The #HOPE4LIVER Single-Arm Pivotal Trial for Histotripsy of Primary and Metastatic Liver Tumors.

Background Histotripsy is a nonthermal, nonionizing, noninvasive, focused US technique that relies on cavitation for mechanical tissue breakdown at the focal point. Preclinical data have shown its safety and technical success in the ablation of liver tumors. Purpose To evaluate the safety and technical success of histotripsy in destroying primary or metastatic liver tumors. Materials and Methods The parallel United States and European Union and England #HOPE4LIVER trials were prospective, multicenter, single-arm studies. Eligible patients were recruited at 14 sites in Europe and the United States from January 2021 to July 2022. Up to three tumors smaller than 3 cm in size could be treated. CT or MRI and clinic visits were performed at 1 week or less preprocedure, at index-procedure, 36 hours or less postprocedure, and 30 days postprocedure. There were co-primary end points of technical success of tumor treatment and absence of procedure-related major complications within 30 days, with performance goals of greater than 70% and less than 25%, respectively. A two-sided 95% Wilson score CI was derived for each end point. Results Forty-four participants (21 from the United States, 23 from the European Union or England; 22 female participants, 22 male participants; mean age, 64 years ± 12 [SD]) with 49 tumors were enrolled and treated. Eighteen participants (41%) had hepatocellular carcinoma and 26 (59%) had non-hepatocellular carcinoma liver metastases. The maximum pretreatment tumor diameter was 1.5 cm ± 0.6 and the maximum post-histotripsy treatment zone diameter was 3.6 cm ± 1.4. Technical success was observed in 42 of 44 treated tumors (95%; 95% CI: 84, 100) and procedure-related major complications were reported in three of 44 participants (7%; 95% CI: 2, 18), both meeting the performance goal. Conclusion The #HOPE4LIVER trials met the co-primary end-point performance goals for technical success and the absence of procedure-related major complications, supporting early clinical adoption. Clinical trial registration nos. NCT04572633, NCT04573881 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Nezami and Georgiades in this issue.

Mortality and postinterventional complications after ablative treatment of liver malignancies: A cohort study of 4374 patients.

PURPOSE: Ablative therapies for primary and secondary liver malignancies are increasingly adopted in current guidelines. Nevertheless, surgical resection remains the gold standard in most curative therapy settings. Extensive studies on mortality and morbidity after ablative treatment of the liver are missing. We investigated complications and mortality after ablative treatment in a large, unselected study cohort. MATERIALS AND METHODS: Standardized patient and treatment data in 4374 percutaneous and angiographic ablative procedures of the liver from the DRG-based hospital reimbursement system (diagnosis-related groups) of an academic hospital in Germany were retrospectively evaluated. We analyzed descriptive patient data, length of stay (LOS), pre-existing medical conditions, previous gastrointestinal surgeries, severe complications, and occurrence of death. RESULTS: Treatment of secondary liver malignancies constituted over two-thirds of all procedures (71%, n = 3053). The mean LOS was 4.1 ± 3.5 days. Severe complications were documented in 1.4% and in-house death in 0.2% of cases, significantly more often after treatment with chemoembolization of primary liver malignancies (p = 0.003; p = 0.0001). Previous partial liver resection, partial bowel resection, and chronic renal failure were independent risk factors for the occurrence of severe complications. CONCLUSION: Severe complications and in-hospital death are rare in the treatment of primary and secondary liver malignancies with percutaneous and angiographic procedures. They are a viable alternative or addition to a surgical approach in treating liver lesions.

CCL2 Predicts Survival in Patients with Inoperable Hepatocellular Carcinoma Undergoing Selective Internal Radiotherapy.

