Light Converts Endosymbiotic Fungus to Pathogen, Influencing Seedling Survival and Niche-Space Filling of a Common Tropical Tree, Iriartea deltoidea

Pathogens are hypothesized to play an important role in the maintenance of tropical forest plant species richness. Notably, species richness may be promoted by incomplete filling of niche space due interactions of host populations with their pathogens. A potentially important group of pathogens are endophytic fungi, which asymptomatically colonize plants and are diverse and abundant in tropical ecosystems. Endophytes may alter competitive abilities of host individuals and improve host fitness under stress, but may also become pathogenic. Little is known of the impacts of endophytes on niche-space filling of their hosts

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus Advagraf™ in liver transplant recipients

Background Graft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients. Methods The EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus Advagraf™ (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period. Discussion C/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022

Transjugular Portosystemic Stent Shunt: Impact of Right Atrial Pressure on Portal Venous Hemodynamics Within the First Week

Purpose!#!Porto-systemic pressure gradient is used to prognosticate rebleeding and resolution of ascites after TIPS. This study investigates the reliability of portal pressure characteristics as quantified immediately after TIPS placement and at short-term control.!##!Patients and methods!#!Portal venous pressure (PVP) and right atrial pressure (RAP) were prospectively obtained before and after TIPS as well as ≥ 48 h after TIPS procedure. Porto-systemic pressure gradients (PSG) and pressure changes were calculated. A multivariate regression analysis was performed to predict portal hemodynamics at short-term control.!##!Results!#!The study included 124 consecutive patients. Indications for TIPS were refractory ascites, variceal bleeding or combinations of both. Pre- and post-interventional PSG yielded 16.4 ± 5.3 mmHg and 5.9 ± 2.7 mmHg, respectively. At that time, 105/124 patients (84.7%) met the target (PSG ≤ 8 mmHg). After 4 days (median), PSG was 8.5 ± 3.5 mmHg and only 66 patients (53%) met that target. In patients exceeding the target PSG at follow-up, PVP was significantly higher and RAP was lower resulting in the increased PSG. The highly variable changes of RAP were the main contributor to different pressure gradients. In the multivariate regression analysis, PVP and RAP immediately after TIPS were predictors for PSG at short-term control with moderately predictive capacity (AUC = 0.75).!##!Conclusion!#!Besides the reduction of portal vein pressure, the highly variable right atrial pressure was the main contributor to different pressure gradients. Thus, immediate post-TIPS measurements do not reliably predict portal hemodynamics during follow-up. These findings need to be further investigated with respect to the corresponding clinical course of the patients

Surgical therapy of primary hepatic angiosarcoma

Abstract Background Primary hepatic angiosarcoma (PHA) is a rare tumor entity. Radical surgical resection is currently considered the best treatment choice. The aim of this analysis is to report our experience with surgery for PHA. Methods All resections of PHA from 01/2002 until 06/2017 were identified from our prospective institutional database. All cases were re-confirmed by a second pathologist. We analyzed completeness of resection, overall (OS) and disease-free survival (DFS). Results Nine patients with PHA underwent hepatic resection. Median follow-up after surgery was 15.5 months (range: 3–144). At last follow-up 4/9 patients were alive, three of them without recurrence 15, 21 and 144 months after surgery. Five patients developed PHA recurrence. Four of these died 3 to 17 months after surgery. One patient with PHA recurrence is alive 15 months after surgery. Another patient without PHA recurrence died 59 months after surgery from pancreatic cancer. Median OS and DFS after resection was 18 months (range: 3–144 months) and 10 months (range: 2–144 months), respectively. After R-0 resection (n = 8), the median OS and DFS was 59 and 11 months. Conclusions Resection of PHA is the only approach to achieve complete tumor removal and offers a chance for long-term survival and should be evaluated in cases of PHA

Elderly Patients with Hepatocellular Carcinoma benefit from Liver Transplantation as much as younger ones

