Factors Affecting Recurrence and Survival for Patients with High-Risk Stage II Melanoma.

BACKGROUND: In the current era of effective adjuvant therapies and de-escalation of surgery, distinguishing which patients with high-risk stage II melanoma are at increased risk of recurrence after excision of the primary lesion is essential to determining appropriate treatment and surveillance plans. METHODS: A single-center retrospective study analyzed patients with stage IIB or IIC melanoma. Demographic and tumor data were collected, and genomic analysis of formalin-fixed, paraffin-embedded tissue samples was performed via an internal next-generation sequencing (NGS) platform (SNaPshot). The end points examined were relapse-free survival (RFS), distant metastasis-free survival (DMFS), overall survival (OS), and melanoma-specific survival (MSS). Uni- and multivariable Cox regressions were performed to calculate the hazard ratios. RESULTS: The study included 92 patients with a median age of 69 years and a male/female ratio of 2:1. A Breslow depth greater than 4 mm, a higher mitotic rate, an advanced T stage, and a KIT mutation had a negative impact on RFS. A primary lesion in the head and neck, a mitotic rate exceeding 10 mitoses per mm2, a CDH1 mutation, or a KIT mutation was significantly associated with a shorter DMFS. Overall survival was significantly lower with older age at diagnosis and a higher mitotic rate. An older age at diagnosis also had a negative impact on MSS. CONCLUSION: Traditional histopathologic factors and specific tumor mutations displayed a significant correlation with disease recurrence and survival for patients with high-risk stage II melanoma. This study supported the use of genomic testing of high-risk stage II melanomas for prognostic prediction and risk stratification.

Profiling of Natural Killer Interactions With Cancer Cells Using Mass Cytometry.

We developed a comprehensive method for functional assessment of the changes in immune populations and killing activity of peripheral blood mononuclear cells after cocultures with cancer cells using mass cytometry. In this study, a 43-marker mass cytometry panel was applied to a coculture of immune cells from healthy donors' peripheral blood mononuclear cells with diverse cancer cell lines. DNA content combined with classical CD45 surface staining was used as gating parameters for cocultures of immune cells (CD45high/DNAlow) with hematological (CD45low/DNAhigh) and solid cancer cell lines (CD45neg/DNAhigh). This strategy allows for universal discrimination of cancer cells from immune populations without the need for a specific cancer cell marker and simultaneous assessment of phenotypical changes in both populations. The use of mass cytometry allows for simultaneous detection of changes in natural killer, natural killer T cell, and T cell phenotypes and degranulation of immune populations upon target recognition, analysis of target cells for cytotoxic protein granzyme B content, and cancer cell death. These findings have broad applicability in research and clinical settings with the aim to phenotype and assess functional changes following not only NK-cancer cell interactions but also the effect of those interactions on other immune populations.

EISOR Delivery: Regional experience with sharing equipe, equipment & expertise to increase cDCD donor pool in time of pandemic.

Donation after circulatory death (DCD) programs are expanding in Europe, in the attempt to expand donors pool. Even in controlled DCD donors, however, a protracted warm ischemia time occurring in the perimortem period might damage organs, making these unsuitable for transplantation. Implementing a strategy of extracorporeal interval support for organ retrieval (EISOR), a regional reperfusion with normothermic, oxygenated blood provides a physiologic environment allowing extensive assessment of potential grafts, and potentially promotes recovery of native function. Here we report the results of a multi-center retrospective cohort study including 29 Maastricht Category III controlled DCD donors undergoing extracorporeal support in a regional DCD/EISOR Training Center, and in the network of referring In-Training Centers, under the liaison of the regional Transplant Coordination Center during COVID-19 pandemic, between March 2020 and November 2021. The study aims to understand whether a mobile, experienced EISOR team implementing a consistent technique and sharing its equipe, expertise and equipment in a regional network of hospitals, might be effective and efficient in implementing the regional DCD program activity even in a highly stressed healthcare system.

Efficient T-Cell Compartment in HIV-Positive Patients Receiving Orthotopic Liver Transplant and Immunosuppressive Therapy.