PURPOSE: Hepatocellular carcinoma (HCC) is the largest subgroup of primary liver tumors. Ablative therapies, such as selective internal radiation therapy (SIRT), are used in late stages for patients with unresectable liver metastases and no response to other therapies. CCL2 (C-C motif chemokine ligand 2) is a potent monocyte chemoattractant. It is associated with tumor progression and metastasis. The role of circulating CCL2 as a biomarker in HCC undergoing selective internal radiation therapy remains unclear. METHODS: A total of 41 patients (8 female, 33 male) suffering from HCC and undergoing SIRT were enrolled. Pre- and post-therapy changes in circulating CCL2 levels were determined by bead-based immunoassay and compared with clinical laboratory parameters and patient data. RESULTS: A total of 32 patients exhibited survival beyond 60 days. It was observed that levels of CCL2 correlated with scores indicating a higher likelihood of non-survival and with the severity of the disease. Moreover, a significant inverse correlation was discovered between CCL2 levels and the survival of patients over 60 days in relation to counts of leukocytes, granulocytes, monocytes, and C-reactive protein. CONCLUSIONS: CCL2 may serve as a potential marker for patient survival after SIRT. The prediction of which HCC patients are likely to benefit from SIRT may be helpful in guiding therapeutic management.

Predictive value of platelet-to-lymphocyte and neutrophil-to-lymphocyte ratio in HCC treated with sorafenib and radioembolization.

Background & Aims: Herein we used data derived from the SORAMIC trial to explore the predictive value of systemic inflammatory markers (neutrophil-to-lymphocyte ratio [NLR] and platelet-to-lymphocyte ratio [PLR]) in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib monotherapy or the combination of selective internal radiation therapy (SIRT)/sorafenib. Methods: Patients randomized to sorafenib monotherapy or SIRT/sorafenib within the per-protocol population of the SORAMIC trial were evaluated in this exploratory post hoc analysis. The median baseline values of NLR and PLR were used as cut-off values to describe subgroups. Kaplan-Meier curves with log-rank tests were used to evaluate median survival in the sorafenib and SIRT/sorafenib arms in each subgroup. Multivariable Cox regression analysis was applied to eliminate the effect of confounding factors. Results: A total of 275 patients with a median overall survival of 12.4 months were included in this analysis. The median NLR value of the cohort was 2.77 and the median PLR was 26.5. There was no significant difference in overall survival between the sorafenib and SIRT/sorafenib arms in patients with low NLR (p = 0.72) and PLR (p = 0.35) values. In patients with high NLR values, there was no statistically significant difference in median overall survival between SIRT/sorafenib and sorafenib cohorts (12.1 vs. 9.2 months, p = 0.21). In patients with high PLR values, overall survival in the SIRT/sorafenib arm was significantly longer than in the sorafenib arm (15.9 vs. 11.0 months, p = 0.029). This significant difference was preserved in the multivariable analysis (SIRT/sorafenib arm: hazard ratio 0.65, 95% CI 0.44-0.96, p = 0.03) incorporating age, Child-Pugh grade, and alpha-fetoprotein levels. Conclusions: PLR is a potential predictive factor of benefit from additional SIRT in patients with HCC receiving sorafenib therapy. The potential predictive value of PLR should be further evaluated in future trials. Impact and implications: Systemic therapies are the mainstay of treatment in patients with hepatocellular carcinoma at advanced stages. However, not all patients respond well to these treatments. In our analysis, using blood test parameters showing systemic inflammation status, we were able to identify patients who would benefit more from combined treatment with a locoregional treatment of radioembolization (or selective internal radiation therapy).

In vivo evaluation of tumor uptake and bio-distribution of 99mTc-labeled 1-thio-ß-D-glucose and 5-thio-D-glucose in mice model.

BACKGROUND: To investigate the capacity of 99mTc-labeled 1-thio-ß-D-glucose (1-TG) and 5-thio-D-glucose (5-TG) to act as a marker for glucose consumption in tumor cells in vivo as well as to evaluate the biodistribution of 1-TG and 5-TG. We investigated the biodistribution, including tumor uptake, of 1-TG and 5-TG at various time points after injection (0.5, 2 and 4 h) in human colorectal carcinoma (HCT-116) and human lung adenocarcinoma (A549) xenograft bearing nude mice (N = 4 per tracer and time point). RESULTS: Ex vivo biodistribution studies revealed a moderate uptake with a maximum tumor-to-muscle ratio of 4.22 ± 2.7 and 2.2 ± 1.3 (HCT-116) and of 3.2 ± 1.1 and 4.1 ± 1.3 (A549) for 1-TG and 5-TG, respectively, with a peak at 4 h for 1-TG and 5-TG. Biodistribution revealed a significantly higher uptake compared to blood in kidneys (12.18 ± 8.77 and 12.69 ± 8.93%ID/g at 30 min) and liver (2.6 ± 2.8%ID/g) for 1-TG and in the lung (7.24 ± 4.1%ID/g), liver (6.38 ± 2.94%ID/g), and kidneys (4.71 ± 1.97 and 4.81 ± 1.91%ID/g) for 5-TG. CONCLUSIONS: 1-TG and 5-TG showed an insufficient tumor uptake with a moderate tumor-to-muscle ratio, not reaching the levels of commonly used tracer, for diagnostic use in human colorectal carcinoma and human lung adenocarcinoma xenograft model.

