IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction.

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

The Value of Textbook Outcome in Benchmarking Pancreatoduodenectomy for Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Textbook outcome (TO) is a composite variable that can define the quality of pancreatic surgery. The aim of this study is to evaluate TO after pancreatoduodenectomy (PD) for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). PATIENTS AND METHODS: All patients who underwent PD for NF-PanNETs (2007-2016) in different centers were included in this retrospective study. TO was defined as the absence of severe postoperative complications and mortality, length of hospital stay ≤ 19 days, R0 resection, and at least 12 lymph nodes harvested. RESULTS: Overall, 477 patients were included. The TO rate was 32%. Tumor size [odds ratio (OR) 1.696; p = 0.013], a minimally invasive approach (OR 12.896; p = 0.001), and surgical volume (OR 2.062; p = 0.023) were independent predictors of TO. The annual frequency of PDs increased over time as well as the overall rate of TO. At a median follow-up of 44 months, patients who achieved TO had similar disease-free (p = 0.487) and overall survival (p = 0.433) rates compared with patients who did not achieve TO. TO rate in patients with NF-PanNET > 2 cm was 35% versus 27% in patients with NF-PanNET ≤ 2 cm (p = 0.044). Considering only NF-PanNETs > 2 cm, patients with TO and those without TO had comparable 5-year overall survival rates (p = 0.766) CONCLUSIONS: TO is achieved in one-third of patients after PD for NF-PanNETs and is not associated with a benefit in terms of long-term survival.

A simple scoring model for predicting early graft failure and postoperative mortality after liver transplantation.

INTRODUCTION AND OBJECTIVES: Graft failure and postoperative mortality are the most serious complications after liver transplantation. The aim of this study is to establish a prognostic scoring system to predict graft and patient survival based on serum transaminases levels that are routinely used during the postoperative period in human cadaveric liver transplants. PATIENTS AND METHODS: Postoperative graft failure and patient mortality after liver transplant were analyzed from a consecutive series of 1299 patients undergoing cadaveric liver transplantation. This was correlated with serum liver function tests and the rate of reduction in transaminase levels over the first postoperative week. A cut-off transaminase level correlating with graft and patient survival was calculated and incorporated into a scoring system. RESULTS: Aspartate-aminotransferase (AST) on postoperative day one showed significant correlation with early graft failure for levels above 723U/dl and early postoperative mortality for levels above 750U/dl. AST reduction rate (day 1 to 3) greater than 1.8 correlated with reduced graft failure and greater than 2 with mortality. Alanine-aminotransferase (ALT) reduction in the first 48h post transplantation also correlated with outcomes. CONCLUSION: A scoring system with these three variables allowed us to classify our patients into three groups of risk for early graft failure and mortality.

Recipient body mass index and infectious complications following liver transplantation.

BACKGROUND: Nutritional problems are common in patients requiring liver transplantation. Recipient obesity or malnutrition are thought to increase postoperative complications. Body mass index (BMI) is commonly used prior to major surgery but its value specifically in liver transplant assessment has not been established. This is a retrospective study assessing the correlation between the BMI of individuals undergoing liver transplant and the development of postoperative infectious complications. METHODS: Data were collected from a prospectively maintained database regarding all consecutive patients over a period of 23 years. Preoperative recipient BMI was correlated with the number, nature and outcome of postoperative infective complications. RESULTS: Of a total of 1156 consecutive patients, 13.2% developed infectious complications. Thirty-day mortality was 7.2% and 90-day mortality was 10%. Higher BMI was associated with higher risk of infections (p = 0.002). Wound infections occurred predominantly in obese patients (p = 0.001) while other types of infections were more common in malnourished patients (p < 0.001). CONCLUSION: Extremes of BMI are associated with increased infectious complications following liver transplantation. Patients with lower BMI had a higher rate of overall infectious complications whereas those with a higher BMI had increased general and wound complications.

Impact of postoperative intravenous fluid administration on complications following elective hepato-pancreato-biliary surgery.

