Low plasma PD-L1 levels, early tumor onset and absence of peritoneal carcinomatosis improve prognosis of women with advanced high-grade serous ovarian cancer.

BACKGROUND: The most common subtype of ovarian cancer (OC) showing immunogenic potential is represented by the high-grade serous ovarian cancer (HGSOC), which is characterized by the presence of tumor-infiltrating immune cells able to modulate immune response. Because several studies showed a close correlation between OC patient's clinical outcome and expression of programmed cell death protein-1 or its ligand (PD-1/PD-L1), the aim of our study was to investigate if plasma levels of immunomodulatory proteins may predict prognosis of advanced HGSOC women. PATIENTS AND METHODS: Through specific ELISA tests, we analyzed plasma concentrations of PD-L1, PD-1, butyrophilin sub-family 3A/CD277 receptor (BTN3A1), pan-BTN3As, butyrophilin sub-family 2 member A1 (BTN2A1), and B- and T-lymphocyte attenuator (BTLA) in one hundred patients affected by advanced HGSOC, before surgery and therapy. The Kaplan-Meier method was used to generate the survival curves, while univariate and multivariate analysis were performed using Cox proportional hazard regression models. RESULTS: For each analyzed circulating biomarker, advanced HGSOC women were discriminated based on long (≥ 30 months) versus short progression-free survival (PFS < 30 months). The concentration cut-offs, obtained by receiver operating characteristic (ROC) analysis, allowed to observe that poor clinical outcome and median PFS ranging between 6 and 16 months were associated with higher baseline levels of PD-L1 (> 0.42 ng/mL), PD-1 (> 2.48 ng/mL), BTN3A1 (> 4.75 ng/mL), pan-BTN3As (> 13.06 ng/mL), BTN2A1 (> 5.59 ng/mL) and BTLA (> 2.78 ng/mL). Furthermore, a lower median PFS was associated with peritoneal carcinomatosis, age at diagnosis > 60 years or Body Mass Index (BMI) > 25. A multivariate analysis also suggested that plasma concentrations of PD-L1 ≤ 0.42 ng/mL (HR: 2.23; 95% CI: 1.34 to 3.73; p = 0.002), age at diagnosis ≤ 60 years (HR: 1.70; 95% CI: 1.07 to 2.70; p = 0.024) and absence of peritoneal carcinomatosis (HR: 1.87; 95% CI: 1.23 to 2.85; p = 0.003) were significant prognostic marker for a longer PFS in advanced HGSOC patients. CONCLUSIONS: The identification of high-risk HGSOC women could be improved through determination of the plasma PD-L1, PD-1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA levels.

NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response.

Non-alcoholic fatty liver (NAFL) and related syndromes affect one-third of the adult population in industrialized and developing countries. Lifestyle and caloric oversupply are the main causes of such array of disorders, but the molecular mechanisms underlying their etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs including liver. Recently, we reported NUPR1 actively participates in the activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions including lipid metabolism. As increases in UPR and NUPR1 in obesity and liver disease have been well documented, the goal of this study was to investigate the roles of NUPR1 in this context. To establish whether NUPR1 is involved in these liver conditions we used patient-derived liver biopsies and in vitro and in vivo NUPR1 loss of functions models. First, we analyzed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild-type (Nupr1+/+ ) or Nupr1 knockout mice (Nupr1-/- ) fed with a high-fat diet (HFD) for 15 weeks. Immunohistochemical and mRNA analysis revealed NUPR1 expression is inversely correlated to hepatic steatosis progression. Mechanistically, we found NUPR1 participates in the activation of PPAR-α signaling via UPR. As PPAR-α signaling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.

Laparoscopic versus robotic right colectomy with extra-corporeal or intra-corporeal anastomosis: a systematic review and meta-analysis.

