Septin 6 (SEPT6) is a member of the GTP-binding protein family that is highly conserved in eukaryotes and regulates various biological functions, including filament dynamics, cytokinesis and cell ...migration. However, the functional importance of SEPT6 in hepatocellular carcinoma (HCC) is not completely understood. The present study aimed to investigate the expression levels and roles of SEPT6 in HCC, as well as the underlying mechanisms. The reverse transcription quantitative PCR, western blotting and immunohistochemistry staining results demonstrated that SEPT6 expression was significantly elevated in HCC tissues compared with corresponding adjacent non-tumor tissues, which indicated that SEPT6 expression may serve as a marker of poor prognosis for HCC. By performing plasmid transfection and G418 treatment, stable SEPT6-knockdown and SEPT6-overexpression cell lines were established. The Cell Counting Kit-8, flow cytometry and Transwell assay results demonstrated that SEPT6 overexpression significantly increased HCC cell proliferation, cell cycle transition, migration and invasion compared with the Vector group, whereas SEPT6 knockdown displayed significant suppressive effects on HCC cell lines in vitro compared with the control group. Mechanistically, SEPT6 might facilitate F-actin formation, which induced large tumor suppressor kinase 1 dephosphorylation, inhibited Hippo signaling, upregulated yes-associated protein (YAP) expression and nuclear translocation, and upregulated cyclin D1 and matrix metallopeptidase 2 (MMP2) expression. Furthermore, YAP overexpression significantly reversed SEPT6 knockdown-induced inhibitory effects on HCC, whereas YAP knockdown significantly inhibited the oncogenic effect of SEPT6 overexpression on HCC. Collectively, the present study demonstrated that SEPT6 may promote HCC progression by enhancing YAP activation, suggesting that targeting SEPT6 may serve as a novel therapeutic strategy for HCC. Key words: hepatocellular carcinoma, septin 6, proliferation, migration, invasion, Hippo/yes-associated protein signaling pathway
Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. ...TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC.
A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial.
A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A;
= 54), sorafenib (group B;
= 82) or TACE (group C;
= 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3-9.7), 4.1 months (95% CI: 3.6-4.7) and 5.0 months (95% CI: 2.9-7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0-18.1), 8.4 months (95% CI: 6.0-10.8) and 10.5 months (95% CI: 7.5-13.6), respectively (group A vs. group B:
< 0.001; group A vs. group C:
= 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A.
Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.
BACKGROUNDAllocation of patients with hepatocellular carcinoma (HCC) to the adequate therapy is determined by both tumor burden and liver function. The Barcelona Clinic Liver Cancer (BCLC) staging ...system and therapeutic algorithm recommends transarterial chemoembolization (TACE) based on the best evidence available to patients with intermediate-stage HCC (BCLC-B). However, many centers also treat subgroups of patients outside these recommendations and with more advanced disease by TACE. The purpose of this study was to identify prognostic factors in a TACE cohort, including BCLC-B patients, as well as patients treated outside of BCLC-B, to test the prognostic capabilities of published staging systems and to optimize prognostication for TACE patients.
PATIENTS AND METHODSA cohort of 186 first-line TACE patients was analyzed. Independent prognostic factors were identified and used to construct the Munich-TACE score (M-TACE). M-TACE was tested against established staging systems (including BCLC and two recently published TACE-specific scores) and a ranking using concordance index and Akaike Information Criterion was performed. Finally, an external validation in an independent TACE cohort (n=71) was conducted.
RESULTSBilirubin, Quick/international normalized ratio, C-reactive protein, creatinine, α-feto protein, and tumor extension were identified as independent prognostic factors and used to construct M-TACE. M-TACE identifies three distinct subgroups (P<0.0001) with median survival times of 35.2, 16.9, and 8.6 months, respectively. Compared with established staging systems, M-TACE showed the best prognostic capabilities in both cohorts of patients (cohort 1c-index, 0.71; Akaike Information Criterion1276; cohort 2c-index, 0.754).
