Detection of inflammasome activation in liver tissue during the donation process as potential biomarker for liver transplantation.

Deceased donor liver transplantation (LT) is a crucial lifesaving option for patients with end-stage liver diseases. Although donation after brain death (DBD) remains the main source of donated organs, exploration of donation after circulatory death (DCD) addresses donor scarcity but introduces challenges due to warm ischemia. While technical advances have improved outcomes, challenges persist, with a 13% mortality rate within the first year. Delving into liver transplantation complexities reveals the profound impact of molecular signaling on organ fate. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation play a pivotal role, influencing inflammatory responses. The NLRP3 inflammasome, found in hepatocytes, contributes to inflammation, fibrosis, and liver cell death. This study explores these dynamics, shedding light on potential biomarkers and therapeutic targets. Samples from 36 liver transplant patients were analyzed for ASC specks detection and inflammasome-related gene expression. Liver biopsies, obtained before and after cold ischemia storage, were processed for immunofluorescence, qRT-PCR, and Western blot. One year post-LT clinical follow-up included diagnostic procedures for complications, and global survival was assessed. Immunofluorescence detected activated inflammasome complexes in fixed liver tissues. ASC specks were identified in hepatocytes, showing a trend toward more specks in DCD livers. Likewise, inflammasome-related gene expression analysis indicated higher expression in DCD livers, decreasing after cold ischemia. Similar results were found at protein level. Patients with increased ASC specks staining exhibited lower overall survival rates, correlating with IL1B expression after cold ischemia. Although preliminary, these findings offer novel insights into utilizing direct detection of inflammasome activation in liver tissue as a biomarker. They suggest its potential impact on post-transplant outcomes, potentially paving the way for improved diagnostic approaches and personalized treatment strategies in LT.

Cell-specific Extracellular Vesicles and Their miRNA Cargo Released Into the Organ Preservation Solution During Cold Ischemia Storage as Biomarkers for Liver Transplant Outcomes.

BACKGROUND: Liver transplantation (LT) is crucial for end-stage liver disease patients, but organ shortages persist. Donation after circulatory death (DCD) aims to broaden the donor pool but presents challenges. Complications like acute rejection, hepatic artery thrombosis, and biliary issues still impact posttransplant prognosis. Biomarkers, including extracellular vesicles (EVs) and microRNAs (miRNAs), show promise in understanding and monitoring posttransplant events. This study explores the role of EVs and their miRNA cargo in LT, including their potential as diagnostic tools. METHODS: EVs from intrahepatic end-ischemic organ preservation solution (eiOPS) in 79 donated livers were detected using different techniques (nanosight tracking analysis, transmission electron microscopy, and flow cytometry). EV-derived miRNAs were identified by quantitative real time-polymerase chain reaction. Bioinformatics analysis was performed using the R platform. RESULTS: Different-sized and origin-specific EVs were found in eiOPS, with significantly higher concentrations in DCD compared with donation after brain death organs. Additionally, several EV-associated miRNAs, including let-7d-5p, miR-28-5p, miR-200a-3p, miR-200b-3p, miR-200c-3p, and miR-429, were overexpressed in DCD-derived eiOPS. These miRNAs also exhibited differential expression patterns in liver tissue biopsies. Pathway analysis revealed enrichment in signaling pathways involved in extracellular matrix organization and various cellular processes. Moreover, specific EVs and miRNAs correlated with clinical outcomes, including survival and early allograft dysfunction. A predictive model combining biomarkers and clinical variables showed promise in acute rejection detection after LT. CONCLUSIONS: These findings provide new insights into the use of EVs and miRNAs as biomarkers and their possible influence on posttransplantation outcomes, potentially contributing to improved diagnostic approaches and personalized treatment strategies in LT.

Neoadjuvant Chemotherapy plus Interval Cytoreductive Surgery with or without Hyperthermic Intraperitoneal Chemotherapy (NIHIPEC) in the Treatment of Advanced Ovarian Cancer: A Multicentric Propensity Score Study.

