Heme Oxygenase-1 Inhibition Modulates Autophagy and Augments Arsenic Trioxide Cytotoxicity in Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form, accounting for more than 90% of all pancreatic malignancies. In a previous study, we found that hypoxia and chemotherapy induced expression of Heme Oxygenase-1 (HO-1) in PDAC cells and tissues. Arsenic trioxide (ATO) is the first-line chemotherapeutic drug for acute promyelocytic leukemia (APL). ATO increases the generation of reactive oxidative species (ROS) and induces apoptosis in treated cells. The clinical use of ATO for solid tumors is limited due to severe systemic toxicity. In order to reduce cytotoxic side effects and resistance and improve efficacy, it has become increasingly common to use combination therapies to treat cancers. In this study, we used ATO-sensitive and less sensitive PDAC cell lines to test the effect of combining HO-1 inhibitors (SnPP and ZnPP) with ATO on HO-1 expression, cell survival, and other parameters. Our results show that ATO significantly induced the expression of HO-1 in different PDAC cells through the p38 MAPK signaling pathway. ROS production was confirmed using the oxygen-sensitive probes DCFH and DHE, N-acetyl cysteine (NAC), an ROS scavenger, and oxidized glutathione levels (GSSG). Both ATO and HO-1 inhibitors reduced PDAC cell survival. In combined treatment, inhibiting HO-1 significantly increased ATO cytotoxicity, disrupted the GSH cycle, and induced apoptosis as measured using flow cytometry. ATO and HO-1 inhibition modulated autophagy as shown by increased expression of autophagy markers ATG5, p62, and LC3B in PDAC cells. This increase was attenuated by NAC treatment, indicating that autophagy modulation was through an ROS-dependent mechanism. In conclusion, our work explored new strategies that could lead to the development of less toxic and more effective therapies against PDAC by combining increased cellular stress and targeting autophagy.

Prediction of peritoneal soiling in acute appendicitis with simple clinical and laboratory data. Prospective, multicenter, cohort study of 2,645 adult patients nationwide.

BACKGROUND AND AIMS: In order to facilitate the preoperative prediction of complicated appendicitis, we propose a complementary approach by selecting an endpoint defined by the intraoperative finding of peritoneal soiling (PS). METHODS: Over a 6-month period, 38 centers (5% of all public hospitals) attending emergency general surgery patients on a 24-h, 7-days a week basis, enrolled consecutive adult patients requiring appendectomy. Patients were stratified according to the absence or the finding of PS during the surgical procedure. RESULTS: A total of 2645 patients were included; median age (IQR) was 35 (22-51) years, 44.3% were female. The laparoscopic approach was used in 70.8% of appendectomies. In a third of patients (31.7%), there was PS with pus around the appendix, or bowel contents, free pus, or blood in the peritoneal cavity. To develop the prediction model, 1764 patients were randomly selected for the derivation cohort and the remaining 881 patients were assigned to the validation cohort. On multivariable logistic regression analysis of all patients, two clinical variables (age, and pulse) and three laboratory variables (serum urea, serum sodium, and white blood cell count) were individually associated (P < .05) with a greater probability of having PS (Hosmer-Lemeshow chi, 1.63; P = .99; C-statistic, 0.7). Based on the multivariable regression model, both static and dynamic nomograms were developed for the prediction of PS in patients with acute appendicitis. CONCLUSIONS: The entry of simple clinical and laboratory variables in the dynamic nomogram may be useful in guiding the initial management of patients with acute appendicitis in resource-limited settings.

Reaching a consensus on the definition of "difficult" cholecystectomy among Spanish experts. A Delphi project. A qualitative study.