Abstract: Introduction: The literature on liver transplantation (LT) for cirrhosis-associated hepatocellular carcinoma (cirr-HCC) in elderly patients (≥65 years of age) is scarce. The aim of this study was therefore to analyze the outcome after LT for cirr-HCC in elderly patients in our single-center experience. Methods: All consecutive patients who underwent LT for cirr-HCC at our center were identified from our prospectively collected LT database and stratified into an elderly (≥65 years) and a younger (<65 years) cohort. Perioperative mortality as well as Kaplan-Meier estimations of overall (OS) and recurrence-free survival (RFS) were compared between age strata. A sub-group analysis was performed for patients with HCC only inside Milan criteria. For further oncological comparison, outcome in the subgroup of elderly LT recipients with HCC inside Milan was also compared to a group of elderly patients undergoing liver resection for cirr-HCC inside Milan extracted from our institutional liver resection database. Results: Out of 369 consecutive patients with cirr-HCC who underwent LT between 1998 and 2022 at our center, we identified 97 elderly (with a subgroup of 14 septuagenarians) and 272 younger LT patients. 5- and 10-year OS in elderly compared to younger LT patients was 63% and 52% vs. 63% and 46% (p = 0.67), respectively, while 5- and 10-year RFS was 58% and 49% vs. 58% and 44% (p = 0.69). 5-/10-year OS and RFS in 50 elderly LT recipients with HCC inside Milan were 68%/55% and 62%/54%, respectively, which compared to 46%/38% (p = 0.07)and 26%/14% (p < 0.0001) in elderly patients after liver resection for cirr-HCC inside Milan. Discussion/Conclusion: Our results in almost 100 elderly patients after LT for cirr-HCC show that older age per se should not be considered a contraindication to LT and that selected elderly patients older than 65 and even 70 years benefit from LT as much as younger ones

Quantitative assessment of washout in hepatocellular carcinoma using MRI

Background Arterial hyperenhancement and washout on computed tomography and magnetic resonance imaging (MRI) are described by all major guidelines as specific criteria for non-invasive diagnosis of hepatocellular carcinoma (HCC). However, publications on the quantitative assessment of washout in MRI are lacking. Therefore, we evaluated a method for quantitatively measuring and defining washout in MRI in order to determine a cutoff value that allows objective HCC diagnosis. Methods We analyzed all patients who underwent liver transplantation for cirrhosis or liver resection for HCC at our institution between 2003 and 2014. Washout was quantitatively investigated by placing a 25-mm2 region of interest (ROI) over each nodule and two 25-mm2 ROIs over adjacent liver parenchyma. The percentage signal ratio (PSR = 100 × ratio of signal intensity of adjacent liver to that of the lesion) was calculated for each series in both groups. Accordingly, this quantitative measurement was compared to a qualitative approach. Results A total of 16 hypervascularized non-HCC nodules and 69 HCC nodules were identified. Interobserver reliability was reasonably good for the measurement of PSRs and readers showed a substantial agreement for the qualitative assessment. In the HCC group, the median PSR was 116.2 at equilibrium and 112.9 in the delayed phase. In the non-HCC group, the median PSR was 93.8 at equilibrium and 96.0 in the delayed phase. Receiver operating characteristic analysis indicated areas under the curve of 0.902 (p < 0.001) and 0.873 (p < 0.001) at equilibrium and in the delayed phase. PSR values of 102 at equilibrium and 101.5 in the delayed phase led to the highest Youden’s index of 0.82 and 0.77, respectively. These PSR cutoffs yielded sensitivities of 82 and 77 %, respectively, with specificities of 100 %. The sensitivity for the qualitative assessment of washout was 88 and 93 % and the specificity was 48 and 56 %. For the classification of HCC, sensitivity yielded 95 and 97 % and specificity was 68 and 56 %, respectively. Conclusion Quantitatively measuring HCC washout in MRI is easy and reproducible. It can objectify and support diagnosis of HCC. However, the quantitative measurement of washout can only serve as one of several components of HCC assessment

Outcome after Resection for Hepatocellular Carcinoma in Noncirrhotic Liver—A Single Centre Study

Liver cirrhosis is the most common risk factor for the development of hepatocellular carcinoma (HCC). However, 10 to 15% of all HCC arise in a non-cirrhotic liver. Few reliable data exist on outcome after liver resection in a non-cirrhotic liver. The aim of this single-centre study was to evaluate the outcome of resection for HCC in non-cirrhotic liver (NC-HCC) and to determine prognostic factors for overall (OS) and intrahepatic recurrence-free (RFS) survival. From 2008 to 2020, a total of 249 patients were enrolled in this retrospective study. Primary outcome was OS and RFS. Radiological and pathological findings, such as tumour size, number of nodules, Tumour-, Nodes-, Metastases- (TNM) classification and vascular invasion as well as extent of surgical resection and laboratory liver function were collected. Here, 249 patients underwent liver resection for NC-HCC. In this case, 50% of patients underwent major liver resection, perioperative mortality was 6.4%. Median OS was 35.4 months (range 1–151 months), median RFS was 10.5 months (range 1–128 moths). Tumour diameter greater than three centimetres, multifocal tumour disease, vascular invasion, preoperative low albumin and increased alpha-fetoprotein (AFP) values were associated with significantly worse OS. Our study shows that resection for NC-HCC is an acceptable treatment approach with comparatively good outcome even in extensive tumours