INTRODUCTION: Epithelial ovarian cancer (EOC) is primarily confined to the peritoneal cavity. When primary complete surgery is not possible, neoadjuvant chemotherapy (NACT) is provided; however, the peritoneum-plasma barrier hinders the drug effect. The intraperitoneal administration of chemotherapy could eliminate residual microscopic peritoneal tumor cells and increase this effect by hyperthermia. Intraperitoneal hyperthermic chemotherapy (HIPEC) after interval cytoreductive surgery could improve outcomes in terms of disease-free survival (DFS) and overall survival (OS). MATERIALS AND METHODS: A multicenter, retrospective observational study of advanced EOC patients who underwent interval cytoreductive surgery alone (CRSnoH) or interval cytoreductive surgery plus HIPEC (CRSH) was carried out in Spain between 07/2012 and 12/2021. A total of 515 patients were selected. Progression-free survival (PFS) and OS analyses were performed. The series of patients who underwent CRSH or CRSnoH was balanced regarding the risk factors using a statistical analysis technique called propensity score matching. RESULTS: A total of 170 patients were included in each subgroup. The complete surgery rate was similar in both groups (79.4% vs. 84.7%). The median PFS times were 16 and 13 months in the CRSH and CRSnoH groups, respectively (Hazard ratio (HR) 0.74; 95% CI, 0.58-0.94; p = 0.031). The median OS times were 56 and 50 months in the CRSH and CRSnoH groups, respectively (HR, 0.88; 95% CI, 0.64-1.20; p = 0.44). There was no increase in complications in the CRSH group. CONCLUSION: The addition of HIPEC after interval cytoreductive surgery is safe and increases DFS in advanced EOC patients.

Endothelial cell activation mediated by cold ischemia-released mitochondria is partially inhibited by defibrotide and impacts on early allograft function following liver transplantation.

DAMPs (danger-associated molecular patterns) are self-molecules of the organism that appear after damage. The endothelium plays several roles in organ rejection, such as presenting alloantigens to T cells and contributing to the development of inflammation and thrombosis. This study aimed to assess whether DAMPs present in the organ preservation solution (OPS) after cold ischemic storage (CIS) contribute to exacerbating the endothelial response to an inflammatory challenge and whether defibrotide treatment could counteract this effect. The activation of cultured human umbilical vein endothelial cells (HUVECs) was analyzed after challenging with end-ischemic OPS (eiOPS) obtained after CIS. Additionally, transwell assays were performed to study the ability of eiOPS to attract lymphocytes across the endothelium. The study revealed that eiOPS upregulated the expression of MCP-1 and IL-6 in HUVECs. Moreover, eiOPS increased the membrane expression of ICAM-1and HLA-DR, which facilitated leukocyte migration toward a chemokine gradient. Furthermore, eiOPS demonstrated its chemoattractant ability. This activation was mediated by free mitochondria. Defibrotide was found to partially inhibit the eiOPS-mediated activation. Moreover, the eiOPS-mediated activation of endothelial cells (ECs) correlated with early allograft dysfunction in liver transplant patients. Our finding provide support for the hypothesis that mitochondria released during cold ischemia could trigger EC activation, leading to complications in graft outcomes. Therefore, the analysis and quantification of free mitochondria in the eiOPS samples obtained after CIS could provide a predictive value for monitoring the progression of transplantation. Moreover, defibrotide emerges as a promising therapeutic agent to mitigate the damage induced by ischemia in donated organs.

GECOP-MMC: phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases.

BACKGROUND: The French PRODIGE 7 trial, published on January 2021, has raised doubts about the specific survival benefit provided by HIPEC with oxaliplatin 460 mg/m2 (30 minutes) for the treatment of peritoneal metastases from colorectal cancer. However, several methodological flaws have been identified in PRODIGE 7, specially the HIPEC protocol or the choice of overall survival as the main endpoint, so its results have not been assumed as definitive, emphasizing the need for further research on HIPEC. It seems that the HIPEC protocol with high-dose mytomicin-C (35 mg/m2) is the preferred regime to evaluate in future clinical studies. METHODS: GECOP-MMC is a prospective, open-label, randomized, multicenter phase IV clinical trial that aims to evaluate the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal), after complete surgical cytoreduction. This study will be performed in 31 Spanish HIPEC centres, starting in March 2022. Additional international recruiting centres are under consideration. Two hundred sixteen patients with PCI ≤ 20, in which complete cytoreduction (CCS 0) has been obtained, will be randomized intraoperatively to arm 1 (with HIPEC) or arm 2 (without HIPEC). We will stratified randomization by surgical PCI (1-10; 11-15; 16-20). Patients in both arms will be treated with personalized systemic chemotherapy. Primary endpoint is peritoneal recurrence-free survival at 3 years. An ancillary study will evaluate the correlation between surgical and pathological PCI, comparing their respective prognostic values. DISCUSSION: HIPEC with high-dose mytomicin-C, in patients with limited (PCI ≤ 20) and completely resected (CCS 0) peritoneal metastases, is assumed to reduce the expected risk of peritoneal recurrence from 50 to 30% at 3 years. TRIAL REGISTRATION: EudraCT number: 2019-004679-37; Clinicaltrials.gov: NCT05250648 (registration date 02/22/2022, ).