BACKGROUND: Being able to predict preoperatively the difficulty of a cholecystectomy can increase safety and improve results. However, there is a need to reach a consensus on the definition of a cholecystectomy as "difficult". The aim of this study is to achieve a national expert consensus on this issue. METHODS: A two-round Delphi study was performed. Based on the previous literature, history of biliary pathology, preoperative clinical, analytical, and radiological data, and intraoperative findings were selected as variables of interest and rated on a Likert scale. Inter-rater agreement was defined as "unanimous" when 100% of the participants gave an item the same rating on the Likert scale; as "consensus" when ≥80% agreed; as "majority" when the agreement was ≥70%. The delta of change between the two rounds was calculated. RESULTS: After the two rounds, the criteria that reached "consensus" were bile duct injury (96.77%), non-evident anatomy (93.55%), Mirizzi syndrome (93.55%), severe inflammation of Calot's triangle (90.32%), conversion to laparotomy (87.10%), time since last acute cholecystitis (83.87%), scleroatrophic gallbladder (80.65%) and pericholecystic abscess (80.65%). CONCLUSION: The ability to predict difficulty in cholecystectomy offers important advantages in terms of surgical safety. As a preliminary step, the items that define a surgical procedure as difficult should be established. Standardization of the criteria can provide scores to predict difficulty both preoperatively and intraoperatively, and thus allow the comparison of groups of similar difficulty.

Benefica chirurgia. A global surgery project focusing on hernia surgery.

BACKGROUND: The aim of international health cooperation projects is to alleviate the deficiencies in the area of health in low resource settings. Hernia surgery is a procedure that is well suited to these missions, due to its low morbidity, the fact that it can be performed on an outpatient basis, and the improvement in quality of life that it provides. OBJECTIVE: To describe the results of Benefica Chirurgia (BC), a Spanish non-profit humanitarian association in hernia pathology. METHODS: Five one-week surgical campaigns were carried out in Ecuador between 2015 and 2019, involving anesthetists, general and pediatric surgeons. Surgical and medical equipment was provided and transported by BC. ASA I/II patients underwent surgery. RESULTS: Surgery was performed on 240 patients with hernia pathology on 27 days. Sixty-three per cent of patients were male and the mean age was 48.2 years (range: 1-83). Hernia location was inguinal in 113 patients, umbilical in 101, and other in 26. The anesthetic technique used was spinal in 185 patients (77.1%), local plus intravenous sedation in 31 (12.9%), and general in 24 (10%). The surgical technique used was hernioplasty in 191 patients, herniorrhaphy in 31, incisional hernia repair in 15 and herniotomy in three. Surgery was performed on an outpatient basis in 98.4% of cases. Morbidity was 2%. Long-term postoperative evaluation is very complex. CONCLUSION: These campaigns make a significant contribution to health in low resource settings and provide great personal satisfaction for those involved. Standards achieved in the immediate postoperative period were similar to those obtained at the surgeons' centers in Europe. However, it is difficult to establish the rates of recurrence and chronic pain.

Simplified risk-prediction for benchmarking and quality improvement in emergency general surgery. Prospective, multicenter, observational cohort study.

BACKGROUND AND AIMS: Emergency General Surgery (EGS) conditions account for millions of deaths worldwide, yet it is practiced without benchmarking-based quality improvement programs. The aim of this observational, prospective, multicenter, nationwide study was to determine the best benchmark cutoff points in EGS, as a reference to guide improvement measures. METHODS: Over a 6-month period, 38 centers (5% of all public hospitals) attending EGS patients on a 24-h, 7-days a week basis, enrolled consecutive patients requiring an emergent/urgent surgical procedure. Patients were stratified into cohorts of low (i.e., expected morbidity risk <33%), middle and high risk using the novel m-LUCENTUM calculator. RESULTS: A total of 7258 patients were included; age (mean ± SD) was 51.1 ± 21.5 years, 43.2% were female. Benchmark cutoffs in the low-risk cohort (5639 patients, 77.7% of total) were: use of laparoscopy ≥40.9%, length of hospital stays ≤3 days, any complication within 30 days ≤ 17.7%, and 30-day mortality ≤1.1%. The variables with the greatest impact were septicemia on length of hospital stay (21 days; adjusted beta coefficient 16.8; 95% CI: 15.3 to 18.3; P < .001), and respiratory failure on mortality (risk-adjusted population attributable fraction 44.6%, 95% CI 29.6 to 59.6, P < .001). Use of laparoscopy (odds ratio 0.764, 95% CI 0.678 to 0.861; P < .001), and intraoperative blood loss (101-500 mL: odds ratio 2.699, 95% CI 2.152 to 3.380; P < .001; and 500-1000 mL: odds ratio 2.875, 95% CI 1.403 to 5.858; P = .013) were associated with increased morbidity. CONCLUSIONS: This study offers, for the first time, clinically-based benchmark values in EGS and identifies measures for improvement.

