Robot-Assisted Versus Laparoscopic Distal Pancreatectomy in Patients with Resectable Pancreatic Cancer: An International, Retrospective, Cohort Study.

BACKGROUND: Robot-assisted distal pancreatectomy (RDP) is increasingly used as an alternative to laparoscopic distal pancreatectomy (LDP) in patients with resectable pancreatic cancer but comparative multicenter studies confirming the safety and efficacy of RDP are lacking. METHODS: An international, multicenter, retrospective, cohort study, including consecutive patients undergoing RDP and LDP for resectable pancreatic cancer in 33 experienced centers from 11 countries (2010-2019). The primary outcome was R0-resection. Secondary outcomes included lymph node yield, major complications, conversion rate, and overall survival. RESULTS: In total, 542 patients after minimally invasive distal pancreatectomy were included: 103 RDP (19%) and 439 LDP (81%). The R0-resection rate was comparable (75.7% RDP vs. 69.3% LDP, p = 0.404). RDP was associated with longer operative time (290 vs. 240 min, p < 0.001), more vascular resections (7.6% vs. 2.7%, p = 0.030), lower conversion rate (4.9% vs. 17.3%, p = 0.001), more major complications (26.2% vs. 16.3%, p = 0.019), improved lymph node yield (18 vs. 16, p = 0.021), and longer hospital stay (10 vs. 8 days, p = 0.001). The 90-day mortality (1.9% vs. 0.7%, p = 0.268) and overall survival (median 28 vs. 31 months, p = 0.599) did not differ significantly between RDP and LDP, respectively. CONCLUSIONS: In selected patients with resectable pancreatic cancer, RDP and LDP provide a comparable R0-resection rate and overall survival in experienced centers. Although the lymph node yield and conversion rate appeared favorable after RDP, LDP was associated with shorter operating time, less major complications, and shorter hospital stay. The specific benefits associated with each approach should be confirmed by multicenter, randomized trials.

Benchmarking of minimally invasive distal pancreatectomy with splenectomy: European multicentre study.

BACKGROUND: Benchmarking is the process to used assess the best achievable results and compare outcomes with that standard. This study aimed to assess best achievable outcomes in minimally invasive distal pancreatectomy with splenectomy (MIDPS). METHODS: This retrospective study included consecutive patients undergoing MIDPS for any indication, between 2003 and 2019, in 31 European centres. Benchmarks of the main clinical outcomes were calculated according to the Achievable Benchmark of Care (ABC™) method. After identifying independent risk factors for severe morbidity and conversion, risk-adjusted ABCs were calculated for each subgroup of patients at risk. RESULTS: A total of 1595 patients were included. The ABC was 2.5 per cent for conversion and 8.4 per cent for severe morbidity. ABC values were 160 min for duration of operation time, 8.3 per cent for POPF, 1.8 per cent for reoperation, and 0 per cent for mortality. Multivariable analysis showed that conversion was associated with male sex (OR 1.48), BMI exceeding 30 kg/m2 (OR 2.42), multivisceral resection (OR 3.04), and laparoscopy (OR 2.24). Increased risk of severe morbidity was associated with ASA fitness grade above II (OR 1.60), multivisceral resection (OR 1.88), and robotic approach (OR 1.87). CONCLUSION: The benchmark values obtained using the ABC method represent optimal outcomes from best achievable care, including low complication rates and zero mortality. These benchmarks should be used to set standards to improve patient outcomes.

PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma.

BACKGROUND: After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209-040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3-4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC. METHODS: The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC. DISCUSSION: The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population. TRIAL REGISTRATION: EudraCT Number: 2018-000987-27 Clinical trial registry & ID: ClinicalTrials.gov : NCT03682276 .

Evaluation of clinical and genetic factors in the population pharmacokinetics of carbamazepine.

AIMS: Carbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11-epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics (PK) of carbamazepine and 3 metabolites known to be chemically reactive or formed through reactive intermediates. METHODS: A combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 single nucleotide polymorphisms in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11-epoxide. Nonlinear mixed effects modelling was used to build a population-PK model. RESULTS: In total, 248 observations were collected from 80 subjects. A 1-compartment PK model with first-order absorption and elimination best described the parent carbamazepine data, with a total clearance of 1.96 L/h, central distribution volume of 164 L and absorption rate constant of 0.45 h-1 . Total daily dose and coadministration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1-416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11-epoxide. CONCLUSION: Our data indicate that carbamazepine clearance was affected by total dose and phenytoin coadministration, but not by genetic factors, while carbamazepine 10,11-epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.