PURPOSE: The aim of the present systematic review and meta-analysis is to compare laparoscopic right colectomy (LRC) versus robotic right colectomy (RRC) using homogeneous subgroup analyses for extra-corporeal anastomosis (EA) and intra-corporeal anastomosis (IA). METHODS: MEDLINE, Scopus, and Web of Science databases were searched up to April 2020 for prospective or retrospective studies comparing LRC versus RRC on at least one short- or long-term outcome. The primary outcome was the length of hospital stay (LOS). The secondary outcomes included operative and pathological results, survival, and total costs. LRC and RRC were compared using three homogeneous subgroups: without distinction by the type of anastomosis, EA only, and IA only. Pooled data analyses were performed using mean difference (MD) and random effects model. RESULTS: Thirty-seven of 448 studies were selected. The included patients were 21,397 for the LRC group and 2796 for the RRC group. Regardless for the type of anastomosis, RRC showed shorter LOS, lower blood loss, lower conversion rate, shorter time to flatus, and lower overall complication rate compared with LRC, but longer operative time and higher total costs. In the EA subgroup, RRC showed similar LOS, longer operative time, and higher costs compared with LRC, the other outcomes being similar. In the IA subgroup, RRC showed shorter LOS and longer operative time compared with LRC, with no difference for the remaining outcomes. CONCLUSIONS: Most included articles are retrospective, providing low-quality evidence and limiting conclusions. The more frequent use of the IA seems to explain the advantages of RRC over LRC.

Knockdown of NANOG Reduces Cell Proliferation and Induces G0/G1 Cell Cycle Arrest in Human Adipose Stem Cells.

The core components of regenerative medicine are stem cells with high self-renewal and tissue regeneration potentials. Adult stem cells can be obtained from many organs and tissues. NANOG, SOX2 and OCT4 represent the core regulatory network that suppresses differentiation-associated genes, maintaining the pluripotency of mesenchymal stem cells. The roles of NANOG in maintaining self-renewal and undifferentiated status of adult stem cells are still not perfectly established. In this study we define the effects of downregulation of NANOG in maintaining self-renewal and undifferentiated state in mesenchymal stem cells (MSCs) derived from subcutaneous adipose tissue (hASCs). hASCs were expanded and transfected in vitro with short hairpin Lentivirus targeting NANOG. Gene suppressions were achieved at both transcript and proteome levels. The effect of NANOG knockdown on proliferation after 10 passages and on the cell cycle was evaluated by proliferation assay, colony forming unit (CFU), qRT-PCR and cell cycle analysis by flow-cytometry. Moreover, NANOG involvement in differentiation ability was evaluated. We report that downregulation of NANOG revealed a decrease in the proliferation and differentiation rate, inducing cell cycle arrest by increasing p27/CDKN1B (Cyclin-dependent kinase inhibitor 1B) and p21/CDKN1A (Cyclin-dependent kinase inhibitor 1A) through p53 and regulate DLK1/PREF1. Furthermore, NANOG induced downregulation of DNMT1, a major DNA methyltransferase responsible for maintaining methylation status during DNA replication probably involved in cell cycle regulation. Our study confirms that NANOG regulates the complex transcription network of plasticity of the cells, inducing cell cycle arrest and reducing differentiation potential.

NANOG Plays a Hierarchical Role in the Transcription Network Regulating the Pluripotency and Plasticity of Adipose Tissue-Derived Stem Cells.

The stromal vascular cell fraction (SVF) of visceral and subcutaneous adipose tissue (VAT and SAT) has increasingly come into focus in stem cell research, since these compartments represent a rich source of multipotent adipose-derived stem cells (ASCs). ASCs exhibit a self-renewal potential and differentiation capacity. Our aim was to study the different expression of the embryonic stem cell markers NANOG (homeobox protein NANOG), SOX2 (SRY (sex determining region Y)-box 2) and OCT4 (octamer-binding transcription factor 4) and to evaluate if there exists a hierarchal role in this network in ASCs derived from both SAT and VAT. ASCs were isolated from SAT and VAT biopsies of 72 consenting patients (23 men, 47 women; age 45 ± 10; BMI between 25 ± 5 and 30 ± 5 range) undergoing elective open-abdominal surgery. Sphere-forming capability was evaluated by plating cells in low adhesion plastic. Stem cell markers CD90, CD105, CD29, CD31, CD45 and CD146 were analyzed by flow cytometry, and the stem cell transcription factors NANOG, SOX2 and OCT4 were detected by immunoblotting and real-time PCR. NANOG, SOX2 and OCT4 interplay was explored by gene silencing. ASCs from VAT and SAT confirmed their mesenchymal stem cell (MSC) phenotype expressing the specific MSC markers CD90, CD105, NANOG, SOX2 and OCT4. NANOG silencing induced a significant OCT4 (70 ± 0.05%) and SOX2 (75 ± 0.03%) downregulation, whereas SOX2 silencing did not affect NANOG gene expression. Adipose tissue is an important source of MSC, and siRNA experiments endorse a hierarchical role of NANOG in the complex transcription network that regulates pluripotency.