BACKGROUND: In patients undergoing orthotopic liver transplant (OLT), immunosuppressive treatment is mandatory and infections are leading causes of morbidity/mortality. Thus, it is essential to understand the functionality of cell-mediated immunity after OLT. The aim of the study was to identify changes in T-cell phenotype and polyfunctionality in human immunodeficiency virus-positive (HIV+) and -negative (HIV-) patients undergoing immunosuppressive treatment after OLT. METHODS: We studied peripheral blood mononuclear cells from 108 subjects divided into 4 groups of 27: HIV+ transplanted patients, HIV- transplanted patients, HIV+ nontransplanted patients, and healthy subjects. T-cell activation, differentiation, and cytokine production were analyzed by flow cytometry. RESULTS: Median age was 55 years (interquartile range, 52-59 years); the median CD4 count in HIV+ patients was 567 cells/mL, and all had undetectable viral load. CD4+ and CD8+ T-cell subpopulations showed different distributions between HIV+ and HIV- OLT patients. A cluster representing effector cells expressing PD1 was abundant in HIV- transplanted patients and they were characterized by higher levels of CD4+ T cells able to produce interferon-γ and tumor necrosis factor-α. CONCLUSIONS: HIV- transplanted patients have more exhausted or inflammatory T cells compared to HIV+ transplanted patients, suggesting that patients who have already experienced a form of immunosuppression due to HIV infection respond differently to anti-rejection therapy.

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

BACKGROUND & AIMS: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. METHODS: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. RESULTS: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. CONCLUSIONS: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. LAY SUMMARY: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Shear wave elastography and transient elastography in HCV patients after direct-acting antivirals.

PURPOSE: To compare the ultrasound (US) and pulse shear wave elastography (pSWE, Elast PQ®) methods with transient elastography (TE), clinical scores and laboratory tests, during the follow-up of HCV patients receiving direct-acting antiviral drugs (DAA). METHODS: Our prospective study from June 2016 to December 2017 included 22 consecutively enrolled HCV-positive patients (59.7 ± 12.3 years, 11 male) which were subjected to antiviral therapy. All patients underwent B-mode ultrasound, color-Doppler, pSWE and TE five times: before therapy (T0), at the end of therapy (post-Tx), and at 12, 24, 48 weeks post-therapy. The liver stiffness (LS) values obtained with pSWE and TE and the data coming from US assessment and clinical evaluation were compared. RESULTS: We obtained a statistically significant reduction of LS values (kPa) measured by pSWE, between T0 (14.3 ± 9.3), post-Tx (11.8 ± 10.5), 12 weeks (7.5 ± 3.3), 24 weeks (8 ± 3.8) and 48 weeks (8.5 ± 4.6) (p = 0.02). The reduction of kPa measured by TE was not significant between T0 (14.7 ± 9.3), post-Tx (12 ± 9.5), 12 weeks (11.6 ± 7.7), 24 weeks (10.3 ± 6) and 48 weeks (10.8 ± 7.5) (p > 0.05). Multivariate baseline analysis showed significant independent association among measurement of TE stiffness with cirrhosis, type of vein hepatic flow and showed significant independent association between delta-pSWE measurement (difference between stiffness measurements at the baseline and 12 months after treatment) with staging of fibrosis (p = 0.006) and sustained virologic response after 12 weeks of treatment (SVR12, p = 0.017). CONCLUSION: The pSWE method has shown better ability than TE to identify a reduction in LS. Therefore, pSWE allow to evaluate stiffness reduction in HCV patient during DAA treatment follow-up, which is related to SVR12.

Laparoscopic versus open liver resection for intrahepatic cholangiocarcinoma: the first meta-analysis.