Liver and lung hydatid cysts with transdiaphragmatic rupture treated by radical surgery.

Hydatidosis is a parasitic disease caused by Echinococcus granulosus, a tapeworm that is endemic in certain parts of the world. We present a case of hepatopulmonary hydatidosis with diaphragm involvement and close contact with the suprahepatic inferior vena cava treated with radical surgery. We discuss therapeutical surgical options (approach and type of surgery).

Liver resection and ablation for squamous cell carcinoma liver metastases.

BACKGROUND: Limited evidence exists to guide the management of patients with liver metastases from squamous cell carcinoma (SCC). The aim of this retrospective multicentre cohort study was to describe patterns of disease recurrence after liver resection/ablation for SCC liver metastases and factors associated with recurrence-free survival (RFS) and overall survival (OS). METHOD: Members of the European-African Hepato-Pancreato-Biliary Association were invited to include all consecutive patients undergoing liver resection/ablation for SCC liver metastases between 2002 and 2019. Patient, tumour and perioperative characteristics were analysed with regard to RFS and OS. RESULTS: Among the 102 patients included from 24 European centres, 56 patients had anal cancer, and 46 patients had SCC from other origin. RFS in patients with anal cancer and non-anal cancer was 16 and 9 months, respectively (P = 0.134). A positive resection margin significantly influenced RFS for both anal cancer and non-anal cancer liver metastases (hazard ratio 6.82, 95 per cent c.i. 2.40 to 19.35, for the entire cohort). Median survival duration and 5-year OS rate among patients with anal cancer and non-anal cancer were 50 months and 45 per cent and 21 months and 25 per cent, respectively. For the entire cohort, only non-radical resection was associated with worse overall survival (hazard ratio 3.21, 95 per cent c.i. 1.24 to 8.30). CONCLUSION: Liver resection/ablation of liver metastases from SCC can result in long-term survival. Survival was superior in treated patients with liver metastases from anal versus non-anal cancer. A negative resection margin is paramount for acceptable outcome.

Spanish multicenter study of surgical resection of pancreatic tumors infiltrating the celiac axis: does the type of pancreatectomy affect results?

Background Pancreatectomy plus celiac axis resection (CAR) is performed in patients with locally advanced pancreatic cancer. The morbidity rates are high, and no survival benefit has been confirmed. It is not known at present whether it is the type of pancreatectomy, or CAR itself, that is the reason for the high complication rates. Methods Observational retrospective multicenter study. Inclusion criteria: patient undergoing TP, PD or DP plus CAR for a pancreatic cancer. Results Sixty-two patients who had undergone pancreatic cancer surgery (PD,TP or DP) plus CAR were studied. Group 1: 17 patients who underwent PD/TP-CAR (13TP/4PD); group 2: 45 patients who underwent DP-CAR. Groups were mostly homogeneous. Operating time was longer in the PD/TP group, while operative complications did not differ statistically in the two groups. The number of lymph nodes removed was higher in the PD/TP group (26.5 vs 17.3), and this group also had a higher positive node ratio (17.9% vs 7.6%). There were no statistical differences in total or disease-free survival between the two groups. Conclusion It seems that CAR, and not the type of pancreatectomy, influences morbidity and mortality in this type of surgery. International multicenter studies with larger numbers of patients are now needed to validate the data presented here (AU)

Spanish multicenter study of surgical resection of pancreatic tumors infiltrating the celiac axis: does the type of pancreatectomy affect results?