A headlight on liquid biopsies: a challenging tool for breast cancer management.

Breast cancer is the most frequent carcinoma and second most common cause of cancer-related mortality in postmenopausal women. The acquisition of somatic mutations represents the main mechanism through which cancer cells overcome physiological cellular signaling pathways (e.g., PI3K/Akt/mTOR, PTEN, TP53). To date, diagnosis and metastasis monitoring is mainly carried out through tissue biopsy and/or re-biopsy, a very invasive procedure limited only to certain locations and not always feasible in clinical practice. In order to improve disease monitoring over time and to avoid painful procedure such as tissue biopsy, liquid biopsy may represent a new precious tool. Indeed, it represents a basin of "new generation" biomarkers that are spread into the bloodstream from both primary and metastatic sites. Moreover, elevated concentrations of circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs) have been found in blood plasma of patients with various tumor types. Nowadays, several new approaches have been introduced for the detection and characterization of CTCs and ctDNA, allowing a real-time monitoring of tumor evolution. This review is focused on the clinical relevance of liquid biopsy in breast cancer and will provide an update concerning CTCs and ctDNA utility as a tool for breast cancer patient monitoring during the course of disease.

Clinical relevance of exosome-derived microRNAs in Ovarian Cancer: Looking for new tumor biological fingerprints.

Specific tumor-derived extracellular vesicles, called exosomes, are considered as potential key players in cross-talk between immune system and tumor microenvironment in several solid tumors. Different studies highlighted the clinical relevance of exosomes in ovarian cancer (OC) for their role in early diagnosis, prognosis, chemoresistance, targeted therapy. The exosomes are nanosize vesicles carrying lipids, proteins, and nucleic acids. In particular, exosomes shuttle a wide spectrum of microRNAs (miRNAs) able to induce phenotypic reprogramming of target cells, contributing to tumor progression. In this review, we will discuss the promising role of miRNAs shuttled by exosomes, called exosomal miRNAs (exo-miRNAs), as potential biomarkers for early detection, tumour progression and metastasis, prognosis, and response to therapy in OC women, in order to search for new potential biological fingerprints able to better characterize the evolution of this malignancy and provide a clinically relevant non-invasive approach useful for adopting, in future, personalized therapeutic strategies.

KPC - 3 Klebsiella pneumoniae ST258 clone infection in postoperative abdominal surgery patients in an intensive care setting: analysis of a case series of 30 patients.