Genetic variants associated with T cell-mediated cutaneous adverse drug reactions: A PRISMA-compliant systematic review-An EAACI position paper.

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.

A systematic review and meta-analysis of metal versus plastic stents for drainage of pancreatic fluid collections: metal stents are advantageous.

BACKGROUND: The use of fully covered metal stents (FCSEMS) and specifically designed lumen apposing metal stents for transmural drainage of pancreatic fluid collections has become widespread. A systematic review published in 2015 did not support the routine use of metal stents for drainage of pancreatic fluid collections. However, recent studies have shown conflicting data; therefore a systematic review and meta-analysis was performed. METHOD: We conducted a database search for original comparative studies between plastic and metal stents. The random effects model was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Outcomes analysed were clinical success, adverse events and requirement of further intervention. RESULTS: The search identified 936 studies, 7 studies with 681 (340 metal, 341 plastic) patients met inclusion criteria and were included in the meta-analysis. Clinical success was achieved in 93.8% versus 86.2% in the metal and plastic groups, respectively, RR 1.08 [95% CI 1.02-1.14]; p = 0.009. Adverse events were reduced for metal stents when compared with plastic (10.2% vs. 25.0%), RR 0.42 [95% CI 0.22-0.81]; p = 0.010. Metal stent usage reduced bleeding (2.8% vs. 7.9%), RR 0.37; [95% CI 0.18-0.75]; p = 0.006. Further intervention was required in 12.4% of patients in the metal stent group versus 26.7% for plastic stents, RR 0.54; [95% CI 0.22-1.29]; p = 0.165. CONCLUSIONS: The use of metal stents for drainage of pancreatic fluid collections is associated with improved clinical success, fewer adverse events and reduced bleeding compared to plastic stents.

Multidisciplinary management of refractory insulinomas.

Insulinomas are predominantly benign (~90%), pancreatic neuroendocrine tumours characterized by hyperinsulinaemic hypoglycaemia. They usually present as a small (<2 cm), well-demarcated, solitary nodule that can arise in any part of the organ. Treatment for sporadic insulinomas is generally aimed at curative surgical resection with special consideration in genetic syndromes. Patients with significant hypoglycaemia can pose a difficult management challenge. In isolated cases where the patient is not medically fit for surgery or with metastatic spread, other treatment options are employed. Medical therapy with diazoxide or somatostatin analogues is commonly used first line for symptom control, albeit with variable efficacy. Other medical options are emerging, including newer targeted biological therapies, including everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor) and pasireotide, a multisomatostatin receptor ligand. Pasireotide and everolimus both cause hyperglycaemia by physiological mechanisms synergistic with its antitumour/antiproliferative effects. Minimally invasive treatment modalities such as ethanol ablation are available in selected cases (particularly in patients unfit for surgery), peptide receptor radionuclide therapy (PRRT) can effectively control tumour growth or provide symptomatic benefit in metastatic disease, while cytotoxic chemotherapy can be used in patients with higher-grade tumours. This review considers the developments in the medical and other nonsurgical management options for cases refractory to standard medical management. Early referral to a dedicated neuroendocrine multidisciplinary team is critical considering the array of medical, oncological, interventional radiological and nuclear medical options. We discuss the evolving armamentarium for insulinomas when standard medical therapy fails.

The diagnostic value of Rosemont and Japanese diagnostic criteria for 'indeterminate', 'suggestive', 'possible' and 'early' chronic pancreatitis.