BACKGROUND: Pancreatectomy plus celiac axis resection (CAR) is performed in patients with locally advanced pancreatic cancer. The morbidity rates are high, and no survival benefit has been confirmed. It is not known at present whether it is the type of pancreatectomy, or CAR itself, that is the reason for the high complication rates. METHODS: Observational retrospective multicenter study. INCLUSION CRITERIA: patient undergoing TP, PD or DP plus CAR for a pancreatic cancer. RESULTS: Sixty-two patients who had undergone pancreatic cancer surgery (PD,TP or DP) plus CAR were studied. Group 1: 17 patients who underwent PD/TP-CAR (13TP/4PD); group 2: 45 patients who underwent DP-CAR. Groups were mostly homogeneous. Operating time was longer in the PD/TP group, while operative complications did not differ statistically in the two groups. The number of lymph nodes removed was higher in the PD/TP group (26.5 vs 17.3), and this group also had a higher positive node ratio (17.9% vs 7.6%). There were no statistical differences in total or disease-free survival between the two groups. CONCLUSION: It seems that CAR, and not the type of pancreatectomy, influences morbidity and mortality in this type of surgery. International multicenter studies with larger numbers of patients are now needed to validate the data presented here.

Systematic review of the mesopancreas: concept and clinical implications.

BACKGROUND: In 2007, Gockel et al. coined the term mesopancreas (MP). In the next 10 years, a limited number of publications about MP have been published, but little is known about the oncological benefit of MP resection. We performed a systematic review of the literature on MP. METHODS: An electronic search was performed in PubMed, EMBASE, Cochrane, Latindex, Scielo, and Koreamed databases until 15 June 2017 to identify all published articles dealing with the subject of MP. Some language restriction was done (Chinese and Rumanian). RESULTS: The search yielded 51 articles; 28 articles were selected as relevant. All were retrospective studies focused more on describing technical variants, feasibility and safety than on the cancer results. The R0 rate in patients with MP resection ranged between 57 and 96.7%. In all the articles with a control group, the R0 rate was higher in the MP excision group. Survival data were explicitly stated only in five series. CONCLUSION: MP is a difficult-to-excise retropancreatic area. In theory, it is agreed that MP excision raises the rate of R0 resections, which in turn reflected in an improvement in the oncological results; however, at present there are no randomized studies to prove this. Achieving a worldwide consensus on its concept, landmarks, excision technique and oncological results is essential.

Community cognitive interviewing to inform local adaptations of an e-mental health intervention in Lebanon.

BACKGROUND: Lebanon has a need for innovative approaches to increase access to mental health care to meet the country's current high demand. E-mental health has been included in its national mental health strategy while in parallel the World Health Organization has produced an online intervention called 'Step-by-Step' to treat symptoms of depression that is being tested in Lebanon over the coming years. AIM: The primary aim of this study is to conduct bottom-up, community-driven qualitative cognitive interviewing from a multi-stakeholder perspective to inform the cultural adaptation of an Internet-delivered mental health intervention based on behavioural activation in Lebanon. METHODS: National Mental Health Programme staff conducted a total of 11 key informant interviews with three mental health professionals, six front-line workers in primary health care centres (PHCCs) and two community members. Also, eight focus group discussions, one with seven front-line workers and seven others with a total of 66 community members (Lebanese, Syrians and Palestinians) were conducted in several PHCCs to inform the adaptation of Step-by-Step. Results were transcribed and analysed thematically by the project coordinator and two research assistants. RESULTS: Feedback generated from the cognitive interviewing mainly revolved around amending the story, illustrations and the delivery methods to ensure relevance and sensitivity to the local context. The results obtained have informed major edits to the content of Step-by-Step and also to the model of provision. Notably, the intervention was made approximately 30% shorter; it includes additional videos of content alongside the originally proposed comic book-style delivery; there is less emphasis on total inactivity as a symptom of low mood and more focus on enjoyable activities to lift mood; the story and ways to contact participants to provide support were updated in line with local gender norms; and many of the suggested or featured activities have been revised in line with suggestions from community members. CONCLUSIONS: These findings promote and advocate the use of community-driven adaptation of evidence-based psychological interventions. Some of the phenomena recorded mirror findings from other research about barriers to care seeking in the region and so changes made to the intervention should be useful in improving utility and uptake of 'Step-by-Step'.