BACKGROUND: The impact of perioperative intravenous fluid administration on surgical outcomes has been documented in literature, but not specifically studied in the context of hepato-pancreato-biliary (HPB) surgery. This study aimed to investigate the impact of postoperative intravenous fluid administration on intensive care unit (ICU), in this subgroup of patients. METHODS: A single-center retrospective cohort of 241 HPB patients was assessed, focusing on intravenous fluid administration in ICU, during the first 24 h. Intravenous fluid variables were compared to hospital stay and postoperative complications. Data were assessed using Spearman's correlation test for bivariate correlations and logistic regression for multivariate analysis. RESULTS: The median volume of intravenous fluid administered in the first 24 h postoperatively was 4380 mL, of which 2200 mL was crystalloid, 1500 mL colloid and 680 mL "other" fluid. Patients with one or more complications had a higher median total intravenous fluid input (4790 vs. 4300 mL), higher colloid volume (2000 vs. 1500 mL), lower urine output (1595 vs. 1900 mL) and greater overall fluid balance (+3040 vs.+2553 mL) than those without complications. There were correlations between total intravenous fluid volume administered (r = 0.278, P < 0.001), intravenous colloid input (r = 0.278, P < 0.001), urine output (r = -0.295, P < 0.001), positive fluid balance (r = 0.344, P < 0.001) and length of hospital stay. Logistic regression model was constructed to predict the occurrence of one or more complications; total intravenous fluid volume and overall fluid balance were both independent significant predictors (OR = 2.463, P = 0.007; OR = 1.001, P = 0.011; respectively). CONCLUSIONS: Administration of high volumes of intravenous fluids in the first 24 hours post-HPB surgery, along with higher positive fluid balance is associated with a higher rate of complications and longer hospital stay. Moreover, lower urine output is associated with longer hospital stay. Whether these are the cause of complications or the result of them remains unclear.

Uncommon benign lesions of the adrenal glands mimicking sinister pathologies: report of 8 cases.

PURPOSE: To present series of patients with large rare primary lesions of the adrenal glands that were operated in our department. The initial indication for surgery was decided based on their impressive similarity to other more sinister adrenal pathologies. METHODS: The clinical records of the department and histopathology reports, covering the 1986-2015 period were assessed. Rare adrenal pathologies that preoperatively were clinically mimicking other adrenal tumors were included. RESULTS: In total, 8 patients (age range 20-75 years) with rare tumors of the adrenal glands were found. Seven patients had a preoperative indication for adrenalectomy due to the possibility of malignancy. In one patient surgery was undertaken due to the possible diagnosis of adrenal hemorrhagic cyst. Among these patients 4 had a histopathologic diagnosis of hemangiomas, one of a lymphangiomatous cyst and 3 of myelolipomas. CONCLUSION: Rare benign tumors of the adrenal glands can present as very large lesions that can be either diagnosed incidentally or due to atypical symptoms. Though unusual, they should be considered in the differential diagnostic approach of adrenal lesions, because they share common clinical and radiological characteristics with more sinister and frequent lesions such as malignant tumors and also hematomas.

Laparoscopic left lateral hepatectomy for colorectal metastasis is the standard of care.

PURPOSE: Over the last decade, laparoscopic liver surgery has significantly evolved. The aim of this study was to analyse the outcomes of Laparoscopic Left Lateral Hepatectomy (LLLH) for colorectal cancer (CRC) metastases in a tertiary referral hepato-pancreato-biliary centre. METHODS: A consecutive series of patients undergoing LLLH between January 2009 and April 2013 were analysed using prospectively collected data in a tertiary referral HPB centre. In particular, the study focused on patients who had LLLH for colorectal liver metastasis (CRLM). The following features were analysed: operative time, intraoperative blood loss, number and size of tumours, resection margins, complication rates, follow up period and recurrence rates. RESULTS: A total of 17 patients were finally included. There were no bile leaks or collections and no postoperative bleeding. The median hospital stay was 4 days (range 2-10). The median size of the metastatic lesions was 28.1 mm (range 8-56). The resection was R0 in all except 2 patients (11%) where the margin was less than 1 mm. The mean resection margin was 14.6 mm (range 1-50). Eight patients (47%) did not develop any recurrence till latest follow up. Seven patients (41%) developed recurrence in the liver or lungs. The median time to recurrence was 11 months (range 2-12). There was only one death in the follow up period (22-77 months). Sixteen patients (94%) were alive at the latest follow up. CONCLUSION: LLLH for CRLM is safe and can be performed with low complication rates, adequate resection margins, short hospital stay, and oncologic outcomes similar to those of open surgery.

The impact of intestinal and mammary microbiomes on breast cancer development: A review on the microbiota and oestrobolome roles in tumour microenvironments.

Microbiota affects carcinogenesis by altering energy equilibrium, increasing fat mass, synthesizing small signaling molecules, and formulating and regulating immune response and indigestible food ingredient, xenobiotic, and pharmaceutical compound metabolism. The intestinal microbiome can moderate oestrogen and other steroid hormone metabolisms, and secrete bioactive metabolites that are important for tumour microenvironment. Specifically, the breast tissue microbiome could become altered and lead to breast cancer development. The study of oestrobolome, the microbiomic component that metabolizes oestrogens, can contribute to better breast cancer understanding and subsequent treatment. Investigating oestrobolome-related oestrogen metabolism mechanisms in immune system regulation can shed light on how intestinal microorganisms regulate tumour microenvironment. Intestinal and regional breast microbiomes can determine treatment lines and serve as possible biomarkers for breast cancer. The aim of this study is to summarise current evidence on the role of microbiome in breast cancer progression with particular interest in therapeutic and diagnostic implementation.

