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.

Local tumor control of intermediate and advanced stage hepatocellular carcinoma after local ablative treatment with image-guided interstitial high-dose-rate brachytherapy: A subgroup analysis of 286 HCC nodules.

PURPOSE: Image-guided interstitial high-dose-rate brachytherapy (iBT) has been demonstrated to offer high local tumor control rates (LTC) of >90% after local ablation of intermediate and advanced hepatocellular carcinoma (HCC; BCLC B and C). The purpose of this study was to show the efficacy of iBT stratified by subgroups and to identify clinical characteristics associated with superior local tumor control (LTC) based on a highly heterogenous patient population METHODS AND MATERIALS: A cumulative number of 286 HCC nodules in 107 patients were retrospectively analyzed. Clinical and imaging follow-ups were conducted every 3 months after treatment. Analyzed clinical factors were: etiology, presence of liver cirrhosis, radiographic features, lesion size, pretreatment, administered dose, presence of portal hypertension, portal vein thrombosis, and level of alpha-fetoprotein (AFP). RESULTS: LTC rate was 88.8% for a median follow-up of 14.3 months (range 3-81 months; 95% CI: 85-92%). Median minimal enclosing tumor dose (D100) was 16.1 Gy (range 7.1-30.3 Gy; reference dose 15 Gy). Subgroup analysis showed significant fewer local recurrences for alcoholic liver disease (ALD)-related HCCs compared to those related to other causes of liver cirrhosis (nonalcoholic fatty liver disease, virus-related liver cirrhosis and other causes) (p = 0.015). LTC was significantly lower after prior surgical resection (p = 0.046). No significant variance was observed for the applied D100 in each group or for all other clinical factors tested. CONCLUSIONS: IBT achieves high LTC rates across treated subgroups. However, further studies should particularly address the possible impact of underlying etiology on local recurrence with emphasis on a possible higher radiosensitivity of ALD-related HCCs.

Can alternative liver function scores facilitate the establishment of an indication for radioablative therapy in patients with hepatocellular carcinoma?

BACKGROUND AND PURPOSE: ALBI and IBI are new scores to evaluate the liver function in patients with hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the prognostic abilities of those scores in patients treated with interstitial brachytherapy (iBT). MATERIALS AND METHODS: 190 patients treated with iBT between 01.01.2006 and 01.01.2018 were included in this study. The clinical target dose was 15 Gy. The patients were all in Child-Pugh stadium A or B and across the Barcelona Clinic Liver Cancer (BCLC) Stages 0-C. Retrospectively ALBI and IBI were calculated pre- and post-therapeutic until 6 months after iBT. Hazards ratios were calculated, and p values corrected using the false discovery rate according to Benjamini and Hochberg. RESULTS: The median overall survival was 23.5 months (CI 19-28.5 months), and the median progression-free survival was 7.5 months (CI 6-9 months). Elevated ALBI showed a significantly higher risk to die with a hazard ratio (HR) of 2.010 (ALBI 2 vs. 1) and 4082 (ALBI 3 vs. 1), respectively. The IBI did also show a higher risk with an HR of 1.816 (IBI 1 vs. 0) and 4608 (IBI 2 vs. 0), respectively. Even 3 months after therapy elevated ALBI and IBI showed poor overall survival. Concerning progression-free survival, ALBI and IBI could not provide any relevant additional information. CONCLUSION: ALBI and IBI are useful tools to predict the overall survival in patients treated with iBT and might be helpful to assign the patients to the appropriate therapy.

Apparent Diffusion Coefficient Can Predict Therapy Response of Hepatocellular Carcinoma to Transcatheter Arterial Chemoembolization.

