Efficacy and Safety of Local Liver Radioablation in HCC Lesions within and beyond Limits of Thermal Ablation.

INTRODUCTION: CT-guided interstitial Brachytherapy (iBT) Radiotherapy has been established in the treatment of liver tumors. With iBT, HCC lesions can be treated beyond the limits of thermal ablation (i.e., size and location). However, a comprehensive analysis of the efficacy of iBT in patients within and beyond thermal ablation limits is lacking. MATERIALS AND METHODS: 146 patients with 216 HCC lesions have been analyzed retrospectively. Clinical and imaging follow-up data has been collected. Lesions were evaluated in terms of suitability for thermal ablation or not. The correlation between local tumor control (LTC), time-to-progression (TTP), and overall survival (OS), and clinical and imaging parameters have been evaluated using univariable and multivariable Cox regression analyses. RESULTS: LTC rates at 12 months, 24 months, and 36 months were 87%,75%, and 73%, respectively. 65% of lesions (n=141) were not suitable for RFA. The median TTP was 13 months, and the median OS was not reached (3-year OS rate: 70%). No significant difference in LTC, TTP, or OS regarding RFA suitability existed. However, in the overall multivariable analysis, lesion diameter > 5 cm was significantly associated with lower LTC (HR: 3.65, CI (1.60-8.31), p=0.002) and shorter TTP (HR: 2.08, CI (1.17-3.70), p=0.013). Advanced BCLC stage, Child-Pugh Stage, and hepatitis B were associated with shorter OS. CONCLUSION: iBT offers excellent LTC rates and OS in local HCC treatment regardless of the limits of thermal ablation, suggesting further evidence of its alternative role to thermal ablation in patients with early-stage HCC.

Utility of clinical and MR imaging parameters for prediction and monitoring of response to capecitabine and temozolomide (CAPTEM) therapy in patients with liver metastases of neuroendocrine tumors.

BACKGROUND: This study explores the predictive and monitoring capabilities of clinical and multiparametric MR parameters in assessing capecitabine and temozolomide (CAPTEM) therapy response in patients with neuroendocrine tumors (NET). PATIENTS AND METHODS: This retrospective study (n = 44) assessed CAPTEM therapy response in neuroendocrine liver metastases (NELM) patients. Among 33 monitored patients, as a subgroup of the overall study cohort, pretherapeutic and follow-up MRI data (size, apparent diffusion coefficient [ADC] values, and signal intensities), along with clinical parameters (chromogranin A [CgA] and Ki-67%), were analyzed. Progression-free survival (PFS) served as the reference. Responders were defined as those with PFS ≥ 6 months. RESULTS: Most patients were male (75%) and had G2 tumors (76%) with a pancreatic origin (84%). Median PFS was 5.7 months; Overall Survival (OS) was 25 months. Non-responders (NR) had higher Ki-67 in primary tumors (16.5 vs. 10%, p = 0.01) and increased hepatic burden (20% vs. 5%, p = 0.007). NR showed elevated CgA post-treatment, while responders (R) exhibited a mild decrease. ADC changes differed significantly between groups, with NR having decreased ADCmin (-23%) and liver-adjusted ADCmean/ADCmean liver (-16%), compared to R's increases of ADCmin (50%) and ADCmean/ADCmean liver (30%). Receiver operating characteristic (ROC) analysis identified the highest area under the curve (AUC) (0.76) for a single parameter for ∆ ADC mean/liver ADCmean, with a cut-off of < 6.9 (76% sensitivity, 75% specificity). Combining ∆ Size NELM and ∆ ADCmin achieved the best balance (88% sensitivity, 60% specificity) outperforming ∆ Size NELM alone (69% sensitivity, 65% specificity). Kaplan-Meier analysis indicated significantly longer PFS for ∆ ADCmean/ADCmean liver < 6.9 (p = 0.024) and ∆ Size NELM > 0% + ∆ ADCmin < -2.9% (p = 0.021). CONCLUSIONS: Survival analysis emphasizes the need for adapted response criteria, involving combined evaluation of CgA, ADC values, and tumor size for monitoring CAPTEM response in hepatic metastasized NETs.

miRNome profiling analysis reveals novel hepatocellular carcinoma diagnostic, prognostic and treatment-related candidate biomarkers: post-hoc analysis of SORAMIC trial.

