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.

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.

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.

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.

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.

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.

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.

A Critical Role of the IL-22-IL-22 Binding Protein Axis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22-IL-22BP axis in HCC.

Robotic-assisted harvest of latissimus dorsi muscle flap for breast reconstruction: review of the literature.

Robotic-assisted surgery continues to gain ground over conventional surgical methods, due to reported better results regarding the aesthetic outcome and the decreased percentage of complications. Although latissimus dorsi flap harvesting for breast reconstruction has been already used for several years, a plethora of serious complications has been reported. Recently, minimally invasive surgical approaches, such as robotic-assisted technique, have been suggested with conflicting outcomes to overcome technical difficulties. Therefore, the literature review was conducted regarding robotic-assisted harvesting of the latissimus dorsi flap for breast reconstruction. A narrative review of the contemporary literature was performed in the PubMed database for the use of robotic-assisted surgery of latissimus dorsi muscle flap harvesting for breast reconstruction. Appropriate search terms were used, and specific inclusion and exclusion criteria were applied. Five studies met the inclusion criteria. A total of 32 cases of robotically assisted harvesting of pedicled latissimus dorsi muscle flap for implant-based breast reconstruction have been identified. All flaps were successfully harvested without converting in the traditional open procedure. There were no significant postoperative complications, expect from few cases of postoperative seromas, which were conservatively managed. Additionally, all patients were satisfied with their postoperative cosmetic outcome. The robotic-assisted harvesting technique of the latissimus dorsi flap for breast reconstruction is safe and comparable to the conventional methods. Reduced hospital stays and superior aesthetic outcome are the main advantages, while total cost and the difficulty of reaching the learning curve plateau are the main concerns regarding this modern and minimally invasive surgical approach.

Estrogen Receptor Expression in Pancreatic Adenocarcinoma: Time to Reconsider Evidence.

ABSTRACT: Pancreatic adenocarcinoma remains a chemotherapy-resistant and refractory malignancy with high mortality, unaffected by recent progress in anticancer treatment. Expression of estrogen receptors was detected almost 50 years ago, in both benign and malignant pancreatic cells. However, early preclinical studies in pancreatic cancer led to contradictory findings, and most clinical studies failed to demonstrate an effect with tamoxifen treatment. The identification of a second form of estrogen receptor seems to provide some explanation for these discrepancies. Predominantly expressed in malignant cells and structurally different from what was considered the only estrogen receptor, estrogen receptor ß was recognized as a negative prognostic factor and a possible therapeutic target in pancreatic ductal adenocarcinoma. Therefore, findings of research before the identification of estrogen receptor ß should be reconsidered, and further studies should be designed to reassess the expression and effect of this specific estrogen receptor type in pancreatic cancer.

Current evidence on laparoscopic vs. open resection for gastric stromal tumours.

Although the use of laparoscopic surgery is increasing, controversy still surrounds its application for malignant conditions. Gastrointestinal stromal tumours (GISTs) are less demanding in terms of lymphadenectomy, meaning that laparoscopic resection might have a more defined benefit when compared with open resection. To the best of our knowledge, no randomized study exists that compares the laparoscopic and open resection of GISTs. The current study aimed to examine the relevant literature by means of a systematic review. A systematic literature search was performed individually by two authors, in which three independent databases were searched using specific search-terms. Titles, abstracts and full texts were screened, as well as references to relevant articles, in order to comprise a comprehensive list of studies. Data were extracted using a detailed pre-agreed spreadsheet. Studies were evaluated according to the modified MINORS criteria. A total of 10 studies were included in the present review, yielding a total of 14 entries. The majority of studies reported significantly improved perioperative outcomes for the laparoscopic approach, including improved duration of operation, blood loss and length of hospital stay. Only four studies reported long-term outcomes and findings that were controversial, with some studies detecting no statistically significant differences, one reporting improved and one reporting worse disease-free and overall survival for the laparoscopic group. Three studies were deemed to be good quality, two of which had not reported significantly different long-term outcomes, while the third had reported significantly improved outcomes in the open resection group. While there is a clear benefit for performing laparoscopic surgery in patients with GIST with regards to perioperative outcomes, when it comes to long-term oncological outcomes, uncertainty over its application remains. The lack of randomized trials, as well as the poor reporting of retrospective studies, limits the amount of evidence that is currently available. Laparoscopic surgery for GIST is certainly safe, feasible and likely cost-effective; however, further studies are required to inform on whether this technique is superior to open resection.