AIM: The goal of this meta-analysis was to assess the apparent diffusion coefficient (ADC) as a pre- and posttreatment (ADC value changes [ΔADC]) predictive imaging biomarker of response to transcatheter arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). METHODS: Scopus database, Embase database, and MEDLINE library were scanned for connections between pre- and posttreatment ADC values of HCC and response to TACE. Six studies qualified for inclusion. The following parameters were collected: authors, publication year, study design, number of patients, drugs for TACE, mean ADC value, standard deviation, measure method, b values, and Tesla strength. The Quality Assessment of Diagnostic Studies 2 instrument was employed to check the methodological quality of each study. The meta-analysis was performed by utilizing RevMan 5.3 software. DerSimonian and Laird random-effects models with inverse-variance were used to regard heterogeneity. The mean ADC values and 95% confidence intervals were computed. RESULTS: Six studies (n = 271 patients with 293 HCC nodules) were included. The pretreatment mean ADC in the responder group was 1.20 × 10-3 mm2/s (0.98, 1.42) and 1.14 × 10-3 mm2/s (0.89, 1.39) in the nonresponder group. The analysis of post-TACE ΔADC revealed a threshold of ≥20% to identify treatment responders. No suitable pretreatment ADC threshold to predict therapy response or discriminate between responders and nonresponders before therapy could be discovered. CONCLUSION: ΔADC can facilitate early objective response evaluation through post-therapeutic ADC alterations ≥20%. Pretreatment ADC cannot predict response to TACE.

Radioablation of Upper Abdominal Malignancies by CT-Guided, Interstitial HDR Brachytherapy: A Multivariate Analysis of Catheter Placement Assisted by Ultrasound Imaging.

PURPOSE: To evaluate the use of ultrasound (US) during catheter placement in interstitial brachytherapy (iBT) of abdominal malignancies as an alternative to computed tomography (CT) fluoroscopy. MATERIALS AND METHODS: Catheter placement for CT-guided iBT was, if US visibility was sufficient, assisted by sonography in 52 consecutive patients with 82 lesions (liver N = 62; kidney N = 16; peritoneum N = 4) of various malignancies. We collected data on lesion visibility, location, depth, size, and dosimetry. Comparison of CT fluoroscopy versus US-assisted catheter placement was performed by Fisher's exact test for frequencies and U-test for lesion visibility and dosimetric data. Factors predicting the utility of sonography were determined in a lesion-based multivariate regression analysis. A p-value < 0.05 was regarded as statistically significant. RESULTS: 150 catheters (1 to 6 per lesion; mean diameter 3.6 ±â€Š2.4 cm) were implanted. CT fluoroscopy was used for 44 catheters, and US was used for 106 catheters. Lesion visibility assessed by 5-point Likert scale was significantly better in US (median 2 vs. 3; p = 0.011) and effective dose was significantly reduced if US guidance was applicable (median 1.75 vs. 8.19 mSv; p = 0.014). In a multivariate regression analysis, we identified increased lesion size and caudal location within the target organ to independently predict the utility of ultrasound in catheter placement for iBT. CONCLUSION: Sonography is a helpful technique to assist CT-guided interstitial brachytherapy of upper abdominal malignancies. Especially for larger lesions localized in the lower liver segments or lower half of the kidney, superior visibility can be expected. As the effective dose of the patient is also reduced, radiation exposure of the medical staff may be indirectly lowered. KEY POINTS: · Ultrasound-assisted catheter placement in CT-guided brachytherapy of upper abdominal malignancies significantly improves lesion visibility.. · Predictors of successful ultrasound application are larger lesions within the lower portion of the liver and kidney.. · By reducing the need for CT fluoroscopy during intervention, radiation exposure to the medical staff may be indirectly lowered.. CITATION FORMAT: · Damm R, Damm R, Heinze C et al. Radioablation of Upper Abdominal Malignancies by CT-Guided, Interstitial HDR Brachytherapy: A Multivariate Analysis of Catheter Placement Assisted by Ultrasound Imaging. Fortschr Röntgenstr 2022; 194: 62 - 69.

Bi-Centric Independent Validation of Outcome Prediction after Radioembolization of Primary and Secondary Liver Cancer.