Association between sacroiliac joint forms and subchondral changes in patients with Crohn's disease.

AIM: To assess the relationship between anatomical variants of sacroiliac joint (SIJ) and subchondral changes detected in magnetic resonance enterography (MRE) in patients with Crohn's disease (CD). METHODS: This was a retrospective study of 60 CD patients, who were divided into two groups: with (n = 16) and without SIJ (n = 44) involvement, depending on the presence of inflammatory (bone marrow edema) and structural changes (sclerosis and erosions) in MRE. Anatomical variants of SIJ were assessed in CT of the abdomen and/or pelvis, distinguishing typical form with convex iliac surface and atypical forms. Univariate and multivariate analyses were performed to reveal an association between joint changes and forms. RESULTS: Our study included 60 patients (38 males; mean age 38.72 years ± 13.33). Patients with SIJ changes were older (p = .044). No significant differences in CD localization and behavior were found. The most common SIJ lesions were structural changes (in 75% of patients); the main atypical form was the iliosacral complex. The univariate and multivariate analyses showed a significant association of atypical forms with total subchondral changes (odds ratio [OR]: 3.429, 95% confidence interval [CI] 1.043-11.268; p = .042; OR: 5.066, 95% CI: 1.273-20.167; p = .021, respectively), and with structural changes (OR: 4.185, 95% CI: 1.155-15.160; p = .029; OR: 5.986, 95% CI: 1.293-27.700; p = .022, respectively). CONCLUSION: Atypical forms of SIJ are a risk factor for the occurrence of structural joint changes in CD patients. An association between bone marrow edema and atypical forms was not found.

Assessing regional hepatic function changes after hypertrophy induction by radioembolisation: comparison of gadoxetic acid-enhanced MRI and 99mTc-mebrofenin hepatobiliary scintigraphy.

BACKGROUND: To compare Gd-ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and 99mTc-labelled mebrofenin hepatobiliary scintigraphy (HBS) as imaging-based liver function tests after unilateral radioembolisation (RE) in patients with primary or secondary liver malignancies. METHODS: Twenty-three patients with primary or secondary liver malignancies who underwent Gd-EOB-DTPA-enhanced MRI within a prospective study (REVoluTion) were evaluated. REVoluTion was a prospective open-label, non-randomised, therapy-optimising study of patients undergoing right-sided or sequential RE for contralateral liver hypertrophy at a single centre in Germany. MRI and hepatobiliary scintigraphy were performed before RE (baseline) and 6 weeks after (follow-up). This exploratory subanalysis compared liver enhancement on hepatobiliary phase MRI normalised to the spleen (liver-to-spleen ratio (LSR)) and the muscle (liver-to-muscle ratio (LMR)) with mebrofenin uptake on HBS for the total liver (TL) and separately for the right (RLL) and left liver lobe (LLL). RESULTS: Mebrofenin uptake at baseline and follow-up each correlated significantly with LSR and LMR on MRI for TL (≤ 0.013) and RLL (≤ 0.049). Regarding the LLL, mebrofenin uptake correlated significantly with LMR (baseline, p = 0.013; follow-up, p = 0.004), whereas with LSR, a borderline significant correlation was only seen at follow-up (p = 0.051; p = 0.046). CONCLUSION: LSRs and LMR correlate with mebrofenin uptake in HBS. This study indicates that Gd-EOB-DTPA-enhanced MRI and 99mTc-labelled mebrofenin HBS may equally be used to assess an increase in contralateral liver lobe function after right-sided RE. RELEVANCE STATEMENT: MRI may be a convenient and reliable method for assessing the future liver remnant facilitating treatment planning and monitoring of patients after RE-induced hypertrophy induction. KEY POINTS: • Both MRI and HBS can assess liver function after RE. • Liver enhancement on MRI correlates with mebrofenin uptake on HBS. • MRI might be a convenient alternative for estimating future liver remnants after hypertrophy induction.

