes in apparent diffusion coefficient (ΔADC) and volume (ΔV) after neoadjuvant treatment (NT), and tumour regression grade (TRG) in gastro-oesophageal cancers (GEC), and to discriminate responders from non-responders. Methods: Thirty-two patients with biopsy-proven locally-advanced GEC underwent diffusion weighted magnetic resonance imaging (DWI) pre- and post-NT. Lesion ADC, volume, ΔADC and ΔV were calculated. TRG 1-2-3 patients were classified as R; TRG 4-5 as non-responders. ΔADC-TRG and ΔV-TRG correlations, pre-NT and post-NT ADC, ΔADC and ΔV cut-off values for responders and non-responders were calculated. Two readers measured mean tumour ADCs and interobserver variability was calculated. (Spearman's and intraclass correlation coefficient [ICC]). Results: The interobserver reproducibility was very good both for pre-NT (Spearman's rho = 0.8160; ICC = 0.8993) and post-NT (Spearman's rho = 0.8357; ICC = 0.8663). Responders showed lower pre-NT ADC (1.32 versus 1.63 × 10 mm/s; P = 0.002) and higher post-NT ADC (2.22 versus 1.51 × 10 mm/s; P = 0.001) than non-responders and ADC increased in responders (ΔADC, 85.45 versus −8.21 %; P = 0.00005). ΔADC inversely correlated with TRG ( r = −0.71, P = 0.000004); no difference in ΔV between responders and non-responders (−50.92 % versus −14.12 %; P = 0.068) and no correlation ΔV-TRG ( r = 0.02 P = 0.883) were observed. Conclusions: The ADC can be used to assess gastro-oesophageal tumour response to neoadjuvant treatment as a reliable expression of tumour regression. Key Points: • DWI is now being used to assess many cancers. • Change in ADC measurements offer new information about oesophageal tumours. • ADC changes are more reliable than dimensional criteria in assessing neoadjuvant treatment. • Such ADC assessment could optimise management of locally advanced gastro-oesophageal cancers. [ABSTRACT FROM AUTHOR]