CONCLUSIONWe identified independent risk factors for patients treated with TACE. The newly constructed M-TACE score is superior to established staging systems and might prove helpful to identify patients who are most suitable for TACE.
The recently proposed Munich-transarterial chemoembolisation-score (M-TACE) was tailored to suit hepatocellular Carcinoma (HCC) patients evaluated for TACE. M-TACE outperformed the established ...HCC-staging-systems and successfully passed external validation. Modifications of staging-systems through the rearrangement of stages or by adding prognostic factors are methods of improving prognostic power. M-TACEs performance compared to scores modified this way should be tested.
Seven well-known HCC staging-systems (including Cancer of the Liver Italian Program-score CLIP and Barcelona Clinic liver cancer BCLC) and 2 TACE-specific scores (Selection for Transarterial Chemoembolisation Treatment STATE and Hepatoma Arterial embolisation Prognostic HAP) were rearranged in a cohort of 186 TACE-patients through score-point-analysis and subsequent linking of non-significant adjacent score-points. Additionally, a new score was constructed by combining the top established staging-system in TACE patients (CLIP-TACE) and the prognostic parameter with the highest hazard ratio for death in the TACE-cohort C-reactive protein (CRP). Additionally, the TACE-tailored-scores were applied to an external TACE-cohort (n = 71). -Results: Rearrangement resulted in optimal stratification and monotonicity. CLIP-TACE demonstrated the best prognostic capability of all rearranged scores (c-index 0.668, AIC 1294) and the addition of CRP yielded further prognostic improvement (c-index 0.680, AIC 1289). However, superiority over M-TACE could not be achieved by any of the new scores in the internal and external cohort.
M-TACE outperforms TACE-tailored modifications of all relevant HCC-staging-systems. Prospective validation of M-TACE to promote its role as the preferred staging-system for TACE-patients is therefore justified.
ObjectiveObtaining a systematic medical history (MH) from a patient is a core competency in medical education and plays a vital role in the diagnosis of diseases. At the Faculty of Medicine at LMU ...Munich, students have their first course in MH taking during their second year. Due to the COVID-19 pandemic, the traditional bedside MH taking course had to be transformed into an online course (OC). Our objectives were to implement an online MH taking course, to evaluate its feasibility and to compare the evaluation results to a historic cohort that had undertaken the traditional bedside teaching course (BTC). Methods874 second-year students participated in the OC (BTC=827). After teaching the theoretical background via asynchronous online lectures, students participated in a practical exercise with fellow students using the video communication platform Zoom where they were able to practice taking a MH on the basis of fictitious, text-based patient cases. Students were then asked to evaluate the course through a standardized online survey with 31 questions on teaching quality and self-perceived learning success, which had also been used in previous years. The survey results were compared to the results of the historic cohort using the Mann-Whitney U test. ResultsA total of n=162 students (18.5%) evaluated the OC. In the historic cohort, n=252 (30.5%) completed the survey. 85.3% of the OC respondents thought that the atmosphere during the practical exercise was productive and 83.0% greatly appreciated the flexibility in terms of time management. Moreover, they appreciated the online resources as well as having the opportunity to undertake a MH taking course during the COVID-19 pandemic. 27.7% of the respondents thought that traditional BTCs should be supplemented through more online activities in the future. With respect to the ability of independently taking a MH upon completion of the course, the OC was rated significantly lower relative to the BTC (mean OC=2.4, SD=±1.1 vs. mean BTC=1.9, SD=±1.1 (1=strongly agree; 5=strongly disagree); p<0.0001). ConclusionOCs are a feasible format and seem to convey the theory and practical implementation in a peer-exercise format of MH taking to medical students. The theoretical background can be acquired with great flexibility. Nevertheless, the students' self-appraisal suggested that the traditional teaching format was more effective at teaching MH taking skills. Thus, we propose a blended learning concept, combining elements of both formats. In this context, we suggest prospective, randomized trials to evaluate blended learning approaches.