Multi-class Tissue Segmentation of CT images using an Ensemble Deep Learning method.

Microwave ablation (MWA) therapy is a well-known technique for locally destroying lung tumors with the help of computed tomography (CT) images. However, tumor recurrence occurs because of insufficient ablation of the tumor. In order to perform an accurate treatment of lung cancer, there is a demand to determine the tumor area precisely. To address the problem at hand, which involves accurately segmenting organs and tumors in CT images obtained during MWA therapy, physicians could benefit from a semantic segmentation method. However, such a method typically requires a large number of images to achieve optimal results through deep learning techniques. To overcome this challenge, our team developed four different (multiple) U-Net based semantic segmentation models that work in conjunction with one another to produce a more precise segmented image, even when working with a relatively small dataset. By combining the highest weight value of segmentation from multiple methods into a single output, we can achieve a more reliable and accurate segmentation outcome. Our approach proved successful in segmenting four different tissue structures, including lungs, lung tumors, and ablated tissues in CT medical images. The Intersection over Union (IoU) is employed to quantitatively evaluate the proposed method. The method shows the highest average IoU, with 0.99 for the background, 0.98 for the lung, 0.77 for the ablated, and 0.54 for the tumor tissue. The results show that employing multiple DL methods is superior to that of individual base-learner models for all four different tissue structures, even in the presence of the relatively small dataset.Clinical relevance- An essential issue of tumor ablation therapy is to know when the entire tumor tissue has completely been destroyed. However, as it is difficult to distinguish between destroyed and living tumor, this is hardly reliable in clinical practice during MWA therapy, especially when working with a small dataset. Improved AI segmentation methods can help to improve performance to reduce recurrence.

Prognostic value of baseline MRI features in patients treated with thermal ablation for hepatocellular carcinoma.

PURPOSE: To investigate prognostic value of baseline MRI features for time-to-recurrence (TTR) and local recurrence in patients with early hepatocellular carcinoma (HCC). METHOD: Baseline and follow-up images of 88 patients treated with thermal ablation followed by adjuvant sorafenib or matching placebo due to HCC within the phase II prospective randomized trial (SORAMIC) were included. Baseline MRI images were evaluated in terms of atypical enhancement (lack of wash-in or wash-out), lesion diameter, tumor capsule, peritumoral enhancement on arterial phase, intratumoral fat, irregular margin, satellite lesions, and peritumoral hypointensity on hepatobiliary phase. Prognostic value of these features for TTR and local recurrence were assessed with univariable and multivariable Cox proportional hazard models. RESULTS: Recurrence at any location was diagnosed during follow-up in 30 patients, and the median TTR was 16.4 (95% CI, 15 - NA) months. The presence of more than one lesion (p = 0.028) and peritumoral hypointensity on hepatobiliary phase images (p = 0.012) at baseline were significantly associated with shorter TTR in univariable analysis. AFP > 15 mg/dL (p = 0.084), and history of cirrhosis (p = 0.099) were marginally non-significant. Peritumoral hypointensity on hepatobiliary phase images was the only significant risk factor for recurrence in multivariable analysis (p = 0.003). Local recurrence (adjacent to thermal scar) was diagnosed in eleven (8.3%) out of 132 lesions that underwent thermal ablation. The only significant risk factor for local recurrence was a lesion diameter larger than 3 cm (22.2% vs. 4.5%, p = 0.007). CONCLUSIONS: Peritumoral hypointensity on hepatobiliary phase can serve as imaging biomarker to identify increased recurrence risk in patients undergoing thermal ablation for early-stage HCC.

Selective Internal Radiotherapy Alters the Profiles of Systemic Extracellular Vesicles in Hepatocellular Carcinoma.