BACKGROUND: Laparoscopic liver resection (LLR) has gained increasing acceptance for surgical treatment of malignant and benign liver tumors. LLR for intrahepatic cholangiocarcinoma (ICC) is not commonly performed because of the concern for the frequent need for major hepatectomy, vascular-biliary reconstructions, and lymph node dissection (LND). The aim of this present meta-analysis is to compare surgical and oncological outcomes of laparoscopic (LLR) versus open liver resection (OLR) for ICC. MATERIALS AND METHODS: A systematic review was conducted using the PubMed, MEDLINE, and Cochrane library database of published studies comparing LLR and OLR up to October 2019. Two reviewers independently assessed the eligibility and quality of the studies. Dichotomous data were calculated by odds ratio (OR), and continuous data were calculated by mean difference (MD) with 95% confidence intervals (95% CI). RESULTS: Four retrospective observational studies describing 204 patients met the inclusion criteria. With respect to surgical outcomes, laparoscopic compared with open liver resection was associated with lower blood loss [MD - 173.86, (95% CI - 254.82, -92.91) p < 0.0001], less requirement of blood transfusion [OR 0.34, (95% CI 0.14, 0.82) p = 0.02], less need for Pringle maneuver [OR 0.17, (95% CI 0.07, 0.43) p = 0.0002], shorter hospital stay [MD - 3.77, (95% CI - 5.09, - 2.44; p < 0.0001], and less morbidity [OR 0.44, (95% CI 0.21, 0.94) p = 0.03]. With respect to oncological outcomes, the LLR group was prone to lower rates of lymphadenectomy [OR 0.12, (95% CI 0.06, 0.25) p < 0.0001], but surgical margins R0 and recurrence rate were not significantly different. CONCLUSION: Laparoscopic liver resection for ICC seems to achieve better surgical outcomes, providing short-term benefits without negatively affecting oncologic adequacy in terms of R0 resections and disease recurrence. However, a higher LND rate was observed in the open group. Due to the risk of bias and the statistical heterogeneity between the studies included in this review, further RCTs are needed to reach stronger scientific conclusions.

Gain of FGF4 is a frequent event in KIT/PDGFRA/SDH/RAS-P WT GIST.

Gastrointestinal stromal tumors (GIST) lacking mutations in KIT/PDGFRA or RAS pathways and retaining an intact SDH complex are usually referred to as KIT/PDGFRA/SDH/RAS-P WT GIST or more simply quadruple WT GIST (~5% of all GIST). Despite efforts made, no recurrent genetic event in quadruple WT GIST has been identified so far. To further investigate this disease, we performed high throughput copy number analysis on quadruple WT GIST specimens identifying a recurrent focal gain in band 11q13.3 (involving FGF3/FGF4) in 6/8 cases. This event was not found in the other molecular GIST subgroups. FGF3/FGF4 duplication was associated with high expression of FGF4, both at mRNA and protein level, a growth factor normally not expressed in adult tissues or in KIT/PDGFRA-mutated GIST. FGFR1 was found to be the predominant FGF receptor expressed and phosphorylation of AKT was detected, suggesting that a FGF4-FGFR1 autocrine loop could stimulate downstream signaling in quadruple WT GIST. Together with the recent reports of quadruple WT cases carrying FGFR1 activating alterations, these findings strengthen the hypothesis of a potential involvement of FGFR pathway deregulation in quadruple WT GIST, which may represent a rationale for novel therapeutic approaches.

Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy for which there is still no effective therapy. In order to identify genetic alterations useful for a new treatment design, we used whole-exome sequencing to analyze 14 BPDCN patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program to be the most significantly undermined (P<0.0001). In particular, twenty-five epigenetic modifiers were found mutated (e.g. ASXL1, TET2, SUZ12, ARID1A, PHF2, CHD8); ASXL1 was the most frequently affected (28.6% of cases). To evaluate the impact of the identified epigenetic mutations at the gene-expression and Histone H3 lysine 27 trimethylation/acetylation levels, we performed additional RNA and pathology tissue-chromatin immunoprecipitation sequencing experiments. The patients displayed enrichment in gene signatures regulated by methylation and modifiable by decitabine administration, shared common H3K27-acetylated regions, and had a set of cell-cycle genes aberrantly up-regulated and marked by promoter acetylation. Collectively, the integration of sequencing data showed the potential of a therapy based on epigenetic agents. Through the adoption of a preclinical BPDCN mouse model, established by CAL-1 cell line xenografting, we demonstrated the efficacy of the combination of the epigenetic drugs 5'-azacytidine and decitabine in controlling disease progression in vivo.