HCC is diagnosed in approximately half a million people per year, worldwide. Staging is a more complex issue than in most other cancer entities and, mainly due to unique geographic characteristics of ...the disease, no universally accepted staging system exists to date. Focusing on survival rates we analyzed demographic, etiological, clinical, laboratory and tumor characteristics of HCC-patients in our institution and applied the common staging systems. Furthermore we aimed at identifying the most suitable of the current staging systems for predicting survival.
Overall, 405 patients with HCC were identified from an electronic medical record database. The following seven staging systems were applied and ranked according to their ability to predict survival by using the Akaike information criterion (AIC) and the concordance-index (c-index): BCLC, CLIP, GETCH, JIS, Okuda, TNM and Child-Pugh. Separately, every single variable of each staging system was tested for prognostic meaning in uni- and multivariate analysis. Alcoholic cirrhosis (44.4%) was the leading etiological factor followed by viral hepatitis C (18.8%). Median survival was 18.1 months (95%-CI: 15.2-22.2). Ascites, bilirubin, alkaline phosphatase, AFP, number of tumor nodes and the BCLC tumor extension remained independent prognostic factors in multivariate analysis. Overall, all of the tested staging systems showed a reasonable discriminatory ability. CLIP (closely followed by JIS) was the top-ranked score in terms of prognostic capability with the best values of the AIC and c-index (AIC 2286, c-index 0.71), surpassing other established staging systems like BCLC (AIC 2343, c-index 0.66). The unidimensional scores TNM (AIC 2342, c-index 0.64) and Child-Pugh (AIC 2369, c-index 0.63) performed in an inferior fashion.
Compared with six other staging systems, the CLIP-score was identified as the most suitable staging system for predicting prognosis in a large German cohort of predominantly non-surgical HCC-patients.
Cirrhotic patients show an increased risk of variceal bleeding upon bacterial infections. Kupffer cells (KC) constitute the first macrophage population to become activated by bacterial beta-glucans ...and endotoxins derived from the gut. We therefore investigated whether and how KC activation increases portal pressure.
KC in normal and fibrotic livers from bile duct ligated (BDL) rats were activated by the beta-glucan component of zymosan in vivo and during isolated rat liver perfusion.
Activation of KC in normal livers resulted in a severalfold increase of portal pressure in vivo as well as in isolated perfused liver preparations. This increase and the accompanying 40-fold stimulation of hepatic prostaglandin F(2alpha)/D(2) and thromboxane A(2) (TxA(2)) production in isolated perfused livers were attenuated by KC blockade. The TxA(2) synthase inhibitor furegrelate and the TxA(2) receptor antagonist BM 13.177 reduced the increase of portal perfusion pressure supporting TxA(2) as pivotal vasoconstrictor released by activated KC. Importantly, a more pronounced vasopressor response in fibrotic livers was related to a raise in KC density and a 10-fold increase of TxA(2) production after KC activation.
KC activated by beta-glucans increase portal pressure through the release of TxA(2). This vasopressor response is augmented in BDL induced fibrosis.
Infection with Entamoeba histolytica and associated complications are relatively rare in developed countries. The overall low prevalence in the Western world as well as the possibly prolonged latency ...period between infection with the causing pathogen and onset of clinical symptoms may delay diagnosis of and adequate treatment for amoebiasis. Amoebic liver abscess (ALA) is the most common extraintestinal manifestation of invasive amoebiasis. Pregnancy has been described as a risk factor for development of invasive amoebiasis and management of these patients is especially complex.
A 30-year-old Caucasian woman in early pregnancy presented to our emergency department with abdominal pain alongside elevated inflammatory markers and liver function tests. Travel history revealed multiple journeys to tropic and subtropic regions during the past decade and a prolonged episode of intermittently bloody diarrhea during a five month stay in Indonesia seven years prior to admission. Sonographic and magnetic resonance imaging revealed a 5 × 4 cm hepatic abscess. After ultrasound-guided transcutaneous liver drainage, both abscess fluids and blood cultures showed neither bacterial growth nor microscopic signs of parasitic disease. Serological testing confirmed an infection with Entamoeba histolytica, which was treated with metronidazole, followed by eradication therapy with paromomycin. Subsequent clinical, laboratory and imaging follow-up exams showed regression of the ALA. In addition, the pregnancy completed without complications and a healthy baby boy was born 7 months after termination of treatment.