BACKGROUND: Abdominal surgery carries significant morbidity and mortality, which is in turn associated with an enormous use of healthcare resources. We describe the clinical course of 30 Intensive Care Unit (ICU) patients who underwent abdominal surgery and showed severe infections caused by Klebsiella pneumoniae sequence type (ST) 258 producing K. pneumoniae carbapenemase (KPC-Kp). The aim was to evaluate risk factors for mortality and the impact of a combination therapy of colistin plus recommended regimen or higher dosage of tigecycline. METHODS: A prospective assessment of severe monomicrobial KPC-Kp infections occurring after open abdominal surgery carried out from August 2011 to August 2012 in the same hospital by different surgical teams is presented. Clinical and surgical characteristics, microbiological and surveillance data, factors associated with mortality and treatment regimens were analyzed. A combination regimen of colistin with tigecycline was used. A high dose of tigecycline was administered according to intra-abdominal abscess severity and MICs for tigecycline. RESULTS: The mean age of the patients was 56.6 ± 15 and their APACHE score on admission averaged 22.72. Twenty out of 30 patients came from the surgical emergency unit. Fifteen patients showed intra-abdominal abscess, eight anastomotic leakage, four surgical site infection (SSI) and three peritonitis. The overall crude ICU mortality rate was 40% (12 out of 30 patients). Twelve of the 30 patients were started on a combination treatment of high-dose tigecycline and intravenous colistin. A significantly lower mortality rate was observed among those patients compared to patients treated with approved dose of tigecycline plus colistin. No adverse events were reported with high doses of tigecycline. CONCLUSIONS: Critically-ill surgical patients are prone to severe post-surgical infectious complications caused by KPC-Kp. Timely microbiological diagnosis and optimizing antibiotic dosing regimens are essential to prevent worse outcomes. Further studies and well-controlled clinical trials are needed to define the optimal treatment of infections by KPC-Kp and, more generally, carbapenem-resistant bacteria.

Navigating the liquid biopsy Minimal Residual Disease (MRD) in non-small cell lung cancer: Making the invisible visible.

Liquid biopsy has gained increasing interest in the growing era of precision medicine as minimally invasive technique. Recent findings demonstrated that detecting minimal or molecular residual disease (MRD) in NSCLC is a challenging matter of debate that need multidisciplinary competencies, avoiding the overtreatment risk along with achieving a significant survival improvement. This review aims to provide practical consideration for solving data interpretation questions about MRD in NSCLC thanks to the close cooperation between biologists and oncology clinicians. We discussed with a translational approach the critical point of view from benchside, bedside and bunchside to facilitate the future applicability of liquid biopsy in this setting. Herein, we defined the clinical significance of MRD, focusing on relevant practical consideration about advantages and disadvantages, speculating on future clinical trial design and standardization of MRD technology.

Risk factors for bile leakage after liver resection for neoplastic disease.

Biliary leakage (BL) remains the most frequent and feared complication after hepatoresective surgery. Placement of the abdominal drainage at the end of liver surgery remains controversial due to the delicate balance between risks and potential benefits in case of BL. The study was aimed to detect possible risk factors for BL occurrence after liver surgery. We enrolled all oncologic patients who underwent liver resection from June 2016 to March 2021. BL was diagnosed according to the ISGLS definition. We have examined demographic characteristics of the patients, type of neoplasia, presence of cirrhosis, neoadjuvant chemotherapy and type of intervention. Uni- and multivariable analyses were performed to assess the predictive value of potential predictor of BL. A total of 379 patients were enrolled in the study, 16 (4.2%) of which developed BL. Among others, at univariate analysis the occurrence of BL was found to be associated with bilio-digestive anastomosis (OR: 9.75, C.I. 2.7-34.7, p < 0.001) and neoadjuvant chemotherapy (OR: 0.09, C.I 0.01,-0.88, p = 0.039). Multivariable analysis selected the body mass index (OR: 1.21, 95%C.I.: 1.04-1.41, p = 0.015), anatomical resection (OR: 8.35, 95% C.I.: 2.01-34.74, p = 0.004), and blood loss (OR: 1.09, 95%C.I.: 1.05-1.13, p < 0.001). Identification of patients at greater risk of BL can help in the choice of positioning the drainage at the end of liver surgery.

MUTYH-associated tumor syndrome: The other face of MAP.

