Toward a rational design of surface textures promoting endothelialization.

The safe integration of cardiovascular devices requires the sustainable coverage of their luminal surface by endothelial cells (ECs). The engineering of active surface textures has the potential to coordinate cellular adhesion and migration under the action of hemodynamic forces. We define a paradigm to rationally design textures maximizing EC activities as a function of the applied stresses. This is based on harnessing the adhesions established by ECs through fine-tuning of the vertical extend of the underlying surface nanotopography.

Calcified telangiectatic hyperplastic nodule associated with vascular malformation in a child: a case report.

This is a case report of an asymptomatic 4-year-old girl who was found to have a nodule at the lateral left lobe of the liver. She underwent transabdominal liver ultrasound and abdominal MRI that showed calcification and intense arterial enhancement but they failed to clearly exclude malignancy. The patient underwent an unremarkable laparoscopic wedge liver resection of the lesion because of its location and size. Pathological examination showed features compatible with a benign telangiectatic hyperplastic nodule with vascular malformation and calcification. CD34 immunostained the proliferative vascular lining cells while CK7 and CK19 highlighted the normal bile ducts present within the lesion. The diagnosis of a telangiectatic hyperplastic nodule associated with vascular malformation has been scarcely reported in children and our case shows for the first time that it can also present with calcifications.

Comparing two-year outcomes of balloon-expandable Myval and self-expanding Evolut R in severe aortic valve stenosis.

BACKGROUND: The new balloon-expandable (BE) Myval transcatheter heart valves (THV) has shown promising early results with low paravalvular leak (PVL) and permanent pacemaker implantation (PPI) rates. Limited data are available regarding its long-term performance. We aimed to compare the 2-year clinical and echocardiographic outcomes of transcatheter aortic valve replacement (TAVR) using the self-expanding (SE) Evolut R and the BE Myval THVs. METHODS: The EVAL study included 166 patients with severe aortic valve stenosis who underwent TAVR either with SE Evolut R (n = 108) or BE Myval (n = 58) THV. Primary objectives include comparison on clinical efficacy (freedom from all-cause mortality, stroke, and cardiovascular hospitalization), echocardiographic performance and PPI rates between the two THVs. RESULTS: At 2-year the BE Myval group showed higher clinical efficacy (86% vs. 66%,HR:2.62, 95%CI 2.2-5.1;p = 0.006), with fewer cardiac hospitalizations (3.4% vs. 13.9%,p = 0.03). No significant differences in all-cause mortality, cardiovascular mortality, or stroke rates were observed. The proportion of patients with ≥moderate PVL was significantly lower in the BE Myval compared to the SE Evolut R group (4%vs. 22%,p = 0.008). The mean transvalvular gradient was significantly higher in the SE group compared to the BE group (9.5 ± 4.3 vs. 6.9 ± 2.2 mmHg,p < 0.001), however there was no difference in the percentage of patients with a mean gradient ≥20 mmHg between the two groups. CONCLUSIONS: Both THVs offer similar 2-year clinical outcomes. The BE Myval THV demonstrated advantages with higher clinical efficacy and lower PVL incidence. Longer follow-up and randomized trials are needed to validate these results and assess Myval's sustained performance and durability.

Treatment of haemorrhoids in pregnancy: A retrospective review.

AIM: Haemorrhoids are varicose veins of the rectum covered by mucosa at or near the anal canal. They are normally asymptomatic, can occur at any age and affect both males and females. Haemorrhoids are common in young women and commoner during pregnancy and the puerperium. In this review, we address the issue of the approach of the obstetrician and surgeons to haemorrhoids and their management. This is significant because there are currently no recommendations for pregnant patients with hemorrhoids. METHODS: The literature search comprised all the inherent published original papers; also abstract were included. No language selection was done. Search terms used were: "hemorrhoid", "hemorrhoid therapy", "hemorrhoid in pregnancy", "hemorrhoid complication". Data research was conducted using MEDLINE, EMBASE, Web of Sciences, Scopus, Clinical Trial. gov, OVID and Cochrane Library querying for all articles related to treatment of hemorrhoidis in pregnancy. RESULTS: Fiber supplement, stool softener and mild laxatives are generally safe for pregnant women. Topical medication or oral phlebotonics may be used with special caution because the strong evidence of their safety and efficacy in pregnancy is lacking. In case of massive bleeding, anal packing could be a simple and useful maneuver. Hemorrhoidectomy is reserved in strangulated or extensively thrombosed hemorrhoids, and hemorrhoids with intractable bleeding. KEY WORDS: Hemorrhoid, Hemorrhoid Therapy, Hemorrhoid in Pregnancy, Hemorrhoid Complication.

