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Background: The aim of this national survey on liver hypertrophy techniques was to track the trends of their use and implementation in Italy and to detect analogies and heterogeneities among centers., Methods: In December 2022, Italian centers with liver resection activity were specifically contacted and asked to fill an online questionnaire composed of 6 sections including a total of 51 questions., Results: 46 Italian centers filled the questionnaire. The proportion of major/total number of liver resections was 27% and the use of hypertrophy techniques was required in 6,2% of cases. The most frequent reason of drop out was disease progression in 58.5% of cases. Most frequently used techniques were PVE and ALPPS with an increasing use of hepatic venous deprivation (HVD). Heterogeneous answers were provided regarding the cutoff values to indicate the need for hypertrophy techniques. Criteria to allocate a patient to different hypertrophy techniques are not standardized., Conclusions: The use of hypertrophy techniques is deep-rooted in Italy, documenting the established value of their role in improving resectability rate. While an evolution of techniques is detectable, still significant heterogeneity is perceived in terms of cutoff values, indications and managing protocols., (© 2024. Italian Society of Surgery (SIC).)

Objective: The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC)., Background: Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking., Methods: The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines., Results: Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population ( https://rediscover.unipi.it/ )., Conclusions: The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population., Competing Interests: S.G.B.: support from Flinders Foundation grant: 49358025, NHMRC Ideas Grant: 2021009, Pankind 21.R7.INV.CB.UOSA.6.2. F.M.: Tsumura, Inc., Scientific Advisory Board. M.D.C. is a co-PI of a Boston Scientific–sponsored study and he has been awarded an industry grant by Haemonetics, Inc. M.H.: Intuitive Surgical—teaches courses and proctors. The remaining authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Stereotactic radiotherapy (SRT) and Proton therapy (PT) are both options in the management of liver lesions. Limited clinical-dosimetric comparison are available. Moreover, dose-constraint routinely used in liver PT and SRT considers only the liver spared, while optimization strategies to limit the liver damaged are poorly reported., Methods: Primary endpoint was to assess and compare liver sparing of four contemporary RT techniques. Secondary endpoints were freedom from local recurrence (FFLR), overall survival (OS), acute and late toxicity. We hypothesize that Focal Liver Reaction (FLR) is determined by a similar biologic dose. FLR was delineated on follow-up MRI. Mean C.I. was computed for all the schedules used. A so-called Fall-off Volume (FOV) was defined as the area of healthy liver (liver-PTV) receiving more than the isotoxic dose. Fall-off Volume Ratio (FOVR) was defined as ratio between FOV and PTV., Results: 213 lesions were identified. Mean best fitting isodose (isotoxic doses) for FLR were 18Gy, 21.5 Gy and 28.5 Gy for 3, 5 and 15 fractions. Among photons, an advantage in terms of healthy liver sparing was found for Vmat FFF with 5mm jaws (p = 0.013) and Cyberknife (p = 0.03). FOV and FOVR resulted lower for PT (p < 0.001). Three years FFLR resulted 83%. Classic Radiation induced liver disease (RILD, any grade) affected 2 patients., Conclusions: Cyberknife and V-MAT FFF with 5mm jaws spare more liver than V-MAT FF with 10 mm jaws. PT spare more liver compared to photons. FOV and FOVR allows a quantitative analysis of healthy tissue sparing performance showing also the quality of plan in terms of dose fall-off., (© 2024. The Author(s).)

Objective: To develop and update evidence-based and consensus-based guidelines on laparoscopic and robotic pancreatic surgery., Summary Background Data: Minimally invasive pancreatic surgery (MIPS), including laparoscopic and robotic surgery, is complex and technically demanding. Minimizing the risk for patients requires stringent, evidence-based guidelines. Since the International Miami Guidelines on MIPS in 2019, new developments and key publications have been reported, necessitating an update., Methods: Evidence-based guidelines on 22 topics in 8 domains were proposed: terminology, indications, patients, procedures, surgical techniques and instrumentation, assessment tools, implementation and training, and artificial intelligence. The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS, September 2022) used the Scottish Intercollegiate Guidelines Network (SIGN) methodology to assess the evidence and develop guideline recommendations, the Delphi method to establish consensus on the recommendations among the Expert Committee, and the AGREE II-GRS tool for guideline quality assessment and external validation by a Validation Committee., Results: Overall, 27 European experts, 6 international experts, 22 international Validation Committee members, 11 Jury Committee members, 18 Research Committee members, and 121 registered attendees of the 2-day meeting were involved in the development and validation of the guidelines. In total, 98 recommendations were developed, including 33 on laparoscopic, 34 on robotic, and 31 on general MIPS, covering 22 topics in 8 domains. Out of 98 recommendations, 97 reached at least 80% consensus among the experts and congress attendees, and all recommendations were externally validated by the Validation Committee., Conclusions: The EGUMIPS evidence-based guidelines on laparoscopic and robotic MIPS can be applied in current clinical practice to provide guidance to patients, surgeons, policy-makers, and medical societies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To reach global expert consensus on the definition of TOLS in minimally invasive and open liver resection among renowned international expert liver surgeons using a modified Delphi method., Background: Textbook outcome is a novel composite measure combining the most desirable postoperative outcomes into one single measure and representing the ideal postoperative course. Despite a recently developed international definition of Textbook Outcome in Liver Surgery (TOLS), a standardized and expert consensus-based definition is lacking., Methods: This international, consensus-based, qualitative study used a Delphi process to achieve consensus on the definition of TOLS. The survey comprised 6 surgical domains with a total of 26 questions on individual surgical outcome variables. The process included 4 rounds of online questionnaires. Consensus was achieved when a threshold of at least 80% agreement was reached. The results from the Delphi rounds were used to establish an international definition of TOLS., Results: In total, 44 expert liver surgeons from 22 countries and all 3 major international hepato-pancreato-biliary associations completed round 1. Forty-two (96%), 41 (98%), and 41 (98%) of the experts participated in round 2, 3, and 4, respectively. The TOLS definition derived from the consensus process included the absence of intraoperative grade ≥2 incidents, postoperative bile leakage grade B/C, postoperative liver failure grade B/C, 90-day major postoperative complications, 90-day readmission due to surgery-related major complications, 90-day/in-hospital mortality, and the presence of R0 resection margin., Conclusions: This is the first study providing an international expert consensus-based definition of TOLS for minimally invasive and open liver resections by the use of a formal Delphi consensus approach. TOLS may be useful in assessing patient-level hospital performance and carrying out international comparisons between centers with different clinical practices to further improve patient outcomes., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Radiochemotherapy (RCHT) for the treatment of anal squamous cell carcinoma (ASCC) has evolved dramatically, also thanks to intensity-modulated RT (IMRT) and 3D image guidance (3D IGRT). Despite most patients presenting fair outcomes, unmet needs still exist. Predictors of poor tumor response are lacking; acute toxicity remains challenging; and local relapse remains the main pattern of failure., Patients and Methods: Between 2010 and 2020, ASCC stages I-III treated with 3D conformal radiotherapy or IMRT and CDDP-5FU or Mytomicine-5FU CHT were identified. Image guidance accepted included 2D IGRT or 3D IGRT. The study endpoints included freedom from locoregional recurrence (FFLR), colostomy free survival (CFS), freedom from distant metastasis (FFDM), overall survival (OS), and acute and late toxicity as measured by common terminology criteria for adverse events (CTCAE) version 5.0. An exploratory analysis was performed to identify possible radiomic predictors of tumor response. Feature extraction and data analysis were performed in Python™, while other statistics were performed using SPSS ® v.26.0 software (IBM ® )., Results: A total of 131 patients were identified. After a median FU of 52 months, 83 patients (63.4%) were alive. A total of 35 patients (26.7%) experienced locoregional failure, while 31 patients (23.7%) relapsed with distant metastasis. Five year FFLR, CFS, DMFS and PS resulted 72.3%, 80.1%, 74.5% and 64.6%. In multivariate analysis, 2D IGRT was associated with poorer FFLR, OS, and CFS (HR 4.5, 4.1, and 5.6, respectively); 3DcRT was associated with poorer OS and CFS (HR 3.1 and 6.6, respectively). IMRT reduced severe acute gastro-intestinal (GI) and severe skin acute toxicity in comparison with 3DcRT. In the exploratory analysis, the risk of relapse depended on a combination of three parameters: Total Energy, Gray Level Size Zone Matrix's Large Area High Gray Level Emphasis (GLSZM's LAHGLE), and GTV volume., Conclusions: Advances in radiotherapy have independently improved the prognosis of ASCC patients over years while decreasing acute GI and skin toxicity. IMRT and daily 3D image guidance may be considered standard of care in the management of ASCC. A combination of three pre-treatment MRI parameters such as low signal intensity (SI), high GLSZM's LAHGLE, and GTV volume could be integrated in risk stratification to identify candidates for RT dose-escalation to be enrolled in clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bonù, La Mattina, Singh, Toraci, Spiazzi, Terraneo, Barbera, Vitali, Frassine, Guerini, Triggiani, Tomasini, Morelli, Imbrescia, Andreuccetti, Frittoli, Pittiani, Grazioli, Portolani, Nicosia, Albano, Bertagna, Magrini and Buglione.)