Goiter surgery recommendations in sub-Saharan Africa in humanitarian cooperation.

Background: The standard treatment for endemic goiter is usually total thyroidectomy. In low- and middle-income countries, the management of thyroid disease, which is commonplace in fully developed countries, is not always possible. The purpose of this study is to establish a treatment algorithm to calculate the extent of thyroidectomy based on the risk factors of each patient. Methods: This is a retrospective observational study conducted during the period between 2017 and 2019. A total of 287 patients with thyroid pathology were treated in Maragua Hospital (Kenya). The results of surgical treatment were analyzed after the implementation of an individualized treatment protocol. Results: One hundred and sixty patients with different types of goiter underwent surgery: solitary nodule (54.4%), multi-nodular goiter (30.6%), diffuse goiter (10.6%), and intrathoracic goiter (3.8%). The techniques used were hemithyroidectomy (78.8%), Dunhill thyroidectomy (9.4%), bilateral subtotal thyroidectomy (6.9%), and total thyroidectomy (3.1%). There was no mortality. The surgical morbidity rate was 16% (only one major complication (3b)). Two cases of dysphonia were resolved in the first week. There were three cases of symptomatic hypocalcaemia, two of which resolved in the first week and the other of which was definitive. The follow-up at 6 months was 67%. The cancer rate found in the resection specimens was 5%. Discussion: The implementation of individualized surgical protocols for thyroid surgery in sub-Saharan Africa can improve outcomes. The cooperation projects can increase access to complex surgical treatment for patients with limited resources in low- and middle-income countries.

The impact of information and communications technology and broadcasting on YouTube for improving attitude toward organ donation in secondary education with the creation of short films.

OBJECTIVE: There is a lack of awareness about organ donation among teenagers, a fact that could decrease future donation rates. The objective is to analyze the impact of an educational proposal based on the creation of short films. METHODS: Fifteen schools were randomly selected: ten for the experimental group (EG), and five for the control group (CG). In both groups all students from the selected classes participated (EG: n = 543, CG: n = 320). An intervention was undertaken in the EG, providing a website to make a short film about organ donation and transplantation (ODT) to be broadcast on YouTube. The students completed a questionnaire before and after the proposal. STATISTICS: Mann-Whitney test was conducted to compare the pre-test data, McNemar test compare the pre and post test results of each group, and Chi-square test to compare the change in responses between the two groups. RESULTS: The change to a more favorable response was greater in the EG in all variables. The YouTube channel received 104,912 viewings. CONCLUSIONS: An innovative educational intervention has a positive influence on teenage attitude and knowledge about ODT; it also has important social repercussions. PRACTICE IMPLICATIONS: Implementing this educational proposal about ODT could help improve future donation rates.

Is prophylactic gastrectomy indicated for healthy carriers of CDH1 gene mutations associated with hereditary diffuse gastric cancer?

INTRODUCTION: hereditary diffuse gastric cancer (HDGC) is a recently reported hereditary cancer syndrome. Patients with suspected HDGC must be under surveillance via endoscopy and multiple biopsies. As an alternative, some studies suggest prophylactic gastrectomy (PG) for disease carriers. The goal of this article was to report our experience with a CDH1 mutation positive family who underwent PG. PATIENTS AND METHODS: the index case was a 34-year-old female diagnosed with diffuse gastric adenocarcinoma and massive carcinomatosis. There was a family history of gastric adenocarcinoma in seven family members. A genetic study identified the c.1577G>A mutation, in exon 11 of the CDH1 gene via sequencing analysis. RESULTS: this mutation was also present in other six family members, who subsequently underwent prophylactic gastrectomy. The pathology study of resected gastric segments revealed multiple microscopic foci of adenocarcinoma in five of these individuals. These foci were not detected in the multiple endoscopies performed before surgery. CONCLUSIONS: we recommend prophylactic gastrectomy for CDH1 mutation carriers even in the absence of lesions during endoscopic screening.

2-methoxyestradiol in the pathophysiology of endometriosis: focus on angiogenesis and therapeutic potential.