Fluorescence and Ultrasound-guided Laparoscopic Resection of Caudate Lobe for Hepatocellular Carcinoma Located in the Retrocaval Portion.

BACKGROUND: Contrast-enhanced intraoperative ultrasonography (CEIOUS) and indocyanine green fluorescence were interesting tool for the visualization of intrahepatic neoplastic nodules. The combinations of the 2 technologies could increase tumor detection and the radicality of resection, allowing the use of a pure laparoscopic approach. METHODS: The patient was an 81-year-old man with a history of hypertension and treated hepatitis C infection, with a sustained serological response from 2018, previously undergoing laparotomic resection for hepatocellular carcinoma (HCC) in segment 8.During his regular hepatological follow-up, a 25 mm nodule was detected in segment 1, in a retrocaval position. Considering clinical presentation, good liver function (Child A5-MELD 8) and imaging, pure laparoscopic resection of the caudate lobe was performed using fluorescence imaging and CEIOUS navigation guidance. RESULTS: The operation last for 205 minutes. Blood loss was 100 mL and no blood transfusion was required. She resumed diet on the next day and was discharged 4 days after the operation. Histopathologic examination showed 27 mm HCC with a clear margin. Contrast computed tomography scan performed 3 months after the operation showed no recurrence of the disease. CONCLUSIONS: A laparoscopic isolated caudate resection for HCC located in the retrocaval portion of the cirrhotic liver seems to be feasible in selected patients and fluorescence imaging and CEIOUS navigation guidance could guarantee a safe and successful surgery.

Guidelines Adaptation to the COVID-19 Outbreak for the Management of Hepatocellular Carcinoma.

Background: COVID-19 pandemic rendered the surgical approach as well as the surgical indication very complex due to the outstanding consumption of public health system' resources, especially in the intensive care subdivision. A multidisciplinary team-based strategy is necessary to adapt guidelines and medical practices to the actual situation. The aim of this study is to evaluate the changes in the therapeutic algorithm in a small group of patients with hepatocellular carcinoma (HCC) enlisted for surgery during the COVID-19 outbreak. Materials and Methods: A multidisciplinary strategy has been adopted to allocate HCC patients to a treatment that permitted to reduce the risk of complications and the hospital stay, thus preventing contamination by the virus. Nasopharyngeal swab and a chest radiograph were performed in all patients within 48 hours before the surgical procedure: in the suspected cases with negative COVID tests, we prudently postponed surgery and repeated the diagnostic tests after 15 days. Results: During the emergency state, 11 HCC patients were treated (8 laparoscopic ablations and 3 hepatic resections). We reported only 1 postoperative complication (hemothorax) and 1 death during the follow-up for COVID pneumonia. Comparing our performances with those in the same time frame in the past 4 years, we treated a similar number of HCC patients, obtaining a decrease in operative timing (P = .0409) and hospital stay (P = .0412) (Fig. 2b) with similar rates of immediate postoperative complications, without ICU admissions. Conclusions: An adapted algorithm for the treatment of HCC to COVID outbreak permitted to manage safely these patients by identifying those most at risk of evolution of the neoplastic disease.

Micronvasive behaviour of single small hepatocellular carcinoma: which treatment?