Introduction Early diagnosis of hepatocellular carcinoma as well as evaluation of prognosis and prediction of treatment efficacy remain challenging due to the missing specific non-invasive biomarkers. The aim of this study is to identify disease-specific microRNA (miRNA) patterns for diagnosis, prediction of prognosis and treatment response in patients with hepatocellular carcinoma (HCC). Methods The study population included 42 HCC patients from SORAMIC clinical trial: 22 patients received sorafenib monotherapy, 20 patients underwent 90Y radioembolization in combination with sorafenib. 20 individuals were included in the control group. Hepatocellular carcinoma patients underwent collection of plasma samples before and 7-9 weeks after the beginning of the treatment. Isolation of circulating miRNAs, preparation of small RNA sequencing libraries and next-generation sequencing were performed. Association analysis for novel diagnostic, prognostic and treatment-related candidate biomarkers was performed. Results A total of 42 differentially expressed (16 up-regulated and 26 down-regulated) miRNAs were identified comparing baseline and control group plasma samples. hsa-miR-215-5p and hsa-miR-192-5p were down-regulated, while hsa-miR-483-5p and hsa-miR-23b-3p were up-regulated comparing baseline and 7-9 weeks post-sorafenib monotherapy samples. hsa-miR-215-5p was the sole down-regulated miRNA in the same combination therapy comparison. hsa-miR-183-5p, hsa-miR-28-3p and hsa-miR-1246 were found to be significantly up-regulated comparing non-responders versus responders to sorafenib. High hsa-miR-215-5p expression was significantly associated with worse HCC patients' prognosis. Conclusions Systematic miRNA profiling of highly characterized samples from SORAMIC study revealed a subset of potential miRNA biomarkers for hepatocellular carcinoma diagnosis and prognosis of sorafenib-treated patients' survival.

Metabolomic Analysis of Human Cirrhosis and Hepatocellular Carcinoma: A Pilot Study.

BACKGROUND: Molecular changes in HCC development are largely unknown. As the liver plays a fundamental role in the body's metabolism, metabolic changes are to be expected. AIMS: We aimed to identify metabolomic changes in HCC in comparison to liver cirrhosis (LC) patients, which could potentially serve as novel biomarkers for HCC diagnosis and prognosis. METHODS: Metabolite expression from 38 HCC from the SORAMIC trial and 32 LC patients were analyzed by mass spectrometry. Metabolites with significant differences between LC and HCC at baseline were analyzed regarding expression over follow-up. In addition, association with overall survival was tested using univariate Cox proportional-hazard analysis. RESULTS: 41 metabolites showed differential expression between LC and HCC patients. 14 metabolites demonstrated significant changes in HCC patients during follow-up. Campesterol, lysophosphatidylcholine, octadecenoic and octadecadienoic acid, and furoylglycine showed a differential expression in the local ablation vs. palliative care group. High expression of eight metabolites (octadecenoic acid, 2-hydroxybutyrate, myo-inositol, isocitrate, erythronic acid, creatinine, pseudouridine, and erythrol) were associated with poor overall survival. The association between poor OS and octadecenoic acid and creatinine remained statistically significant even after adjusting for tumor burden and LC severity. CONCLUSION: Our findings give promising insides into the metabolic changes during HCC carcinogenesis and provide candidate biomarkers for future studies. Campesterol and furoylglycine in particular were identified as possible biomarkers for HCC progression. Moreover, eight metabolites were detected as predictors for poor overall survival.

Unresectable biliary tract cancer: Current and future systemic therapy.

