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Objective: Colorectal tumours are often densely infiltrated by immune cells that have a role in surveillance and modulation of tumour progression but are burdened by immunosuppressive signals, which might vary from primary to metastatic stages. Here, we deployed a multidimensional approach to unravel the T-cell functional landscape in primary colorectal cancers (CRC) and liver metastases, and genome editing tools to develop CRC-specific engineered T cells., Design: We paired high-dimensional flow cytometry, RNA sequencing and immunohistochemistry to describe the functional phenotype of T cells from healthy and neoplastic tissue of patients with primary and metastatic CRC and we applied lentiviral vectors (LV) and CRISPR/Cas9 genome editing technologies to develop CRC-specific cellular products., Results: We found that T cells are mainly localised at the front edge and that tumor-infiltrating T cells co-express multiple inhibitory receptors, which largely differ from primary to metastatic sites. Our data highlighted CD39 as the major driver of exhaustion in both primary and metastatic colorectal tumours. We thus simultaneously redirected T-cell specificity employing a novel T-cell receptor targeting HER-2 and disrupted the endogenous TCR genes (TCR editing (TCR ED )) and the CD39 encoding gene ( ENTPD1 ), thus generating TCR ED ENTPD1 KO HER-2-redirected lymphocytes. We showed that the absence of CD39 confers to HER-2-specific T cells a functional advantage in eliminating HER-2 + patient-derived organoids in vitro and in vivo ., Conclusion: HER-2-specific CD39 disrupted engineered T cells are promising advanced medicinal products for primary and metastatic CRC., Competing Interests: Competing interests: CBo has been member of Advisory Board and Consultant for Intellia, TxCell, Novartis, GSK, Allogene, Kite/Gilead, Kiadis, Evir, Janssen, Genyo, Epsilen and received research support from Intellia Therapeutics. AP, PDB, GC, ER, BCC and CBo are inventors on different patents on cancer immunotherapy and genetic engineering., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The objective was to evaluate the supplementation strategy's effect on beef cattle during the growing phase and two systems during the finishing phase. One hundred and twenty young bulls were randomly divided in a 2 × 2 factorial design to receive either mineral (ad libitum) or protein + energy (3 g/kg body weight (BW)/day) during the growing phase and pasture plus concentrate supplementation (20 g/kg BW/day) or feedlot (25:75% corn silage:concentrate) during the finishing phase. Feedlot-fed bulls had meat ( Longissimus thoracis -LT) with a higher content of lipids and saturated and monounsaturated fatty acids and a greater upregulation of stearoyl-CoA desaturase and sterol regulatory element-binding protein-1c than animals that fed on pasture ( p < 0.05). On the other hand, pasture-fed bulls had meat with a higher content of α-linoleic acid, linolenic acid, and n6 and a greater n6:n3 ratio compared to the feedlot-fed group ( p < 0.05). In addition, meat from pasture-fed bulls during the finishing phase had 17.6% more isocitrate dehydrogenase enzyme concentration than the feedlot group ( p = 0.02). Mineral-fed and pasture-finished bulls showed down-regulation of peroxisome proliferator-activated receptor gamma ( p < 0.05), while the bulls fed protein + energy and finished in the feedlot had higher carnitine palmitoyltransferase 2 expression ( p ≤ 0.013). In conclusion, mineral or protein + energy supplementation in the growing does not affect the fatty acid composition of intramuscular fat of LT muscle. In the finishing phase, feeding bulls in the feedlot upregulates the lipogenic genes and consequently improves the intramuscular fat content in the meat.

Worldwide, social healthcare systems must face the challenges of a growing scarcity of resources and of its inevitable distributional effects. Explicit criteria are needed to define the boundaries of public reimbursement decisions. As Germany stands at the beginning of such a discussion, more formalised priority setting procedures seem in order. Recent research identified multi-criteria decision analysis (MCDA) as a promising approach to inform and to guide decision-making in healthcare systems. In that regard, this paper aims to analyse the relative weight assigned to various criteria in setting priority interventions in Germany. A discrete choice experiment (DCE) was employed in 2015 to elicit equity and efficiency preferences of 263 decision makers, through six attributes. The experiment allowed us to rate different policy interventions based on their features in a composite league table (CLT). As number of potential beneficiaries, severity of disease, individual health benefits and cost-effectiveness are the most relevant criteria for German decision makers within the sample population, the results display an overall higher preference towards efficiency criteria. Specific high priority interventions are mental disorders and cardiovascular diseases., (© 2023. The Author(s).)

Peer victimization is a public health concern that affects a significant proportion of children and adolescents. The study evaluated the prevalence of peer victimization among 440 subjects referred to Emergency Department for a psychiatric consultation and analyzed the association with psychopathological symptoms. Sample was divided into two categories (6-13 and 14-18 years old). Logistics regression analysis was performed. Peer victimized were reported in 16.3% of subjects; 27.7% were younger than13 years old and 72.3% were between 14-18 years old, representing the main targets for peer victimization.A significant association was found between being peer victimized and depressive disorder (OR=4.57) in subjects younger than 13 years old and, with post-traumatic stress disorder (PTSD)(OR=6.52) in subjects older than 13 years old. Furthermore, linkage between being peer victimized and obsessive-compulsive disorder (OCD)(OR=4.45) was noted. Increased frequency of repeated hospitalizations was also documented.This is the first Italian study about children and adolescent peer victimization in psychiatric setting, showing a significant higher risk for depressive disorder in subjects younger than 13 years old and PTSD and OCD in subjects older than 13 years old. Investigating experiences of peer victimization provides an early diagnosis and a more efficient treatment plans, guaranteeing an improved clinical outcome.