Introduction: Indocyanine green (ICG) fluorescence is an emerging technique in the surgical field. Among its various applications, it allows surgeons to have real-time visualization of the lymphatic drainage of an organ. The primary outcome of our study is the feasibility and safety of ICG-guided colorectal surgery. Our secondary outcome is the efficacy of ICG-guided lymphadenectomy and whether or not ICG positivity correlates with the identification of nodal metastasis., Material and Methods: We conducted a single-center prospective study including 32 patients who underwent surgery for colorectal cancer. For each case, ICG was injected into the tumor area either prior to or during surgery. Tumor specimens and excised lymph nodes were analyzed using hematoxylin and eosin (H&E) staining., Results: In all patients, ICG injected in the tumor area allowed clear visualization of the lymphatic drainage. A total of 499 lymph nodes were collected, with a mean of 16 per patient. Fifty ICG positive lymph nodes outside the standard lymphadenectomy zone were examined; however, none of the nodes showed signs of nodal metastasis., Conclusions: ICG-guided colorectal surgery is safe, feasible and easily reproducible, with a relatively low cost and no radiation exposure. ICG can help the surgeon to visualize the anatomical structures. We did not find an oncological diagnostic advantage in the use of ICG-guided nodal navigation.

Non-coding RNAs are transcribed from telomeres and the telomeric repeat-containing RNAs ( TERRA ) are implicated in telomere homeostasis and in cancer. In this study, we aimed to assess in hepatocellular carcinoma (HCC) the cellular and extracellular expression of TERRA , the telomerase RNA subunit ( TERC ) and the telomerase catalytic subunit ( TERT ). We determined by qPCR the expression level of TERRA 1&#95;2&#95;10&#95;13q, TERRA 15q, TERRA XpYp, TERC and of TERT mRNA in HCC tissues and in the plasma of HCC patients. Further, we profiled the same transcripts in the HCC cell lines, HA22T/VGH and SKHep1C3, and in the extracellular vesicles (EVs) derived from their secretomes. We found that the expression of TERRA and TERT mRNA was significantly deregulated in HCC, being TERRA downregulated and TERT mRNA upregulated in HCC tissues vs. the peritumoral (PT) ones, and the receiver operating characteristic (ROC) curve analyses revealed a significant ability in discriminating HCC from PT tissue. Further, the determinations of circulating TERRA and TERC showed higher amounts of these transcripts in the plasma of HCC patients vs. controls and ROC analyses gave significant results. The expression characterization of the cultured HCC cells showed their ability to produce and secrete TERRA and TERC into the EVs; the ability to produce TERT mRNA that was not detectable in the EVs; and the ability to respond to sorafenib treatment increasing TERRA expression. Our results highlight that: (i) both cellular and extracellular expressions of TERRA and TERC are dysregulated in HCC as well as the cellular expression of TERT mRNA and (ii) the combined detection of TERRA and TERC in plasma may represent a promising approach for non-invasive diagnostic molecular indicators of HCC.

Background: This study compared patients undergoing colorectal cancer surgery in 20 hospitals of northern Italy in 2019 versus 2020, in order to evaluate whether COVID-19-related delays of colorectal cancer screening resulted in more advanced cancers at diagnosis and worse clinical outcomes., Method: This was a retrospective multicentre cohort analysis of patients undergoing colorectal cancer surgery in March to December 2019 versus March to December 2020. Independent predictors of disease stage (oncological stage, associated symptoms, clinical T4 stage, metastasis) and outcome (surgical complications, palliative surgery, 30-day death) were evaluated using logistic regression., Results: The sample consisted of 1755 patients operated in 2019, and 1481 in 2020 (both mean age 69.6 years). The proportion of cancers with symptoms, clinical T4 stage, liver and lung metastases in 2019 and 2020 were respectively: 80.8 versus 84.5 per cent; 6.2 versus 8.7 per cent; 10.2 versus 10.3 per cent; and 3.0 versus 4.4 per cent. The proportions of surgical complications, palliative surgery and death in 2019 and 2020 were, respectively: 34.4 versus 31.9 per cent; 5.0 versus 7.5 per cent; and 1.7 versus 2.4 per cent. Cancers in 2020 (versus 2019) were more likely to be symptomatic (odds ratio 1.36 (95 per cent c.i. 1.09 to 1.69)), clinical T4 stage (odds ratio 1.38 (95 per cent c.i. 1.03 to 1.85)) and have multiple liver metastases (odds ratio 2.21 (95 per cent c.i. 1.24 to 3.94)), but were not more likely to be associated with surgical complications (odds ratio 0.79 (95 per cent c.i. 0.68 to 0.93))., Conclusion: Colorectal cancer patients who had surgery between March and December 2020 had an increased risk of advanced disease in terms of associated symptoms, cancer location, clinical T4 stage and number of liver metastases., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Hepatocellular carcinoma (HCC) is poorly beneficiated by intravenous chemotherapy due to inadequate availability of drugs at the tumor site. We previously demonstrated that human micro-fragmented adipose tissue (MFAT) and its devitalized counterpart (DMFAT) could be effective natural scaffolds to deliver Paclitaxel (PTX) to tumors in both in vitro and in vivo tests, affecting cancer growth relapse. Here we tested the efficacy of DMFAT-PTX in a well-established HCC in nude mice. MFAT-PTX and DMFAT-PTX preparations were tested for anti-cancer activity in 2D and 3D assays using Hep-3B tumor cells. The efficacy of DMFAT-PTX was evaluated after a single-shot subcutaneous injection near a Hep-3B growing tumor by assessing tumor volumes, apoptosis rate, and drug pharmacokinetics in an in vivo model. Potent antiproliferative activity was seen in both in vitro 2D and 3D tests. Mice treated with DMFAT-PTX (10 mg/kg) produced potent Hep-3B growth inhibition with 33% complete tumor regressions. All treated animals experienced tumor ulceration at the site of DMFAT-PTX injection, which healed spontaneously. Lowering the drug concentration (5 mg/kg) prevented the formation of ulcers, maintaining statistically significant efficacy. Histology revealed a higher number of apoptotic cancer cells intratumorally, suggesting prolonged presence of PTX that was confirmed by the pharmacokinetic analysis. DMFAT may be a potent and valid new tool for local chemotherapy of HCC in an advanced stage of progression, also suggesting potential effectiveness in other human primary inoperable cancers.

Background: Preoperative biliary drainage may be essential to reduce the risk of postoperative liver failure after hepatectomy for perihilar cholangiocarcinoma. However, infectious complications related to preoperative biliary drainage may increase the risk of postoperative mortality. The strategy and optimal drainage method continues to be controversial., Methods: This is a retrospective multicenter study including patients who underwent hepatectomy for perihilar cholangiocarcinoma between 2000 and 2016 at 14 Italian referral hepatobiliary centers. The primary end point was to evaluate independent predictors for postoperative outcome in patients undergoing liver resection for perihilar cholangiocarcinoma after preoperative biliary drainage., Results: Of the 639 enrolled patients, 441 (69.0%) underwent preoperative biliary drainage. Postoperative mortality was 8.9% (12.5% after right-side hepatectomy versus 5.7% after left-side hepatectomy; P = .003). Of the patients, 40.5% underwent preoperative biliary drainage at the first admitting hospital, before evaluation at referral centers. Use of percutaneous preoperative biliary drainage was significantly more frequent at referral centers than at community hospitals where endoscopic preoperative biliary drainage was the most frequent type. The overall failure rate after preoperative biliary drainage was 43.3%, significantly higher at community hospitals than that at referral centers (52.7% v 36.9%; P = .002). Failure of the first preoperative biliary drainage was one of the strongest predictors for postoperative complications after right-side and left-side hepatectomies and for mortality after right-side hepatectomy. Type of preoperative biliary drainage (percutaneous versus endoscopic) was not associated with significantly different risk of mortality., Conclusion: Failure of preoperative biliary drainage was significantly more frequent at community hospitals and it was an independent predictor for postoperative outcome. Centers' experience in preoperative biliary drainage management is crucial to reduce the risk of failure that is closely associated with postoperative morbidity and mortality., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the third cause of cancer-related deaths. The multikinase inhibitor sorafenib is a systemic drug for unresectable HCC. The identification of molecular biomarkers for the early diagnosis of HCC and responsiveness to treatment are needed. In this work, we performed an exploratory study to investigate the longitudinal levels of cell-free long ncRNA GAS5 and microRNAs miR-126-3p and -23b-3p in a cohort of 7 patients during the period of treatment with sorafenib. We used qPCR to measure the amounts of GAS5 and miR-126-3p and droplet digital PCR (ddPCR) to measure the levels of miR-23b-3p. Patients treated with sorafenib displayed variable levels of GAS5, miR-126-3p and miR-23b-3p at different time-points of follow-up. miR-23b-3p was further measured by ddPCR in 37 healthy individuals and 25 untreated HCC patients. The amount of miR-23b-3p in the plasma of untreated HCC patients was significantly downregulated if compared to healthy individuals. The ROC curve analysis underlined its diagnostic relevance. In conclusion, our results highlight a potential clinical significance of circulating miR-23b-3p and an exploratory observation on the longitudinal plasmatic levels of GAS5, miR-126-3p and miR-23b-3p during sorafenib treatment.