Not just minor resections: robotic approach for cystic echinococcosis of the liver.

INTRODUCTION: Human echinococcosis is among the 17 neglected tropical diseases recognized by the World Health Organization. It is responsible for over $3 billion of health costs every year being endemic in large areas worldwide, and liver is affected in 70% of the cases. Surgery associated to medical treatment is the gold standard and robotic approach may be a valuable tool to achieve safe, parenchyma sparing resections. METHODS: We retrospectively analyzed the outcomes of patients that underwent robotic radical surgical treatment for hydatid liver disease, from prospectively maintained databases of three Italian centers. RESULTS: 15 patients were included in this study, median age 51 years (24-76). 1 right hepatectomy, 2 left lateral sectionectomies, 5 segmentectomies (including 1 caudatectomy), 3 wedge resections and 5 cyst-pericystectomies were performed. Median estimated blood loss was of 100 ml (50-550 ml), and median operative time including docking was 210 min (95-590 min), with no need for conversion to open. Median hospital stay was 4 days, with only one readmission for fever. Only one patient experienced recurrence in a different liver segment. CONCLUSIONS: In our experience, robotic approach for cystic echinococcosis of the liver proved to be a safe and effective strategy also in the so-called "difficult segments", with short post-operative stay and quick return to daily activities, along with the absence of surgical site recurrences. To the best of our knowledge, this is the largest report of robotic approach to hydatid liver disease.

Ultrasound-Guided Robotic Enucleation of Pancreatic Neuroendocrine Tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are relatively rare neoplasms with a low to mild malignant potential. They can be further divided into functioning and nonfunctioning, according to their secretive activity. Surgery is an optimal approach, but the classic open approach is challenging, with some patients having long hospitalization and potentially life-threatening complications. The robotic approach for PanNETs may represent an option to optimize their management. METHODS: We retrospectively reviewed our prospectively maintained databases from 2 high-volume Italian centers for pancreatic surgery. Demographics, pathological characteristics, perioperative outcome, and medium-term follow-up of patients who underwent robotic pancreatic enucleations were collected. RESULTS: Twelve patients with final diagnosis of PanNET were included. The mean age of the patients was 53.8 years (25-77). The median body mass index was 26 (24-29). Three lesions were functioning insulinomas, while the others were nonfunctioning tumors. No deaths occurred. Mild postoperative complications occurred, except for 1 grade B pancreatic fistula. The mean postoperative stay was 3.9 days (2-5). CONCLUSIONS: Our results confirm that robotic enucleation is a feasible and safe approach for the treatment of PanNETs, with short hospital stay and low incidence of morbidity.

Novel intra-genic large deletions of CTNNB1 gene identified in WT desmoid-type fibromatosis.

A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy. However, predictive factors to select the risk of progressive disease are still lacking. A translational project was run in order to identify genomic signatures in patients enrolled within an Italian prospective observational study. Among 12 DT patients (10 CTNNB1-mutated and 2 wild type) enrolled from our institution only two patients (17%) showed a progressive disease. Tumor biopsies were collected for whole exome sequencing. Overall, DT exhibited low somatic sequence mutation rate and no additional recurrent mutation was found. In the two wild type (WT) cases, two novel alterations were detected: a complex deletion of APC and a pathogenic mutation of LAMTOR2. Focusing on WT DT subtype, deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 11 WT DT using a targeted approach. No other mutation of LAMTOR2 was detected, while APC was mutated in two cases. Low-frequency (mean reads of 16%) CTNNB1 mutations were discovered in five samples (45%) and two novel intra-genic deletions in CTNNB1 were detected in two cases. Both deletions and low frequency mutations of CTNNB1 were highly expressed. In conclusion, a minority of DT is WT for either CTNNB1, APC or any other gene involved in the WNT pathway. In this subgroup novel and hard to be detected molecular alterations in APC and CTNNB1 were discovered, contributing to explain a portion of the allegedly WT DT cases.

Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene.

Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST.

Identification of an Actionable Mutation of KIT in a Case of Extraskeletal Myxoid Chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare soft tissue sarcoma, marked by a translocation involving the NR4A3 gene. EMC is usually indolent and moderately sensitive to anthracycline-based chemotherapy. Recently, we reported on the therapeutic activity of sunitinib in a series of EMC cases, however the molecular target of sunitinib in EMC is unknown. Moreover, there is still the need to identify alternative therapeutic strategies. To better characterize this disease, we performed whole transcriptome sequencing in five EMC cases. Peculiarly, in one sample, an in-frame deletion (c.1735_1737delGAT p.D579del) was identified in exon 11 of KIT. The deletion was somatic and heterozygous and was validated both at DNA and mRNA level. This sample showed a marked high expression of KIT at the mRNA level and a mild phosphorylation of the receptor. Sanger sequencing of KIT in additional 15 Formalin Fixed Paraffin Embedded (FFPE) EMC did not show any other mutated cases. In conclusion, exon 11 KIT mutation was detected only in one out of 20 EMC cases analyzed, indicating that KIT alteration is not a recurrent event in these tumors and cannot explain the EMC sensitivity to sunitinib, although it is an actionable mutation in the individual case in which it has been identified.

HSPA8 as a novel fusion partner of NR4A3 in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma most often arising in the soft tissue. Rare EMC of the bone have been reported. EMC exhibits distinctive clinico-pathological and genetic features; however, despite the name, it lacks any feature of cartilaginous differentiation. EMC is characterized by the rearrangement of the NR4A3, which, in most cases (about 62-75%), is fused with EWSR1 and less frequently with other partners, including TAF15 (27%), TCF12 (4%), TFG, and FUS. We herein report the identification by whole-transcriptome sequencing of HSPA8 as a novel fusion partner of NR4A3 in a case of EMC. FISH analysis confirmed the presence of a genomic HSPA8-NR4A3 translocation in the vast majority of tumor cells. Our findings expand the spectrum of NR4A3 fusion partners involved in EMC pathobiology.

Laparoscopic versus robotic surgery for hepatocellular carcinoma: the first 46 consecutive cases.

BACKGROUND: Hepatocellular carcinoma has a growing incidence worldwide, and represents a leading cause of death in patients with cirrhosis. Nowadays, minimally invasive approaches are spreading in every field of surgery and in liver surgery as well. MATERIALS AND METHODS: We retrospectively reviewed demographics, clinical, and pathologic characteristics and short-term outcomes of patients who had undergone minimally invasive resections for hepatocellular carcinoma at our institution between June 2012 and May 2016. RESULTS: No significant differences in demographics and comorbidities were found between patients in the laparoscopic (n = 24) and robotic (n = 22) groups, except for the rates of cirrhotic patients (91.7% and 68.2%, respectively, P = 0.046). Perioperative data analysis showed that the operative time (mean, 211 and 318 min, respectively, P < 0.001) was the only parameter in favor of laparoscopy. Conversely, robotic-assisted resections were related to less Clavien I-II postoperative complications (22 cases versus 13 cases; P = 0.03). As regards resection margins, the two groups were similar with no statistically significant differences in rates of disease-free resection margins. CONCLUSIONS: A modern hepatobiliary center should offer both open and minimally invasive approaches to liver disease to provide the best care for each patient, according to the individual comorbidities, risk factors, and personal quality of life expectations. Our results show that the robotic approach is a reliable tool for accurate oncologic surgery, comparable to the laparoscopic approach. Robotic surgery also allows the surgeon to safely approach liver segments that are difficult to resect in laparoscopy, namely segments I-VII-VIII.

A frailty index predicts post-liver transplant morbidity and mortality in HIV-positive patients.