Background: Portal or superior mesenteric vein (PV-SMV) resection and reconstruction is sometimes required during pancreatic tumor resection. In patients requiring segmental venous resection with interposition grafting, the left renal vein (LRV) is an accessible autologous solution. However, long-term patency outcomes of the LRV as an interposition conduit in this setting have not been analyzed., Study Design: We conducted a retrospective analysis of patients undergoing pancreatic resection with PV-SMV reconstruction using LRV between 2002 and 2022. The primary outcome was PV-SMV patency at last follow-up, assessed with postoperative CT scans and analyzed using Kaplan-Meier survival methods that account for variation in follow-up duration. Development of any postoperative acute kidney injury within 7 days of surgery and morbidity were secondary outcomes., Results: The study cohort includes 65 patients who underwent LRV harvest; 60 (92%) ultimately underwent successful reconstruction with harvested LRV graft. Kaplan-Meier 2-year estimated patency rate of the LRV graft was 88%, with no cases of complete occlusion. Six (10%) patients experienced graft stenosis. Nine of 61 (15%) patients experienced grade II or III acute kidney injury, 6 of 9 returning to normal renal function before discharge. No difference in median serum creatinine was observed at baseline, 6 and 12 months from surgery. LRV remnant thrombosis was seen in 7 of 65 (11%) patients. Only 3 of 61 (5%) patients had persistent acute kidney injury caused by complications unrelated to LRV harvesting., Conclusions: Autologous LRV graft was a reliable conduit for segmental PV-SMV reconstruction, resulting in a high patency rate and marginal impact on renal function. LRV harvest is a safe and potentially ideal surgical option for PV-SMV reconstruction in pancreatic surgery., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electro-hyperthermia (mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer., Aim: To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer., Methods: This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer (stage III and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128 (59%) of them were treated with CHT (no-mEHT) and 89 (41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT., Results: Median patients' age was 67 years (range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group (20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses (45% vs 24%, P = 0.0018) and a lower number of progressions (4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions., Conclusion: mEHT seems safe and has beneficial effects on survival and tumor response of stage III-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Metabolic syndrome (MS) is rapidly growing as risk factor for HCC. Liver resection for HCC in patients with MS is associated with increased postoperative risks. There are no data on factors associated with postoperative complications., Aims: The aim was to identify risk factors and develop and validate a model for postoperative major morbidity after liver resection for HCC in patients with MS, using a large multicentric Western cohort., Materials and Methods: The univariable logistic regression analysis was applied to select predictive factors for 90 days major morbidity. The model was built on the multivariable regression and presented as a nomogram. Performance was evaluated by internal validation through the bootstrap method. The predictive discrimination was assessed through the concordance index., Results: A total of 1087 patients were gathered from 24 centers between 2001 and 2021. Four hundred and eighty-four patients (45.2%) were obese. Most liver resections were performed using an open approach (59.1%), and 743 (68.3%) underwent minor hepatectomies. Three hundred and seventy-six patients (34.6%) developed postoperative complications, with 13.8% major morbidity and 2.9% mortality rates. Seven hundred and thirteen patients had complete data and were included in the prediction model. The model identified obesity, diabetes, ischemic heart disease, portal hypertension, open approach, major hepatectomy, and changes in the nontumoral parenchyma as risk factors for major morbidity. The model demonstrated an AUC of 72.8% (95% CI: 67.2%-78.2%) ( https://childb.shinyapps.io/NomogramMajorMorbidity90days/ )., Conclusions: Patients undergoing liver resection for HCC and MS are at high risk of postoperative major complications and death. Careful patient selection, considering baseline characteristics, liver function, and type of surgery, is key to achieving optimal outcomes., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Objective: This survey sought to appraise the degree of consistency in the management of disappeared colorectal liver metastases (dCRLM) among liver surgeons in different countries., Background: Colorectal liver metastases (CRLM) account for half of the deaths secondary to colorectal cancer. Due to the high utilization of chemotherapy before surgery, some or all CRLM can disappear (dCRLM) but management of dCRLMs remains unclear., Methods: Seven simulated scenarios of dCRLM were presented to experienced liver surgeons using an online platform. Treatment decisions were submitted and analysed using the multi-rater kappa method. The effect of the experience, complexity of scenarios, and location and number of dCRLM on treatment decision were analysed., Results: Sixty-seven liver surgeons from 25 countries completed the survey. There was no agreement about the therapeutic strategies of dCRLM in all scenarios (kappa 0.12, IQR 0.20-0.32). In scenarios with lower difficulty scores, surgeons tended to offer surgical resection for dCRLM alongside the visible CRLM (vCRLM), however, with poor agreement (kappa 0.32, IQR 0.19-0.51). No agreement was seen for clinical scenario in which all CRLM lesions disappeared (kappa 0.20)., Conclusion: There are clear inconsistencies in the management decisions of dCRLM. Better evidence is required to define optimal management strategies., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Minimally invasive approach represents the gold standard for the resection of the left lateral section of the liver. Recently, the American Minimally Invasive Liver Resection (AMILES) registry has become available to track outcomes of laparoscopic and robotic liver resection in the Americas. The aim of the present study is to determine the benchmark performance of MILLS throughout the AMILES database., Methods: The AMILES registry was interrogated for cases of minimally invasive left lateral sectionectomies (MILLS). Centers with best practices according to the achievement of textbook outcomes (TOs) were identified and were used to define benchmark performances., Results: Seven institutions from US and Canada entered 1665 minimally invasive liver resections, encompassing 203 MILLS. Overall, 49% of cases of MILLS satisfied contemporarily all textbook outcomes. While all centers obtained TOs with different rates of success, the outcomes of the top-ranking centers were used for benchmarking. Benchmark performance metrics of MILLS across North America are: conversion rate ≤ 3.7%, blood loss ≤ 200 ml, OR time ≤ 199 min, transfusion rate ≤ 4.5%, complication rate ≤ 7.9%, LOS ≤ 4 days., Conclusion: Benchmark performances of MILLS have been defined on a large multi-institutional database in North America. As more institutions join the collaboration and more prospective cases accrue, benchmark for additional procedures and approaches will be defined., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Glioblastoma is one of the most difficult to treat and most aggressive brain tumors, having a poor survival rate. The use of non-invasive modulated electro-hyperthermia (mEHT) and Tumor Treating Fields (TTF) devices has been introduced in the last few decades, both of which having proven anti-tumor effects., Methods: A meta-analysis of randomized and observational studies about mEHT and TTF was conducted., Results: A total of seven and fourteen studies about mEHT and TTF were included, with a total number of 450 and 1309 cases, respectively. A 42% [95% confidence interval (95% CI): 25-59%] 1-year survival rate was found for mEHT, which was raised to 61% (95% CI: 32-89%) if only the studies conducted after 2008 were investigated. In the case of TTF, 1-year survival was 67% (95% CI: 53-81%). Subgroup analyses revealed that newly diagnosed patients might get extra benefits from the early introduction of the devices (mEHT all studies: 73% vs. 37%, p = 0.0021; mEHT studies after 2008: 73% vs. 54%, p = 0.4214; TTF studies: 83% vs. 52%, p = 0.0083), compared with recurrent glioblastoma., Conclusions: Our meta-analysis showed that both mEHT and TTF can improve glioblastoma survival, and the most benefit may be achieved in newly diagnosed cases.