Polychlorinated biphenyls (PCBs) are human carcinogens, based on sufficient evidence for melanoma and limited evidence for non-Hodgkin lymphoma and breast cancer. Few data are available for liver cancer, although PCBs cause it in rats and determined liver damage in poisoned people. We investigated the association between PCB serum levels and hepatocellular carcinoma (HCC) with a case-control study in a PCB-polluted area in North Italy. We enrolled prospectively 102 HCC incident cases and 102 age and gender-matched hospital controls. Serum concentrations of 33 PCB congeners were determined by a gas chromatograph coupled to mass spectrometry. Of 102 HCC cases, 62 who had lost < 3 kg of body weight in past 3 years were included in the analysis (67.7% males, mean age 68 years). The odds ratio (OR) for HCC for 3rd compared to 1st tertile of PCB distribution was 1.76 (95% confidence interval 0.62-5.03) for total PCB, adjusting for socio-demographic variables and risk factors for HCC by logistic regression. For most PCB congeners, ORs > 1.5 or 2 were found, although the 95% CIs included the null value for almost all of them. This preliminary study suggests that PCBs might play a role in HCC development.

Background: The existence of a link between Graves' Disease (GD) and Thyroid Cancer (TC) has long been investigated, however a clear pathogenic correlation is yet to be found., Objective: We verified the presence of TC in patients submitted to surgery for GD, both with and without thyroid nodules (TN)., Methods: In this study we analyzed retrospectively a cohort of 151 patients treated at our clinic with total thyroidectomy between 2013 and 2018. All the patients were symptomatic at the time of surgery, preoperatively ultrasonographic (US) study was performed to evaluate the presence of nodules and their distribution. All patients reached euthyroid state before surgery., Results: Nodules were detected in 53% of cases, above 60 years of age, at least one nodule was found; however, younger patients were mostly nodules free. Bilateral diffusion of nodules appeared with increasing age. Cancer was found in 19 of 151 subjects (12.5%), all were papillary carcinomas, and among them 93% were microcarcinomas. Among cancer-proven patients, 14 had thyroid nodules while 5 were nodule-free. During the follow up period, no cancer recurrence was recorded. The most common complication after surgery was transient hypocalcemia (36%)., Conclusions: Graves' patients are burdened by major incidence of TC in the context of their TN. Pre-operative assessment in GD patients should consider the risk of cancer, US scan can help in rapid evaluation of nodules and new rising frontiers in molecular biomarkers analysis may help defining pathogenic basis of Graves' neoplastic development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Improvement of survival rates for hepatocellular carcinoma during the last two decades and related factors are still debated. This study aimed to evaluate the risk of death and the role of prognostic factors in patients with hepatocellular carcinoma diagnosed in 1995-2001 and 2004-2006., Methods: We performed univariate and multivariable survival analyses of subjects with a first hepatocellular carcinoma diagnosis in 1995-2001 and in 2004-2006, all residing in Brescia province, Italy. Mediation analysis of treatment role in survival was conducted., Results: During follow-up (median 21.1 months) 913 subjects died (95.5%). The 1-, 3- and 5-year survival rates were higher for cases diagnosed in 2004-2006 (64.4%, 35.9% and 24.3%) than in 1995-2001 (60.8%, 34.5% and 20.7%). T stage, metastasis, cirrhosis, Child-Pugh class, portal vein invasion, serum creatinine level, treatment approach and diabetes were survival predictors in both periods. Patients with diagnosis in 2004-2006 had 36% lower risk of death than those with diagnosis in 1995-2001 using adjusted Cox proportional hazard model. The association between diagnosis period and risk of death was mediated by changes in treatment approach., Conclusion: We observed a decreased risk of death for first hepatocellular carcinoma diagnosis from 2004-2006 to 1995-2001, which was partially attributable to improvements in treatment approach., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Importance: There are limited data on mortality and complications rates in patients with coronavirus disease 2019 (COVID-19) who undergo surgery., Objective: To evaluate early surgical outcomes of patients with COVID-19 in different subspecialties., Design, Setting, and Participants: This matched cohort study conducted in the general, vascular and thoracic surgery, orthopedic, and neurosurgery units of Spedali Civili Hospital (Brescia, Italy) included patients who underwent surgical treatment from February 23 to April 1, 2020, and had positive test results for COVID-19 either before or within 1 week after surgery. Gynecological and minor surgical procedures were excluded. Patients with COVID-19 were matched with patients without COVID-19 with a 1:2 ratio for sex, age group, American Society of Anesthesiologists score, and comorbidities recorded in the surgical risk calculator of the American College of Surgeons National Surgical Quality Improvement Program. Patients older than 65 years were also matched for the Clinical Frailty Scale score., Exposures: Patients with positive results for COVID-19 and undergoing surgery vs matched surgical patients without infection. Screening for COVID-19 was performed with reverse transcriptase-polymerase chain reaction assay in nasopharyngeal swabs, chest radiography, and/or computed tomography. Diagnosis of COVID-19 was based on positivity of at least 1 of these investigations., Main Outcomes and Measures: The primary end point was early surgical mortality and complications in patients with COVID-19; secondary end points were the modeling of complications to determine the importance of COVID-19 compared with other surgical risk factors., Results: Of 41 patients (of 333 who underwent operation during the same period) who underwent mainly urgent surgery, 33 (80.5%) had positive results for COVID-19 preoperatively and 8 (19.5%) had positive results within 5 days from surgery. Of the 123 patients of the combined cohorts (78 women [63.4%]; mean [SD] age, 76.6 [14.4] years), 30-day mortality was significantly higher for those with COVID-19 compared with control patients without COVID-19 (odds ratio [OR], 9.5; 95% CI, 1.77-96.53). Complications were also significantly higher (OR, 4.98; 95% CI, 1.81-16.07); pulmonary complications were the most common (OR, 35.62; 95% CI, 9.34-205.55), but thrombotic complications were also significantly associated with COVID-19 (OR, 13.2; 95% CI, 1.48-∞). Different models (cumulative link model and classification tree) identified COVID-19 as the main variable associated with complications., Conclusions and Relevance: In this matched cohort study, surgical mortality and complications were higher in patients with COVID-19 compared with patients without COVID-19. These data suggest that, whenever possible, surgery should be postponed in patients with COVID-19.

Objective: The goal of this study was to analyze our 10-year experience in the treatment of aneurysms of the collateral circulation secondary to steno-occlusions of the celiac trunk (CT) or superior mesenteric artery (SMA)., Methods: In the last 10 years, 32 celiac-mesenteric aneurysms were detected (25 true aneurysms and seven pseudoaneurysms) in 25 patients with steno-occlusion of the CT or SMA. All cases were diagnosed and treated at our center, with either surgical or endovascular approach. As open surgery, we performed aneurysmectomy and revascularization; as endovascular treatment we performed both the embolization (or graft exclusion) of the aneurysm sac, and embolization of afferent and efferent arteries., Results: Sixteen patients (64%) underwent endovascular treatment, accounting for 66% of aneurysms (21/32). Six patients (24%) and seven associated aneurysms (22%) underwent open surgery. Three asymptomatic patients (12%), representing a total of four aneurysms (12%), were not treated. For endovascular procedures, the technical success rate was 90%, with a 56% clinical success rate. For open surgery, clinical and technical success were achieved in five patients (83%) and six procedures (86%), respectively. Sixty-eight percent of patients (17/25) were treated in an emergency setting, using either endovascular (88%) or open (12%) approaches. Although technical success was achieved in more than 85% of these procedures for both approaches, clinical success was reached less frequently among patients with an acute presentation (P = .041). Regardless of the type of treatment, CT or SMA revascularization during the first procedure did not show an increased rate of clinical success (P = .531). However, we reported four cases of visceral ischemia after an endovascular approach without revascularization, with three open surgical corrections required. The mean follow-up was 41 months (range, 0-136 months)., Conclusions: Neither of the approaches described qualifies as a standard optimal choice. We suggest a tailored therapeutic approach based on the clinical condition at the time of diagnosis and specific vascular anatomy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The epidemiology and the outcomes of acute appendicitis in elderly patients are very different from the younger population. Elderly patients with acute appendicitis showed higher mortality, higher perforation rate, lower diagnostic accuracy, longer delay from symptoms onset and admission, higher postoperative complication rate and higher risk of colonic and appendiceal cancer. The aim of the present work was to investigate age-related factors that could influence a different approach, compared to the 2016 WSES Jerusalem guidelines on general population, in terms of diagnosis and management of elderly patient with acute appendicitis. During the XXIX National Congress of the Italian Society of Surgical Pathophysiology (SIFIPAC) held in Cesena (Italy) in May 2019, in collaboration with the Italian Society of Geriatric Surgery (SICG), the World Society of Emergency Surgery (WSES) and the Italian Society of Emergency Medicine (SIMEU), a panel of experts participated to a Consensus Conference where eight panelists presented a number of statements, which were developed for each of the four topics about diagnosis and management of acute appendicitis in elderly patients, formulated according to the GRADE system. The statements were then voted, eventually modified and finally approved by the participants to the Consensus Conference. The current paper is reporting the definitive guidelines statements on each of the following topics: diagnosis, non-operative management, operative management and antibiotic therapy.