Overcoming geographical and socioeconomic limitations in colorectal cancer screening.

Despite colorectal cancer's (CRC) high global incidence, residents of low- and middle- income countries, as well as low-income minorities in advanced economies have low screening rates. Observational studies demonstrate that in these groups higher incidence of CRC is observed, yet screening rates remain low for consistent reasons. Low income, low educational background, and lack of awareness in combination with inadequate social security of certain population groups impede access and compliance rates to CRC screening. On the other hand, despite the global availability of multiple screening approaches (colonoscopy, sigmoidoscopy, faecal occult blood test, faecal immunochemical test, computed tomography-colonography, etc.) with proven diagnostic validity, many low-income countries still lack established screening programs. The absence of screening guidelines in these countries along with the heterogeneity of guidelines in the rest of the world, demonstrate the need for global measures to tackle this issue comprehensively. An essential step forward is to develop a global approach that will link specific elements of screening with the incidence and available resources in each country, to ensure the achievement of at least a minimum screening program in low-income countries. Utilizing cheaper, cost-effective techniques, which can be carried out by less specialized healthcare providers, might not be equivalent to endoscopy for CRC screening but seems more realistic for areas with fewer resources. Awareness has been highlighted as the most pivotal element for the effective implementation of any screening program concerning CRC. Moreover, multiple studies have demonstrated that outreach strategies and community-based educational programs are associated with encouraging outcomes, yet a centrally coordinated expansion of these programs could provide more consistent results. Additionally, patient navigator programs, wherever implemented, have increased CRC screening and improved follow-up. Therefore, global coordination and patient education seem to be the main areas on which policy making needs to focus.

Bringing gut microbiota into the spotlight of clinical research and medical practice.

Despite the increasing scientific interest and expanding role of gut microbiota (GM) in human health, it is rarely reported in case reports and deployed in clinical practice. Proteins and metabolites produced by microbiota contribute to immune system development, energy homeostasis and digestion. Exo- and endogenous factors can alter its composition. Disturbance of microbiota, also known as dysbiosis, is associated with various pathological conditions. Specific bacterial taxa and related metabolites are involved in disease pathogenesis and therefore can serve as a diagnostic tool. GM could also be a useful prognostic factor by predicting future disease onset and preventing hospital-associated infections. Additionally, it can influence response to treatments, including those for cancers, by altering drug bioavailability. A thorough understanding of its function has permitted significant development in therapeutics, such as probiotics and fecal transplantation. Hence, GM should be considered as a ground-breaking biological parameter, and it is advisable to be investigated and reported in literature in a more consistent and systematic way.

Current remarks and future directions on the interactions between metabolic dysfunction-associated fatty liver disease and COVID-19.

During the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, particular interest rose regarding the interaction between metabolic dysfunction-associated fatty liver disease (MAFLD) and the COVID-19 infection. Several studies highlighted the fact that individuals with MAFLD had higher probability of severe acute respiratory syndrome coronavirus 2 infection and more severe adverse clinical outcomes. One of the proposed mechanisms is the inflammatory response pathway, especially the one involving cytokines, such as interleukin 6, which appeared particularly elevated in those patients and was deemed responsible for additional insult to the already damaged liver. This should increase our vigilance in terms of early detection, close follow up and early treatment for individuals with MAFLD and COVID-19 infection. In the direction of early diagnosis, biomarkers such as cytokeratin-18 and scoring systems such as Fibrosis-4 index score are proposed. COVID-19 is a newly described entity, expected to be of concern for the years to come, and MAFLD is a condition with an ever-increasing impact. Delineating the interaction between these two entities should be brought into the focus of research. Reducing morbidity and mortality of patients with COVID-19 and MAFLD should be the ultimate objective, and the optimal way to achieve this is by designing evidence-based prevention and treatment policies.

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas: An individual participant data meta-analysis.

Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGCs) of the pancreas is a rare neoplasm that accounts for less than 1% of all pancreatic malignancies. The aim of this study was to review the literature regarding UC-OGC, and to highlight its biological behavior, clinicopathologic characteristics, prognosis, and therapeutic options. A systematic review of the literature in PubMed/Medline and Scopus databases was performed (last search October 31st, 2023) for articles concerning pancreatic UC-OGC in the adult population. Fifty-seven studies met the inclusion criteria, involving 69 patients with a male-to-female ratio of 1.1:1 and a mean age of 62.96. Main symptoms included abdominal pain (33.3%), jaundice (14.5%), weight loss (8.7%), while fourteen patients (20.3%) were asymptomatic. Surgical resection was performed in 88.4% of cases. Survival rates at one, three, and five years were 58%, 44.7%, and 37.3% respectively. Sex, age, size (cut-off of 4 cm), location, and adjuvant treatment did not significantly affect patient survival. UC-OGC of the pancreas is a rare subtype of undifferentiated pancreatic carcinoma with a better prognosis than conventional pancreatic ductal adenocarcinoma or undifferentiated carcinoma without giant cells. The establishment of a dedicated patient registry is imperative to further delineate the optimal treatment for this uncommon clinical entity.