Endometriosis is a common condition among women of childbearing potential in which ectopic endometrial tissue is found outside the uterine cavity. Neoangiogenesis plays a major role in the development of endometriotic implants. Some evidence suggests that a disorder in the balance of proangiogenic and antiangiogenic factors that favors the former is induced by local hypoxia and is mediated by the hypoxia-inducible factor-vascular endothelium growth factor pathway could partially explain the development of this condition in some women. 2-methoxyestradiol is a biologically active metabolite of estradiol having antiangiogenic action. Changes in estradiol homeostasis have been locally observed in endometriosis. In this review, we summarize current knowledge of endometriosis pathophysiology, in particular, the balance between local 2-methoxyestradiol production and angiogenesis, which could promote the development of endometriotic lesions. 2-Methoxyestradiol emerges as a promising new candidate for the treatment of endometriosis.

[Urinary tract surgery in patients with ovarian peritoneal carcinomatosis treated with cytoreduction and hyperthermic intraoperative intraperitoneal chemotherapy]. / Cirugía del tracto urinario en pacientes con carcinomatosis peritoneal ovárica tratadas con citorreducción y quimioterapia intraperitoneal intraoperatoria hipertérmica.

INTRODUCTION: The objective of the present work is to describe our experience in the surgery of the ureter and bladder in patients with primary and recurrent ovarian cancer subjected to peritonectomy procedures and the administration of hyperthermic intraoperative intraperitoneal chemotherapy (HIIC). PATIENTS AND METHOD: Those patients who required surgical procedures on the distal ureter or bladder, were selected from a prospective data base constructed at the beginning of the peritoneal carcinomatosis program in our centre. Seven patients fulfilled this requirement and were included in the study. A total of 81 patients diagnosed with primary or recurrent ovarian cancer from December 2007 to April 2011 were included for maximum effort cytoreduction and HIIC. RESULTS: It was necessary to perform some surgical manoeuvre on the ureter or bladder in seven patients, with a median age of 46 years (40-71). Four patients were operated on due to recurrence of the ovarian disease and in the other 3 patients the indication was surgical rescue after non-optimal surgery in another centre. There was direct tumour involvement of the lower urinary tract in 4 of them. Three patients (42%) in the series developed at least one postoperative complication. CONCLUSION: The performing of peritonectomy procedures that include the eventual resection of the ureter or bladder, and the subsequent application of HIIC in a selected group of patients with peritoneal dissemination due to an ovarian carcinoma can be done with reasonable rates of postoperative morbidity. These surgical procedures may be necessary to achieve optimal surgery.

[Spirometric evaluation of respiratory involvement in asymptomatic multinodular goiter with an intrathoracic component]. / Valoración espirométrica de la afectación respiratoria en el bocio multinodular asintomático con componente intratorácico.

Respiratory tract obstruction is underestimated in asymptomatic intrathoracic goiter. Our aim was to evaluate the involvement of the upper airway of asymptomatic patients with intrathoracic multinodular goiter, assessing the effect on respiratory function by means of spirometry. We selected 21 patients with asymptomatic intrathoracic goiter on whom a thyroidectomy had been performed. Spirometry was done in supine decubitus and in standing position before and 3 months after surgery. The preoperative study in decubitus showed mild obstruction in 4 cases (20%). In 2 of these cases this condition was also present in standing position (10%). Spirometry became normal after surgery in the 4 patients with obstruction. To conclude, spirometry in asymptomatic intrathoracic goiter shows mild obstruction of respiratory function in 10% to 20% of cases, depending on position. Surgery was associated with normalization of the abnormal parameters and an improvement in the remaining parameters. These data support the need to schedule surgery as soon as possible.

The approach of fused fissures with fissureless technique decreases the incidence of persistent air leak after lobectomy.