MUTYH gene is involved in the base excision repair (BER) mechanism and its pathogenic alterations are associated with colorectal polyposis and cancer. MUTYH-associated polyposis (MAP) is a condition which is inherited in an autosomal recessive manner. MAP patients, beyond colorectal cancer (CRC), may develop other types of tumors, including duodenal, breast, ovarian, pancreatic, bladder and skin cancers. Carriers of biallelic MUTYH likely pathogenic/pathogenic variants exhibit a high lifetime risk of CRC, though cancer risk evidence becomes less clear when monoallelic carriers and extraintestinal tumors are considered. However, several studies recently reported an increased genetic susceptibility to cancer also for carriers of germline monoallelic MUTYH mutations. Moreover, experimental evidence highlighted the MUTYH involvement in many other biological functions. In future, MUTYH mutation carriers might benefit from new target therapies involving the use of PD-1 or KRAS inhibitors. Therefore, "MUTYH-associated tumor syndrome" might be the most appropriate term, due to the multiplicity of tumors observed in MAP patients and different biological contexts in which MUTYH acts as a "playmaker". In this Review, we will investigate the impact of germline mono- and biallelic MUTYH mutations on cancer risk, providing a proposal for clinical surveillance of mutation carriers.

Can circulating PD-1, PD-L1, BTN3A1, pan-BTN3As, BTN2A1 and BTLA levels enhance prognostic power of CA125 in patients with advanced high-grade serous ovarian cancer?

The most common subtype of ovarian cancer (OC) is the high-grade serous ovarian carcinoma (HGSOC), accounting for 70%-80% of all OC deaths. Although HGSOC is a potentially immunogenic tumor, clinical studies assessing the effectiveness of inhibitors of programmed death protein and its ligand (PD-1/PD-L1) in OC patients so far showed only response rates <15%. However, recent studies revealed an interesting prognostic role of plasma PD-1/PD-L1 and other circulating immunoregulatory molecules, such as the B- and T-lymphocyte attenuator (BTLA), butyrophilin sub-family 3A/CD277 receptors (BTN3A), and butyrophilin sub-family 2 member A1 (BTN2A1), in several solid tumors. Since evidence showed the prognostic relevance of pretreatment serum CA125 levels in OC, the aim of our study was to investigate if soluble forms of inhibitory immune checkpoints can enhance prognostic power of CA125 in advanced HGSOC women. Using specific ELISA tests, we examined the circulating PD-1, PD-L1, pan-BTN3As, BTN3A1, BTN2A1, and BTLA levels in 100 advanced HGSOC patients before treatment, correlating them with baseline serum CA125, age at diagnosis, body mass index (BMI), and peritoneal carcinomatosis. A multivariate analysis revealed that plasma BTN3A1 ≤4.75 ng/ml (HR, 1.94; 95% CI, 1.23-3.07; p=0.004), age at diagnosis ≤60 years (HR, 1.65; 95% CI, 1.05-2.59; p=0.03) and absence of peritoneal carcinomatosis (HR, 2.65; 95% CI, 1.66-4.22; p<0.0001) were independent prognostic factors for a longer progression-free survival (PFS) (≥30 months) in advanced HGSOC women. However, further two-factor multivariate analyses highlighted that baseline serum CA125 levels >401 U/ml and each soluble protein above respective concentration cutoff were covariates associated with shorter PFS (<30 months) and unfavorable clinical outcome, suggesting that contemporary measurement of both biomarkers than CA125 only could strengthen prognostic power of serum CA125 in predicting PFS of advanced HGSOC women. Plasma PD-L1, PD-1, BTN3A1, pan-sBTN3As, BTN2A1, or BTLA levels could be helpful biomarkers to increase prognostic value of CA125.

Can the tumor-agnostic evaluation of MSI/MMR status be the common denominator for the immunotherapy treatment of patients with several solid tumors?

Alterations in short-repetitive DNA sequences, known as microsatellite instability (MSI), can reflect deficiencies in Mismatch Repair (MMR) system which represents a major player in DNA integrity maintenance. The incidence of MSI-H/dMMR has been shown to be variable depending on the tumor type. Several studies confirmed that dMMR/MSI status, although less frequent than PD-L1 expression, may better predict response to immune-checkpoint inhibitors (ICIs) in patients with solid tumors. In October 2016, the FDA granted pembrolizumab as breakthrough therapy for the treatment of non-CRC, MSI-H/dMMR tumors, providing, for the first time, a tumor-agnostic indication. In the next future, the tissue-agnostic evaluation of MSI-H/dMMR could become the common denominator for the immunotherapy treatment of patients with different advanced solid tumors, in order to select patient subgroups which may benefit from this therapy. In this Review we provided an overview of the main clinical studies describing the association between MSI-H/dMMR tumors and immunotherapy response.

