Protective hepatocyte signals restrain liver fibrosis in metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly 40% of the global adult population and may progress to metabolic dysfunction-associated steatohepatitis (MASH), and MASH-associated liver fibrosis and cirrhosis. Despite numerous studies unraveling the mechanism of hepatic fibrogenesis, there are still no approved antifibrotic therapies. The development of MASLD and liver fibrosis results from complex cell-cell interactions that often initiate within hepatocytes but remain incompletely understood. In this issue of the JCI, Yan and colleagues describe an ATF3/HES1/CEBPA/OPN pathway that links hepatocyte signals to fibrogenic activation of hepatic stellate cells and may provide new perspectives on therapeutic options for MASLD-induced liver fibrosis.

Liver Fibrosis Is Associated with Poorer Overall Survival and Higher Recurrence Rate in Patients with Cholangiocarcinoma.

INTRODUCTION: Cholangiocarcinoma is the second most common primary liver tumour worldwide with an increasing incidence in recent decades. While the effects of fibrosis on hepatocellular carcinoma have been widely demonstrated, the impact on cholangiocarcinoma remains unclear. The aim of this study was to evaluate the impact of liver fibrosis on overall survival (OS) and disease-free survival (DFS) in patients who have undergone liver resection for cholangiocarcinoma. METHODS: Eighty patients with cholangiocarcinoma who underwent curatively intended liver surgery between January 2007 and December 2020 were included in this retrospective single-centre study. Clinical and histopathological features were analysed. The primary endpoint was cause-specific survival. Secondary endpoints were DFS and identification of prognostic factors. RESULTS: The present study shows that the median OS is significantly reduced in patients with fibrosis (p < 0.001). The median OS in patients with fibrosis was three times shorter than in the group without fibrosis. In addition, a significantly shorter DFS was observed in patients with fibrosis (p < 0.002). Multivariate analysis showed that fibrosis is the strongest independent factor with a negative impact on OS and DFS. CONCLUSION: Liver fibrosis has a significant impact on OS and DFS in patients with cholangiocarcinoma. Patients with known liver fibrosis require thorough perioperative care and postoperative follow-up.

Gut microbiota promote liver regeneration through hepatic membrane phospholipid biosynthesis.

BACKGROUND & AIMS: Hepatocyte growth and proliferation depends on membrane phospholipid biosynthesis. Short-chain fatty acids (SCFAs) generated by bacterial fermentation, delivered through the gut-liver axis, significantly contribute to lipid biosynthesis. We therefore hypothesized that dysbiotic insults like antibiotic treatment not only affect gut microbiota, but also impair hepatic lipid synthesis and liver regeneration. METHODS: Stable isotope labeling and 70% partial hepatectomy (PHx) was carried out in C57Bl/6J wild-type mice, in mice treated with broad-spectrum antibiotics, in germ-free mice and mice colonized with minimal microbiota. The microbiome was analyzed by 16S rRNA gene sequencing and microbial culture. Gut content, liver, blood and primary hepatocyte organoids were tested by mass spectrometry-based lipidomics, quantitative reverse-transcription PCR (qRT-PCR), immunoblot and immunohistochemistry for expression of proliferative and lipogenic markers. Matched biopsies from hyperplastic and hypoplastic liver tissue of patients subjected to surgical intervention to induce hyperplasia were analyzed by qRT-PCR for lipogenic enzymes. RESULTS: Three days of antibiotic treatment induced persistent dysbiosis with significantly decreased beta-diversity and richness, but a massive increase of Proteobacteria, accompanied by decreased colonic SCFAs. After PHx, antibiotic-treated mice showed delayed liver regeneration, increased mortality, impaired hepatocyte proliferation and decreased hepatic phospholipid synthesis. Expression of the lipogenic enzyme SCD1 was upregulated after PHx but delayed by antibiotic treatment. Germ-free mice essentially recapitulated the phenotype of antibiotic treatment. Phospholipid biosynthesis, hepatocyte proliferation, liver regeneration and survival were rescued in gnotobiotic mice colonized with a minimal SCFA-producing microbial community. SCFAs induced the growth of murine hepatocyte organoids and hepatic SCD1 expression in mice. Further, SCD1 was required for proliferation of human hepatoma cells and was associated with liver regeneration in human patients. CONCLUSION: Gut microbiota are pivotal for hepatic membrane phospholipid biosynthesis and liver regeneration. IMPACT AND IMPLICATIONS: Gut microbiota affect hepatic lipid metabolism through the gut-liver axis, but the underlying mechanisms are poorly understood. Perturbations of the gut microbiome, e.g. by antibiotics, impair the production of bacterial metabolites, which normally serve as building blocks for membrane lipids in liver cells. As a consequence, liver regeneration and survival after liver surgery is severely impaired. Even though this study is preclinical, its results might allow physicians in the future to improve patient outcomes after liver surgery, by modulation of gut microbiota or their metabolites.