Is radical surgery feasible in liver hydatid cysts in contact with the inferior vena cava?

BACKGROUND: Cysts in contact with the inferior vena cava (IVC) represent a challenge for hepato-pancreatico-biliary surgeons. Although the literature on the topic is scarce, the most widely accepted approach is conservative surgery. Partial cyst resection is recommended, because radical resection is considered a high-risk procedure. STUDY DESIGN: This was a retrospective study over the period January 2007-December 2012. We operated on 103 patients with liver hydatidosis. A total of 32 patients (31 %) had a liver cyst in contact with the IVC. We proposed a cyst classification based on location of the cyst and length of contact and degrees of involvement of the IVC. RESULTS: Median size of the contacting cyst measured by computed tomography (CT) was 12 cm. On CT, median length of contact with the IVC was 37 mm. The median degree of involvement was 90°. Radical surgery was performed in 20 patients (62.5 %). No IVC resection was done. Morbidity rate was 28 %, and mortality was 3 %. In follow-up (median 27 months), no relapses or problems related to IVC flow were detected. Postoperative stay and transfusion rate were higher in the conservative surgery group, but these patients presented fewer complications. There was no relationship between circumferential grades and length of contact with the IVC and the type of surgery performed. CONCLUSIONS: Liver hydatid cysts in contact with the IVC are large cysts usually located in the right liver. They do not normally cause clinical symptoms related to IVC contact. Radical surgery is feasible, and was performed in 60 % of our series, but it is technically demanding. We propose a classification of cysts in contact with the IVC.

Walled-off pancreatic necrosis.

Acute severe pancreatitits may be complicated by the development of 'walled-off pancreatic necrosis' (WOPN), which is characterised by a mixture of solid components and fluids on imaging studies as a consequence of organised pancreatic tissue necrosis. We present here an overview of the definition, clinical features, and diagnostic and therapeutic management of this clinical condition, which is mostly based on consensus as adequate clinical trials are lacking.

Cysto-biliary communication in liver hydatidosis.

BACKGROUND: Liver hydatidosis is a severe health problem in endemic areas. Due to migration from these countries to other zones, now it is a worldwide problem. Liver hydatidosis can provoke many complications (abscess, fistula to adjacent organs, migration, etc.), but the most frequent and one of the most severe complication is the communication between the cyst and the biliary tree. AIM: The aim of this study is to perform a review on the epidemiology, clinical features, diagnostic methods, and therapeutic options to treat the communication between the cyst and the biliary tree. RESULTS: Due to the lack of randomized clinical trial or meta-analysis on this topic, we performed a classical review and included our personal algorithm. CONCLUSIONS: The communication between the cyst and the biliary tree varies from a small communication to a frank intrabiliary rupture. The percentage of patients with the communication between the cyst and the biliary tree is not well known because there is no accepted definition. The therapeutic options are multiple and related to the size of the communication, the location of the cyst, and the experience of the hepatobiliary surgeon. ERCP is now an important tool for the treatment of the communication between the cyst and the biliary tree.

Three trocars laparoscopic resection of angiomyolipoma of the liver.