OBJECTIVE: To evaluate two different approaches used to perform fused fissures in lobectomies in terms of persistent air leak (PAL) and their impact on length of hospital stay. METHODS: One hundred and nineteen patients underwent lobectomy or bilobectomy in our unit. We focused on patients with fused fissures (63 patients), all of whom were selected intraoperatively based on predefined criteria. These patients with incomplete fissures were randomly assigned to two groups: Group A patients who underwent a 'traditional technique' to approach fused fissures and Group B patients who underwent a 'fissureless technique'. The latter technique avoids dissecting the lung parenchyma over the pulmonary artery, reducing the chances of air leak. Patients in both groups had shown no significant difference in preoperative variables (p>0.05). RESULTS: The incidence of PAL was significantly higher among patients with incomplete or fused fissures (0 case vs 8 cases (Groups A and B), p<0.005). Furthermore, the incidence of PAL was significantly higher in the Group A (traditional technique) (7 vs 1) (p<0.05, OR=3.1, CI 0.22-0.51). The probability for air leak cessation was significantly higher in patients of Group B (fissureless technique) (log rank p<0.0001). The length of hospital stay was higher in Group A (5.76+/-3.1) compared with Group B (4.9+/-1.7) (p<0.05). No other variables were identified as risk factors for PAL in this series. CONCLUSIONS: The fissureless technique appears to be a superior approach for fused fissures in terms of both preventing persistent air leak and reducing the length of hospitalisation. This technique can be performed safely at no additional cost and without adverse consequences.

Poorly differentiated primary monophasic synovial sarcoma of the lung.

Primary monophasic synovial sarcoma of the lung is rarely seen in clinical practice. We report the case of a 60-year-old male who underwent a left lower lobectomy for lung sarcoma. The patient received adjuvant therapy after surgery. Diagnosis was confirmed with SYT-SSX2 translocation detection.

Successful use of a single chest drain postlobectomy instead of two classical drains: a randomized study.

OBJECTIVE: To compare surgical results and complications in the immediate postoperative course between the use of a single drain and two-drain post-anatomical pulmonary resections. PATIENTS AND METHODS: Between January 2004 and September 2005, 143 patients were scheduled for pulmonary lobectomy or bilobectomy for non-small cell lung cancer (NSCLC) in our department. Pneumonectomies, wedge resection, and nonresectable thoracotomies were excluded from the study. Hundred and nineteen patients were enrolled in this study. Clinical and surgical variables were collected prospectively. Lobectomy or bilobectomy and systematic mediastinal node dissection were performed in all cases. The patients were randomly assigned to receive single (group A) or two (group B) drains, independent of any preoperative or intraoperative variables. Group A consisted of 60 patients who had one single drain sited in the mid-position and group B consisted of 59 patients who had two classical drains (apical and basal). There were no surgical, oncological, or physiological differences between the groups (p=NS). RESULTS: There were no statistically significant differences detected between the groups in relation to postsurgical morbidity or mortality and other issues studied, except in analgesia requirements (group A less than group B, p<0.05). After drain removal there were no significant differences between the groups in terms of subcutaneous emphysema, new drains needed, residual pleural effusion, or residual space (p>0.05). CONCLUSIONS: In our study, we did not find significant differences between the use of one or two drains after lobectomy or bilobectomy in relation to early postoperative outcome. However, the use of only one drain is more economical and is less painful for patients, without any additional adverse consequences.

[Toward zero mortality in liver resection. Presentation of 200 consecutive cases]. / Hacia la mortalidad cero en las resecciones hepáticas. Presentación de 200 casos consecutivos.

INTRODUCTION: Liver resection (LR) morbidity and mortality rates have dropped in recent decades. Mortality is now below 5% and morbidity is less than 30%. Our objective was to present a series of 200 LRs without mortality and to analyze the factors that may be related to complications. PATIENTS AND METHOD: Between January 1996 and October 2003, 200 LRs were performed in 177 patients. The most common indication was liver metastases in 123 patients (61.5%), primary malignant liver tumors in 27 patients (13.5%), bile duct tumors in 27 patients (13.5%) and benign disease in 23 patients (11.5%). Fifty-one percent of the resections were performed under hemihepatic vascular control and 49% were resections of central segments, segmentary and atypical resections. We studied the association between morbidity and age, sex, previous comorbidity, liver status, indication for surgery, number of resections, major and minor resections, resection extended to other organs, type of vascular occlusion, transfusion requirements, operating time, length of hospital stay and experience of the surgical team. RESULTS: There was no postoperative mortality. The morbidity rate was 17.5% (35 patients) and the most common complications were biliary (8%). Morbidity was related to transfusion (transfused patients presented more complications) (P < .001). Transfusion was greater in major resections, the first 100 resections and prolonged operations. Among the segmentary resections the Pringle maneuver reduced transfusion requirements but this difference was not statistically significant. Morbidity decreased in the second 100 resections, without significant differences. CONCLUSION: LRs can be performed with low mortality and morbidity. Biliary complications and blood transfusion should be avoided whenever possible.