BACKGROUND: Microinvasion (MI), defined as infiltration of the portal or hepatic vein or bile duct and intrahepatic metastasis are accurate indicators of a poor prognosis for mall hepatocellular carcinomas (HCC). A previous study showed that intraoperative ultrasound (IOUS) definition of MI-HCC had a high concordance with histological findings. Aim of this study is to evaluate overall survival and recurrence patterns of patients with MI-HCC submitted to hepatic resection (HR) or laparoscopic ablation therapies (LAT). METHODS: A total of 171 consecutive patients (78 h; 93 LAT) with single, small HCC (< 3 cm) with a MI pattern at IOUS examination were compared analyzing overall survival and recurrence patterns using univariate and multivariate analysis and weighting by propensity score. RESULTS: Overall recurrences were similar in the 2 groups (HR: 51 patients (65%); LAT: 66 patients (71%)). The rate of local tumor progression in the HR group was very low (5 pts; 6%) in comparison to LAT group (22 pts; 24%; p = 0.002). The overall survival curves of HR are significantly better than that of the LAT group (p = 0.0039). On the propensity score Cox model, overall mortality was predicted by the surgical treatment with a Hazard ratio 1.68 (1.08-2.623) (p = 0.022). CONCLUSIONS: If technically feasible and in patients fit for surgery, HR with an adequate tumor margin should be preferred to LAT in patients with MI-HCC at IOUS evaluation, to eradicate MI features near the main nodule, which are relatively frequent even in small HCC (< 3 cm).

Laparoscopic thermoablation for hepatocellular carcinoma in patients with liver cirrhosis: an effective procedure for tricky tumors.

The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are amenable to this option. Percutaneous radiofrequency interstitial thermal ablation (TA) proved to be effective in the treatment of unresectable HCC. Recent advances in laparoscopic ultrasound have improved the accuracy in detecting small intrahepatic HCC nodules missed by pre-operative imaging techniques. Our objective was to evaluate an operative combination of laparoscopic ultrasound with laparoscopic thermoablation (LTA) in the treatment of HCC not amenable to liver resection. The aim of our review was to evaluate the advantages and limits of the laparoscopic approach according the criteria of the evidence-based medicine. LTA of HCC proved to be a safe and effective technique both in the short- and long-term follow-up period. This technique may be indicated in selected cases when the percutaneous approach to the lesion is very difficult or contraindicated.

Aggressive surgery for advanced ovarian cancer performed by a multidisciplinary team: A retrospective analysis on a large series of patients.

BACKGROUND: To evaluate the impact of extended surgical treatment performed by a team of gynecologists and general surgeons on postoperative morbidity and survival of patients with advanced ovarian cancer. METHODS: We collected data of 156 patients with advanced ovarian cancer stage IIb-III-IV according to International Federation of Gynecology and Obstetrics classification and treated with primary cytoreduction. End points were perioperative and postoperative complications and cancer-related survival. RESULTS: In 51 cases (51/156, 32.7%) a multivisceral resection was completed. Postoperative complications occurred in 52 cases (33.3%). The duration of the surgical procedure as well as the need for diaphragmatic peritonectomy were the factors independently associated with the development of postoperative complications. Five-year cancer-related survival rate was of 50.7%: only histotype and residual tumor resulted significantly associated. CONCLUSIONS: Our results highlight the importance of a team of gynecologists and general surgeons with specific interests and skills to achieve cytoreduction as rapidly as possible, even when it implies very complex maneuvers.

Association between neuroendocrine tumor of the ileum and two colonic primary malignancies. A case report and review of literature.

BACKGROUND: A high rate of association between neuroendocrine tumors (NETs) and secondary primary malignancy (SPM) has been described in literature and this association can occur either in a synchronous or a metachronous presentation. A wide range of hypothesis has been postulated to explain the high rate of association between NETs and SPM, without definitive conclusions. CASE PRESENTATION: We report a case of an ileal neuroendocrine tumor found incidentally at the histologic examination of the surgical specimen in a 72 years old male underwent to right hemi colectomy for two colic adenomatous polips with high grade dysplasia. CONCLUSION: Large multicentric epidemiological studies should be considered to assess the association between NETs and SPM. KEY WORDS: Neuroendocrine tumors (NETs), Progression-Free Survival (PFS), Secondary primary malignancy (SPM).