Background: The initial policy response to the COVID-19 pandemic has differed widely across countries. Such variability in government interventions has made it difficult for policymakers and health research systems to compare what has happened and the effectiveness of interventions across nations. Timely information and analysis are crucial to addressing the lag between the pandemic and government responses to implement targeted interventions to alleviate the impact of the pandemic., Methods: To examine the effect government interventions and technological responses have on epidemiological and economic outcomes, this policy paper proposes a conceptual framework that provides a qualitative taxonomy of government policy directives implemented in the immediate aftermath of a pandemic announcement and before vaccines are implementable. This framework assigns a gradient indicating the intensity and extent of the policy measures and applies the gradient to four countries that share similar institutional features but different COVID-19 experiences: Italy, New Zealand, the United Kingdom and the United States of America., Results: Using the categorisation framework allows qualitative information to be presented, and more specifically the gradient can show the dynamic impact of policy interventions on specific outcomes. We have observed that the policy categorisation described here can be used by decision-makers to examine the impacts of major viral outbreaks such as SARS-CoV-2 on health and economic outcomes over time. The framework allows for a visualisation of the frequency and comparison of dominant policies and provides a conceptual tool to assess how dominant interventions (and innovations) affect different sets of health and non-health related outcomes during the response phase to the pandemic., Conclusions: Policymakers and health researchers should converge toward an optimal set of policy interventions to minimize the costs of the pandemic (i.e., health and economic), and facilitate coordination across governance levels before effective vaccines are produced. The proposed framework provides a useful tool to direct health research system resources and build a policy benchmark for future viral outbreaks where vaccines are not readily available., (© 2023. The Author(s).)

Aim: Pseudomyxoma peritonei (PMP) is an uncommon pathology, and its rarity causes a lack of scientific evidence, precluding the design of a prospective trial. A diagnostic and therapeutic algorithm (DTA) is necessary in order to standardize the disease treatment while balancing optimal patient management and the correct use of resources. The Consensus of the Italian Society of Surgical Oncology (SICO) Oncoteam aims at defining a diagnostic and therapeutic pathway for PMP and appendiceal primary tumors applicable in Italian healthcare. Method: The consensus panel included 10 delegated representatives of oncological referral centers for Peritoneal Surface Malignancies (PSM) affiliated to the SICO PSM Oncoteam. A list of statements regarding the DTA of patients with PMP was prepared according to recommendations based on the review of the literature and expert opinion. Results: A consensus was obtained on 33 of the 34 statements linked to the DTA; two flowcharts regarding the management of primary appendiceal cancer and peritoneal disease were approved. Conclusion: Currently, consensus has been reached on pathological classification, preoperative evaluation, cytoreductive surgery technical detail, and systemic treatment; some controversies still exist regarding the exclusion criteria for HIPEC treatment. A shared Italian model of DTA is an essential tool to ensure the appropriateness and equity of treatment for these patients., Competing Interests: The authors declare no conflict of interest.

Real-time monitoring of meat quality requires fast, accurate, low-cost, and non-destructive analytical methods that can be used throughout the entire production chain, including the packaged product. The aim of this work was to evaluate the potential of a portable near-infrared (NIR) spectroscopy tool for the on-site detection of freshness of pork loin fillets in modified atmosphere packaging (MAP) stored on display counters. Pork loin slices were sealed in MAP trays under two proportions of O2/CO2/N2: High-Ox-MAP (30/40/30) and Low-Ox-MAP (5/20/75). Changes in pH, color, thiobarbituric acid reactive substances (TBARS), Warner−Bratzler shear force (WBSF), and microbiology (total viable counts, Enteriobacteriaceae, and lactic acid bacteria) were monitored over 15 days post-mortem at 4 °C. VIS-NIR spectra were collected from pork fillets before (through the film cover) and after opening the trays (directly on the meat surface) with a portable LABSPEC 5000 NIR system in diffuse reflectance mode (350−2500 nm). Quantitative NIR models by partial least squares regression (PLSR) showed a promising prediction ability for meat color (L*, a*, C*, and h*) and microbiological variables (R2VAL > 0.72 and RPDVAL > 2). In addition, qualitative models using PLS discriminant analysis obtained good accuracy (over 90%) for classifying pork samples as fresh (acceptable for consumption) or spoiled (not acceptable) based on their microbiological counts. VIS-NIR spectroscopy allows rapid evaluation of product quality and shelf life and could be used for on-site control of pork quality.

Background and Objectives: The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8-14 days/month) or chronic migraine (CM)., Methods: This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician's choice, or patient's preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks., Results: Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57-11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05-2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15-3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04-2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07-0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42-8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14-2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22-3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM., Conclusions: A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms., (© 2022. The Author(s).)

Background: The benefits of pure laparoscopic and robot-assisted liver resections (LLR and RALR) are known in comparison to open surgery. The aim of the present retrospective comparative study is to investigate the role of RALR and LLR according to different levels of difficulty., Methods: The institutional databases of six high-volume hepatobiliary centers were retrospectively reviewed. The study population was divided in two groups: LLR and RALR. The procedures were stratified for difficulty levels accordingly to three classifications. A propensity score matching was implemented to mitigate selection bias. Short-term outcomes were the object of comparison., Results: Nine hundred and thirty-six LLR and 403 RALR were collected. RALR exhibited fewer cases of intraoperative blood loss, lower transfusion and conversion rates (especially for oncological radicality) than LLR in the setting of highly difficult operations, whereas LLR had lower postoperative morbidity and fewer low-grade complications. For intermediate and low-difficulty resections, the intraoperative advantages of RALR gradually decreased to nonsignificant results and LLR remained associated with lower postoperative morbidity., Conclusion: Robot-assisted liver resections do not show operative nor clinically significant benefits over LLR for low- and intermediate-difficulty resections. By reducing conversion rates, RALR can favour the operative feasibility of difficult resections possibly extending the indications of minimally invasive approaches for liver resection., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: This prospective cohort, real-life study aimed to evaluate whether galcanezumab, a monoclonal antibody anti-calcitonin gene-related peptide (CGRP) ligand, can reduce caregivers' distress and improve their mutuality with patients., Background: Migraine is a highly disabling chronic disease that negatively impacts patients' and often their relatives' lives, occurring during an active phase of life with direct consequences on leisure- and work-related activities. The figure of caregiver is crucial in several neurological conditions but poorly accounted for in migraine care so far. Studies on monoclonal antibodies against the CGRP pathway, recently introduced as migraine-preventive treatments, demonstrated that they significantly reduce migraine frequency and disability in the first weeks of treatment., Methods: Consecutive patient-caregiver dyads were evaluated at baseline and after 6 months of treatment with galcanezumab (V6) at our headache center from September 2020 to September 2021. Enrolled patients were requested to report their monthly migraine days, monthly intake of acute medications, attack pain intensity (on the Numeric Rating Scale), concomitant preventives, and disability questionnaires (Headache Impact Test, Migraine Disability Assessment). Each dyad filled in the Mutuality Scale to check their reciprocity; moreover, the Relatives' Stress Scale was used to detect caregivers' distress., Results: We enrolled 27 patient-caregiver dyads. At 6 months, migraine burden significantly improved with reductions in monthly migraine days (falling from 14.8 [SD = 4.8] days by 10.3 [SD = 4.8] days; 95% CI: 8.4, 12.2; p < 0.001) and Migraine Disability Assessment scores (lowering from 83.6 [SD = 46.7] by 71.5 points [SD = 49.3]; 95% CI: 51.2, 91.9; p < 0.001). From baseline to month 6, the caregiver Relatives' Stress Scale score significantly decreased (falling from 20.7 [SD = 13.7] by 6.5 [SD = 14.1] points; 95% CI: 0.8, 12.2; p = 0.027), while the Mutuality Scale's caregiver total score increased (from 3.04 [SD = 0.61] by 0.29 [SD = 0.49] points; 95% CI: -0.508, -0.064; p = 0.014)., Conclusions: Our findings preliminarily demonstrated that patients' migraine improvement after 6 months of galcanezumab treatment could be favorably perceived by caregivers, significantly reducing their distress with better reciprocity within the dyad., (© 2022 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