BACKGROUND: Longitudinal data are lacking to support consensus criteria for diagnosing early chronic pancreatitis. METHODS: Retrospective single centre study of the initial evidence for chronic pancreatitis (CP), with reassessment after follow-up (January 2003-November 2016). RESULTS: 807 patients were previously diagnosed with chronic pancreatitis. This diagnosis was rejected in 118 patients: 52 had another pathology altogether, the remaining 66 patients formed the study population. 38 patients with 'normal' imaging were reclassified as chronic abdominal pain syndrome (CAPS), and 28 patients had minimal change features of CP on EUS (MCEUS) but never progressed. Strict application of the Japanese diagnostic criteria would diagnose only two patients with early CP and eleven as possible CP. Patients were more likely to have MCEUS if the EUS was performed within 12 months of an attack of acute pancreatitis. 40 patients with MCEUS were identified, including an additional 12 who progressed to definite CP after a median of 30 (18.75-36.5) months. Those continuing to consume excess alcohol and/or continued smoking were significantly more likely to progress. Those who progressed were more likely to develop pancreatic exocrine insufficiency, require pancreatic surgery and had higher mortality. CONCLUSION: There needs to be more stringent application of the systems used for diagnosing chronic pancreatitis with revision of the current terminology 'indeterminate', 'suggestive', 'possible', and 'early' chronic pancreatitis. All patients with MCEUS features of CP require ongoing clinical follow up of at least 30 months and all patients with these features should be strongly counselled regarding smoking cessation and abstinence from alcohol.

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from Epoxide Metabolites of Carbamazepine in Patients.

Carbamazepine (CBZ) is an effective antiepileptic drug that has been associated with hypersensitivity reactions. The pathogenesis of those reactions is incompletely understood but is postulated to involve a complex interplay between the drug's metabolism, genetic variation in human leukocyte antigens, and adverse activation of the immune system. Multiple T-cell activation mechanisms have been hypothesized including activation by drug-peptide conjugates derived from proteins haptenated by reactive metabolites. However, definitive evidence of the drug-protein adducts in patients has been lacking. In this study, mass spectrometry was used to characterize protein modifications by microsomally-generated metabolites of CBZ and in patients taking CBZ therapy. CBZ 10,11-epoxide (CBZE), a major electrophilic plasma metabolite of CBZ, formed adducts with glutathione-S-transferase pi (GSTP; Cys47) and human serum albumin (HSA; His146 and His338, but not Cys34) in vitro via notably divergent side-chain selectivity. Both proteins were adducted at the same residues by undefined monoxygenated metabolites ([O]CBZ) when they were incubated with human liver microsomes, NADPH and CBZ. There was also evidence for formation of a CBZ adduct at His146 and His338 of HSA derived via dehydration from an intermediate arene oxide adduct. Glutathione trapping of reactive metabolites confirmed microsomal production of CBZE and indicated simultaneous production of arene oxides. In 15 patients prescribed CBZ therapy, [O]CBZ-modified HSA (His146) was detected in all subjects. The relative amount of adduct was moderately positively correlated with plasma concentrations of CBZ (r2 = 0.44, p = 0.002) and CBZE (r2 = 0.35, p = 0.006). Our results have provided the first chemical evidence for microsomal production of [O]CBZ species that are able to escape the microsomal domain to react covalently with soluble proteins. This study has also demonstrated the presence of circulating [O]CBZ-modified HSA in patients without hypersensitivity reactions who were receiving standard CBZ therapy. The implications of those circulating adducts for susceptibility to CBZ hypersensitivity merit further immunological investigation in hypersensitive patients.

Cost-effectiveness of screening for HLA-A*31:01 prior to initiation of carbamazepine in epilepsy.

OBJECTIVE: Carbamazepine causes severe cutaneous adverse drug reactions that may be predicted by the presence of the HLA-A*31:01 allele in northern European populations. There is uncertainty as to whether routine testing of patients with epilepsy is cost-effective. We conducted an economic evaluation of HLA-A*31:01 testing from the perspective of the National Health Service (NHS) in the United Kingdom. METHODS: A short-term, decision analytic model was developed to estimate the outcomes and costs associated with a policy of routine testing (with lamotrigine prescribed for patients who test positive) versus the current standard of care, which is carbamazepine prescribed without testing. A Markov model was used to estimate total costs and quality-adjusted life-years (QALYs) over a lifetime to account for differences in drug effectiveness and the long-term consequences of adverse drug reactions. RESULTS: Testing reduced the expected rate of cutaneous adverse drug reactions from 780 to 700 per 10,000 patients. The incremental cost-effectiveness ratio for pharmacogenetic testing versus standard care was £12,808 per QALY gained. The probability of testing being cost-effective at a threshold of £20,000 per QALY was 0.80, but the results were sensitive to estimated remission rates for alternative antiepileptic drugs (AEDs). SIGNIFICANCE: Routine testing for HLA-A*31:01 in order to reduce the incidence of cutaneous adverse drug reactions in patients being prescribed carbamazepine for epilepsy is likely to represent a cost-effective use of health care resources.