For decades, treatment of advanced biliary tract cancer (BTC) was confined to the use of chemotherapy. In recent years however, the number of therapeutic options available for patients with unresectable BTC have drastically increased, with immunotherapy and targeted treatment gradually joining the ranks of guideline-recommended treatment regimens. The aim of the present review is to summarise the current knowledge on unresectable BTC focusing on epidemiology, anatomical distribution and current strategies for systemic treatment. We further outline ongoing clinical trials and provide an outlook on future therapeutic interventions. In the realm of gastrointestinal malignancies, the increasing number of systemic treatment options for BTC is finally delivering on the longstanding commitment to personalised oncology. This emphasises the need for considering a comprehensive genomic-based pathology assessment right from the initial diagnosis to fully leverage the expanding array of therapeutic options that have recently become accessible.

Extracranial Vascular Anomalies Driven by RAS/MAPK Variants: Spectrum and Genotype-Phenotype Correlations.

BACKGROUND: We aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen-activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification. METHODS AND RESULTS: This retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen-activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies. PVs were detected by the targeted sequencing of panels of genes known to be associated with vascular anomalies, performed using DNA from affected tissue. Subgroup analyses were performed according to the affected genes with regard to phenotypic characteristics in a descriptive manner. Twenty-five vascular malformations, 3 vascular tumors, and 1 patient with both a vascular malformation and vascular tumor presented the following distribution of PVs in genes: Kirsten rat sarcoma viral oncogene (n=10), neuroblastoma ras viral oncogene homolog (n=1), Harvey rat sarcoma viral oncogene homolog (n=5), V-Raf murine sarcoma viral oncogene homolog B (n=8), and mitogen-activated protein kinase kinase 1 (n=5). Patients with RAS PVs had advanced disease stages according to the Schobinger classification (stage 3-4: RAS, 9/13 versus non-RAS, 3/11) and more frequent progression after treatment (RAS, 10/13 versus non-RAS, 2/11). Lesions with Kirsten rat sarcoma viral oncogene PVs infiltrated more tissue layers compared with the other PVs including other RAS PVs (multiple tissue layers: Kirsten rat sarcoma viral oncogene, 8/10 versus other PVs, 6/19). CONCLUSIONS: This comparison of patients with various PVs in genes of the RAS/MAPK pathway provides potential associations with certain morphological and clinical phenotypes. RAS variants were associated with more aggressive phenotypes, generating preliminary data and hypothesis for future larger studies.

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.

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).

Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma.

Lymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes (LN) in staging imaging are a frequent topic of discussion in multidisciplinary tumor boards. Predictive markers are needed to facilitate stratification and improve treatment of STS patients. In this study, 56 STS patients with radiologically suspicious and subsequently histologically examined LN were reviewed. Patients with benign (n = 26) and metastatic (n = 30) LN were analyzed with regard to clinical, laboratory and imaging parameters. Patients with LNM exhibited significantly larger short axis diameter (SAD) and long axis diameter (LAD) vs. patients with benign LN (median 22.5 vs. 14 mm, p < 0.001 and median 29.5 vs. 21 mm, p = 0.003, respectively). Furthermore, the presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scans were significantly associated with LNM (60 vs. 11.5% of patients, p < 0.001 and median 8.59 vs. 3.96, p = 0.013, respectively). With systemic therapy, a slight median size regression over time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/L, p = 0.005 and 1.5 vs. 0.55 mg/dL, p = 0.039, respectively). This study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs.

Clinical benefits of MRI-guided freehand biopsy of small focal liver lesions in comparison to CT guidance.