Local anesthesia in laparoscopic operations is gaining increasing consensus. To standardize analgesia, a prospective case-control study was created over a 1-year period, in collaboration with the anesthesiology service in our community hospital. Starting from February 2016, we prospectively enrolled adult patients (more than 16 years old) undergoing laparoscopic appendectomy or cholecystectomy, either in emergency or elective setting. Patients were preoperatively assigned (based on the chart-admission number) either to transversus abdominis plane (TAP) block treatment (Group 1-experimental arm) or trocar-site anesthesia (TSA) (Group 2-experimental arm), and then compared with group of patients not submitted to treatment (Group 3-control arm). Demographic and clinical characteristics of each patient were recorded. Post-operative pain level (primary outcome) was assessed with visual analog scale (VAS) score; analgesic use and length of stay in hospital were defined as secondary outcomes. Forty-two patients were assigned to TAP block treatment (Group 1), fifty-two to TSA (Group 2), and thirty-nine underwent no pre-incisional treatment (Group 3). In the comparison between patients undergoing TAP block or TSA with the control arm, a significance difference in reported pain was recorded in every scheduled time (p < 0.05 at 0, 6, 12, 18, 24, and 48 h from awakening). Both local anesthesia groups share a benefit in terms of primary outcome. The use of pre-incisional TSA for all the patients undergoing laparoscopic cholecystectomy and appendectomy could become a routine practice to reduce post-operative pain both in the elective and emergency setting.

Long non-coding RNAs (lncRNAs) and microRNAs are involved in numerous physio-pathological conditions included cancer. To better understand the molecular mechanism of the oral antitumor multikinase inhibitor sorafenib, we profiled the expression of a panel of lncRNAs and miRNAs by qPCR array in a sorafenib-treated hepatocellular carcinoma (HCC) cell line. Among the most affected ncRNAs, we found that sorafenib mediated the dysregulation of the lncRNAs GAS5, HOTTIP and HOXA-AS2 and the miR-126-3p, in a panel of human cancer cell lines (HCC, renal and breast carcinomas). By luciferase gene reporter assay, we discovered that GAS5 may act as a sponge for miR-126-3p in HCC cells. The expression level of GAS5 and miR-126-3p was verified in human liquid and/or solid biopsies from HCC patients. miR-126-3p expression in HCC tissues was decreased respect to their correspondent peritumoral tissues. The levels of plasmatic circulating miR-126-3p and GAS5 were significantly higher and lower in HCC patients compared to healthy subjects, respectively. This study highlighted the capability of sorafenib to modulate the expression of a wide range of ncRNAs and specifically, GAS5 and miR-126-3p were involved in the response to sorafenib of different cancer cell types.

Background: About 10% of cervico-mediastinal goiter need to associate cervicotomy with a total or partial sternotomy to allow a safe removal of the goiter. Aim of this study is to identify preoperative predictors of sternotomy for mediastinal goiter., Methods: Between January 2008 and December 2015, 586 patients were submitted to total thyroidectomy at Surgical Clinic of Brescia, Italy. Among these, patients with cervico-mediastinal goiter have been divided in two groups based on the necessity of an associated sternotomy in the operating field: Group 1 (n = 40 patients) did not need sternotomy and Group 2 (n = 4 patients) underwent cervicotomy associated with sternotomy. Clinical and pathological characteristics of patients were retrospectivelly recorded., Results: Among study group, 44 patients had cervico-mediastinal goiter. Thoracic CT was performed in all patients: an extension above aortic arch was found in 41 patients (93.18%) while an extention below aortic arch was found in 3 patients (6.82%). The extension of the goiter below the aortic arch resulted as a predictive value in the choice of surgical treatment (p = 0.0001). The thyroiditis process was found to be a significant predictive of the extention to a sternotomic approach (p = 0.029). The years of goiter's presence were on average 8.40 years in Group 1 and 14.75 years in Group 2. These parameters proved to be predictive when choosing a cervicotomy with sternotomy., Conclusions: Our study, despite limitations posed by small sample and its retrospective analisys, highlights the role of goiter's extention (below the aortic arch), disease length (for more than 14.75 years) and flogistic process (positivity of Tg Ab and anti-TPO-Ab) in the choice of combined (cervicotomic and sternotomic) approach to goiter's removal.

To analyze the available evidence on the role of treatment-oriented surgery in stage IV gastric cancer (metastatic disease), a systematic literature search was undertaken using Medline, Embase, Cochrane, and Web-of-Science libraries. The search was not restricted to articles published within a given year range. Articles written in English language (or with abstracts written in English) were considered. All references in the chosen articles were further screened to find additional relevant publications. Both clinical series and literature reviews were included. Stage IV gastric cancer is classified into four subcategories: positive peritoneal cytology without clear macroscopic peritoneal involvement (surgery is usually performed in these cases); gross appearance peritoneal carcinomatosis [surgery, eventually with hyperthermic intraoperative peritoneal chemotherapy (HIPEC) may be considered in very selected cases with limited PCI]; nodal metastases outside the loco-regional nodes (surgery may not be denied for metastatic nodes in stations 13 and 16); and hematogenous metastases (surgery should be performed in selected cases with liver metastases suitable to R0 resection). The analysis incorporated the new biological classification of stage IV gastric cancer recently proposed by Japanese researchers (Yoshida et al. in Gastric Cancer 19:329-338. https://doi.org/10.1007/s10120-015-0575-z , 2015) into the four aforementioned subcategories to make the comparison of the issues discussed meaningful. The take home message from the existing literature is that treatment-oriented surgery may be performed in a significant proportion of patients with stage IV gastric cancer.