Comparison of Survival Outcomes Between Right Posterior Sectionectomy and Right Hepatectomy for Hepatocellular Carcinoma in Cirrhotic Liver: A Single-Centre Experience.

BACKGROUND: Right hepatectomy (RH) instead of right posterior sectionectomy (RPS) is commonly performed for hepatocellular carcinoma (HCC) in cirrhotic livers located lateral to the right hepatic vein in order to ensure adequate resection margin. This potentially increased the risk of postoperative liver failure. This study aims to compare survival outcomes and surgical morbidities between RH and RPS. METHODS: All patients between 2003 and 2013 with resection for solitary HCC in cirrhotic livers at segment 6/7 were reviewed. Baseline demographics, liver function, perioperative outcomes, and overall (OS) and disease-free survival (DFS) were compared between RH and RPS. RESULTS: Eighty-one patients were included in this study. Thirty-two patients had RH and forty-nine with RPS were selected as controls. Majority of the HCC patients (91.4 %) suffered from chronic hepatitis B. There was no significant difference in age, gender and Child-Pugh grade between the two groups. The median tumour size of RH group was 6 vs. 4 cm in the RPS group (p < 0.0001). Both groups had no statistical difference in resection margin and their associated morbidities. The 5-year OS for RH and RPS was 76 and 83.8 %, respectively (p = 0.766), whereas their corresponding DFS was 52.6 and 52.2 % (p = 0.859). Despite the discrepancy of tumour size among the two groups, there was no statistical difference in subgroup analysis based on their corresponding stage of disease. CONCLUSION: RPS can achieve similar OS and DFS as RH for HCC, and should be considered as the treatment of choice in order to optimise the postoperative remnant parenchymal liver functions.

Evolution of surgical microwave ablation for the treatment of colorectal cancer liver metastasis: review of the literature and a single centre experience.

Surgical resection is the gold standard treatment for colorectal liver metastasis, with reported five-year survival rates of 40 %. Unfortunately, despite progress in systemic therapies and surgical techniques, only 20-30 % of patients can be offered this potentially curative treatment modality. Ablative therapies have recently been suggested to treat unresectable lesions or to extend the margins of resectability. Additionally, cases of local recurrence after hepatic surgery might require alternative strategies and options for re-intervention. Microwave ablation (MWA) has recently become a matter of particular interest for such indications. We, herein, present a review of the literature published between January 1999 and June 2013 from a database search with the following keywords: microwave, ablation, liver metastases, colorectal neoplasm, resection, hepatectomy, colonic neoplasm, cancer. Furthermore, we provide insight based on our own data for 28 consecutive patients who underwent hepatic resection combined with MWA from 2005 to 2012 in a single centre.

Enhanced recovery in the resection of colorectal liver metastases.

BACKGROUND: There is limited evidence for the use of enhanced recovery after surgery (ERAS) in patients undergoing hepatectomy, and the impact of the evolution of ERAS over time has not been examined. This study sought to evaluate the effect of an evolving ERAS program in patients undergoing hepatectomy for colorectal liver metastases (CRLM). METHODS: A multimodal ERAS program was introduced in 2/2008. Consecutive patients undergoing hepatectomy for CRLM between 2/2008 and 9/2012 were included in the study. Data were collected prospectively. Retrospective analysis compared an early ERAS cohort (2/2008-4/2010) with a later cohort with a matured ERAS program (5/2010-8/2012). RESULTS: Length of stay reduced as experience of ERAS increased (Log-rank χ(2) = 10.43, P = 0.001). Although median length of stay remained unchanged (6 days), the probability of hospitalization beyond 10 days was 25% in the early cohort compared with 7% in the later cohort. Critical care utilization reduced over time (75.5% vs. 54.7%, P < 0.0001). Complications occurred in 38.2%, with no difference in between cohorts. One postoperative death occurred in the early cohort (<0.3%). CONCLUSIONS: This study suggests that as experience of ERAS evolves, there is a progressive reduction in hospitalization and critical care admission. This is without any increase in morbidity and mortality.