We estimate the effects of a chronic disease management program (CDMP) which adapts various supply-side interventions to specific demand-side conditions (disease-staging) for patients with chronic kidney disease (CKD). Using a unique dataset on the entire population of the Emilia-Romagna region of Italy with hospital-diagnosed CKD, we estimate the causal effects of the CDMP on adherence indicators and health outcomes. As CKD is a progressive disease with clearly-defined disease stages and a treatment regimen that can be titrated by disease severity, we calculate dynamic, severity-specific, indicators of adherence as well as several long-term health outcomes. Our empirical work produces statistically significant and sizeable causal effects on many adherence and health outcome indicators across all CKD patients. More interestingly, we show that the CDMP produces larger effects on patients with early-stage CKD, which is at odds with some of the literature on CDMP that advocates intensifying interventions for high-cost (or late-stage) patients. Our results suggest that it may be more efficient to target early-stage patients to slow the deterioration of their health capital. The results contribute to a small, recent literature in health economics that focuses on the marginal effectiveness of CDMPs after controlling either for supply- or demand-side sources of heterogeneity., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Italian Migraine Registry (I-GRAINE) is a multicenter (n = 38), prospective, observational, non-interventional study aimed at providing big data on migraine to ensure proper clinical disease management, according to scientific, and sustainability criteria. We enrolled consecutive patients affected by episodic or chronic migraine according to the systematic random method. Information on sociodemographic characteristics, lifestyle, migraine features, patient's journey, and healthcare resource use were gathered using face-to-face interviews.On the date of 31 December 2021, we enrolled 231 patients at 12 headache centers. Most of them were women (84.4%), with high migraine frequency (9.6 ± 6.9 days/month) and severe disability (MIDAS score: 43.0 ± 40.8; HIT-6 score: 60.4 ± 10.6). Only a minority of patients (38.1%) had previously visited a headache center.A clear-cut difference emerged in the proportion of responders to nonspecific acute treatments (43.5-66.7%) compared to triptans (76.3%) and in responders to unspecific prophylaxis (5.4-35%) compared to anti-CGRP monoclonal antibodies (69.2-78.6%). Most patients underwent ≥ 1 specialist visit (66.9%) or diagnostic investigation (77.4%) over the last 3 years-mostly subsidized by our national health system-inappropriate in 64.9% and 25% of the cases, respectively.The I-GRAINE registry is expected to provide a large and exponentially increasing collection of clinical, biological, and epidemiologic information and will contribute to moving migraine out of the shadow cone of marginalization, which has been often relegated up to now., (© 2022. Fondazione Società Italiana di Neurologia.)

The Italian National Healthcare Service relies on per capita allocation for healthcare funds, despite having a highly detailed and wide range of data to potentially build a complex risk-adjustment formula. However, heterogeneity in data availability limits the development of a national model. This paper implements and ealuates machine learning (ML) and standard risk-adjustment models on different data scenarios that a Region or Country may face, to optimize information with the most predictive model. We show that ML achieves a small but generally statistically insignificant improvement of adjusted R 2 and mean squared error with fine data granularity compared to linear regression, while in coarse granularity and poor range of variables scenario no differences were observed. The advantage of ML algorithms is greater in the coarse granularity and fair/rich range of variables set and limited with fine granularity scenarios. The inclusion of detailed morbidity- and pharmacy-based adjustors generally increases fit, although the trade-off of creating adverse economic incentives must be considered., (© 2022 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Background: Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs)., Methods: In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected., Results: Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64)., Conclusions: This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials., (© 2022. The Author(s).)

We describe a multi-step high-dimensional (HD) flow cytometry workflow for the deep phenotypic characterization of T cells infiltrating metastatic tumor lesions in the liver, particularly derived from colorectal cancer (CRC-LM). First, we applied a novel flow cytometer setting approach based on single positive cells rather than fluorescent beads, resulting in optimal sensitivity when compared with previously published protocols. Second, we set up a 26-color based antibody panel designed to assess the functional state of both conventional T-cell subsets and unconventional invariant natural killer T, mucosal associated invariant T, and gamma delta T (γδT)-cell populations, which are abundant in the liver. Third, the dissociation of the CRC-LM samples was accurately tuned to preserve both the viability and antigenic integrity of the stained cells. This combined procedure permitted the optimal capturing of the phenotypic complexity of T cells infiltrating CRC-LM. Hence, this study provides a robust tool for high-dimensional flow cytometry analysis of complex T-cell populations, which could be adapted to characterize other relevant pathological tissues., (© 2022 Faccani et al.)