Bilirubin is a specific marker for the diagnosis of acute appendicitis.

Total serum bilirubin and other biochemical parameters have been associated with acute appendicitis, mainly in complicated cases. The present study aimed to evaluate the role of biochemical parameters in the diagnosis of acute appendicitis, and to further investigate the role of bilirubin as a diagnostic marker irrespective of the severity of the pathology. All recorded cases of appendicectomies in a 1-year period in a single institution were reviewed. The median values of white cell count, C-reactive protein and total serum bilirubin on admission were associated with final histology, and their respective rates of abnormal and normal values were compared between patients who were proven to have negative histology and patients who were proven to have acute appendicitis. A total of 300 patients were studied. Median total serum bilirubin, white cell count and C-reactive protein on admission were significantly associated with acute appendicitis (P<0.001). Respective rates of normal and abnormal values were significantly associated with final histology (P<0.001). Total serum bilirubin demonstrated higher specificity (0.88) but lower sensitivity (0.26) and diagnostic accuracy (0.40) for acute appendicitis. In conclusion, total serum bilirubin on admission should be considered in the diagnostic workup to confirm rather than exclude appendicitis, without focusing on subgroups of specific severity of the disease. White cell count and C-reactive protein may also contribute to the diagnostic work-up, although with limited accuracy.

Laparostomy and temporary abdominal closure outcomes in emergency non-trauma surgery and parameters affecting early definite primary fascial closure.

BACKGROUND: The open abdomen or laparostomy is a great advance of surgery based on the concept of damage control surgery. Aim of the study is to review the laparostomy outcomes of non-trauma emergency surgery patients in a district general hospital and identify parameters affecting early definite primary fascial closure. METHODS: The records of all non-trauma emergency surgical patients who underwent laparostomy in a three-year period in a single institute were studied retrospectively. Outcomes included length of stay, morbidity, mortality, readmission rates, number of re-look operations, rate of definite primary fascial closure and time to closure. RESULTS: Thirty-two patients were included. Morbidity was 84.4% and mortality rates were 21.9% (in-hospital), 18.8% (30-day) and 46.9% (overall). Median length of hospital stay was 22 days. Rate of primary fascial closure was 87.5% and median time to closure was two days. The number of relook operations was the only independent prognostic factor of definite early primary fascial closure, with higher rates of closure in patients with 1-2 relooks. CONCLUSIONS: Although the open abdomen has been demonstrated to improve survival, the precise role in abdominal sepsis has not been elucidated. Current consensus does not support use of open abdomen routinely, however in selected situations it becomes unavoidable. Laparostomy is a valid option in non-trauma emergency surgery and can be managed safely in a district hospital. High closure rates can be achieved if one or two re-look operations are performed with an early attempt for closure.

Single Port Laparoscopic Total and Subtotal Colectomies for Inflammatory Bowel Disease in a District General Hospital.

Background: Single incision laparoscopic surgery (SILS) is expanding, enhancing the advantages of multi-port laparoscopic surgery (MLS). Limited literature exists regarding SILS total/subtotal colectomies for inflammatory bowel disease (IBD). Aim of the study was to present the initial experience with this type of approach in a district general hospital and extrapolate its feasibility and safety in this specific context based on gold standard outcomes reported in literature. Materials and Methods: Preoperative parameters, operative details and surgical outcomes of consecutive patients who underwent colonic SILS for IBD in a 5-year period were reviewed retrospectively. Median length of follow-up was 26 months. Results: Fourteen patients underwent SILS subtotal/total colectomy. Median body mass index was 25 (18.1-35). Two patients had previous abdominal surgeries. Median operating time was 202.5 minutes. Two cases were converted to open. Median length of stay was 5 days. Three patients presented complications. Three patients developed parastomal hernias (21.4%). Five out of 12 patients with ulcerative colitis declined further surgery, 3 are awaiting laparoscopic/SILS pouch formation, 1 underwent SILS pouch formation, 1 SILS ileo-rectal anastomosis and 1 patient had SILS completion proctectomy. One patient was not followed up. Conclusions: Despite literature data heterogeneity, these results provide support to the feasibility and applicability of SILS in the subgroup of patients who undergo subtotal/total colectomies for IBD, offering the option for subsequent SILS completion or restorative procedures. Further studies are required to explore the benefit of SILS over MLS (including cosmesis and quality of life) and non-inferiority of SILS regarding the parastomal hernia issue and the operative duration.