Influence of body habitus on feasibility and outcome of laparoscopic liver resections: a prospective study.

BACKGROUND: The aim of the present study was to prospectively investigate whether the anthropometric measures of A Body Shape Index (ABSI, taking into account waist circumference adjusted for height and weight) affects feasibility and outcome of laparoscopic liver resections. METHODS: One hundred patients undergoing laparoscopic liver resection were prospectively included in the study (2014-2015). Preoperative clinical parameters, including body mass index (BMI) and ABSI were evaluated for associations with intraoperative outcome and postoperative results (morbidity, mortality and functional recovery). RESULTS: Twenty-two and 78 patients underwent major and minor hepatectomies, respectively. Conversion rate was 9%, mean blood loss was 210 ± 115 ml. Postoperative morbidity was 15% and mortality was nil. Mean length of stay was 4 days. When considering the entire series, ABSI was not associated with intra and postoperative outcome. After stratification of patients according to difficulty score, Pearson's correlation demonstrated an association between ABSI and intraoperative blood loss (P = 0.03) and time for functional recovery (P = 0.05) in patients undergoing resections with high score of difficulty. CONCLUSION: Body habitus has an influence on outcome of laparoscopic liver resections with high degree of difficulty, while feasibility and outcome of low difficulty resections seem not to be affected by anthropometric measures.

The Proprotein Convertase Furin Contributes to Rhabdomyosarcoma Malignancy by Promoting Vascularization, Migration and Invasion.

The proprotein convertase (PC) furin cleaves precursor proteins, an important step in the activation of many cancer-associated proteins. Substrates of furin and furin-like PCs play a role in proliferation, metastasis and invasion. Some of them are involved in the progression of the pediatric soft tissue sarcoma rhabdomyosarcoma (RMS). In this study, we show that PCs, and in particular furin, are expressed in RMS cell lines. To investigate the functional role of furin, we generated RMS cell lines with modulated furin activity. Silencing or stable inhibition of furin delayed tumor growth in Rh30 and RD xenografts in vivo, and was correlated with lower microvessel density. Reduced furin activity also decreased migration and invasion abilities in vitro, and inhibition of furin in RMS cells diminished processing of IGF1R, VEGF-C, PDGF-B and MT1-MMP, leading to lower levels of mature proteins. Furthermore, we found that furin activity is required for proper IGF signaling in RMS cells, as furin silencing resulted in reduced phosphorylation of Akt upon IGF1 stimulation. Taken together, our results suggest that furin plays an important role in the malignant phenotype of RMS cells by activating proteins involved in tumor growth and vascularization, metastasis and invasion.

Physical exercise and antidepressants enhance BDNF targeting in hippocampal CA3 dendrites: further evidence of a spatial code for BDNF splice variants.

Brain-derived neurotrophic factor (BDNF) is encoded by multiple BDNF transcripts, whose function is unclear. We recently showed that a subset of BDNF transcripts can traffic into distal dendrites in response to electrical activity, while others are segregated into the somatoproximal domains. Physical exercise and antidepressant treatments exert their beneficial effects through upregulation of BDNF, which is required to support survival and differentiation of newborn dentate gyrus (DG) neurons. While these DG processes are required for the antidepressant effect, a role for CA1 in antidepressant action has been excluded, and the effect on CA3 neurons remains unclear. Here, we show for the first time that physical exercise and antidepressants induce local increase of BDNF in CA3. Voluntary physical exercise for 28 consecutive days, or 2-week treatment with 10 mg/kg per day fluoxetine or reboxetine, produced a global increase of BDNF mRNA and protein in the neuronal somata of the whole hippocampus and a specific increase of BDNF in dendrites of CA3 neurons. This increase was accounted for by BDNF exon 6 variant. In cultured hippocampal neurons, application of serotonin or norepinephrine (10-50 µM) induced increase in synaptic transmission and targeting of BDNF mRNA in dendrites. The increased expression of BDNF in CA3 dendrites following antidepressants or exercise further supports the neurotrophin hypothesis of antidepressants action and confirms that the differential subcellular localization of BDNF mRNA splice variants provides a spatial code for a selective expression of BDNF in specific subcellular districts. This selective expression may be exploited to design more specific antidepressants.