Incidence of hepatocellular carcinoma (HCC) is increasing globally. Radioembolization (RE)/selective internal radiotherapy (SIRT) is a promising treatment for inoperable HCC. RE triggers an immune response, involving extracellular vesicles (EVs) which are crucial for cell communication and tumor development. This study explores EV immune profiles and origins in patients with inoperable HCC before and after SIRT/RE. Blood samples from 50 HCC-patients treated with SIRT/RE were collected before and after therapy to determine cytokines and isolate EVs using size exclusion chromatography. The dynamic range and EV quality required for detecting variations in surface markers were assessed. Thirty-seven EV surface markers were analyzed using flow cytometry and correlated with clinical parameters. Several immunological markers (CD4, CD2, CD40, CD45, CD49e, CD69, CD209-EVs) were present in the circulation of HCC patients. These markers positively correlated with therapy response and survival. Conversely, B cell CD20, endothelial cell CD146, platelet CD49e, and CD41b EV markers negatively correlated with 60-day survival. Elevated levels of IL-6 and IL-8 before therapy correlated negatively with patient survival, coinciding with a positive correlation with CD20-positive EVs. Plasma EVs from HCC patients exhibit immunological, cancer, and coagulation markers, including potential biomarkers (CD4, CD20, CD49e, CD146). These may enhance our understanding of cancer biology and facilitate SIRT therapy monitoring.

Cholecystitis induced by Yttrium-90 radioembolization of advanced liver tumors: prospective evaluation of a management algorithm in 197 consecutive patients.

BACKGROUND: Cholecystitis is a rare but dolorous complication after Y90-radioembolization of liver malignancies. PURPOSE: To decide the occlusion of the cystic artery (CA) to prevent cholecystitis after Y90 radioembolization using an algorithm. MATERIAL AND METHODS: In 130 patients, the gallbladder was at risk of embolization as the right liver lobe was targeted. Precautionary measures (e.g. coil occlusion of the cystic artery) were decided by enhancement of the gallbladder in pre-treatment Tc99m-MAA SPECT/CT and performed directly before Y90 radioembolization. In non-enhancing cases, the CA was left open. The outcome was determined by clinical symptoms of acute or chronic cholecystitis as well as imaging and laboratory parameters. Findings were additionally classified according to the Tokyo Guidelines of acute cholecystitis. RESULTS: Only 16 patients demonstrated enhancement of the gallbladder in Tc99m-MAA SPECT/CT. Including additional indications from angiographic findings, prophylactic measures were scheduled in 22 patients (standard of care). Thus, 121 patients were at risk of non-target embolization to the gallbladder during Y90 microsphere administration (investigative arm). Four cases (3.0%) of cholecystitis occurred by clinical presentation: two patients with onset of acute symptoms within 48 h after Y90 radioembolization ("embolic cholecystitis") and two patients with late onset of symptoms ("radiogenic cholecystitis"). The incidence of cholecystitis was not significantly more frequent without indication of precautionary measures (investigative cohort 2.9% vs. standard of care 4.7%; P = 0.53). CONCLUSION: The overall incidence of cholecystitis after Y90 radioembolization is low. Determination of cystic artery intervention using Tc99m-MAA SPECT/CT successfully balances the incidence of symptomatic cholecystitis with unnecessary vessel occlusion.

Prognostic role of radiomics-based body composition analysis for the 1-year survival for hepatocellular carcinoma patients.