Background: The implementation of minimally invasive liver resection surgery (MILS) programs starts from procedures with a low degree of technical difficulty. Data regarding the real short-term advantage of laparoscopy according to technical difficulty are still lacking. The aim of the present study is to evaluate the differential benefit of laparoscopic over open technique according to the technical difficulty of the procedures and to investigate if efforts associated with laparoscopic approach are always justified., Methods: Nine hundred and thirty-six MILS resections performed between 2005 and 2018 were stratified according to technical complexity (low, intermediate and high difficulty) and to approach (MILS or open) and matched in a 1:1 ratio using propensity scores to obtain three pairs of groups (Pair 1: Low-MILS and Low-Open, including 274 cases respectively; Pair 2: Int-MILS and Int-Open, including 237 patients respectively; Pair 3: High-MILS and High-Open, including 226 patients respectively)., Results: MILS approach resulted in a statistically significant lower blood loss, reduced morbidity, reduced and shorter time for functional recover and length of stay within all pairs. The evaluation of the differential benefit showed a greater advantage of laparoscopic approach in high degree procedures compared with intermediate and low degree, both in terms of blood loss (-250 and -200 mL respectively) and morbidity rate (-5.7% and -4.1% respectively)., Conclusions: The favorable biological scenario associated with laparoscopic approach allows to obtain significant benefits in the setting of technically complex procedures. The commitment towards MILS approach should be therefore stronger in this setting, where the advantage of laparoscopy seems to be enhanced., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-20-562/coif). LA serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2022 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: Even though breast cancer is the most frequent extra-abdominal tumor causing peritoneal metastases, clear clinical guidelines are lacking. Our aim is to establish whether cytoreductive surgery (CRS) could be considered in selected patients with peritoneal metastases from breast cancer (PMBC) to manage abdominal spread and allow patients to resume or complete other medical treatments., Methods: We considered patients with PMBC treated in 10 referral centers from January 2002 to May 2019. Clinical data included primary cancer characteristics (age, histology, and TNM) and data on metastatic disease (interval between primary BC and PM, molecular subtype, other metastases, and peritoneal spread). Overall survival (OS) was estimated using the Kaplan-Meier method. Univariate and multivariable data for OS were analyzed using the Cox proportional hazards model., Results: Of the 49 women with PMBC, 20 were treated with curative aim (CRS with or without HIPEC) and 29 were treated with non-curative procedures. The 10-year OS rate was 27%. Patients treated with curative intent had a better OS than patients treated with non-curative procedures (89.2% vs. 6% at 36 months, p < 0.001). Risk factors significantly influencing survival were age at primary BC, interval between BC and PM diagnosis, extra-peritoneal metastases, and molecular subtype., Conclusions: The improved outcome in selected cases after a multidisciplinary approach including surgery should lead researchers to regard PMBC patients with greater attention despite their scarce epidemiological impact. Our collective efforts give new information, suggest room for improvement, and point to further research for a hitherto poorly studied aspect of metastatic BC., 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 Cardi, Pocard, Dico, Fiorentini, Valle, Gelmini, Vaira, Pasqual, Asero, Baiocchi, Di Giorgio, Spagnoli, Di Marzo, Sollazzo, D’Ermo, Biacchi, Iafrate and Sammartino.)

Future liver remnant (FLR) volume is an important indicator of the risk of posthepatectomy liver failure (PHLF) and limits the feasibility of major hepatectomies. A case series of 5 patients treated with a novel approach is presented. Laparoscopic liver partitioning was combined with subsequent liver venous deprivation (embolization of both the portal and the hepatic veins). Baseline average FLR was 28.8%. All procedures were successfully performed without major complications. Mean 1-, 2- and 4-week hypertrophy of the FLR were 35%, 40.3%, and 46.4%, respectively. Four patients underwent planned surgery after a mean interval of 28 days. Of these, 2 patients achieved sufficient FLR volume and function after 2 weeks and underwent surgery before the 4-week volumetric analysis. One patient did not undergo surgery because of intraoperative diagnosis of peritoneal metastases. No cases of PHLF were observed at 5-day follow-up., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Beef consumption and production in Spain and Brazil are different with the consumption of beef in Brazil being three times higher than in Spain. In addition, there are variations in the economic value of production and in the traceability system. Therefore, the aim of this research was to understand the purchasing and consumption patterns using the customer behavior analysis technique of focus groups, which analyzed motivations for the consumption of beef, classifying their preferences by the intrinsic and extrinsic attributes at the time of purchase. The key aspect of the consumption of beef, both for Spanish and Brazilian consumers, was personal satisfaction/flavor. Spanish consumers were more conscious than Brazilians of the beneficial and harmful qualities that meat provides. The presence of fat was the factor that most restricted intake in both countries. The most important intrinsic attributes for Spanish and Brazilian consumers were the visual aspects of the meat: color, freshness, and the quantity and disposition of fat. The most important extrinsic characteristics were the price and expiration date. Spanish consumers see packaged meat as convenient and safe, although it is considered by Brazilians to be over-manipulated. The traceability certification on the label provides credibility to the product for the Spanish but only partially for Brazilians.