Unexpected granular cell tumor in abdominal wall: case report and literature review.

Granular cell tumors (GCTs) are uncommon benign neoplasms deriving from Schwann cells of the peripheral nerve fibers. Although these tumors can be found anywhere in the body, the most frequent site is the tongue, followed by the chest wall and the arm. The abdominal wall is an extremely rare site for GCTs. These tumors are generally asymptomatic and have a slow growth rate. Today, thanks to their immunoreactivity to S-100 and CD68, the differential diagnosis is more straightforward than in the past. We report on a young patient affected by a GCT located in the upper third of the right rectus abdominis muscle. En bloc excision through a diamond-shaped skin incision allowed us to make a correct histological diagnosis, which was confirmed by the immunohistochemical findings. GCT, which is very rare in abdominal wall muscles, should be considered in the differential diagnosis, and surgical excision is the treatment of choice.

CD133 positive embryonal rhabdomyosarcoma stem-like cell population is enriched in rhabdospheres.

Cancer stem cells (CSCs) have been identified in a number of solid tumors, but not yet in rhabdomyosarcoma (RMS), the most frequently occurring soft tissue tumor in childhood. Hence, the aim of this study was to identify and characterize a CSC population in RMS using a functional approach. We found that embryonal rhabdomyosarcoma (eRMS) cell lines can form rhabdomyosarcoma spheres (short rhabdospheres) in stem cell medium containing defined growth factors over several passages. Using an orthotopic xenograft model, we demonstrate that a 100 fold less sphere cells result in faster tumor growth compared to the adherent population suggesting that CSCs were enriched in the sphere population. Furthermore, stem cell genes such as oct4, nanog, c-myc, pax3 and sox2 are significantly upregulated in rhabdospheres which can be differentiated into multiple lineages such as adipocytes, myocytes and neuronal cells. Surprisingly, gene expression profiles indicate that rhabdospheres show more similarities with neuronal than with hematopoietic or mesenchymal stem cells. Analysis of these profiles identified the known CSC marker CD133 as one of the genes upregulated in rhabdospheres, both on RNA and protein levels. CD133(+) sorted cells were subsequently shown to be more tumorigenic and more resistant to commonly used chemotherapeutics. Using a tissue microarray (TMA) of eRMS patients, we found that high expression of CD133 correlates with poor overall survival. Hence, CD133 could be a prognostic marker for eRMS. These experiments indicate that a CD133(+) CSC population can be enriched from eRMS which might help to develop novel targeted therapies against this pediatric tumor.

Furin targeted drug delivery for treatment of rhabdomyosarcoma in a mouse model.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Improvement of treatment efficacy and decreased side effects through tumor-targeted drug delivery would be desirable. By panning with a phage-displayed cyclic random peptide library we selected a peptide with strong affinity for RMS in vitro and in vivo. The peptide minimal binding motif Arg-X-(Arg/Lys)(Arg/Lys) identified by alanine-scan, suggested the target receptor to be a proprotein convertase (PC). Expression profiling of all PCs in RMS biopsies and cell lines revealed consistent high expression levels for the membrane-bound furin and PC7. Direct binding of RMS-P3 peptide to furin was demonstrated by affinity chromatography and supported by activity and colocalization studies. Treatment of RMS in mice with doxorubicin coupled to the targeting peptide resulted in a two-fold increase in therapeutic efficacy compared to doxorubicin treatment alone. Our findings indicate surface-furin binding as novel mechanism for therapeutic cell penetration which needs to be further investigated. Furthermore, this work demonstrates that specific targeting of membrane-bound furin in tumors is possible for and suggests that RMS and other tumors might benefit from proprotein convertases targeted drug delivery.