Two cases of monomicrobial intraabdominal abscesses due to KPC--3 Klebsiella pneumoniae ST258 clone.

BACKGROUND: Knowledge of the etiology of pyogenic liver and pancreatic abscesses is an important factor in determining the success of combined surgical and antibiotic treatment. Literature shows geographical variations in the prevalence and distribution of causative organisms, and the spread of Klebsiella pneumoniae carbapenemase-producing bacteria is an emerging cause of abdominal infections. CASE PRESENTATION: We herein describe two cases of intra-abdominal abscesses due to monomicrobial infection by Klebsiella pneumoniae Sequence Type 258 producing K. pneumoniae carbapenemase 3 (KPC-Kp). In case 1, a 50-year-old HIV-negative Italian woman with chronic pancreatitis showed infection of a pancreatic pseudocystic lesion caused by KPC-Kp. In case 2, a 64-year-old HIV-negative Italian woman with pancreatic neoplasm and liver metastases developed a liver abscess due to KPC after surgery. Both women were admitted to our hospital but to different surgical units. The clonal relationship between the two isolates was investigated by pulsed-field gel electrophoresis (PFGE). In case 2, the patient was already colonized at admission and inter-hospital transmission of the pathogen was presumed. A long-term combination regimen of colistin with tigecycline and percutaneous drainage resulted in full recovery and clearance of the multidrug-resistant (MDR) pathogen. CONCLUSIONS: Timely microbiological diagnosis, the combined use of new and old antibiotics and radiological intervention appeared to be valuable in managing these serious conditions. The emergence and dissemination of MDR organisms is posing an increasing challenge for physicians to develop new therapeutic strategies and control and prevention frameworks.

Type and Gene Location of KIT Mutations Predict Progression-Free Survival to First-Line Imatinib in Gastrointestinal Stromal Tumors: A Look into the Exon.

In previous studies on localized GISTs, KIT exon 11 deletions and mutations involving codons 557/558 showed an adverse prognostic influence on recurrence-free survival. In the metastatic setting, there are limited data on how mutation type and codon location might contribute to progression-free survival (PFS) variability to first-line imatinib treatment. We analyzed the type and gene location of KIT and PDGFRA mutations for 206 patients from a GIST System database prospectively collected at an Italian reference center between January 2005 and September 2020. By describing the mutational landscape, we focused on clinicopathological characteristics according to the critical mutations and investigated the predictive role of type and gene location of the KIT exon 11 mutations in metastatic patients treated with first-line imatinib. Our data showed a predictive impact of KIT exon 11 pathogenic variant on PFS to imatinib treatment: patients with deletion or insertion/deletion (delins) in 557/558 codons had a shorter PFS (median PFS: 24 months) compared to the patients with a deletion in other codons, or duplication/insertion/SNV (median PFS: 43 and 49 months, respectively) (p < 0.001). These results reached an independent value in the multivariate model, which showed that the absence of exon 11 deletions or delins 557/558, the female gender, primitive tumor diameter (≤5 cm) and polymorphonuclear leucocytosis (>7.5 109/L) were significant prognostic factors for longer PFS. Analysis of the predictive role of PDGFRA PVs showed no significant results. Our results also confirm the aggressive biology of 557/558 deletions/delins in the metastatic setting and allow for prediction at the baseline which GIST patients would develop resistance to first-line imatinib treatment earlier.

Not all KIT 557/558 codons mutations have the same prognostic influence on recurrence-free survival: breaking the exon 11 mutations in gastrointestinal stromal tumors (GISTs).