IL-22 promotes liver regeneration after portal vein ligation.

Background: Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL. Methods: Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used. Results: The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes. Conclusion: IL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

Prevalence of Axillary Artery Variants and Their Clinical Significance: A Scoping Review.

Axillary artery (AA) variants occurred quite commonly, presenting clinical implications. A literature search yielded 523 results from which 13 parameters were extracted. Some of the AA variants found were the fusion of two or more branches into common trunks, like the fusion of anterior and posterior circumflex humeral arteries. Moreover, several branches were found to emerge from different points than expected, like the lateral thoracic artery's origin from the subscapular artery instead of the second part of the AA. The importance of the knowledge of the AA variations in clinical practice is undeniable and very useful when planning interventional procedures, as in the case of AA aneurysm treatment or in cases of fracture of the surgical neck of the humerus. The heterogeneity of data limited the possibility of a quantitative summary of data. Therefore, a more systemic study of AA variants based on the origin, course, and branching pattern is suggested. The aim of the current review is to summarize current data literature regarding the AA typical anatomy and its variants, with a focus on their prevalence and possible clinical implications.

Stress, Professional Burnout, and Employee Efficiency in the Greek National Organization for the Provision of Health Services.

BACKGROUND: Workplace stress and burnout in the Greek healthcare system had been considered severe even before the high pressure of the COVID-19 pandemic. We aimed to investigate occupational quality of life and burnout effects on workplace errors among the administrative staff in the Greek healthcare system. METHODS: We enrolled 120 administrative healthcare employee participants between April and May 2019. Occupational burnout was assessed using the Maslach Burnout Inventory-Human Services Survey and the Hospital Anxiety and Depression Scale. FINDINGS: Inadequate staffing, a low sense of well-being, exhaustion, and low family income were associated with workplace errors. Increased workload and staff shortages were associated with occupation related quality of life. CONCLUSIONS: Targeted interventions supporting healthcare staff mental health are warranted. APPLICATION TO PRACTICE: Wellness and professional burnout can affect professional efficiency and are associated with workplace errors in the healthcare sector. Targeted interventions are warranted to support the mental health of healthcare staff during work and to prevent incidents of post-traumatic stress. Shortages of staffing may lead to an increase in the cost of the provided services.

IL-22BP controls the progression of liver metastasis in colorectal cancer.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

Stenting of a gastroduodenal artery aneurysm: report of a case.

We present a case of gastroduodenal artery stenting in a patient with recurrent episodes of pancreatitis due to gastroduodenal artery aneurysm. Stenting was performed under local anesthesia using a 6 × 38-mm primary covered Advanta V12 vascular stent graft. The procedure was successful and the patient is asymptomatic 21 months later. Endovascular treatment of gastroduodenal artery aneurysm should be considered a promising alternative to open surgery, due to lower mortality and morbidity.

Plasma Brain Natriuretic Peptide Levels in Children with Chronic Kidney Disease and Renal Transplant Recipients: A Single Center Study.

Pediatric chronic kidney disease (CKD) patients, as well as kidney transplant patients, are at an increased risk of developing cardiovascular disease. BNP measurement, as a biomarker of cardiovascular risk, has been recommended to this high-risk population. Plasma BNP levels were measured in 56 CKD children in either pre-dialysis stage, hemodialysis (HD) or renal transplant recipients (RTRs) and in 76 sex- and age-matched healthy controls. BNP levels were investigated in HD children, before and after the completion of their HD session. BNP levels in total CKD population, in pre-dialysis stage patients and on HD were significantly higher, compared to the respective controls. HD children had higher BNP levels compared to CKD patients in the pre-dialysis stage. Moreover, post-HD BNP concentration was slightly higher than pre-HD, with the difference being marginally statistically significant. BNP was positively correlated with eGFR, creatinine, cystatin-C and parathormone and negatively with albumin and 25-hydroxyvitamin D. A positive correlation between BNP concentration and the ratio of E/A in pulse-wave Doppler echocardiography was also observed. In conclusion, CKD pediatric patients, mainly those undergoing HD, have high plasma BNP levels which do not decrease after the HD session. This is indicative of a greater risk for future cardiovascular disease.