Background: Nowadays, very few patients with non-variceal upper gastrointestinal bleeding fail endoscopic hemostasis (refractory NVUGIB). This subset of patients poses a clinical dilemma: should they be operated on or referred to transcatheter arterial embolization (TAE)?, Objectives: To carry out a systematic review of the literature and to perform a meta-analysis of studies that directly compare TAE and surgery in patients with refractory NVUGIB., Materials and Methods: We searched PubMed, Ovid MEDLINE, and Embase. A combination of the MeSH terms "gastrointestinal bleeding"; "gastrointestinal hemorrhage"; "embolization"; "embolization, therapeutic"; and "surgery" were used (("gastrointestinal bleeding" or "gastrointestinal hemorrhage") and ("embolization" or "embolization, therapeutic") and "surgery")). The search was performed in June 2018. Studies were retrieved and relevant studies were identified after reading the study title and abstract. Bibliographies of the selected studies were also examined. Statistical analysis was performed using RevMan software. Outcomes considered were all-cause mortality, rebleeding rate, complication rate, and the need for further intervention., Results: Eight hundred fifty-six abstracts were found. Only 13 studies were included for a total of 1077 patients (TAE group 427, surgery group 650). All selected papers were non-randomized studies: ten were single-center and two were double-center retrospective comparative studies, while only one was a multicenter prospective cohort study. No comparative randomized clinical trial is reported in the literature. Mortality . Pooled data (1077 patients) showed a tendency toward improved mortality rates after TAE, but this trend was not statistically significant (OD = 0.77; 95% CI 0.50, 1.18; P  = 0.05; I 2  = 43% [random effects]). Significant heterogeneity was found among the studies. Rebleeding rate . Pooled data (865 patients, 211 events) showed that the incidence of rebleeding was significantly higher for patients undergoing TAE (OD = 2.44; 95% CI 1.77, 3.36; P  = 0.41; I 2  = 4% [fixed effects]). Complication rate . Pooling of the data (487 patients, 206 events) showed a sharp reduction of complications after TAE when compared with surgery (OD = 0.45; 95% CI 0.30, 0.47; P  = 0.24; I 2  = 26% [fixed effects]). Need for further intervention . Pooled data (698 patients, 165 events) revealed a significant reduction of further intervention in the surgery group (OD = 2.13; 95% CI 1.21, 3.77; P  = 0.02; I 2  = 56% [random effects]). A great degree of heterogeneity was found among the studies., Conclusions: The present study shows that TAE is a safe and effective procedure; when compared to surgery, TAE exhibits a higher rebleeding rate, but this tendency does not affect the clinical outcome as shown by the comparison of mortality rates (slight drift toward lower mortality for patients undergoing TAE). The present study suggests that TAE could be a viable option for the first-line therapy of refractory NVUGIB and sets the foundation for the design of future randomized clinical trials., Limitations: The retrospective nature of the majority of included studies leads to selection bias. Furthermore, the decision of whether to proceed with surgery or refer to TAE was made on a case-by-case basis by each attending surgeon. Thus, external validity is low. Another limitation involves the variability in etiology of the refractory bleeding. TAE techniques and surgical procedure also differ consistently between different studies. Frame time for mortality detection differs between the studies. These limitations do not impair the power of the present study that represents the largest and most recent meta-analysis currently available., Competing Interests: Not applicableNot applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Mediastinal leakage (ML) is one of the most feared complications of esophagectomy. A standard strategy for its diagnosis and treatment has been difficult to establish because of the great variability in their incidence and mortality rates reported in the existing series., Aim: To assess the incidence, predictive factors, treatment, and associated mortality rate of mediastinal leakage using the standardized definition of mediastinal leaks recently proposed by the Esophagectomy Complications Consensus Group (ECCG)., Methods: Seven Italian surgical centers (five high-volume, two low-volume) affiliated with the Italian Society for the Study of Esophageal Diseases designed and implemented a retrospective study including all esophagectomies ( n = 501) with intrathoracic esophagogastric anastomosis performed from 2014 to 2017. Anastomotic MLs were defined according to the classification recently proposed by the ECCG., Results: Fifty-nine cases of ML were recorded, yielding an overall incidence of 11.8% (95%CI: 9.1%-14.9%). The surgical approach significantly influenced the occurrence of ML: the proportion of leakage was 10.5% and 9% after open and hybrid esophagectomy (HE), respectively, and doubled (20%) after totally minimally invasive esophagectomy (TMIE) ( P = 0.016). No other predictive factors were found. The 30- and 90-d overall mortality rates were 1.4% and 3.2%, respectively; the 30- and 90-d leak-related mortality rates were 5.1% and 10.2%, respectively; the 90-d mortality rates for TMIE and HE were 5.9% and 1.8%, respectively. Endoscopy was the first-line treatment in 49% of ML cases, with the need for retreatment in 17.2% of cases. Surgery was needed in 44.1% of ML cases. Endoscopic treatment had the lowest mortality rate (6.9%). Removal of the gastric tube with stoma formation was necessary in 8 (13.6%) cases., Conclusion: The incidence of ML after esophagectomy was high mainly in the TMIE group. However, the general and specific (leak-related) mortality rates were low. Early treatment (surgical or endoscopic) of severe leaks is mandatory to limit related mortality., Competing Interests: Conflict-of-interest statement: All authors have received no funding and declare no conflicts of interest in relation to this specific work.

Background: Although gout is a common disease, the presence of gouty tophi outside joints is rare and in literature, there is to date only one report of hepatic tophaceous nodule. We would like to highlight here the difficult diagnostic workup in a patient with history of cancer and the presence of a tophus inside the liver. Moreover, we address the possible etiologic role of chronic inflammation related to tophi and liver cancer., Case Presentation: We present the case of a 72-year-old man with a localization of gouty tophus in the liver, who thereafter developed a hepatocellular carcinoma (HCC) in the same site. The patient was followed up after surgery for left renal cancer from 1992 to 2011, when a hepatic nodule was discovered for the first time. After a detailed evaluation, the nodule was classified as a urate tophus of the liver. However, further follow-up showed that the nodule increased in size and changed its characteristics, bringing to the diagnosis of HCC., Conclusions: With the present case report, we would discuss the possible neoplastic degeneration of a gouty tophus and its etiologic role favouring cellular degeneration linked to chronic inflammation. We would also highlight the importance of histopathological evaluation of hepatic lesions in gouty patients at high risk of liver neoplasm, due to the difficulty in characterizing gouty tophi by imaging.

Background: Detecting small nodules that are grossly unidentifiable remains a major challenge in liver resection for cancer. Novel developments in navigation surgery, especially indocyanine green (ICG)-based fluorescence imaging, are making a clear breakthrough in addressing this issue. ICG is almost routinely administered during the preoperative stage in hepatobiliary surgery. However, its full potential has yet to be realized, partly because there are no precise guidelines regarding the optimal dose or timing of ICG injections before liver surgery. The main goal of this study was to design an algorithm for the management of ICG injections to achieve optimal liver staining results., Methods: Twenty-seven consecutive, unselected patients undergoing liver resection for cancer were enrolled and underwent preoperative liver function assessment by the LiMON test. Extra ICG i.v. injections at different doses and timings were performed. In vivo intraoperative analysis of the stain detected by near-infrared fluorescence imaging of the liver and ex vivo analysis of each resected nodule was performed and compared to the pathological analysis., Results: (i) The success rate of ICG injections in terms of liver staining was 92.6%; (ii) in the absence of or with 7 or more days from a previous ICG injection, the best dose to inject before the operation was 0.2 mg/kg, and the best timing was between 24 and 48 h before the scheduled surgery; and (iii) the ICG fluorescence patterns observed in the tumors were total fluorescence staining (41% of the cases), partial fluorescence staining (15%), rim fluorescence staining surrounding the tumor (30%), and no staining (15%)., Conclusions: This study is a building block for the characterization of liver nodules and the search for additional surface lesions undetected by preoperative radiological work-up-a crucial task for the successful treatment of liver cancer at an early stage using a safe, minimally invasive, and inexpensive technique.

Background: Perioperative complications can affect outcomes after gastrectomy for cancer, with high mortality and morbidity rates ranging between 10 and 40%. The absence of a standardized system for recording complications generates wide variation in evaluating their impacts on outcomes and hinders proposals of quality-improvement projects. The aim of this study was to provide a list of defined gastrectomy complications approved through international consensus., Methods: The Gastrectomy Complications Consensus Group consists of 34 European gastric cancer experts who are members of the International Gastric Cancer Association. A group meeting established the work plan for study implementation through Delphi surveys. A consensus was reached regarding a set of standardized methods to define gastrectomy complications., Results: A standardized list of 27 defined complications (grouped into 3 intraoperative, 14 postoperative general, and 10 postoperative surgical complications) was created to provide a simple but accurate template for recording individual gastrectomy complications. A consensus was reached for both the list of complications that should be considered major adverse events after gastrectomy for cancer and their specific definitions. The study group also agreed that an assessment of each surgical case should be completed at patient discharge and 90 days postoperatively using a Complication Recording Sheet., Conclusion: The list of defined complications (soon to be validated in an international multicenter study) and the ongoing development of an electronic datasheet app to record them provide the basic infrastructure to reach the ultimate goals of standardized international data collection, establishment of benchmark results, and fostering of quality-improvement projects.

Background: Outside the US, FLS certification is not required and its teaching methods are not well standardized. Even if the FLS was designed as "stand alone" training system, most of Academic Institution offer support to residents during training. We present the first systematic application of FLS in Italy. Our aim was to evaluate the role of mentoring/coaching on FLS training in terms of the passing rate and global performance in the search for resource optimization., Methods: Sixty residents in general surgery, obstetrics & gynecology, and urology were selected to be enrolled in a randomized controlled trial, practicing FLS with the goal of passing a simulated final exam. The control group practiced exclusively with video material from SAGES, whereas the interventional group was supported by a mentor., Results: Forty-six subjects met the requirements and completed the trial. For the other 14 subjects no results are available for comparison. One subject for each group failed the exam, resulting in a passing rate of 95.7%, with no obvious differences between groups. Subgroup analysis did not reveal any difference between the groups for FLS tasks., Conclusion: We confirm that methods other than video instruction and deliberate FLS practice are not essential to pass the final exam. Based on these results, we suggest the introduction of the FLS system even where a trained tutor is not available. This trial is the first single institution application of the FLS in Italy and one of the few experiences outside the US. Trial Number: NCT02486575 ( https://www.clinicaltrials.gov ).

In October 2016 the American Joint Committee on Cancer (AJCC) published the 8th edition of the AJCC/TNM cancer staging system and it has been introduced in clinical practice since 1st January 2018. The effect of most of the changes in the new edition was the downstaging of a significant number of patients into lower stages, reflecting their low risk of thyroid cancer-related death. One of the most relevant modification refers to the role of the microscopic extra-thyroidal tumor invasion, which is no longer considered as criterion for the classification of T3 tumors. With the present study we want to assess the impact of the changes of the new staging system and therefore we analyzed or casistic of 84 T1-T3 thyroid-cancer patients. The results of our analysis show that he downstaging of patients according to the 8th TNM edition does not necessarily reflect less aggressive disease: we actually reported 2 lymph-nodal recurrences (40%) in the five patients that were downstaged from pT3 to pT2 and the lypmh-nodal recurrence rate for stage I rises from 0% with the 7th TNM edition to 5.3% with the 8th edition.