Background: Although the gastrointestinal stromal tumor (GIST) genotype is not currently included in risk-stratification systems, a growing body of evidence shows that the pathogenic variant (PV) type and codon location hold a strong prognostic influence on recurrence-free survival (RFS). This information has particular relevance in the adjuvant setting, where an accurate prognostication could help to better identify high-risk tumors and guide clinical decision-making. Materials and Methods: Between January 2005 and December 2020, 96 patients with completely resected GISTs harboring a KIT proto-oncogene receptor tyrosine kinase (KIT) exon 11 PV were included in the study. We analyzed the type and codon location of the PV according to clinicopathological characteristics and clinical outcome; the metastatic sites in relapsed patients were also investigated. Results: Tumors harboring a KIT exon 11 deletion or deletion/insertion involving the 557 and/or 558 codons, showed a more aggressive clinical behavior compared with tumors carrying deletion/deletion/insertion in other codons, or tumors with duplication/insertion/single-nucleotide variant (SNV) (7-year RFS: 50% versus 73.1% versus 88.2%, respectively; p < 0.001). Notably, among 18 relapsed patients with 557 and/or 558 deletion or deletion/insertion, 14 patients (77.8%) harbored deletions simultaneously involving 557 and 558 codons, while only 4 patients (22.2%) harbored deletions involving only 1 of the 557/558 codons. Thus, when 557 or 558 deletions occurred separately, the tumor showed a prognostic behavior similar to the GIST carrying deletions outside the 557/558 position. Remarkably, patients with GISTs stratified as intermediate risk, but carrying the 557/558 deletion, showed a similar outcome to the high-risk patients with tumors harboring deletions in codons other than 557/558, or duplication/insertion/SNV. Conclusion: Our data support the inclusion of the PV type and codon location in routine risk prediction models, and suggest that intermediate-risk patients whose GISTs harbor 557/558 deletions may also need to be treated with adjuvant imatinib like the high-risk patients.

Endothelial Function in Obese Patients Treated with Bariatric Surgery.

PURPOSE: Bariatric surgery (BS) is becoming an increasingly frequent treatment option especially in people with morbid obesity, demonstrating that it is able to reduce total mortality and cardiovascular (CV) risk. Despite endothelial dysfunction is an essential requisite contributing to atherosclerosis and predicting CV events, only some studies have investigated the effects of BS on endothelial function with controversial results. In this study, the effects of weight loss on endothelial function were investigated in obese patients after BS and compared with patients after medical nutrition treatment (MNT). PATIENTS AND METHODS: Seventeen obese patients who underwent BS procedures (9 adjustable gastric bands, 3 gastric by-passes and 5 biliopancreatic diversions) were included in the study and compared with 18 obese individuals who underwent MNT. Endothelial function was investigated by flow-mediated dilation (FMD) of the brachial artery. Also, carotid intima-media thickness (c-IMT) was measured as a marker of subclinical atherosclerosis. RESULTS: At the end of follow-up, the mean weight loss was 18.8% in the BS group and 7.0% in the MNT group. After treatment, FMD significantly decreased in the BS group (mean ± SD before: 9.0 ± 4.7; after: 6.1 ± 2.9%; P= 0.04); however, no significant change was observed in the MNT group (before: 9.4 ± 5.8; after: 8.3 ± 5.3; P= 0.41). The modification of endothelial function was negatively correlated with c-IMT change in the BS group (r= -0.63; P <0.007). CONCLUSION: A significant endothelial dysfunction occurred following BS but not after MNT. Furthermore, the decline of endothelial function observed in the BS group might have contributed to atherosclerosis.

Hepatic and circulating levels of PCSK9 in morbidly obese patients: Relation with severity of liver steatosis.