Liver resection with concomitant inferior vena cava resection: experiences without veno-venous bypass.

PURPOSE: Liver resection offers the chance of a cure for liver cancer. However, when extended hepatectomies were performed in combination with resection of the inferior vena cava (IVC), the procedures were reported to have a surgical mortality rate in excess of 5 %. While most of these operations were performed with the use of veno-venous bypass, this study presents our experience performing the procedure without the bypass. METHODS: Data were collected from a prospectively maintained database. A retrospective evaluation of a consecutive series of concomitant IVC and liver resections was performed. RESULTS: Five hundred and seventy-five liver resections were performed between June 2008 and November 2011. Eleven patients (1.9 %) underwent concomitant IVC and liver resections. One patient required segmental IVC replacement, and four IVC defects were closed using a bovine pericardial patch without bypass. Only one patient had histologically confirmed IVC invasion. There was no postoperative mortality. Nine postoperative complications occurred in five patients. No complications in terms of IVC patency were seen. Five patients had disease recurrence, one of whom died within 12 months of surgery. CONCLUSION: Concomitant liver and IVC resection is safe without using a bypass procedure, with acceptable short-term results. Meticulous technique, careful patient selection and a specialized anesthetic team are key to obtaining low postoperative morbidity and mortality rates and an acceptable oncological outcome.

Management of incidental and suspicious gallbladder cancer: focus on early referral to a tertiary centre.

OBJECTIVES: This study was conducted to assess the management of incidental gallbladder cancer and indeterminate gallbladder lesions. Its secondary aim referred to the devising of a management pathway for these patients. METHODS: Patients referred with incidental gallbladder cancer and indeterminate gallbladder lesions during 2002-2011 were identified from a prospectively maintained database. Collated data included operative findings, histopathological data and survival outcomes. RESULTS: The study included a total of 104 patients, 40 of whom had incidental gallbladder cancer following cholecystectomy. In this group, the index cholecystectomy was considered curative (T-is/T1a stage) in three patients; 11 patients underwent further resection, and 26 patients were inoperable. One-, 3- and 5-year overall survival rates were 91.1%, 91.0% and 60.7%, respectively, in patients who underwent re-resection. Of the 64 patients with indeterminate gallbladder lesions, 54 patients underwent modified radical cholecystectomy. Seven patients were found to have gallbladder cancer. One-, 3- and 5-year overall survival rates were 85.9%, 43.1% and 42.8%, respectively. Five-year overall survival in patients treated with surgery for gallbladder cancer was 59.9%. CONCLUSIONS: The majority of patients with incidental gallbladder cancer were not amenable to further potentially curative resection. The radiological suspicion of gallbladder cancer should lead to prompt referral to a tertiary hepatobiliary unit for further management.

The novel treatment of children with viral warts using microwave technology.

Microwave therapy is emerging as an effective, well-tolerated and safe treatment modality for cutaneous warts but there is limited data in paediatric patients. In our cohort of 35 paediatric patients with recalcitrant warts, 68.6% (24/35) demonstrated complete resolution after an average of three microwave treatment sessions. There were no reports of ulceration or blistering but 22.9% (8/35) of patients reported pain that required discontinuation of microwave therapy. This study provides evidence that microwave therapy can be used for the treatment of warts in paediatric patients.

Costs and clinical benefits of enhanced recovery after surgery (ERAS) in pancreaticoduodenectomy: an updated systematic review and meta-analysis.