Purpose: Aim of this observational case-control study was to assess the prevalence, features, and risk factors of colonic diverticula in patients with ulcerative colitis (UC)., Methods: The data of 896 UC patients aged ≥ 30 years from Brescia IBD database were retrospectively analyzed. Individuals with colonic diverticula were identified and prevalence was compared with that of control patients undergoing screening colonoscopy after gender/age matching. A nested cohort study was then conducted among UC patients in order to define eventual association of diverticula with specific clinico-pathologic parameters., Results: Prevalence of subjects with diverticula was 11.4% among 465 UC patients aged 49 years and older, significantly lower than 35.1% prevalence in control patients of same age and gender (p < 0.001). Advancing age was a significant risk factor for diverticula development in both groups. Among UC patients, a short duration and a late onset of UC were both significantly associated to the presence of diverticula. Moreover, UC patients with diverticula had a significantly lower frequency of flares per year, even if maximal flare severity and frequency of hospital admission were similar to those of subjects without diverticula. UC patients with diverticula had a trend toward more frequent extension of UC to the left colon, possibly because of their older age. The majority of those patients had few sigmoid diverticula without symptoms., Conclusions: Development of colonic diverticula is substantially reduced in patients with UC, markedly among those with an early onset, a long history of inflammatory disease, and a high flare frequency. This study reinforces the hypothesis sustaining a protective role of UC against colonic diverticula.

Background: A wide variety of hemostats are available as adjunctive measures to improve hemostasis during surgical procedures if residual bleeding persists despite correct application of conventional methods for hemorrhage control. Some are considered active agents, since they contain fibrinogen and thrombin and actively participate at the end of the coagulation cascade to form a fibrin clot, whereas others to be effective require an intact coagulation system. The aim of this study is to provide an evidence-based approach to correctly select the available agents to help physicians to use the most appropriate hemostat according to the clinical setting, surgical problem and patient's coagulation status., Methods: The literature from 2000 to 2016 was systematically screened according to PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses] protocol. Sixty-six articles were reviewed by a panel of experts to assign grade of recommendation (GoR) and level of evidence (LoE) using the GRADE [Grading of Recommendations Assessment, Development and Evaluation] system, and a national meeting was held., Results: Fibrin adhesives, in liquid form (fibrin glues) or with stiff collagen fleece (fibrin patch) are effective in the presence of spontaneous or drug-induced coagulation disorders. Mechanical hemostats should be preferred in patients who have an intact coagulation system. Sealants are effective, irrespective of patient's coagulation status, to improve control of residual oozing. Hemostatic dressings represent a valuable option in case of external hemorrhage at junctional sites or when tourniquets are impractical or ineffective., Conclusions: Local hemostatic agents are dissimilar products with different indications. A knowledge of the properties of each single agent should be in the armamentarium of acute care surgeons in order to select the appropriate product in different clinical conditions.

Background: In the development of hypertensive microvascular remodeling, a relevant role may be played by changes in extracellular matrix proteins. Aim of this study was the to evaluate some extracellular matrix components within the tunica media of subcutaneous small arteries in 9 normotensive subjects and 12 essential hypertensive patients, submitted to a biopsy of subcutaneous fat from the gluteal or the anterior abdominal region., Patients and Methods: Subcutaneous small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media to internal lumen ratio was measured. In addition, fibronectin, laminin, transforming growth factor-beta-1 (TGF-β1) and emilin-1 contents within the tunica media were evaluated by immunofluorescence and relative immunomorphometrical analysis (immunopositivity % of area). The total collagen content and collagen subtypes within the tunica media were evaluated using both Sirius red staining (under polarized light) and immunofluorescence assay., Results: Normotensive controls had less total and type III collagen in respect with hypertensive patients. Fibronectin and TGF-β1 tunica media content was significantly greater in essential hypertensive patients, compared with normotensive controls, while laminin and emilin-1 tunica media content was lesser in essential hypertensive patients, compared with normotensive controls. A significant correlation was observed between fibronectin tunica media content and media to lumen ratio., Conclusions: Our results indicate that, in small resistance arteries of patients with essential hypertension, a relevant fibrosis may be detected; fibronectin and TGF-β1 tunica media content is increased, while laminin and emilin-1 content is decreased; these changes might be involved in the development of small resistance artery remodeling in humans.

Introduction: Secondary hyperparathyroidism is common in chronic kidney disease. Parathyroidectomy is indicated in refractory hyperparathyroidism when medical treatments and so the parathyroid hormone levels cannot be lowered to acceptable values without causing significant hyperphosphatemia or hypercalcemia. The aim of this study is to compare the efficacy and safety of total parathyroidectomy with subcutaneous forearm autotransplantation with total parathyroidectomy with intramuscular forearm autotransplantation., Materials and Methods: A single-center retrospective cohort study of total parathyroidectomy with forearm autotransplantation from January 2002 to February 2013 was performed. According to the surgical technique, patients were divided into an intramuscular group (Group 1) and a subcutaneous group (Group 2). 38 patients with secondary hyperparathyroidism were enrolled; 23 patients were subjected to total parathyroidectomy with parathyroid tissue replanting in the subcutaneous forearm of the upper nondominant limb, while 15 patients were subjected to replanting in the intramuscular seat., Results: A total of 38 patients (56 ± 13 years) were enrolled. In both groups, the preoperative iPTH value was markedly high, 1750 ± 619 pg/ml in the intramuscular autotransplantation group and 1527 ± 451 pg/ml in the subcutaneous autotransplantation group ( p = 0.079). Transient hypoparathyroidism was shown in 7 patients, and 1 patient showed persistent hypoparathyroidism ( p = 0.387). 2 patients showed persistent hyperparathyroidism ( p = 0.816), and in 2 others was found recurrent hyperparathyroidism ( p = 0.816); 3 of them underwent autograftectomy. The anterior compartment of the forearm nondominant limb was sacrificed in 1 case of intramuscular autotransplantation with functional arm deficit., Conclusions: The efficacy and safety of parathyroid tissue autotransplantation in the subcutaneous forearm of the upper nondominant limb is confirmed with a good rate of tissue engraftment and with a comparable number of postsurgical transient and persistent hypoparathyroidism and hyperparathyroidism incidence in both techniques. Furthermore, this technique preserves arm functionality in the case of autograftectomy. Consequently, it is our opinion that total parathyroidectomy with subcutaneous forearm autotransplantation is currently the best choice.

Objective: It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th 17 lymphocytes may contribute to the progression of hypertension and microvascular damage while T-regulatory (Treg) lymphocytes seem to be protective in this regard. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed., Design and Methods: We have investigated 32 severely obese patients undergoing bariatric surgery, as well as 24 normotensive lean subjects and 12 hypertensive lean subjects undergoing an elective surgical intervention. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry in order to assess T-effector and Treg lymphocytes., Results: A marked reduction of several Treg subpopulations was observed in obese patients compared with controls, together with an increased in CD4+ effector memory T-effector cells., Conclusion: In severely obese patients, Treg lymphocytes are clearly reduced and CD4+ effector memory cells are increased. It may be hypothesized that they might contribute to the development of marked microvascular alterations previously observed in these patients.

Background: The evaluation of the morphological characteristics of small resistance arteries in humans is challenging. The gold standard method is generally considered to be the measurement by wire or pressure micromyography of the media-to-lumen ratio of subcutaneous small vessels obtained by local biopsies. However, noninvasive techniques for the evaluation of retinal arterioles were recently proposed; in particular, two approaches, scanning laser Doppler flowmetry (SLDF) and adaptive optics, seem to provide useful information; both of them provide an estimation of the wall-to-lumen ratio (WLR) of retinal arterioles. Moreover, a noninvasive measurement of basal and total capillary density may be obtained by videomicroscopy/capillaroscopy. No direct comparison of these three noninvasive techniques in the same population was previously performed; in particular, adaptive optics was never validated against micromyography., Methods: In the current study, we enrolled 41 controls and patients: 12 normotensive lean controls, 12 essential hypertensive lean patients, nine normotensive obese patients and eight hypertensive obese patients undergoing elective surgery. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance artery structure was assessed by wire micromyography and the media-to-lumen ratio was calculated. WLR of retinal arterioles was obtained by SLDF and adaptive optics. Functional (basal) and structural (total) microvascular density was evaluated by capillaroscopy before and after venous congestion., Results and Conclusion: Our data suggest that adaptive optics has a substantial advantage over SLDF in terms of evaluation of microvascular morphology, as WLR measured with adaptive optics is more closely correlated with the M/L of subcutaneous small arteries (r = 0.84, P < 0.001 vs. r = 0.52, P < 0.05, slopes of the relations: P < 0.01 adaptive optics vs. SLDF). In addition, the reproducibility of the evaluation of the WLR with adaptive optics is far better, as compared with SLDF, as intraobserver and interobserver variation coefficients are clearly smaller. This may be important in terms of clinical evaluation of microvascular morphology in a clinical setting, as micromyography has substantial limitations in its clinical application due to the local invasiveness of the procedure.