softALPPS - A novel, individual procedure for patients with advanced liver tumors.

BACKGROUND: The first-line therapy for liver malignancies is a radical extended liver resection. This high-risk operation has a high incidence of post-hepatectomy liver failure (PHLF) due to a small future liver remnant (FLR). One of the procedures to increase the FLR is the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) which is still associated with high morbidity and mortality. Here, we present a new, less invasive ALPPS variant that may be associated with lower morbidity. METHODS: SoftALPPS is characterized by reduced trauma to the liver tissue and individual adaptation to the patient's health constitution. In softALPPS, portal vein embolization (PVE) is performed instead of portal vein ligation (PVL) after complete recovery of liver function. In addition, a non-absorbable foil was avoided in order to be able to extend the interval to step two or skip step two when required. RESULTS: Four patients successfully underwent softALPPS. Two of these patients have been followed-up for over a year (one patient with Klatskin tumor, one patient with extensive HCC). Both patients show no evidence of recurrence after 12 months and are in good medical condition. The other two patients who recently had surgery are also doing well. CONCLUSION: SoftALPPS offers the chance to curatively resect patients with high tumor burden of the liver even when the FLR is inadequate. This individual therapy method can give patients the possibility of complete tumor resection and can help to reduce perioperative morbidity.

Novel Risk Classification Based on Pyroptosis-Related Genes Defines Immune Microenvironment and Pharmaceutical Landscape for Hepatocellular Carcinoma.

Growing evidence has indicated that pyroptosis functions in the development of cancer. Nonetheless, specific roles of pyroptosis-related genes in tumor progression, immune response, prognosis, and immunotherapy have not been thoroughly elucidated. After a comprehensive evaluation of pyroptosis genes, unsupervised clustering was performed to generate three distinct clusters from hepatocellular carcinoma (HCC) samples. Three distinct pyroptosis-related molecular subtypes comprising three gene clusters that had differential prognostic effects on patient survival were then identified. Immune characteristics analyses revealed diversified immune cell infiltration among the subtypes. Two clusters served as immune-hot phenotypes associated with significantly poorer survival compared to a remaining third immune-cold cluster. Among these, the immune-hot clusters were characterized by abundant adaptive immune cell infiltration, active CD4+ and CD8+ T cells, high total leukocyte counts and tumor growth status, and lower Th17 cell and M2 macrophage densities. Then, risk scores indicated that low-risk patients were more sensitive to anti-tumor therapy. Subsequently, we found a significant correlation between pyroptosis and prognosis in HCC and that pyroptosis genes drive the heterogeneity of the tumor microenvironment. The risk scoring system, based on pyroptosis-related differentially expressed genes, was established to evaluate the individual outcomes and contribute to new insights into the molecular characterization of pyroptosis-related subtypes.

Impact of the COVID-19 Pandemic on Surgical Oncology in Europe: Results of a European Survey.