OBJECTIVES: To compare clinical success, procedure time, and complication rates between MRI-guided and CT-guided real-time biopsies of small focal liver lesions (FLL) < 20 mm. METHODS: A comparison of a prospectively collected MRI-guided cohort (n = 30) to a retrospectively collected CT-guided cohort (n = 147) was performed, in which patients underwent real-time biopsies of small FLL < 20 mm in a freehand technique. In both groups, clinical and periprocedural data, including clinical success, procedure time, and complication rates (classified according to CIRSE guidelines), were analyzed. Wilcoxon rank sum test, Pearson's chi-squared test, and Fisher's exact test were used for statistical analysis. Additionally, propensity score matching (PSM) was performed using the following criteria for direct matching: age, gender, presence of liver cirrhosis, liver lobe, lesion diameter, and skin-to-target distance. RESULTS: The median FLL diameter in the MRI-guided cohort was significantly smaller compared to CT guidance (p < 0.001; 11.0 mm vs. 16.3 mm), while the skin-to-target distance was significantly longer (p < 0.001; 90.0 mm vs. 74.0 mm). MRI-guided procedures revealed significantly higher clinical success compared to CT guidance (p = 0.021; 97% vs. 79%) as well as lower complication rates (p = 0.047; 0% vs. 13%). Total procedure time was significantly longer in the MRI-guided cohort (p < 0.001; 38 min vs. 28 min). After PSM (n = 24/n = 38), MRI-guided procedures still revealed significantly higher clinical success compared to CT guidance (p = 0.039; 96% vs. 74%). CONCLUSION: Despite the longer procedure time, freehand biopsy of small FLL < 20 mm under MR guidance can be considered superior to CT guidance because of its high clinical success and low complication rates. CLINICAL RELEVANCE STATEMENT: Biopsy of small liver lesions is challenging due to the size and conspicuity of the lesions on native images. MRI offers higher soft tissue contrast, which translates into a higher success of obtaining enough tissue material with MRI compared to CT-guided biopsies. KEY POINTS: • Image-guided biopsy of small focal liver lesions (FLL) is challenging due to inadequate visualization, leading to sampling errors and false-negative biopsies. • MRI-guided real-time biopsy of FLL < 20 mm revealed significantly higher clinical success (p = 0.021; 97% vs. 79%) and lower complication rates (p = 0.047; 0% vs. 13%) compared to CT guidance. • Although the procedure time is longer, MRI-guided biopsy can be considered superior for small FLL < 20 mm.

CT-guided high dose rate brachytherapy can induce multiple systemic proteins of proliferation and angiogenesis predicting outcome in HCC.

BACKGROUND AND PURPOSE: To determine the potential prognostic value of proliferation and angiogenesis plasma proteins following CT-guided high dose rate brachytherapy (HDR-BT) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: For this prospective study, HDR-BT (1 × 15 Gy) was administered to 24 HCC patients. Plasma was obtained and analyzed using an Olink proteomics Target-96 immuno-oncology-panel that included multiple markers of angiogenesis and proliferation. Fold-change (FC) ratios were calculated by comparing baseline and 48 h post HDR-BT paired samples. Patients were classified as responders (n = 12) if they had no local progression within 6 months or systemic progression within 2 years. Non-responders (n = 12) had recurrence within 6 months and/or tumor progression or extrahepatic disease within 2 years. RESULTS: Proliferation marker EGF was significantly elevated in non-responders compared to responders (p = 0.0410) while FGF-2, HGF, and PlGF showed no significant differences. Angiogenesis markers Angiopoietin-1 and PDGF-B were likewise significantly elevated in non-responders compared to responders (p = 0.0171, p = 0.0462, respectively) while Angiopoietin-2, VEGF-A, and VEGFR-2 did not differ significantly. Kaplan-Meier analyses demonstrated significantly shorter time to systemic progression in patients with increased EGF and Angiopoietin-1 (p = 0.0185, both), but not in patients with one of the remaining proteins elevated (all p > 0.1). Pooled analysis for these 9 proteins showed significantly shorter time to systemic progression for FC ≥1.3 and ≥1.5 for at least 3 proteins elevated (p = 0.0415, p = 0.0193, respectively). CONCLUSION: Increased plasma levels of EGF and Angiopoietin-1 after HDR-BT for HCC are associated with poor response and may therefore function as predictive biomarkers of outcome.

Role of diffusion-weighted imaging in response prediction and evaluation after high dose rate brachytherapy in patients with colorectal liver metastases.