Angiomyolipoma of the liver (AML) is an infrequent neoplasm composed of three tissues (adipose, muscle and vessels). In spite of advances in radiology, preoperative correct diagnosis is difficult. Clasically, a conservative management strategy was adopted in patients with asymptomatic tumors less than 5 cm with undoubtful diagnosis. But after publishing some few cases of malignant angiomyolipoma a more radical has been advocated. Laparoscopic resection of liver tumors is becoming a excellent approach for operating on benign liver tumors. Usually is performed using five trocars but in some cases a less invasive technique with three trocars could be used. We present a laparoscopic resection of liver angiomyolipoma in a 65 year-old male using only three trocars and also discuss the optimal management of AML and technical tips of three-trocar technique.

Early postoperative response of cytokines in liver transplant recipients.

We evaluated the early postoperative response of several cytokines (IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma) prior to liver transplantation (T(0)) as well as 1, 6, and 12 hours and 1, 2, 3, 5, and 7 days afterward. Cytokine concentrations were correlated with serum levels of bilirubin as a predictor of postoperative complications. Cytokine levels were determined in plasma samples from 16 liver transplant recipients (13 men, 3 women) aged 43 to 61 years. IL-6 and IL-10 reached their maximum concentrations 1 hour after transplantation. Each increase in IL-6 correlated to a rise in IL-10. IL-2, IL-4, TNF-alpha, and IFN-gamma had a particular time-course for each patient studied. Bilirubin fell to almost normal values but not in cases of postoperative complications, where IL-6 showed values four times higher compared to those of liver transplant recipients who did not show postoperative complications. IL-6 and IL-10 plasma concentrations and serum bilirubin level might be useful as a predictive factor of postoperative complications in liver transplant recipients.

Time course of intraoperative cytokine levels in liver transplant recipients.

We evaluated the levels of several cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, tumor necrosis factor [TNF]-alpha, and interferon [IFN]-gamma) in plasma samples obtained before surgical intervention (T0) and during intraoperative liver transplantation: after induction of anesthesia (I-1), 15 minutes of anhepatic phase (I-2), 5 minutes before reperfusion (I-3), 10 minutes after reperfusion (I-4), 20 minutes after reperfusion (I-5), 60 minutes after reperfusion (I-6), and 1 hour after liver transplantation (I-7). Cytokine levels were determined using a technique which combines ELISA technique and flow cytometry. The study was approved by the local clinical research (ethics) committee. Written informed consent was obtained from patients' relatives. Twenty patients (14 men, 6 women) aged 23 to 61 years, recipients of a liver transplantation were studied. The cytokine IL-2 plasma values were maintained during the whole study period, with a slight increase at 15 minutes of anhepatic phase (I-2). IL-4 showed a peak value 20 minutes after reperfusion (I-5). IL-6 increased its plasma value starting at 15 minutes of anhepatic phase (I-2), maintaining high concentrations during the whole intraoperative period. IL-10 increased progressively, reaching a maximum 1 hour after transplantation (I-7). TNF-alpha reached maximum plasma levels 20 minutes after reperfusion (I-5), whereas IFN-gamma showed a peak at 15 minutes of anhepatic phase (I-2). Our results indicate that the anhepatic phase (I-2) is the earliest phase during which proinflammatory and anti-inflammatory cytokines, such as IL-6 and IL-10, respectively, are involved during liver transplantation. We conclude that IL-6 is the first cytokine involved in the inflammatory response during liver transplantation.

Gallbladder tuberculosis: false-positive PET diagnosis of gallbladder cancer.

Gallbladder tuberculosis (GT) is an extremely rare disease, and very few cases have been reported in the literature. The first case of GT was described in 1870 by Gaucher. A correct preoperative diagnosis of GT is unusual, and it is frequently confused with various gallbladder diseases. We present a new case of a patient who underwent surgery with the preoperative diagnosis of gallbladder cancer after a false positive positron emission tomography scan in the diagnostic work-up.