Objective: Aim of this study is to evaluate determinants of secondary normocalcemic hyperparathyroidism (SNHPT) persistence in patients who have undergone Roux-en-Y gastric bypass on vertical-banded gastroplasty., Methods: 226 consecutive patients submitted to bariatric surgery were prospectively enrolled and divided in two groups on the basis of preoperative presence of SNHPT. For each patient, we evaluated anthropometric and laboratory parameters. Calcium metabolism (calcemia, PTH, and 25-hydroxy vitamin D serum levels) was studied before surgery and at 6-month intervals (6, 12, and 18 months) as surgical follow-up., Results: Based on presurgical SNHPT presence or absence, we defined group 1- 201 patients and group 2- 25 patients, respectively. Among the group 1 , 153 (76%) recovered from this endocrinopathy within 6 months after surgery ( group 3 ), while the remaining 48 patients (24%) had persistent SNHPT ( group 4 ). Comparing the anthropometric and laboratory data of group 3 with group 2 , the only statistically significant factor was the elapsed time since a prior effective medically controlled diet that led to a steady and substantial weight loss. We found also a statistically significant difference ( p < 0.05) between group 3 and group 4 in term of % of weight loss and PTH levels., Conclusions: Patients suitable for bariatric surgery must have history of at least one efficient medically controlled diet, not dating back more than 5 years before surgery. This elapsed time represent the cut-off time within which it is possible to recover from SNHPT in the first semester after Roux-en-Y gastric bypass on vertical-banded gastroplasty. The treatment of vitamin D insufficiency and the evaluation of SNHPT before bariatric surgery should be recommended. The clinical significance of preoperative SNHPT and in particular SNHPT after bariatric surgery remains undefined and further studies are required.

To analyze the clinical outcomes of patients undergoing minimally invasive surgery for pancreatic neoplasms, in two medium-volume centers in Northern Italy, a retrospective chart review was performed in the operative registries, searching for patients who had undergone pancreatic surgery via laparoscopy, irrespective of the final pathological nature of the resected neoplasm. For each case, a standard data extraction form was completed and the following data was extracted: age and sex, type of resection, estimated blood loss, length of the operation, number of harvested nodes, post-operative pancreatic fistula, major post-operative complications, mortality and final pathological diagnosis. The systematic literature research was also undertaken and the reported results were analyzed. A total of 55 cases were recorded, including 39 distal pancreatectomies and 16 pancreaticoduodenectomies. The most frequent indications leading to surgery were ductal adenocarcinoma (26 pts) and cystic neoplasm (22 pts). No post-operative death occurred in this series; pancreatic fistula occurred in 64% of distal pancreatectomies and 22% of pancreaticoduodenectomies. The mean operating times were 178' and 572', respectively. Both distal pancreatectomy and pancreaticoduodenectomy proved to be feasible and were safely performed by laparoscopy, in two centers with medium-volume pancreatic caseload.

Hepatocellular carcinoma (HCC) is the most common liver cancer and second leading cause of cancer related death worldwide. Most HCCs occur in a damaged cirrhotic background and it may be difficult to discriminate between regenerative nodules and early HCCs. No dependable molecular biomarker exists for the early detection of HCC. MicroRNAs (miRNAs) have attracted attention as potential blood-based biomarkers. To identify circulating miRNAs with diagnostic potential in HCC, we performed preliminary RNAseq studies on plasma samples from a small set of HCC patients, cirrhotic patients and healthy controls. Then, out of the identified miRNAs, we investigated miR-101-3p, miR-106b-3p, miR-1246 and miR-411-5p in plasma of independent HCC patients' cohorts. The use of droplet digital PCR (ddPCR) confirmed the aberrant levels of these miRNAs. The diagnostic performances of each miRNA and their combinations were measured using Receiver Operating Characteristic (ROC) curve analyses: a classifier consisting of miR-101-3p, miR-1246 and miR-106b-3p produced the best diagnostic precision in plasma of HCC vs. cirrhotic patients (AUC = 0.99). A similar performance was found when the levels of miRNAs of HCC patients were compared to healthy controls (AUC = 1.00). We extended the analyses of the same miRNAs to serum samples. In serum of HCC vs. cirrhotic patients, the combination of miR-101-3p and miR-106b-3p exhibited the best diagnostic accuracy with an AUC = 0.96. Thus, circulating miR-101-3p, miR-106b-3p and miR-1246, either individually or in combination, exhibit a considerable potential value as diagnostic biomarkers of HCC., Competing Interests: CONFLICTS OF INTEREST All the authors declare no conflicts of interest to be disclosed with respect to this manuscript.

MicroRNAs (miRNAs) constitute a class of short non coding RNAs that have crucial biological roles by acting mainly as negative regulators of gene expression. The alteration of miRNAs expression has been frequently demonstrated in cancer. Furthermore, miRNAs expression data clearly revealed their possible use as diagnostic, prognostic and predictive biomarkers. In this review, we focus on the biological role of human miR-23b-3p in cancer. Several data demonstrated that miR-23b-3p targeted different genes involved in cancer aggressive properties such as proliferation, migration, invasion, and metastasis. In this context, it is known that miR-23b-3p, as other miRNAs, can target either tumor-suppressor genes or oncogenes in different types of tumors. Therefore, its net biological effect can be tumor-specific, mainly depending on the consequent alterations on the downstream effects of the altered pathways. MiR-23b-3p has been found down-regulated or up-regulated in primary tumors and dysregulated in plasma and serum of cancer patients. Its expression levels correlate with the overall survival, disease-free survival and prognosis in several malignancies, thus assuming a remarkable role as molecular biomarker with clinical relevance. Finally, miR-23b-3p is generally considered a responsive molecular therapeutic target as reported in several in vitro and in vivo studies. This suggests that the ectopic modulation of its expression may potentially be important for translational medicine approaches., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Aim: To analyze the clinicopathological characteristics of patients with both node-negative gastric carcinoma and diagnosis of recurrence during follow-up., Methods: We enrolled 41 patients treated with curative gastrectomy for pT2-4aN0 gastric carcinoma between 1992 and 2010, who developed recurrence (Group 1). We retrospectively selected this group from the prospectively collected database of 4 centers belonging to the Italian Research Group for Gastric Cancer, and compared them with 437 pT2-4aN0 patients without recurrence (Group 2). We analyzed lymphatic embolization, microvascular infiltration, perineural infiltration, and immunohistochemical determination of p53, Ki67, and HER2 in Group 1 and in a subgroup of Group 2 (Group 2bis) of 41 cases matched with Group 1 according to demographic and pathological characteristics., Results: T4a stage and diffuse histotype were associated with recurrence in the group of pN0 patients. In-depth pathological analysis of two homogenous groups of pN0 patients, with and without recurrence during long-term follow-up (groups 1 and 2bis), revealed two striking patterns: lymphatic embolization and perineural infiltration (two parameters that pathologists can easily report), and p53 and Ki67, represent significant factors for recurrence., Conclusion: The reported pathological features should be considered predictive factors for recurrence and could be useful to stratify node-negative gastric cancer patients for adjuvant treatment and tailored follow-up., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest.

Surgery for gastric cancer is associated with significant major morbidity and an estimated mortality rate of about 5%. A reliable comparison of post-operative outcomes is hampered by the lack of a clear, universally recognized, definition of the most frequent complications. This paper reports the final results of a project launched by the Italian Research Group for Gastric Cancer in September 2015, whose goal was to propose a comprehensive list of surgical-related, gastric cancer-specific complications, with their definitions. The project was carried out through a multicentric, mainly web-based, consensus of experts. The proposed list, following assessment and validation by a group of experts of the European Chapter of the International Gastric Cancer Association, will form the basis for implementing a "Complications Recording Sheet" that can be disseminated worldwide for proper and reliable post-operative assessment.

Emergency repair of complicated abdominal wall hernias may be associated with worsen outcome and a significant rate of postoperative complications. There is no consensus on management of complicated abdominal hernias. The main matter of debate is about the use of mesh in case of intestinal resection and the type of mesh to be used. Wound infection is the most common complication encountered and represents an immense burden especially in the presence of a mesh. The recurrence rate is an important topic that influences the final outcome. A World Society of Emergency Surgery (WSES) Consensus Conference was held in Bergamo in July 2013 with the aim to define recommendations for emergency repair of abdominal wall hernias in adults. This document represents the executive summary of the consensus conference approved by a WSES expert panel. In 2016, the guidelines have been revised and updated according to the most recent available literature.