Opinions and use of neoadjuvant therapy for resectable, borderline resectable, and locally advanced pancreatic cancer: International survey and case-vignette study

Background: Several new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC), but the support for their use for resectable, borderline resectable and locally advanced PDAC is unclear. Methods: A survey was distributed to the members of the European-African Hepato-Pancreato Biliary Association (E-AHPBA) and the pancreas group of the European Organization for Research and Treatment of Cancer (EORTC) regarding 1) definitions of local resectability, 2) indications for neoadjuvant therapy and 3) case-vignettes regarding the resectability and treatment of PDAC. Results: In total, 114 participants from 37 countries were registered. About 35% of respondents, each, were of the opinion that borderline resectability is defined by any venous tumor contact and venous involvement < 180° or > 180°, respectively. The majority (75.4%) of participants believed that borderline resectable PDAC has a high risk for R1 resection and that neoadjuvant therapy might increase the R0-resection rate (79.8%) and improve oncological patient selection (84.2%). Chemotherapy was regarded useful to convert locally advanced to resectable PDAC by 55.7% of respondents. In the cases with resectable, borderline resectable, and locally advanced PDAC, 10 (8.8%), 78 (68.4%), 55 (48.2%) of participants would start with chemotherapy, respectively. Conclusions: Although definitions for borderline resectability differ among European surgeons, there seems to be a rather strong support for preoperative chemotherapy in PDAC aiming at minimizing R1 resections while increasing resection rates

Baseline Splenic Volume Outweighs Immuno-Modulated Size Changes with Regard to Survival Outcome in Patients with Hepatocellular Carcinoma under Immunotherapy

Background: An association between immunotherapy and an increase in splenic volume (SV) has been described for various types of cancer. SV is also highly predictive of overall survival (OS) in patients with hepatocellular carcinoma (HCC). We evaluated SV and its changes with regard to their prognostic influence in patients with HCC undergoing immunotherapy. Methods: All patients with HCC who received immunotherapy in first or subsequent lines at our tertiary care center between 2016 and 2021 were screened for eligibility. SV was assessed at baseline and follow-up using an AI-based tool for spleen segmentation. Patients were dichotomized into high and low SV based on the median value. Results: Fifty patients were included in the analysis. The median SV prior to treatment was 532 mL. The median OS of patients with high and low SV was 5.1 months and 18.1 months, respectively (p = 0.01). An increase in SV between treatment initiation and the first follow-up was observed in 28/37 (75.7%) patients with follow-up imaging available. This increase in itself was not prognostic for median OS (7.0 vs. 8.5 months, p = 0.73). However, patients with high absolute SV at the first follow-up continued to have impaired survival (4.0 months vs. 30.7 months, p = 0.004). Conclusion: High SV prior to and during treatment was a significant prognostic factor for impaired outcome. Although a large proportion of patients showed an SV increase after the initiation of immunotherapy, this additional immuno-modulated SV change was negligible compared to long-standing changes in the splanchnic circulation in patients with HCC

Portal hypertension in patients with hepatocellular carcinoma and immunotherapy: prognostic relevance of CT-morphologic estimates

Abstract Background Clinically significant portal hypertension (CSPH) has been identified as an important prognostic factor in patients with hepatocellular carcinoma (HCC) undergoing curative treatment. This study aimed to assess PH estimates as prognostic factors in patients with HCC treated with immunotherapy. Methods All patients with HCC treated with an immunotherapeutic agent in first or subsequent lines at our tertiary care center between 2016 and 2021 were included (n = 50). CSPH was diagnosed using the established PH score for non-invasive PH estimation in pre-treatment CT data (cut-off ≥ 4). Influence of PH on overall survival (OS) and progression-free survival (PFS) was assessed in uni- and multivariable analyses. Results Based on the PH score, 26 patients (52.0%) were considered to have CSPH. After treatment initiation, patients with CSPH had a significantly impaired median OS (4.1 vs 33.3 months, p < 0.001) and a significantly impaired median PFS (2.7 vs 5.3 months, p = 0.02). In multivariable Cox regression, CSPH remained significantly associated with survival (HR 2.9, p = 0.015) when adjusted for established risk factors. Conclusions Non-invasive assessment of CSPH using routine CT data yielded an independent prognostic factor in patients with HCC and immunotherapy. Therefore, it might function as an additional imaging biomarker to detect high-risk patients with poor survival and possibly for treatment decision making