Peritoneal Carcinomatosis (PC) is considered as a terminal disease with short survival. It is treated with palliative therapies, consisting of repeated drainages and sometimes instillation of chemotherapy. Since the nineties, surgery has been combined with more effective systemic chemotherapy, intraperitoneal chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC. This combination therapy significantly increases the overall survival of selected PC patients. The understanding of how intraperitoneal chemotherapy and HIPEC can cure patients is still unclear. Experts hypothesized that the efficacy is obtained by the ability of high peritoneal drug exposure and hyperthermia to directly kill cancer cells. Several studies indicate that cancer cells death directly influences the response of the immune system. For this reason, the protective effect of intraperitoneal chemotherapy and HIPEC could be mediated by its ability to kill cancer cells in an immuno-genic way, causing an efficient anticancer immune response. In this review, we investigate the role of the innate peritoneal or locoregional therapy-induced immune response in PC therapy., Competing Interests: Conflict of interest The authors do not have any conflict of interest to declare. No funding was received., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Treatment strategies for advanced cutaneous melanoma (CM) patients, resistant or not treatable with novel target and immunotherapeutic drugs, remain a significant challenge, particularly for patients with unresectable stage IIIC/D disease localized to inferior limbs and pelvis, for whom specific outcomes are rarely considered., Materials and Methods: This is a prospective study of multidisciplinary treatments, including locoregional melphalan chemotherapy, in 62 BRAF wild-type CM patients with locoregional metastases in the inferior limbs and pelvis, including inguinal regions. Patients were either in progression following or ineligible for, or not treatable with novel immunotherapy. For exclusively inferior limb-localised disease, patients received locoregional melphalan chemotherapy performed by hyperthermic isolated limb perfusion (n = 19) or isolated limb infusion (n = 19), and for synchronous lesions localised to inferior limbs and pelvis, received hypoxic pelvic and limb perfusion (n = 24). Additional multidisciplinary therapy included local, locoregional and systemic treatments and the primary endpoint was tumour response., Results: The objective response rate following first cycle of locoregional chemotherapy was 37.1% at 3 mo and median progression-free survival was 4-mo, with 12.9% procedure-related complications, 30.6% low-grade haematological toxicity and 11.3% severe limb toxic tissue reactions. Multivariate logistic regression showed that the odds of response were significantly higher for patients ≤ 75 y of age and for patients with locoregional metastases exclusively located in the inferior limbs., Conclusion: In this subgroup of CM patients with BRAF wild-type status, locoregional metastases localized to inferior limbs and pelvis, in progression following or ineligible for immunotherapy, melphalan locoregional chemotherapy demonstrated a safe and effective profile., Trial Registration: ClinicalTrials.gov Identifier NCT01920516; date of trial registration: August 6, 2013., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: An increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer; in particular, the use of modulated electro-hyperthermia (mEHT) results in increased survival and tumor response., Aim: To compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer., Methods: This was an observational retrospective study; data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019. A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals; 58 (37%) of these received CHT + mEHT and 100 (63%) CHT. CHT was mainly gemcitabine-based regimens in both groups., Results: Overall (19.5 mo vs 11.02 mo, P < 0.001) and progression-free (12 mo vs 3 mo, P < 0.001) survival were better for the CHT + mEHT group compared to the CHT group. The association of mEHT resulted also in an improvement of tumor response with disease control rate 95% vs 58% ( P < 0.001) at 3 mo. Toxicity was comparable in the two study groups, and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns., Conclusion: The addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity., Competing Interests: Conflict-of-interest statement: No conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Problem: The consistent prevalence and occasionally severe consequences of bullying and victimization suggest the need to include a more accurate assessment of these episodes within the Emergency Departments (ED). However, the literature on mental health related symptoms of bullying/victimization treated in the ED is still scarce. The aim of this study is to assess the prevalence of peer victimization amongst children and adolescents referred to an Italian Pediatric Emergency Department. Differences between Hospital Departments, type of victimization and ages are tested., Methods: A retrospective observational study was conducted with 705 subjects. The age range was from 6 to 18 years old (M = 13.09; SD = 3.048)., Findings: 15.3% of the sample reported to be victimized (8.2% occasionally; 7.1% systematically). For the Child and Adolescent Psychiatry Unit, we found a significant association between peer victimization and being adolescent (Fisher's p = 0.003). In addition, a significant association was found between verbal victimization and Child and Adolescent Psychiatry Unit (Fisher's p = 0.02) and physical victimization and Child Abuse Department (Fisher's p < 0.001)., Conclusion: Findings suggest the importance of an accurate assessment of victimization experiences of children and adolescents with access to ED, to prevent future re-victimization and crystallization of symptoms across time., (© 2021 The Authors. Journal of Child and Adolescent Psychiatric Nursing Published by Wiley Periodicals LLC.)

Background: Local ablation of pancreatic cancer has been suggested as an option to manage locally advanced pancreatic cancer (LAPC) although no robust evidence has been published to date to support its application. The aim of this study is to compare overall survival (OS) and progression-free survival (PFS) in patients receiving both radiofrequency ablation (RFA) and conventional chemoradiotherapy (CHRT) with patients receiving CHRT only., Methods: This is a multicentre prospective randomized controlled trial (RCT). Patients with LAPC diagnosed by the Pancreas-Ablation-Team-Verona were randomly assigned to open RFA (Group A) or CHRT (Group B). Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Statistical significance was set at p < 0.05., Results: One hundred LAPC patients were enrolled from January 2014 to August 2016. 33% of patients in Group A did not receive the designated procedure because of intraoperative findings of liver (18.7%) or peritoneal metastases (43.8%), or technical contraindications (37.5%). We did not observe any statistically significant survival benefit from RFA compared to CHRT, neither in terms of OS (medians of 14.2 months and 18.1 months, respectively, p = 0.639) nor PFS (medians of 8 months and 6 months respectively, p = 0.570). Mortality was nil and RFA-related morbidity was 15.6%. In 13% of subjects, conversion to surgery occurred (2 after RFA and 11 after CHRT)., Conclusions: This is the first RCT evaluating the impact of upfront RFA in the multimodal treatment of LAPC. Compared to CHRT, RFA alone did not provide any advantage in terms of OS or PFS. It could be considered as a therapeutic option for LAPC within a multimodal context and after neoadjuvant therapies., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The range of procedures with documented feasibility by laparoscopic approach is widening in the setting of liver resections. Many technical limits have been overcome in the attempt to reduce the biological impact of major procedures [1-8]. Similarly, associated liver partition and portal vein ligation for staged hepatectomy (ALPPS)-which could be assumed as the paradigm of maxi-invasiveness-has recently been proposed in a minimally invasive fashion to reduce the impact of this procedure [9-12]. Technical insights to perform laparoscopic ALPPS are provided., Methods: Perioperative and intraoperative tips for laparoscopic ALPPS are provided within a SMART (Strategy to Minimize ALPPS Risks by Targeting invasiveness) protocol. Stage 1: After volumetric and functional assessment, partial liver transection is performed, keeping intact both the hilum and the caval plane (to prevent adhesions), therefore avoiding portal ligation. No inert material is left inside the abdominal cavity at the end of procedure to keep the liver surfaces apart. Radiologic portography with portal vein embolization is scheduled on postoperative day (POD) 1. Liver volume (pre-PVE: 29%; post-PVE: 52%) and liver function measured through a Technetium-99 hepatobiliary scintigraphy [13] (pre-PVE: 2.15%/min/sqm; post-PVE: 3.67%/min/sqm) of the future remnant liver are reassessed within 10 days to verify whether size and function are adequate. Stage 2: After 2 weeks from the first stage, laparoscopic right hepatectomy is performed following an anterior approach., Results: No conversion to open was required. Operative time was 100 and 300 minutes for stage 1 and 2, respectively. Intraoperative blood loss was 50 and 300 ml for the two procedures. Postoperative course was uneventful; patient was discharged on POD 6 of the second operation., Conclusions: The implementation of a perioperative protocol to prevent the risk of liver failure by both assessing volume and function of FLR and targeting the invasiveness of the surgical procedure may allow to minimize and control risks of a maximally invasive procedure, such as ALPPS., (© 2021. Society of Surgical Oncology.)