PURPOSE: ERAS is a holistic and multidisciplinary pathway that incorporates various evidence-based interventions to accelerate recovery and improve clinical outcomes. However, evidence on cost benefit of ERAS in pancreaticoduodenectomy remains scarce. This review aimed to investigate cost benefit, compliance, and clinical benefits of ERAS in pancreaticoduodenectomy. METHODS: A comprehensive literature search was conducted on Medline, Embase, PubMed, CINAHL and the Cochrane library to identify studies conducted between 2000 and 2021, comparing effect of ERAS programmes and traditional care on hospital cost, length of stay (LOS), complications, delayed gastric emptying (DGE), readmission, reoperation, mortality, and compliance. RESULTS: The search yielded 3 RCTs and 28 cohort studies. Hospital costs were significantly reduced in the ERAS group (SMD = - 1.41; CL, - 2.05 to - 0.77; P < 0.00001). LOS was shortened by 3.15 days (MD = - 3.15; CI, - 3.94 to - 2.36; P < 0.00001) in the ERAS group. Fewer patients in the ERAS group had complications (RR = 0.83; CI, 0.76-0.91; P < 0.0001). Incidences of DGE significantly decreased in the ERAS group (RR = 0.72; CI, 0.55-0.94; P = 0.01). The number of deaths was fewer in the ERAS group (RR = 0.76; CI, 0.58-1.00; P = 0.05). CONCLUSION: This review demonstrated that ERAS is safe and feasible in pancreaticoduodenectomy, improves clinical outcome such as LOS, complications, DGE and mortality rates, without changing readmissions and reoperations, while delivering significant cost savings. Higher compliance is associated with better clinical outcomes, especially LOS and complications.

TNF-α‒Mediated Keratinocyte Expression and Release of Matrix Metalloproteinase 9: Putative Mechanism of Pathogenesis in Stevens‒Johnson Syndrome/Toxic Epidermal Necrolysis.

Stevens‒Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions characterized by widespread keratinocyte cell death and epidermal detachment. At present, there is little understanding of how the detachment occurs or how it is abrogated by the TNF-α inhibitor etanercept, an effective SJS/TEN treatment. RNA sequencing was used to identify upregulated transcripts in formalin-fixed paraffin-embedded SJS/TEN skin biopsies. Epidermal matrix metalloproteinase 9 (MMP9) expression was assessed by immunohistochemistry in skin biopsies and cultured human skin explants exposed to serum from patients with cutaneous adverse drug reactions. TNF-α‒induced MMP9 expression and activity and its abrogation by etanercept were determined using the HaCaT immortalized keratinocyte cell line. Epidermal MMP9 expression was significantly higher in SJS/TEN skin (70.6%) than in healthy control skin (0%) (P = 0.0098) and nonbullous skin reactions (10.7%) (P = 0.0002). SJS/TEN serum induced significant MMP9 expression and collagenase activity in healthy skin explants, which was reduced by etanercept. Etanercept was also able to negate the TNF-α‒induced MMP9 expression in the HaCaT cell line. Data suggest that elevated epidermal MMP9 expression and collagenase activity are a putative pathogenic mechanism in SJS/TEN, which is limited by etanercept. Modulation of MMP9 expression and activity represents, to our knowledge, a previously unreported therapeutic target for the treatment of SJS/TEN.

TNF-α induced extracellular release of keratinocyte high-mobility group box 1 in Stevens-Johnson syndrome/toxic epidermal necrolysis: Biomarker and putative mechanism of pathogenesis.

Decreased epidermal high-mobility group box 1 (HMGB1) expression is an early marker of epidermal injury in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Etanercept, an anti-tumor necrosis factor therapeutic, is effective in the treatment of SJS/TEN. The objective was to characterize antitumor necrosis factor-alpha (TNF-α)-mediated HMGB1 keratinocyte/epidermal release and etanercept modulation. HMGB1 release from TNF-α treated (± etanercept), or doxycycline-inducible RIPK3 or Bak-expressing human keratinocyte cells (HaCaTs) was determined by western blot/ELISA. Healthy skin explants were treated with TNF-α or serum (1:10 dilution) from immune checkpoint inhibitor-tolerant, lichenoid dermatitis or SJS/TEN patients ± etanercept. Histological and immunohistochemical analysis of HMGB1 was undertaken. TNF-α induced HMGB1 release in vitro via both necroptosis and apoptosis. Exposure of skin explants to TNF-α or SJS/TEN serum resulted in significant epidermal toxicity/detachment with substantial HMGB1 release which was attenuated by etanercept. Whole-slide image analysis of biopsies demonstrated significantly lower epidermal HMGB1 in pre-blistered SJS/TEN versus control (P < 0.05). Keratinocyte HMGB1 release, predominantly caused by necroptosis, can be attenuated by etanercept. Although TNF-α is a key mediator of epidermal HMGB1 release, other cytokines/cytotoxic proteins also contribute. Skin explant models represent a potential model of SJS/TEN that could be utilized for further mechanistic studies and targeted therapy screening.