BACKGROUND: The aim of the study was to assess the role of diffusion-weighted imaging (DWI) to evaluate treatment response in patients with liver metastases of colorectal cancer. PATIENTS AND METHODS: In this retrospective, observational cohort study, we included 19 patients with 18 responding metastases (R-Mets; follow-up at least one year) and 11 non-responding metastases (NR-Mets; local tumor recurrence within one year) who were treated with high-dose-rate brachytherapy (HDR-BT) and underwent pre- and post-interventional MRI. DWI (qualitatively, mean apparent diffusion coefficient [ADCmean], ADCmin, intraindividual change of ADCmean and ADCmin) were evaluated and compared between pre-interventional MRI, first follow-up after 3 months and second follow-up at the time of the local tumor recurrence (in NR-Mets, mean: 284 ± 122 d) or after 12 months (in R-Mets, mean: 387+/-64 d). Sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) for detection of local tumor recurrence were calculated on second follow up, evaluating (1) DWI images only, and (2) DWI with Gd-enhanced T1-weighted images on hepatobiliary phase (contrast-enhanced [CE] T1-weight [T1w] hepatobiliary phase [hb]). RESULTS: ADCmean significantly increased 3 months after HDR-BT in both groups (R-Mets: 1.48 ± 0.44 and NR-Mets: 1.49 ± 0.19 x 10-3 mm2;/s, p < 0.0001 and p = 0.01), however, intraindividual change of ADCmean (175% vs.127%, p = 0.03) and ADCmin values (0.44 ± 0.24 to 0.82 ± 0.58 x 10-3 mm2/s) significantly increased only in R-Mets (p < 0.0001 and p < 0.001). ADCmin was significant higher in R-Mets compared to NR-Mets on first follow-up (p = 0.04). Sensitivity (1 vs. 0.72), specificity (0.94 vs. 0.72), PPV (0.91 vs. 0.61) and NPV (1 vs. 0.81) could be improved by combining DWI with CE T1w hb compared to DWI only. CONCLUSIONS: DW-MRI seems to be helpful in the qualitative and quantitative evaluation of treatment response after HDR-BT of colorectal metastases in the liver.

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.

Diffusion-weighted MRI (DWI) for assessment of response to high-dose-rate CT-guided brachytherapy (HDR-BT) of hepatocellular carcinoma.

BACKGROUND: High-dose-rate computed tomography (CT)-guided brachytherapy (HDR-BT) has shown promising results in patients with hepatocellular carcinoma (HCC). While growing evidence shows clear limitations of mRECIST, diffusion-weighted imaging (DWI) has relevant potential in improving the response assessment. PURPOSE: To assess whether DWI allows evaluation of short- and long-term tumor response in patients with HCC after HDR-BT. MATERIAL AND METHODS: A total of 22 patients with 11 non-responding HCCs (NR-HCC; local tumor recurrence within two years) and 24 responding HCCs (R-HCC; follow-up at least two years) were included in this retrospective bi-center study. HCCs were treated with HDR-BT and patients underwent pre- and post-interventional magnetic resonance imaging (MRI). Analyses of DWI were evaluated and compared between pre-interventional MRI, 1.follow-up after 3 months and 2.follow-up at the time of the local tumor recurrence (in NR-HCC) or after 12 months (in R-HCC). RESULTS: ADCmean of R-HCC increased significantly after HDR-BT on the first and second follow-up (ADCmean: 0.87 ± 0.18 × 10-3 mm2/s [pre-interventional]: 1.14 ± 0.23 × 10-3 mm2/s [1. post-interventional]; 1.42 ± 0.32 × 10-3 mm2/s [2. post-interventional]; P < 0.001). ADCmean of NR-HCC did not show a significant increase from pre-intervention to 1. post-interventional MRI (ADCmean: 0.85 ± 0.24 × 10-3 mm2/s and 1.00 ± 0.30 × 10-3 mm2/s, respectively; P = 0.131). ADCmean increase was significant between pre-intervention and 2. follow-up (ADCmean: 1.03 ± 0.19 × 10-3 mm2/s; P = 0.018). There was no significant increase of ADCmean between the first and second follow-up. There was, however, a significant increase of ADCmin after 12 months (ADCmin: 0.87 ± 0.29 × 10-3 mm2/s) compared to pre-interventional MRI and first follow-up (P < 0.005) only in R-HCC. CONCLUSION: The tumor response after CT-guided HDR-BT was associated with a significantly higher increase in ADCmean and ADCmin in short- and long-term follow-up.