The aim of the present study is to analyze the feasibility and the impact of a two-step approach in the treatment of giant hemangiomas (GH) i.e., exceeding 10 cm in maximum diameter, consisting of transarterial embolization (TAE) followed by laparoscopic liver resection (LLR). Ten patients with 11 GH were treated with TAE and subsequent LLR between 2017 and 2020 (Group A). A matched cohort of 10 patients with GH treated with upfront LLR between 2014 and 2017 was identified for comparison (Group B). Data were analyzed regarding intraoperative and postoperative outcomes, including successful completion of LLR, morbidity, and mortality. Successful microparticle embolization of the GH-feeding arteries was performed in all patients in group A. In three cases a liquid embolic agent (Squid-18) was also injected to obtain complete embolization. No complications were observed after TAE. Successful surgery was performed after a mean time interval of 2.2 days from TAE without any case of conversion to laparotomy. Statistically significant differences between group A and group B were found in intraoperative blood loss (250 ± 200 vs. 400 ± 300 mL, p = 0.039), operative time (245 ± 60 vs. 420 ± 60 min, p = 0.027), and length of stay (5 ± 1 vs. 8 ± 2 days, p = 0.046). Our data suggest that two-step TAE + LLR might be a safe and effective option for surgical treatment of GH >10 cm.

Purpose: The hepato-mesenteric trunk is an extremely rare condition in which the common hepatic artery (CHA) originates from the superior mesenteric artery (SMA). Usually, CHA passes behind the head of the pancreas. A systematic review was performed to provide guidelines for the perioperative management of patients with this anatomical variation who underwent a pancreaticoduodenectomy (PD). A case report was also included., Methods: A systematic search of the literature was conducted and the manuscript was structured following point-by-point the PRISMA guidelines. The risk of bias within individual studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist tools. Case report was structured according to the CARE guidelines., Results: After an initial selection of 141 titles, 9 articles were included in the study (n = 10 patients). A postoperative surgical complication which required a reintervention occurred only one time. In four patients, CHA had a posterior position relative to pancreas, while in three cases, it was anterior. The remaining three patients had an intrapancreatic course. The CHA was resected in two patients, with an end-to-end reconstruction or using the splenic artery stump. In only three patients, a preoperative multidisciplinary presentation was performed and in four cases, the CHA variation was not described by radiologists in formal CT-scan reports., Conclusion: Although there are no definitive guidelines, improvements in the preoperative knowledge of such a rare anatomical variation may ensure better postoperative outcomes, avoiding intraoperative accidents and life-threatening postoperative complications., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Aims: Bevacizumab (B) in association with systemic chemotherapy is commonly used for the treatment of colorectal cancer liver metastases. The aim of this study was to monitor tumor response, overall survival (OS) and progression-free survival (PFS) of patients with colorectal cancer liver metastases treated with transarterial chemoembolization (TACE) + B compared with TACE alone and to correlate the results with KRAS mutational status., Patients & Methods: This was an observational multicentric case-control study (NCT03732235) on the efficacy and safety of B administered after TACE., Results: The disease control rate was significantly higher for the TACE + B than the TACE alone group (p < 0.001). KRAS wild-type patients had a significantly better disease control rate than those with KRAS mutations in the TACE + B group. Median OS and PFS were similar for the TACE + B and TACE groups, whereas median time to progression was significantly higher for the TACE + B group (p < 0.01)., Conclusion: The combination of TACE with B may improve tumor response and delay disease progression., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2021 Giammaria Fiorentini.)

Background: The aim of the present study was to analyze the long-term outcomes of laparoscopic and open surgery for intrahepatic cholangiocarcinoma (iCCA) in a series, collected in a tertiary referral center with a high annual volume of laparoscopic activity., Methods: Between January 2004 and June 2020, 446 liver resections (LR) were performed for iCCA: of these, 179 were performed by laparoscopic surgery (LS) and 267 with the open approach. The two groups were matched through a 1:1 propensity score using covariates representative of patient and disease characteristics. The study and control groups were compared, with specific attention given to oncological outcomes (rate of R0, depth of resection margins, overall and disease-free survival, rate, and site of recurrence)., Results: The number of retrieved nodes, rate, and depth of negative resection margins were comparable between the two groups. The interval time between surgery and subsequent adjuvant treatments was significantly shorter in LS patients. No differences were shown even in the comparison between the LS and the open group in terms of median disease-free and overall survival. Moreover, the disease recurrence rate was comparable between the LS and the open groups (45.2% versus 56.7%), and the recurrence pattern was similar., Conclusions: The minimally invasive approach for iCCA was once again confirmed to be associated with advantages in terms of intraoperative and short-term outcomes, but was also proven to be oncologically non-inferior to the open counterpart. In the present study, overall and disease-free survival were found to be similar between the two approaches.

Background: At the end of a laparoscopic major hepatectomy, an incision wide enough for specimen retrieval is required. Classically, Pfannenstiel (PF) incision is the type of access favored as service incision in laparoscopy. However, in specific settings the use of a midline (ML) incision can be favorable, with doubtful impaction on the outcomes of a purely laparoscopic operation. The aim of this study was to investigate on clinical outcomes after laparoscopic hemihepatectomies using PF/ML incisions in comparison with open. Methods: The institutional clinical database of the Hepatobiliary Division at San Raffaele Hospital (Milan, Italy) was retrospectively reviewed identifying cases of laparoscopic and open hemihepatectomies. Three analyses were performed: whole laparoscopic versus open; ML versus open; PF versus ML. Clinical outcomes such as intraoperative blood loss, operative time, postoperative morbidity, motility resumption, perceived pain, and length of stay (LOS) were used for comparisons. Results: Laparoscopy was confirmed to be superior to open approach also in the present series in terms of lower blood loss (300 versus 400 mL, P  = .041), fewer complications (14.2% versus 25.9%, P  = .024), shorter hospitalization (5 versus 7 days, P  = .033), and enhanced recovery in terms of better pain control ( P  = .035) and mobility resumption ( P  = .047). Similar outcomes were observed comparing ML alone with open (estimated blood loss 300 mL versus 400 mL, P  = .039; complications 13.1% versus 25.9%, P  = .037; LOS 5 days versus 7 days, P  = .04; lower pain perception, P  = .048 and faster mobility resumption, P  = .046). No significant differences were observed in postoperative outcomes of PF versus ML. Conclusions: Suprapubic and ML incisions at the end of a pure laparoscopic case lead to comparable outcomes between each other. The adoption of ML incision for specimen retrieval does not affect outcomes of minimal invasiveness.