BACKGROUND: Parameters of body composition have prognostic potential in patients with oncologic diseases. The aim of the present study was to analyse the prognostic potential of radiomics-based parameters of the skeletal musculature and adipose tissues in patients with advanced hepatocellular carcinoma (HCC). METHODS: Radiomics features were extracted from a cohort of 297 HCC patients as post hoc sub-study of the SORAMIC randomized controlled trial. Patients were treated with selective internal radiation therapy (SIRT) in combination with sorafenib or with sorafenib alone yielding two groups: (1) sorafenib monotherapy (n = 147) and (2) sorafenib and SIRT (n = 150). The main outcome was 1-year survival. Segmentation of muscle tissue and adipose tissue was used to retrieve 881 features. Correlation analysis and feature cleansing yielded 292 features for each patient group and each tissue type. We combined 9 feature selection methods with 10 feature set compositions to build 90 feature sets. We used 11 classifiers to build 990 models. We subdivided the patient groups into a train and validation cohort and a test cohort, that is, one third of the patient groups. RESULTS: We used the train and validation set to identify the best feature selection and classification model and applied it to the test set for each patient group. Classification yields for patients who underwent sorafenib monotherapy an accuracy of 75.51% and area under the curve (AUC) of 0.7576 (95% confidence interval [CI]: 0.6376-0.8776). For patients who underwent treatment with SIRT and sorafenib, results are accuracy = 78.00% and AUC = 0.8032 (95% CI: 0.6930-0.9134). CONCLUSIONS: Parameters of radiomics-based analysis of the skeletal musculature and adipose tissue predict 1-year survival in patients with advanced HCC. The prognostic value of radiomics-based parameters was higher in patients who were treated with SIRT and sorafenib.

Transfer-learning is a key ingredient to fast deep learning-based 4D liver MRI reconstruction.

Time-resolved volumetric magnetic resonance imaging (4D MRI) could be used to address organ motion in image-guided interventions like tumor ablation. Current 4D reconstruction techniques are unsuitable for most interventional settings because they are limited to specific breathing phases, lack temporal/spatial resolution, and have long prior acquisitions or reconstruction times. Deep learning-based (DL) 4D MRI approaches promise to overcome these shortcomings but are sensitive to domain shift. This work shows that transfer learning (TL) combined with an ensembling strategy can help alleviate this key challenge. We evaluate four approaches: pre-trained models from the source domain, models directly trained from scratch on target domain data, models fine-tuned from a pre-trained model and an ensemble of fine-tuned models. For that the data base was split into 16 source and 4 target domain subjects. Comparing ensemble of fine-tuned models (N = 10) with directly learned models, we report significant improvements (P < 0.001) of the root mean squared error (RMSE) of up to 12% and the mean displacement (MDISP) of up to 17.5%. The smaller the target domain data amount, the larger the effect. This shows that TL + Ens significantly reduces beforehand acquisition time and improves reconstruction quality, rendering it a key component in making 4D MRI clinically feasible for the first time in the context of 4D organ motion models of the liver and beyond.

Post-therapeutic microRNA-146a in liquid biopsies may determine prognosis in metastatic gastrointestinal cancer patients receiving 90Y-radioembolization.

PURPOSE: The role of microRNA-146a (miR-146a) in defining the tumor immune microenvironment (TIME) is well established. The aim of this study was to evaluate circulating miR-146a as an early prognostic marker of 90Y-radioembolization (90Y-RE) in metastatic liver cancer and to assess the correlation between circulating miR-146a and TIME cellular composition in distant, yet untreated metastases. METHODS: Twenty-one patients with bilobar liver lesions from gastro-intestinal cancer underwent lobar 90Y-RE. Biopsy of contralateral lobe abscopal tumors was acquired at the onset of a second treatment session at a median of 21 days after initial RE, immediately prior to ablation therapy of the contralateral lobe tumor. miR-146a was measured by RT-qPCR in plasma collected 24 h before (T1) and 48 h after (T2) initial unilobar 90Y-RE. The level of miR-146a was correlated with the infiltration of CD4 + , CD8 + , FoxP3 T cells, CD163 + M2 macrophages and immune-exhausted T cells in the abscopal tumor tissue acquired before the second treatment session. RESULTS: Plasma samples collected at T2 showed a higher concentration of miR-146a with respect to T1 in 43% of the patients (p = 0.002). In these patients, tumors revealed a pro-tumorigenic immune composition with enrichment of Tim3 + immune exhausted cells (p = 0.021), in combination with a higher infiltration of CD163 + M2 macrophages and a lower infiltration of CD8 + T cells. Patients with a higher level of miR-146a after 90Y-RE showed a trend to shorter OS (p = 0.055). CONCLUSION: miR-146a may represent a novel prognostic biomarker for 90Y-radioembolization in metastatic liver cancer.