Non-alcoholic fatty liver disease (NAFLD) is becoming the main cause of liver disease in Western countries, especially in morbidly obese patients (MOPs). The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently studied because of its possible involvement in the pathogenesis of NAFLD, but its role, at least in MOPs, is still controversial. The aim of this study was to clarify the correlation between the circulating levels of the PCSK9 protein (cPCSK9) and its hepatic expression with the severity of liver damage in a population of MOPs with NAFLD undergoing bariatric surgery. PCSK9 mRNA was positively correlated with FASN, PPARγ and PPARα mRNAs, while no significant differences were found in PCSK9 mRNA expression in relation to the severity of liver steatosis, lobular inflammation and hepatocellular ballooning. In addition, hepatic PCSK9 protein expression levels were not related to histological parameters of lobular inflammation and hepatocyte ballooning, decreased significantly only in relation to the severity of hepatic steatosis, and were inversely correlated with ALT and AST serum levels. cPCSK9 levels in the whole population were associated with the severity of hepatic steatosis and were positively correlated to total cholesterol levels. In multivariate analysis, cPCSK9 levels were associated with age, total cholesterol and HbA1c. In conclusion, in MOPs our findings support a role for PCSK9 in liver fat accumulation, but not in liver damage progression, and confirm its role in the increase of blood cholesterol, which ultimately may contribute to increased cardiovascular risk in this population.

The Prevalence of NAFLD and Fibrosis in Bariatric Surgery Patients and the Reliability of Noninvasive Diagnostic Methods.

BACKGROUND: Bariatric surgery patients have a higher prevalence of nonalcoholic fatty liver (NAFL) than the general population; however, its assessment and the accurate staging of fibrosis are often complicated because noninvasive tests are not very accurate in patients with morbid obesity, and liver biopsy cannot be performed as a routine exam. The aim of this study was to evaluate (A) the histological prevalence of NAFL, nonalcoholic steatohepatitis (NASH), and fibrosis in patients undergoing bariatric surgery; (B) the reliability of ultrasound (US) in diagnosing NAFL; and (C) the reliability of various fibrosis scoring systems for defining fibrosis. METHODS: US and intraoperative liver biopsy results were reviewed in 57 bariatric surgery patients. NAFL, NASH, and fibrosis were diagnosed according to the Kleiner scoring system. US diagnosis of liver steatosis was based on the bright liver. Fibrosis scores used were (i) the BMI, AST/ALT Ratio, Diabetes (BARD) scoring system; (ii) the nonalcoholic fatty liver disease (NAFLD) fibrosis score; and (iii) the fibrosis-4 (FIB-4) index. RESULTS: The prevalence of NAFL was 81%, NASH 61.4%, and fibrosis 94% (F3 5.7%, cirrhosis 2.8%). The sensitivity of US was 95%, specificity 50%, and likelihood ratio (LR+, LR-) 1.91 and 0.1. The reliability of fibrosis scores for F ≥ 2 were as follows: BARD score: sensitivity 46%, specificity 54%, and area under the receiver-operating characteristics (AUROC) curve 0.5; NAFLD score: sensitivity 30%, specificity 89%, and AUROC 0.5; and FIB-4: sensitivity 68%, specificity 67%, and AUROC 0.7. CONCLUSIONS: In bariatric surgery patients, the prevalence of NAFL was 81%, NASH 61.4%, and fibrosis 94%. US is able to rule out the presence of NAFL, while the commonly used scores may be inaccurate in defining fibrosis in patients with morbid obesity.

Surgical treatment of primary gastrointestinal stromal tumors (GISTs): Management and prognostic role of R1 resections.

BACKGROUND: Surgery represents the best treatment for primary gastrointestinal stromal tumors (GISTs). The aim of this study is to analyse outcomes of surgical management in order to evaluate the influence of microscopically R1 margins on survival and recurrence in patients affected by GISTs. METHODS: The study reviewed retrospective data from 74 patients surgically treated for primary GISTs without metastasis at diagnosis. Clinical and pathological findings, surgical procedures, information about follow up and outcomes were analyzed. RESULTS: Recurrence rate was low and no patients died in the R1 group during the follow up period. The difference in recurrence free survival for patients undergoing an R0 (n = 54) versus an R1 (n = 20) resections was not statistically significant (76% versus 85% at 3 years, logrank test p-value = 0,14; 63% versus 86% at 5 years, logrank test p-value = 0,48) CONCLUSIONS: Microscopically positive margin has no influence on overall and relapse-free survival in GIST patients. Thus, when R0 surgery implies major functional sequelae, it may be decided to accept possible R1 margins, especially for low risk tumors.