BACKGROUND: The first COVID-19 pandemic wave hit most of the health-care systems worldwide. The present survey aimed to provide a European overview on the COVID-19 impact on surgical oncology. METHODS: This anonymous online survey was accessible from April 24 to May 11, 2020, for surgeons (n = 298) who were contacted by the surgical society European Digestive Surgery. The survey was completed by 88 surgeons (29.2%) from 69 different departments. The responses per department were evaluated. RESULTS: Of the departments, 88.4% (n = 61/69) reported a lower volume of patients in the outpatient clinic; 69.1% (n = 47/68) and 75.0% (n = 51/68) reported a reduction in hospital bed and the operating room capacity, respectively. As a result, the participants reported an average reduction of 29.3% for all types of oncological resections surveyed in this questionnaire. The strongest reduction was observed for oncological resections of hepato-pancreatico-biliary (HPB) cancers. Of the interviewed surgeons, 68.7% (n = 46/67) agreed that survival outcomes will be negatively impacted by the pandemic. CONCLUSION: The first COVID-19 pandemic wave had a significant impact on surgical oncology in Europe. The surveyed surgeons expect an increase in the number of unresectable cancers as well as poorer survival outcomes due to cancellations of follow-ups and postponements of surgeries.

[Effects of the first COVID-19 wave on visceral surgery : A retrospective comparison of case numbers from a university hospital and a primary care hospital]. / Auswirkungen der ersten COVID­19-Welle auf die Viszeralchirurgie : Ein retrospektiver Fallzahlenvergleich an einem Universitätsklinikum und einem Krankenhaus der Grund- und Regelversorgung.

BACKGROUND: During the first wave of the COVID-19 pandemic, the downregulation of all elective interventions during the period from 15 March 2020 to 15 May 2020 in Germany led to a decrease in operations. The impact on the number of specific operations in visceral surgery is so far unknown. METHODS: This retrospective study included 301 patients who underwent a cholecystectomy or appendectomy at a university hospital or a primary care facility between 15 March 2020 and 15 May 2020 (vs. 2018 and 2019). The number of cases and the clinical outcomes were analyzed. RESULTS: The suspension of elective surgery resulted in a significant reduction in elective cholecystectomy and emergency appendectomy. At the University Hospital the number of appendectomies decreased by 33% from 24 in 2018 to 16 in 2020 and the number of cholecystectomies declined by 57% from 30 in 2018 to 13 in 2020. At the primary care hospital, the number of appendectomy patients decreased by 48% from 23 in 2018 to 12 in 2020 and the number of cholecystectomies increased from the year 2018 to 2019 and subsequently declined by 30% in 2020. The duration of surgery, length of hospital stay and clinical course of patients did not significantly differ from the previous year time periods. CONCLUSIONS: During the first wave of the COVID-19 pandemic, the lockdown resulted in a significant reduction in frequently carried out visceral surgical interventions. In order to maintain the optimal medical care for the total population, current options for surgical and conservative treatment must be weighed against each other depending on the numbers of local infections and the individual comorbidities of the patients.

The COVID-19 pandemic: impact on surgical departments of non-university hospitals.