Joint liver and hepatic lesion segmentation in MRI using a hybrid CNN with transformer layers.

Backgound and Objective: Deep learning-based segmentation of the liver and hepatic lesions therein steadily gains relevance in clinical practice due to the increasing incidence of liver cancer each year. Whereas various network variants with overall promising results in the field of medical image segmentation have been successfully developed over the last years, almost all of them struggle with the challenge of accurately segmenting hepatic lesions in magnetic resonance imaging (MRI). This led to the idea of combining elements of convolutional and transformer-based architectures to overcome the existing limitations. METHODS: This work presents a hybrid network called SWTR-Unet, consisting of a pretrained ResNet, transformer blocks as well as a common Unet-style decoder path. This network was primarily applied to single-modality non-contrast-enhanced liver MRI and additionally to the publicly available computed tomography (CT) data of the liver tumor segmentation (LiTS) challenge to verify the applicability on other modalities. For a broader evaluation, multiple state-of-the-art networks were implemented and applied, ensuring direct comparability. Furthermore, correlation analysis and an ablation study were carried out, to investigate various influencing factors on the segmentation accuracy of the presented method. RESULTS: With Dice similarity scores of averaged 98±2% for liver and 81±28% lesion segmentation on the MRI dataset and 97±2% and 79±25%, respectively on the CT dataset, the proposed SWTR-Unet proved to be a precise approach for liver and hepatic lesion segmentation with state-of-the-art results for MRI and competing accuracy in CT imaging. CONCLUSION: The achieved segmentation accuracy was found to be on par with manually performed expert segmentations as indicated by inter-observer variabilities for liver lesion segmentation. In conclusion, the presented method could save valuable time and resources in clinical practice.

Interstitial Brachytherapy for Hepatocellular Carcinoma: Analysis of Prognostic Factors for Overall Survival and Progression-Free Survival and Application of a Risk Stratification Model.

INTRODUCTION: Interstitial brachytherapy (iBT) is an effective treatment for hepatocellular carcinoma (HCC). Identification of prognostic factors is pivotal for patient selection and treatment efficacy. This study aimed to assess the impact of low skeletal muscle mass (LSMM) on overall survival (OS) and progression-free survival (PFS) of iBT in patients with HCC. METHODS: For this single-center study, we retrospectively identified 77 patients with HCC who underwent iBT between 2011 and 2018. Follow-up visits were recorded until 2020. The psoas muscle area, psoas muscle index, psoas muscle density (MD), and the skeletal muscle gauge were assessed on the L3 level on pre-treatment cross-sectional CT scans. RESULTS: Median OS was 37 months. 42 patients (54.5%) had LSMM. An AFP level of >400 ng/ml (hazard ratio [HR] 5.705, 95% confidence interval [CI]: 2.228-14.606, p = 0.001), BCLC stage (HR 3.230, 95% CI: 0.972-10.735, p = 0.026), and LSMM (HR 3.365, 95% CI: 1.490-7.596, p = 0.002) showed a relevant association with OS. Weighted hazard ratios were used to form a predictive risk stratification model with three groups: patients with low risk (median OS 62 months), intermediate risk (median OS 31 months), and high risk (median OS 9 months). The model showed a good prediction of 1-year mortality, with an AUC of 0.71. Higher MD was associated with better PFS (HR 0.920, 95% CI: 0.881-0.962, p < 0.001). CONCLUSION: In patients undergoing iBT for HCC, LSMM is associated with worse OS. A risk stratification model based on LSMM, AFP >400 ng/mL, and BCLC stage successfully predicted patient mortality. The model may support and enhance patient selection.

Impact of body composition in advanced hepatocellular carcinoma: A subanalysis of the SORAMIC trial.