Most surgeons have traditionally been reluctant toward minimally-invasive surgery for bile duct tumors. This study aimed to perform a systematic literature review on perioperative and oncologic results of pure laparoscopic and robotic curative-intent surgery for hilar cholangiocarcinoma. According to the PRISMA statement, a systematic review was conducted into Pubmed, EMBASE and Cochrane. A critical appraisal of study was performed according to the Joanna Briggs Institute tools. Nineteen studies (12 on pure laparoscopy and 7 on robotics) were included: 7 case reports, 9 case series, 3 case-control (193 patients). The pooled conversion, morbidity, biliary leak and mortality rates were 5.5%, 43%, 16.4% and 4%. The weighted mean of operative time, blood loss and postoperative stay were 388 min, 446 mL and 14 days. For pure laparoscopy, the pooled R0 rate was 86%; overall survival and disease-free survival rates ranged from 85 to 100% and from 80 to 100% (median observation time 6-18 months). For robotic surgeries, the pooled R0 rate was 69% and overall survival rates ranged from 90 to 100% (median observation time 5-15 months). Case reports were overall of high quality, case series of moderate / high-quality, case-control studies ranged from low to high quality. In selected patients, minimally-invasive surgery for Klatskin tumors appears feasible, safe, satisfactory for perioperative outcomes and adequate for oncologic results. However, the results are based on few studies, limited in patient numbers and with allocation criteria more restrictive than open, reporting short follow-up and mainly with non-comparative design: evidence of higher quality is recommended.

Background: The aim of the present study is to analyze the outcomes of laparoscopic and open liver resections for (Intrahepatic CholangioCarcinoma) ICC in the modern era of laparoscopic liver surgery., Methods: Patients undergoing laparoscopic and open liver resections for ICC in two European referral centers were included. Finally, 104 patients from the open group and 104 patients from the laparoscopic group were compared after propensity scores matching according to seven covariates representative of patients and disease characteristics. Indications to surgery and short- and long-term outcomes were compared., Results: Operative time, number of retrieved nodes, rate, and depth of negative resection margins were comparable between the two groups. Blood loss was lower in the MILS (150 ± 100 mL, mean ± SD) compared with the Open group (350 ± 250 mL, p = 0.030). Postoperative complications occurred in 14.4% of patients in the MILS and in the 24% of patients in the Open group (p = 0.02). There were no significant differences in long-term outcomes between groups., Conclusions: Our results confirm feasibility, safety, and oncological efficiency of the laparoscopic approach in the management of ICC. However, this surgery is often complex and should be only considered in centers with large experience in laparoscopic liver surgery.

Background: In recent years, the treatment of colorectal liver metastases (CRLM) has undergone significant evolution thanks to technical improvements as well as oncological advances, which have been the subject of targeted studies aimed at understanding the details of this heterogeneous disease. The purpose of this study is to put together pieces of this complex scenario by providing an overview of the evolution that has occurred in the context of a single center within a multidisciplinary management approach., Methods: Between 2005 and 2020, 1212 resections for CRLM were performed at the Hepatobiliary Surgery Division of San Raffaele Hospital, Milan. The series was divided into three historical periods, which were compared in terms of disease characteristics and short- and long-term outcomes: Period 1, 2005-2009 (293 cases); Period 2, 2010-2014 (353 cases); Period 3, 2015-2020 (566 cases). The trends for surgical technical complexity, oncological burden of the disease, use of the laparoscopic approach and use of techniques for hepatic hypertrophy were analyzed year by year. Uni- and multivariate analyses were performed to identify factors associated with inclusion to a laparoscopic approach and with long-term prognosis., Results: The number of resections performed over the years progressively increased, with an increase in the number of cases with a high Clinical Risk Score and a high profile of technical complexity. The proportion of cases performed laparoscopically increased, but less rapidly compared to other malignant tumors. The risk of postoperative morbidity and mortality was similar in the three analyzed periods. Long-term survival, stratified by Clinical Risk Score, improved in Period 3, while overall survival remained unchanged., Conclusion: The cultural background, the maturation of technical expertise and the consolidation of the multidisciplinary team have resulted in safe expansion of the possibility to offer a curative opportunity to patients, while continuously implementing into clinical practice evidence provided by the literature.

Background: There is an increased interest in venous vascular resection associated with pancreatic resection for pancreatic ductal adenocarcinoma as an upfront procedure or after neoadjuvant treatment. The aim of this study was to evaluate the impact of venous vascular resection for pancreatic ductal adenocarcinoma on postoperative and long-term outcomes., Methods: The study is a retrospective analysis of patients who underwent pancreatectomy for pancreatic head pancreatic ductal adenocarcinoma with and without venous vascular resection between January 2010 and April 2018. The impact of venous vascular resection on postoperative and pathologic data was analyzed. Univariate and multivariate analyses of predictors of disease-free and disease-specific survival were analyzed for the entire cohort. A propensity-score matched cohort analysis was subsequently performed to remove selection bias and improve homogeneity., Results: Four hundred and eighty-one patients were included, and 126 (26%) underwent a venous vascular resection. Patients undergoing venous vascular resection had higher morbidity (64% vs 54%; P = .026) with no differences in 90-day postoperative mortality (3.1 vs 2.8%; P = .5). Venous vascular resections were also significantly associated with R1 resections (52% vs 37%; P = .002) and perineural invasion (87% vs 77%; P = .017). Five-year disease-free survival in patients with and without venous vascular resection were 7% and 20% (P = .018), respectively. Independent predictors of worse disease-free survival included venous vascular resection, positive lymph node status, and perineural invasion. Independent predictors of worse disease-specific survival were perineural invasion and positive nodal status, while adjuvant treatment was a protective factor. Five-year disease-specific survival in patients with and without venous vascular resection were 19% and 35% (P = .42)., Conclusion: Pancreatectomy with venous vascular resection can be accomplished safely. Venous vascular resections are associated with poor prognostic factors and with a worse clinical outcome, being a significant predictor of cancer recurrence., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: the surgical workup for colorectal cancer peritoneal metastases (CRCPM) is complex and should be managed in specialized centers. Diagnostic and therapeutic algorithms (DTA) have been proposed to balance optimal patients management and correct use of resources. Aim of this study was to establish a consensus on DTA for CRCPM patients in Italy., Method: a panel of 18 delegated members of centers afferent to Peritoneal Surface Malignancies Onco-team of the Italian Society of Surgical Oncology was established. A list of statements regarding the DTA of patients with CRCPM was prepared according to different activities and decision-making nodes with a defined entry and exit point. Consensus was obtained through RAND UCLA methodology., Results: two different DTA were defined and approved according to the modality of presentation of CRCPM (synchronous and metachronous). A consensus was also obtained on 17 of the 19 statements related to DTA., Conclusion: a shared model of DTA is now available for healthcare providers to monitor appropriateness in diagnosis and treatment of patients with isolated peritoneal metastases from CRC., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6-7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L'Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6-7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6-7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6-7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6-7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6-7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.