High-Dose Rate Brachytherapy Combined with PD-1 Blockade as a Treatment for Metastatic Adrenocortical Carcinoma - A Single Center Case Series.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived. Immune checkpoint inhibitors (CPI) have been examined in patient's refractory to EDP-M, but objective response rates are only approximately 15%. High-dose rate brachytherapy (HDR-BT) is a catheter-based internal radiotherapy and expected to favorably combine with immunotherapies. Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab. None of the tumors were positive for established response markers to CPI. All patients were female, had progressed on EDP-M and received external beam radiation therapy for metastatic ACC. Pembrolizumab was initiated 7 or 23 months after brachytherapy in two cases and prior to brachytherapy in one case. Best response of lesions treated with brachytherapy was complete (n=2) or partial response (n=1) that was ongoing at last follow up after 23, 45 and 4 months, respectively. Considering all sites of tumor, response was complete and partial remission in the two patients with brachytherapy prior to pembrolizumab. The third patient developed progressive disease with severe Cushing's syndrome and died due to COVID-19. Immune-related adverse events of colitis (grade 3), gastroduodenitis (grade 3), pneumonitis (grade 2) and thyroiditis (grade 1) occurred in the two patients with systemic response. HDR-BT controlled metastases locally. Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

Neuroendocrine liver metastases treated using transarterial radioembolization: Identification of prognostic parameters at 68Ga-DOTATATE PET/CT.

PURPOSE: To identify prognostic clinical and imaging parameters for patients with neuroendocrine liver metastases (NELMs) undergoing transarterial radioembolization (TARE). MATERIALS AND METHODS: Forty-seven patients (27 men; mean age, 64 years) with NELMs who received TARE, along with pre-procedure liver MRI and 68Ga-DOTATATE positron emission tomography/computed tomography were included. Apparent diffusion coefficient and standardized uptake value (SUV) of three liver metastases, normal spleen and liver were measured. SUVmax or SUVmean were used for the calculation of tumor-to-organ ratios (tumor-to-spleen and tumor-to-liver ratios) using all possible combinations (including SUVmax/SUVmax, SUVmax/SUVmean, and SUVmean/SUVmean). Clinical parameters (hepatic tumor-burden, presence of extra-hepatic metastases, chromograninA, Ki-67 and bilirubin levels) were assessed. Overall survival, progression-free survival (PFS) and hepatic progression-free survival (HPFS) were calculated using Kaplan-Meier curves. RESULTS: Median overall survival, PFS and HPFS were 49.6, 13.1 and 28.3 months, respectively. In multivariable Cox regression analysis, low Ki-67 (≤ 5%), low hepatic tumor-burden (< 10%), absence of extrahepatic metastases, and increased Tmean/Lmax ratio were significant prognostic factors of longer overall survival and HPFS. High baseline chromograninA (> 1330 ng/mL) was associated with shorter HPFS. Tmean/Lmax > 1.9 yielded a median overall survival of 69 vs. 33 months (P < 0.04), and a median HPFS of 30 vs. 19 months (P = 0.09). For PFS, high baseline SUVmax of NELMs was the single significant parameter in the multivariable model. SUVmax > 28 resulted in a median PFS of 16.9 vs. 6.5 months, respectively (P = 0.001). CONCLUSION: High preinterventional Tmean/Lmax ratios, and high SUVmax on 68Ga-DOTATATE positron emission tomography/computed tomography seem to have prognostic value in patients with NELMs undergoing TARE, potentially aiding patient selection and management alongside conventional variables.