Background: Left-sided gallbladder without situs viscerum inversus (LSG-woSVI) is a rare congenital anomaly. Clinical features and routine presurgical imaging could miss the anomalous position, thereby producing complications during surgery. Laparoscopic cholecystectomy can be performed safely, but the risk of bile duct injury (BDI) is greater than in cholecystectomy of the orthotopic gallbladder. We present a retrospective review of all scientific literature for diagnosed cases of LSG-woSVI undergoing cholecystectomy from 1996 to 2014. Our objectives were to outline empirical top tips for a safe cholecystectomy in incidentally diagnosed LSG-woSVI., Methods: We carried a comprehensive search of PubMed using medical subject headings "left-sided gallbladder," "right-sided ligamentum teres" "situs viscerun inversus," "preoperative diagnoses," "cholecystectomy," and "bile duct injury." We considered a classification of the LSG-woSVI in 2 groups: True LSG-woSVI and LSG-woSVI in patients with right-sided ligamentum teres., Results: Our retrospective review revealed 55 cases of LSG-woSVI. The mean age was 51 years ±17 SD, male/female ratio was 2:1, clinical presentation was pain in the right upper abdominal quadrant in 75.5%, preoperative diagnosis was reached in 16.3%, True LSG was diagnosed in 83%, acute cholecystitis was found in 50%, laparoscopic cholecystectomy was performed in 79.6%, fundus-first dissection technique was used in 16.7%, intraoperative cholangiography was performed in 39.1%, and BDI occurred in 7.3% of the reported cases., Conclusions: Increased awareness of the anatomic aberrations in LSG-woSVI associated with improved preoperative diagnosis and a good knowledge about safe surgical techniques for cholecystectomy could indubitably reduce the incidence of BDI.

Hepatocellular carcinoma (HCC) is the most common cancer of the liver with a very poor prognosis. The dysregulation of microRNAs (miRs) is indeed implicated in HCC onset and progression. In this study, we have evaluated the expression of miR-23b and miR-193a in a large cohort of 59 and 67 HCC patients, respectively. miR-23b and miR-193a resulted significantly down-regulated in primary HCCs compared to their matched peritumoral counterparts. Furthermore, patients with higher miR-193a expression exhibited longer OS and DFS, suggesting that miR-193a may be a molecular prognostic factor for HCC patients. Since the regulation of miRs by DNA methylation may occur in human cancers, we verified whether the down-modulation of miR-23b and miR-193a in HCC tissues could be related to DNA methylation. An inverse trend between miR-23b expression and DNA methylation was observed, indicating that miR-23b can be epigenetically regulated. By contrast, the down-regulation of miR-193a was not mediated by DNA methylation. To verify the potential role of miR-23b and miR-193a as responsive molecular targets in vitro, we used the inhibitor of DNA methylation 5-aza-dC to restore miR-23b expression level in combination with miR-193a transfection. The combined treatment led to a significant inhibition of cellular proliferation and migration. Taken together, our findings provide evidence that miR-23b and miR-193a may be molecular diagnostic and prognostic factors for HCC; furthermore, miR-23b and miR-193a are responsive molecular targets for limiting HCC cell aggressiveness in combination with the epigenetic drug 5-aza-dC. Moreover, our results provide new advances in the epigenetic regulation of these miRs in HCC.

This article aims at analyzing the published literature concerning the treatment of patients with gastric cancer and distant nodal metastases, actually considered metastatic disease. A systematic search was undertaken using Medline, Embase, Cochrane and Web-of-Science libraries. No specific restriction on year of publication was used; preference was given to English papers. Both clinical series and literature reviews were selected. Only 11 papers address the issue of surgery for nodal basins outside the D2 dissection area. From these papers, in selected cases extended surgery may prove useful in prolonging survival, when a comprehensive therapeutic pathway including chemotherapy is scheduled. In conclusion, in presence of nodal metastases outside the loco-regional nodes, surgery may be considered for metastatic nodes in stations 13 and 16, in selected cases., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: The aim of this study was to ascertain the variability and to identify a trend for the outcome of cholecystectomy surgery when used to treat cholelithiasis and acute cholecystitis., Methods: This was a large retrospective cohort study following patients up to 11 years post surgery, based on administrative data collected from 2002 to 2012 in the Emilia-Romagna Region (Northern Italy) and comparing the effectiveness and efficiency of surgical activity (laparoscopic (LC) and open cholecystectomy (OC)). Analyses included patient characteristics, length of hospital stay, type of admission and mortality risk. Outcomes considered were death from all causes (during the index hospital admission or thereafter), hospital readmissions with cholecystitis or cholelithiasis as principal diagnosis and time to surgery., Results: A total of 84,628 cholecystomies were performed from 2002 to 2012 out of 123,061 admissions with primary diagnostic category of cholecystitis or cholelitiasis. Laparoscopic procedure was used in 69,842 patients. Over time there was a rising linear statistically significant trend in the use of LC. Mortality rate at 1 year of OC treated patients showed a statistically significant difference compared to LC treated patients (using a cohorts match with propensity score). Only a small number of patients with acute cholecystitis was operated according guidelines within 72 hours., Conclusions: The analysis of aggregate administrative data is a powerful tool to support regional health management, improve the quality of medical care, and assess the appropriateness of therapeutic or diagnostic approaches. It is important to stress a short hospital stay for laparoscopic cholecystectomy patients (50% less than open surgery): this shorter hospital stay leads to a significant economic advantage. Moreover, mortality is significantly higher in open surgery for acute cholecystitis. Interestingly, the same finding was confirmed after 30 days and 1 year, probably due to comorbidities that are more evident in open surgery., Key Words: Cholecystitis, Cholelithiasis, Delivery of health care, Disease management, Surgical.

Purpose: To analyze the population submitted to gastric cancer surgery in our Institution in order to find those characteristics which could help in the identification of the elderly high-risk patient., Methods: In a cohort of 263 patients (>65 y) we selectively investigated the risk factors for medical and surgical complications and postoperative mortality, focusing on the variable "age". All the significant variables were used to find predictors of complications with Clavien-Dindo>2., Results: Age>75 (AUC 0.61; 95% 0.55-0.67, p = 0.003) and ASA score >2 (AUC 0.60; 95% CI 0.54-0.67, p = 0.01) were significantly associated with an increased risk of medical complications. Operative time >330 min (OR 1.00; 95% CI 1.00-1.01; p = 0.0001- AUC 0.62, 95% CI 0.56-0.68, p = 0.01) was the only significant predictor of surgical complications. In-hospital mortality (6/263 patients) was significantly associated with preoperative albumin ≤2.95 g/dl (OR 0.15; 95% CI 0.04-0.93, p = 0.041 - AUC 0.74 95% CI 0.68-0.80; p = 0.003) and additional procedures (OR 7.05; 1.23-40.32, p = 0.03). Stepwise multivariate analysis showed that albumin ≤2.95 g/dl (OR 3.43; 95% CI 1.06-11.13 p = 0.033), ASA>2 (OR 9.51; 95% CI 1.23-72.97; p = 0.042) and additional resections (OR 3.39; 95% CI 1.36-8.45; p = 0.045) were independent risk factors for complications Clavien Dindo >2., Conclusions: Our work demonstrated that, in our institution, 75 years of age could identify the elderly in gastric surgery as those patients were at higher risk of medical complications. ASA >2, preoperative serum albumin ≤2.95 g/dl and the need of additional procedures could increase the risk of severe postoperative adverse events., (Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: In case of Krukenberg tumor (KT) of gastric origin it is controversial and debated whether radical surgery in case of synchronous KT or metastasectomy in case of metachronous ones is associated with additional benefits. Role of perioperative treatments is unclear., Methods: Among 2515 female patients who were diagnosed with gastric cancer between January 1990 and December 2012 from 9 Italian centers, 63 presented simultaneously or developed KT as recurrence., Results: Thirty patients presented with synchronous KT, while 33 developed metachronous ovarian metastases during follow-up. The differences between the two groups were analyzed and compared. The median age of 63 patients was 48.0 years (range 31-71). Resection was possible in 53 patients (20 synchronous and 33 metachronous). Twelve patients in the synchronous group and 15 patients of the metachronous group underwent hyperthermic intraperitoneal chemotherapy after resection of KT. All of them underwent adjuvant chemotherapy after KT resection. The median survival for all population was 23 months (95 % confidence interval, 7-39 months). The median survival time in the metachronous group was 36 months, which was significantly longer than that in the synchronous group, 17 months, p < 0.0001., Conclusions: KT remains a clinical challenge for gastric cancer therapy. The extent of disease and feasibility of removal of the metastatic lesion must be carefully evaluated prior to surgery to define the patients group who could benefit most from a resection associated with perioperative treatments.