This case of invasive amoebiasis in early pregnancy outside of endemic regions and several years after exposure demonstrates the importance of broad differential diagnostics in the context of liver abscesses. The complex interdisciplinary decisions regarding the choice of imaging techniques as well as interventional and antibiotic therapy in the context of pregnancy are discussed. Furthermore, we present possible explanations for pregnancy as a risk factor for an invasive course of amoebiasis.
Postoperative complications of Clavien-Dindo grade 3 or more are of prognostic significance in patients who undergo liver resection for hepatocellular carcinoma (HCC). However, perioperative ...mortality and patient comorbidities represent relevant factors that interfere with postoperative long-term survival. To clarify this, a retrospective single-center study was carried out.
Patient data were prospectively collected in a continuously updated liver resection database. Overall, 184 consecutive patients who underwent liver resection for HCC with a curative intent between March 2003 and December 2013 were selected for the study. The patients were assigned to two groups according to the presence or absence of postoperative complications. Pre-existing comorbidities, perioperative mortality, surgical outcome, and long-term survival data were analyzed.
Postoperative complications requiring revision surgery were identified in 17.4% of the patients. The in-house mortality rate was 4.8%. Compared with patients without complications, patients with complications were older and had significantly more pre-existing comorbidities, more advanced tumors, more intrahepatic metastasis, longer operation times, greater blood loss, and more extensive resections. The overall 5-year survival rates were 40.1 and 52.5% in patients with or without postoperative complications, respectively. The corresponding 5-year recurrence-free survival rates were 46.3 and 46.7% (perioperative mortality excluded). Multivariate analysis showed that elevation of the Charlson Comorbidity Index was associated independently with decreased overall and recurrence-free survival.
In patients with HCC, posthepatectomy complications are confirmed to have predictive value. However, closer analysis and exclusion of perioperative mortality effects show an independent impact of pre-existing comorbidities on long-term overall und recurrence-free survival.
Background. Percutaneous dilatational tracheostomy (PDT) has become the preferred method in several intensive care units (ICUs), but data on PDT performed in immunosuppressed and thrombocytopenic ...patients are scarce. This study aimed to analyze the feasibility of PDT in immunosuppressed and thrombocytopenic patients compared to conventional open surgical tracheostomy (OST). Methods. We retrospectively analyzed the charts of patients who underwent PDT or OST between May 2017 and November 2020. Our outcomes were stoma site infections and bleeding complications. Results. 63 patients underwent PDT, and 21 patients underwent OST. Distribution of gender ratio, age, SAPS II, time of ventilation before tracheostomy, and preexisting hematooncological diseases was comparable between the two groups. After allogeneic stem cell transplantation (alloSCT), patients were more likely to undergo PDT than OST (p=0.033). The PDT cohort suffered from mucositis more frequently (p=0.043). There were no significant differences in leucocyte or platelet count on the tracheostomy day. Patients with coagulation disorders and patients under immunosuppression were distributed equally among both groups. Stoma site infection was documented in five cases in PDT and eight cases in the OST group. Moderate infections were remarkably increased in the OST group. Smears were positive in six cases in the PDT group; none of these patients had local infection signs. In the OST group, smears were positive in four cases; all had signs of a stroma site infection. Postprocedural bleedings occurred in eight cases (9.5%) and were observed significantly more often in the OST group (p=0.001), leading to emergency surgery in one case of the OST group. Conclusion. PDT is a feasible and safe procedure in a predominantly immunosuppressed and thrombocytopenic patient cohort without an increased risk for stoma site infections or bleeding complications.
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