Reliability and practicability of PSMA-RADS 1.0 for structured reporting of PSMA-PET/CT scans in prostate cancer patients.

OBJECTIVES: As structured reporting is increasingly used in the evaluation of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) for prostate cancer, there is a need to assess the reliability of these frameworks. This study aimed to evaluate the intra- and interreader agreement among readers with varying levels of experience using PSMA-RADS 1.0 for interpreting PSMA-PET/CT scans, even when blinded to clinical data, and therefore to determine the feasibility of implementing this reporting system in clinical practice. METHODS: PSMA-PET/CT scans of 103 patients were independently evaluated by 4 readers with different levels of experience according to the reporting and data system (RADS) for PSMA-PET/CT imaging PSMA-RADS 1.0 at 2 time points within 6 weeks. For each scan, a maximum of five target lesions were freely chosen and stratified according to PSMA-RADS 1.0. Overall scan score and compartment-based scores were assessed. Intra- and interreader agreement was determined using the intraclass correlation coefficient (ICC). RESULTS: PSMA-RADS 1.0 demonstrated excellent interreader agreement for both overall scan scores (ICC ≥ 0.91) and compartment-based scores (ICC ≥ 0.93) across all four readers. The framework showed excellent intrareader agreement for overall scan scores (ICC ≥ 0.86) and compartment-based scores (ICC ≥ 0.95), even among readers with varying levels of experience. CONCLUSIONS: PSMA-RADS 1.0 is a reliable method for assessing PSMA-PET/CT with strong consistency and agreement among readers. It shows great potential for establishing a standard approach to diagnosing and planning treatment for prostate cancer patients, and can be used confidently even by readers with less experience. CLINICAL RELEVANCE STATEMENT: This study underlines that PSMA-RADS 1.0 is a valuable and highly reliable scoring system for PSMA-PET/CT scans of prostate cancer patients and can be used confidently by radiologists with different levels of experience in routine clinical practice. KEY POINTS: PSMA-RADS version 1.0 is a scoring system for PSMA-PET/CT scans. Its reproducibility needs to be analyzed in order to make it applicable to clinical practice. Excellent interreader and intrareader agreement for overall scan scores and compartment-based scores using PSMA-RADS 1.0 were seen in readers with varying levels of experience. PSMA-RADS 1.0 is a reliable tool for accurately diagnosing and planning treatment for prostate cancer patients, and can be used confidently in clinical routine.

Cost-effectiveness of endovascular treatment versus best medical management in basilar artery occlusion stroke: A U.S. healthcare perspective.

INTRODUCTION: Two recent studies showed clinical benefit for endovascular treatment (EVT) in basilar artery occlusion (BAO) stroke up to 12 h (ATTENTION) and between 6 and 24 h from onset (BAOCHE). Our aim was to investigate the cost-effectiveness of EVT from a U.S. healthcare perspective. MATERIALS AND METHODS: Clinical input data were available for both trials, which were analyzed separately. A decision model was built consisting of a short-run model to analyze costs and functional outcomes within 90 days after the index stroke and a long-run Markov state transition model (cycle length of 12 months) to estimate expected lifetime costs and outcomes from a healthcare and a societal perspective. Incremental cost-effectiveness ratios (ICER) were calculated, deterministic (DSA) and probabilistic (PSA) sensitivity analyses were performed. RESULTS: EVT in addition to best medical management (BMM) resulted in additional lifetime costs of $32,063 in the ATTENTION trial and lifetime cost savings of $7690 in the BAOCHE trial (societal perspective). From a healthcare perspective, EVT led to incremental costs and effectiveness of $37,389 and 2.0 QALYs (ATTENTION) as well as $3516 and 1.9 QALYs (BAOCHE), compared to BMM alone. The ICER values were $-4052/QALY (BAOCHE) and $15,867/QALY (ATTENTION) from a societal perspective. In each trial, PSA showed EVT to be cost-effective in most calculations (99.9%) for a willingness-to-pay threshold of $100,000/QALY. Cost of EVT and age at stroke represented the greatest impact on the ICER. DISCUSSION: From an economic standpoint with a lifetime horizon, EVT in addition to BMM is estimated to be highly effective and cost-effective in BAO stroke.

