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3D-tumor sphere (SPH) cultures enriched in CSCs were generated from intrahepatic CCA (iCCA) cell lines and CCA patient-derived organoids (PDOs) were employed. Circulating monocytes were differentiated into M2c MØs and recombinant Gas-6, a MerTK ligand, was used to activate MerTK. MERTK expression in human CCA tissues was analyzed at mRNA level in public database (n=78) and confirmed by immunohistochemistry (IMH) (n=74). Single-cell RNA sequencing of CD45+ sorted cells was performed in paired non-tumoral and tumoral specimens from intrahepatic CCA patients (n=6). Conditioned media (CM) of iCCA SPH induced higher MerTK expression in macrophages. Conversely, soluble mediators released by Gas-6-stimulated M2c MØs, which express MerTK at high levels, increased sphere number and volume, expression of stem-like genes and drug-resistance in iCCA cells. Moreover, the exposure to CM of M2c MØs induced an increase in the cell viability of organoids CCA PDOs, which was further increased when macrophages were stimulated with Gas-6. These effects were reduced following treatment of macrophages with UNC2025, a small molecule inhibitor of MerTK. Transcriptomic analysis of laser-captured, micro-dissected epithelium and stroma from 23 iCCA patients showed that MerTK mRNA expression is significantly higher in intratumoral stroma. These data were further confirmed in a public iCCA dataset showing that high MerTK levels are associated with immunologically hot iCCA. Single-cell RNA sequencing of CD45+ cells from non-tumoral and tumoral areas in iCCA patients showed that MerTK is predominantly expressed at the level of myeloid cells. Further reclustering showed MerTK expression in ID3 MØs, corresponding to Kupffer cells in tumor tissue. Notably, expression of MerTK correlated with greater tumor size, tumor grade, microvascular invasion, and risk of recurrence in iCCA patients. These data indicate that a cross-talk between MerTK-expressing cells in the stroma and iCCA cells results in increased malignant features. [ABSTRACT FROM AUTHOR]

PSVD includes a group of vascular diseases featuring lesions encompassing portal venules and sinusoids, irrespective of the presence of portal hypertension (PH). Liver biopsy (LB) is fundamental for diagnosis. A recent monocenter study showed high rates of PSVD in patients with isolated and unexplained GGT elevation who underwent a LB; due to the small sample, the study could not identify factors associated with PSVD. Aim of this study was to validate in a multicenter cohort the rate of PSVD in patients with isolated GGT elevation and identify clinical factors associated with PSVD. We retrospectively included all patients who underwent a LB for unexplained isolated and persistent GGT elevation in five Italian Hepatology Units from March, 2015 to December, 2021. All LB specimens were reviewed by hepatopathologists. 144 patients met the inclusion criteria and were enrolled in the study. Most patients were males (76/144, 53%) with the mean age being 52 years (range 19-74). 11 patients (7.6%) presented liver stiffness (LS) suggestive of advanced liver disease (>10 kPa) but none showed clinical features of PH. The histological findings were compatible with PSVD in 96 out of 144 patients (67%). In 13 patients (9%) histology was compatible with NASH, in 3 patients (2%) with hepatic sarcoidosis and in 3 patients with congenital hepatic fibrosis (CHF). Histology showed healthy liver in 29 (20%) patients. At univariate analyses male sex, LS <10 kPa and GGT <214 UI/L were associated with PSVD (p<0.05). The same factors were confirmed by logistic regression: LS <10 kPa (OR 7.5 (95%, CI 1.7-32.3), GGT <214 UI/L (OR 2.8 (95%, CI 1.29-6.28) and male gender (OR 2.5 (95%, CI 1.19-5.58). PSVD is common in patients with elevated GGT and no signs of PH. Male gender, LS and GGT levels can be used to identify these patients a priori. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: We investigated in a single institution series of 124 women with operable breast cancer whether tumor clinicopathological features could predict the 70-gene signature (Mammaprint®, MP) results, and whether MP results could help to make decisions for the use of chemotherapy (CT) in patients (pts) with ER positive breast cancer beyond recommendations of international guidelines. Results: Among the 68 ER/PgR positive, HER2 negative tumors, Ki-67 ≥ 20% was the only significant predictor of a high risk-MP among standard clinicopathological features. In candidates for endocrine therapy with undetermined benefit from CT according to international guidelines, MP results would have led to different treatment decisions in 13/46 (28%) and in 20/68 (29%) pts according to NCCN and St. Gallen recommendations, respectively. Conclusions: Ki-67 independently predicted high risk-MP in ER/PgR positive, HER2 negative tumors. MP results would have led to discordant treatment recommendations in about 30% of cases, generally increasing indication rate for CT. The results of large randomized trials are warranted in order to understand whether we should rely on multigene assays rather than on standard clinicopathological features for treatment decisions. [Copyright &y& Elsevier]

Abstract: T1N0M0 (stage I) breast cancer (BC) has been increasing in recent decades but the optimal adjuvant approach remains controversial. To assess the outcome of BC patients stratified and treated with multimodal therapies according to St. Gallen consensus meeting recommendations, we retrospectively evaluated an unselected cohort of T1N0M0 BC patients, with respect to the St. Gallen criteria. At a median follow-up of 5 years, the recurrence rate, recurrence-free survival and overall survival were 7%, 94% and 96% respectively, and 60% of relapses were locoregional. No statistically significant difference was observed between T1a,b/T1c groups, or among risk categories (high/intermediate/low). The very low rate of distant recurrences even in patients with unfavorable prognostic factors seems to support the use of adjuvant systemic therapies but better prognostic and predictive factors are strongly needed for this subset of patients. [Copyright &y& Elsevier]

Objective: To describe our experience of endovascular repair of paraanastomotic aortic aneurysm. Methods and results: From March 2001 to December 2004 we identified 6 patients with a paraanastomotic aortic aneurysms following previous open repair of abdominal aortic aneurysm. All patients were treated with endovascular surgery under epidural anaesthesia. There were no major complications, surgical conversions or deaths. Four patients received a bifurcated aortic stent-graft, and two an aorto-uniliac stent-graft followed by a femoro-femoral bypass. At follow-up (mean 26.1±10.2 months) there were no deaths, endoleaks or graft migrations observed. Conclusion: Endovascular surgery, avoiding general anesthesia and re-laparotomy, is the ideal technique for treatment of this complication resulting from failed primary conventional AAA repair. [Copyright &y& Elsevier]