BACKGROUND: We hypothesized that frailty acts as a measure of health outcomes in the context of LT. The aim of this study was to explore frailty index across LT, as a measure of morbidity and mortality. This was a retrospective observational study including all consecutive 47 HIV+patients who received LT in Modena, Italy from 2003 to June 2015. METHODS: frailty index (FI) was constructed from 30 health variables. It was used both as a continuous score and as a categorical variable, defining 'most frail' a FI > 0.45. FI change across transplant (deltaFI, ΔFI) was calculated as the difference between year 1 FI (FI-Y1) and pre-transplant FI (FI-t0). The outcomes measures were mortality and "otpimal LT" (defined as being alive without multi-morbidity). RESULTS: Median value of FI-t0 was 0.48 (IQR 0.42-0.52), FI-Y1 was 0.31 (IQR 0.26-0.41). At year five mortality rate was 45%, "optimal transplant" rate at year 1 was 38%. All the patients who died in the post-LT were most frail in the pre-LT. ΔFI was a predictor of mortality after correction for age and MELD (HR = 1.10, p = 0.006) and was inversely associated with optimal transplant after correction for age (HR = 1.04, p = 0.01). CONCLUSIONS: We validated FI as a valuable health measure in HIV transplant. In particular, we found a relevant correlation between FI strata at baseline and mortality and a statistically significant correlation between, ΔFI and survival rate.

Surgery in biliary lithiasis: from the traditional "open" approach to laparoscopy and the "rendezvous" technique.

BACKGROUND: According to the current literature, biliary lithiasis is a worldwide-diffused condition that affects almost 20% of the general population. The rate of common bile duct stones (CBDS) in patients with symptomatic cholelithiasis is estimated to be 10% to 33%, depending on patient's age. Compared to stones in the gallbladder, the natural history of secondary CBDS is still not completely understood. It is not clear whether an asymptomatic choledocholithiasis requires treatment or not. For many years, open cholecystectomy with choledochotomy and/or surgical sphincterotomy and cleaning of the bile duct were the gold standard to treat both pathologies. Development of both endoscopic retrograde cholangiopancreatography (ERCP) and laparoscopic surgery, together with improvements in diagnostic procedures, influenced new approaches to the management of CBDS in association with gallstones. DATA SOURCES: We decided to systematically review the literature in order to identify all the current therapeutic options for CBDS. A systematic literature search was performed independently by two authors using PubMed, EMBASE, Scopus and the Cochrane Library Central. RESULTS: The therapeutic approach nowadays varies greatly according to the availability of experience and expertise in each center, and includes open or laparoscopic common bile duct exploration, various combinations of laparoscopic cholecystectomy and ERCP and combined laparoendoscopic rendezvous. CONCLUSIONS: Although ERCP followed by laparoscopic cholecystectomy is currently preferred in the majority of hospitals worldwide, the optimal treatment for concomitant gallstones and CBDS is still under debate, and greatly varies among different centers.

Exploiting NanoLuc luciferase for smartphone-based bioluminescence cell biosensor for (anti)-inflammatory activity and toxicity.

The availability of smartphones with high-performance digital image sensors and processing power has completely reshaped the landscape of point-of-need analysis. Thanks to the high maturity level of reporter gene technology and the availability of several bioluminescent proteins with improved features, we were able to develop a bioluminescence smartphone-based biosensing platform exploiting the highly sensitive NanoLuc luciferase as reporter. A 3D-printed smartphone-integrated cell biosensor based on genetically engineered Hek293T cells was developed. Quantitative assessment of (anti)-inflammatory activity and toxicity of liquid samples was performed with a simple and rapid add-and-measure procedure. White grape pomace extracts, known to contain several bioactive compounds, were analyzed, confirming the suitability of the smartphone biosensing platform for analysis of untreated complex biological matrices. Such approach could meet the needs of small medium enterprises lacking fully equipped laboratories for first-level safety tests and rapid screening of new bioactive products. Graphical abstract Smartphone-based bioluminescence cell biosensor.