Predictive value of pre-infusion tumor growth rate for the occurrence and severity of CRS and ICANS in lymphoma under CAR T-cell therapy.

Chimeric antigen receptor T-cell therapy (CART) can be administered outpatient yet requires management of potential side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The pre-infusion tumor burden is associated with CRS, yet there is no data on the relevance of pre-infusion tumor growth rate (TGR). Our objective was to investigate TGR for the occurrence and severity of CRS and ICANS. Consecutive patients with available pre-baseline and baseline (BL) imaging before CART were included. TGR was determined as both absolute (abs) and percentage change (%) of Lugano criteria-based tumor burden in relation to days between exams. CRS and ICANS were graded according to ASTCT consensus criteria. Clinical metadata was collected including the international prognostic index (IPI), patient age, ECOG performance status, and LDH. Sixty-two patients were included (median age: 62 years, 40% female). The median pre-BL TGR [abs] and pre-BL TGR [%] was 7.5 mm2/d and 30.9%/d. Pre-BL TGR [abs] and pre-BL TGR [%] displayed a very weak positive correlation with the grade of CRS (r[abs] = 0.14 and r[%] = 0.13) and no correlation with ICANS (r[abs] = - 0.06 and r[%] = - 0.07). There was a weak positive correlation between grade of CRS and grade of ICANS (r = 0.35; p = 0.005) whereas there was no significant correlation of CRS or ICANS to any other of the examined parameters. The pre-infusion TGR before CART was weakly associated with the occurrence of CRS, but not the severity, whereas there were no significant differences in the prediction of ICANS. There was no added information when compared to pre-infusion tumor burden alone. Outpatient planning and toxicity management should not be influenced by the pre-infusion TGR.

Quantitative SSTR-PET/CT for predicting response and survival outcomes in patients with pancreatic neuroendocrine tumors receiving CAPTEM.

BACKGROUND: This study aimed to evaluate the predictive and monitoring role of somatostatin receptor (SSTR) positron emission tomography-computed tomography (PET/CT) and clinical parameters in patients with neuroendocrine liver metastases (NELM) from pancreatic neuroendocrine tumors (pNET) receiving capecitabine and temozolomide (CAPTEM). PATIENTS AND METHODS: This retrospective study included twenty-two patients with pNET and NELM receiving CAPTEM who underwent pre- and post-therapeutic 68Ga-DOTATATE/-TOC PET/CT. Imaging (including standardized uptake value [SUV] of target lesions [NELM and pNET], normal spleen and liver) and clinical (Chromogranin A [CgA], Ki-67) parameters were assessed. Treatment outcome was evaluated as response according to RECIST 1.1, progression free survival (PFS) and overall survival (OS). RESULTS: The median PFS (mPFS) was 7 months. Responders had a significantly longer mPFS compared to non-responders (10 vs. 4 months p = 0.022). Median OS (mOS) was 33 months (mOS: responders = 80 months, non-responders = 24 months p = 0.182). Baseline imaging showed higher SUV in responders, including absolute SUV, tumor-to-spleen (T/S), and tumor-to-liver (T/L) ratios (p < 0.02). All SUV parameters changed only in the responders during follow-up. Univariable Cox regression analysis identified baseline Tmax/Smean ratio and percentage change in size of pNETs as significant factors associated with PFS. A baseline Tmax/Smean ratio < 1.5 was associated with a shorter mPFS (10 vs. 4 months, (p < 0.05)). Prognostic factors for OS included age, percentage change in CgA and in T/S ratios in univariable Cox regression. CONCLUSIONS: SSTR-PET/CT can be useful for predicting response and survival outcomes in pNET patients receiving CAPTEM: Higher baseline SUV values, particularly Tmax/Smean ratios of liver metastases were associated with better response and prolonged PFS.