BACKGROUND: During the first wave of the COVID-19 pandemic, German health care centres were restructured for the treatment of COVID-19 patients. This was accompanied by the suspension of the surgical programme. The aim of the survey was to determine the effects of COVID-19 on surgical care in non-university hospitals in Germany. METHODS: This cross-sectional study was based on an anonymous online survey, which was accessible from April 24th to May 10th, 2020 for surgeons of the Konvent der leitenden Krankenhauschirurgen (Convention of leading Hospital Surgeons) in Germany. The analysis comprised of 22.8% (n = 148/649) completed surveys. RESULTS: Communication and cooperation with authorities, hospital administration and other departments were largely considered sufficient. In the early phase of the COVID-19 pandemic, 28.4% (n = 42/148) of the respondents complained about a short supply of protective equipment available for the hospital staff. 7.4% (n = 11/148) of the participants stated that emergency operations had to be postponed or rescheduled. A decreased quantity of emergency surgical procedures and a decreased number of surgical emergency patients treated in the emergency room was reported in 43.9% (n = 65/148) and 63.5% (n = 94/148), respectively. Consultation and treatment of oncological patients in the outpatient clinic was decreased in 54.1% (n = 80/148) of the surveyed hospitals. To increase the capacity for COVID-19 patients, a reduction of bed and operating room occupancy of 50.8 ± 19.3% and 54.2 ± 19.1% were reported, respectively. Therefore, 90.5% (n = 134/148) of all participants expected a loss of revenue of 28.2 ± 12.9% in 2020. CONCLUSION: The first wave of the COVID-19 pandemic had a significant impact on surgical care in Germany. The reduction in the bed and the operating room capacity may have lead to considerable delays in urgent and semi-elective surgical interventions. In addition to the risk of worsening patient care, we anticipate severe financial damage to the clinics in 2020 and beyond. National and supranational planning is urgently needed to ensure the surgical care of patients during the ongoing COVID-19 pandemic.

[Effects of the SARS-CoV-2 pandemic on surgery - a national cross-sectional study]. / Auswirkungen der SARS-CoV-2-Pandemie auf die Chirurgie ­ Eine nationale Querschnittsstudie.

BACKGROUND AND AIMS: From the beginning of the SARS-CoV­2 pandemic the German healthcare system focused on the treatment of COVID-19 patients. This was accompanied by the suspension of all elective operations. The aim of this study was to investigate the impact of the SARS-CoV­2 pandemic on general and visceral surgery in university hospitals in Germany. METHODS: This cross-sectional study was based on an anonymous survey, which was accessible online from 3 April 2020 to 17 April 2020 for the surgical departments of university hospitals in Germany. In total 73% (n = 29/40) of the hospitals participated in the survey. RESULTS: Cooperation with the authorities and the hospital administration was generally considered adequate; however, only 3% (1/29) and 7% (2/29) fully agreed with the statement that the health authorities at the federal and state level, respectively, were supportive of general and visceral surgery. The hospital directors expect an average loss of revenues of 28 ± 16%. There was an average reduction in beds or operating room capacity of 38% and 45%, respectively. In addition, 11% of the medical personnel in general and visceral surgery were reallocated to other departments. CONCLUSION: The SARS-CoV­2 pandemic has a significant impact on academic general and visceral surgery in Germany. The reduction in beds and operating room capacity can lead to considerable delays in urgent surgical interventions and financial burdens in 2020 and subsequent years.

Effects of anti-estrogens on cell invasion and survival in pituitary adenoma cells: A systematic study.

Although the molecular mechanisms underlying the formation of pituitary adenomas are largely unknown, it is clear that estrogen plays a key role in the pathogenesis of pituitary adenomas. Though this is exemplified by an investigation of fulvestrant in the pituitary adenoma cell line GH3, no systematic studies on the effects of selective estrogen receptor modulators (SERMs) on functional properties of pituitary adenoma cell lines to modulate cell migration, cell invasion, and cell survival are available. Here we analyzed the effects of fulvestrant and three SERMs, bazedoxifene, clomifene, and raloxifene, on pituitary adenomas cell lines AtT20, TtT/GF, and GH3. In cell survival assays, clomifene was shown to be the most potent compound in all three cell lines with IC50 values ranging between 2, 6, and 10 µM, respectively, depending on the cell type. Raloxifene and bazedoxifene were also effective but to a lower extent. Also, all SERMs affected migratory and invasive behavior of pituitary adenoma cells. Mechanistically, treatment of cells with SERMs caused cell apoptosis, as demonstrated by Caspase 3/7 activity and western blot assays. In addition, western blots demonstrate activation of p53 in TtT/GF cells and loss of ERK1/2 activation in AtT20 cells. In contrast, fulvestrant was only effective in GH3 cells. Thus, the general applicability of SERMs for pituitary adenoma cells might be promising in clinical applications for the treatment of pituitary adenomas.