BACKGROUND: Body composition parameters have been reported to be prognostic factors in patients with oncologic diseases. However, the available data on patients with HCC are conflicting. The aim of this study was to assess the impact of body composition on survival in patients with HCC treated with sorafenib or selective internal radioembolization (SIRT) and sorafenib. METHODS: This is an exploratory subanalysis of the prospective, randomized controlled SORAMIC trial. Within the palliative arm of the study, patients were selected if a baseline abdominal CT was available. A broad set of skeletal muscle and adipose tissue parameters were measured at the L3 level. Low skeletal muscle mass (LSMM) and density parameters were defined using published cutoffs. The parameters were correlated with overall survival. RESULTS: Of 424 patients in the palliative study arm, 369 patients were included in the analysis. There were 192 patients in the combined sorafenib/SIRT and 177 patients in the sorafenib group. Median overall survival was 9.9 months for the entire cohort and 10.8 and 9.2 months for the SIRT/sorafenib and sorafenib groups, respectively. There was no relevant association of either body composition parameter with overall survival in either the overall cohort or in the SIRT/sorafenib or sorafenib subgroups. CONCLUSIONS: This subanalysis of the prospective SORAMIC trial does not suggest a relevant influence of body composition parameters of survival in patients with advanced HCC. Body composition parameters therefore do not serve in patient allocation in this palliative treatment cohort.

Multidisciplinary Treatment of Patients with Progressive Biliary Tract Cancer after First-Line Gemcitabine and Cisplatin: A Single-Center Experience.

BACKGROUND: Patients with unresectable biliary tract cancer (uBTC) who progress despite first-line gemcitabine plus cisplatin (GC) treatment have limited systemic options with a modest survival benefit. Data are lacking on the clinical effectiveness and safety of personalized treatment based on multidisciplinary discussion for patients with progressing uBTC. METHODS: This retrospective single-center study included patients with progressive uBTC who received either best supportive care or personalized treatment based on multidisciplinary discussion, including minimally invasive, image-guided procedures (MIT); FOLFIRI; or both (MIT and FOLFIRI), between 2011 and 2021. RESULTS: Ninety-seven patients with progressive uBTC were identified. Patients received best supportive care (n = 50, 52%), MIT (n = 14, 14%), FOLFIRI (n = 19, 20%), or both (n = 14, 14%). Survival after disease progression was better in patients who received MIT (8.8 months; 95% CI: 2.60-15.08), FOLFIRI (6 months; 95% CI: 3.30-8.72), or both (15.1 months; 95% CI: 3.66-26.50) than in patients receiving BSC (0.36 months; 95% CI: 0.00-1.24, p < 0.001). The most common (>10%) grade 3-5 adverse events were anemia (25%) and thrombocytopenia (11%). CONCLUSION: Multidisciplinary discussion is critical for identifying patients with progressive uBTC who might benefit the most from MIT, FOLFIRI, or both. The safety profile was consistent with previous reports.

Prevention of radiation-induced liver toxicity after interstitial HDR brachytherapy by pentoxifylline and ursodeoxycholic acid: patient compliance and outcome in a randomized trial.

AIM: To investigate the impact of pentoxifylline (PTX, 3 × 400 mg per day) and ursodeoxycholic acid (UDCA, 3 × 250 mg per day) administered for 12 weeks on radiation-induced liver toxicity. MATERIALS AND METHODS: Inclusion criteria were liver metastases of extrahepatic malignancies undergoing HDR-BT. 36 patients were prospectively randomized to the medication (N = 18) or control arm (N = 18) and follow-up by hepatobiliary magnetic resonance imaging (MRI) was scheduled 6 and 12 weeks after local ablation by HDR-BT. We determined the threshold doses of fRILI by image fusion of MRI with the dosimetry data. RESULTS: 32 patients completed the study schedule. Per-protocol treatment was limited to 8 patients in the medication group and 16 patients in the control group. 22 adverse events of any grade likely or certainly related to PTX were recorded in 12 patients leading to the discontinuation of the study medication in 7 patients and to a dose reduction of PTX in 2 patients. In the per-protocol population, statistical analysis failed to prove a reduction of fRILI 6 and 12 weeks after HDR-BT. The incidence of adverse effects attributed to PTX (70.6%) was well above the data found in the literature for its approved indication. CONCLUSION: The study endpoint was not met mainly attributed to the low statistical power of the small per-protocol cohort. Independently, PTX cannot be recommended for the reduction of radiation-induced liver toxicity in oncologic patients undergoing HDR-BT of liver metastases. Further studies might focus on a combination of UDCA with other potential drugs to help establish a preventive and tolerable regimen.

Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.