BACKGROUND: Yttrium-90 radioembolization (RE) plays an important role in the treatment of liver malignancies. Optimal patient selection is crucial for an effective and safe treatment. In this study, we aim to validate the prognostic performance of a previously established random survival forest (RSF) with an external validation cohort from a different national center. Furthermore, we compare outcome prediction models with different established metrics. METHODS: A previously established RSF model, trained on a consecutive cohort of 366 patients who had received RE due to primary or secondary liver tumor at a national center (center 1), was used to predict the outcome of an independent consecutive cohort of 202 patients from a different national center (center 2) and vice versa. Prognostic performance was evaluated using the concordance index (C-index) and the integrated Brier score (IBS). The prognostic importance of designated baseline parameters was measured with the minimal depth concept, and the influence on the predicted outcome was analyzed with accumulated local effects plots. RSF values were compared to conventional cox proportional hazards models in terms of C-index and IBS. RESULTS: The established RSF model achieved a C-index of 0.67 for center 2, comparable to the results obtained for center 1, which it was trained on (0.66). The RSF model trained on center 2 achieved a C-index of 0.68 on center 2 data and 0.66 on center 1 data. CPH models showed comparable results on both cohorts, with C-index ranging from 0.68 to 0.72. IBS validation showed more differentiated results depending on which cohort was trained on and which cohort was predicted (range: 0.08 to 0.20). Baseline cholinesterase was the most important variable for survival prediction. CONCLUSION: The previously developed predictive RSF model was successfully validated with an independent external cohort. C-index and IBS are suitable metrics to compare outcome prediction models, with IBS showing more differentiated results. The findings corroborate that survival after RE is critically determined by functional hepatic reserve and thus baseline liver function should play a key role in patient selection.

Impact of Pharmaceutical Prophylaxis on Radiation-Induced Liver Disease Following Radioembolization.

BACKGROUND: Radioembolization (RE) with yttrium-90 (90Y) resin microspheres yields heterogeneous response rates in with primary or secondary liver cancer. Radiation-induced liver disease (RILD) is a potentially life-threatening complication with higher prevalence in cirrhotics or patients exposed to previous chemotherapies. Advances in RILD prevention may help increasing tolerable radiation doses to improve patient outcomes. This study aimed to evaluate the impact of post-therapeutic RILD-prophylaxis in a cohort of intensely pretreated liver metastatic breast cancer patients; Methods: Ninety-three patients with liver metastases of breast cancer received RE between 2007 and 2016. All Patients received RILD prophylaxis for 8 weeks post-RE. From January 2014, RILD prophylaxis was changed from ursodeoxycholic acid (UDCA) and prednisolone (standard prophylaxis [SP]; n = 59) to pentoxifylline (PTX), UDCA and low-dose low molecular weight heparin (LMWH) (modified prophylaxis (MP); n = 34). The primary endpoint was toxicity including symptoms of RILD; Results: Dose exposure of normal liver parenchyma was higher in the modified vs. standard prophylaxis group (47.2 Gy (17.8-86.8) vs. 40.2 Gy (12.5-83.5), p = 0.017). All grade RILD events (mild: bilirubin ≥ 21 µmol/L (but <30 µmol/L); severe: (bilirubin ≥ 30 µmol/L and ascites)) were observed more frequently in the SP group than in the MP group, albeit without significance (7/59 vs. 1/34; p = 0.140). Severe RILD occurred in the SP group only (n = 2; p > 0.1). ALBI grade increased in 16.7% patients in the MP and in 27.1% patients in the SP group, respectively (group difference not significant); Conclusions: At established dose levels, mild or severe RILD events proved rare in our cohort. RILD prophylaxis with PTX, UDCA and LMWH appears to have an independent positive impact on OS in patients with metastatic breast cancer and may reduce the frequency and severity of RILD. Results of this study as well as pathophysiological considerations warrant further investigations of RILD prophylaxis presumably targeting combinations of anticoagulation (MP) and antiinflammation (SP) to increase dose prescriptions in radioembolization.

Apparent Diffusion Coefficient Can Predict Response to Chemotherapy of Liver Metastases in Colorectal Cancer.

RATIONALE AND OBJECTIVES: The aim of this meta-analysis was to evaluate the suitability of apparent diffusion coefficient (ADC) as a predictor of response to systemic chemotherapy in patients with metastatic colorectal carcinoma (CRC). MATERIALS AND METHODS: MEDLINE library, SCOPUS database, and EMBASE database were screened for relationships between pretreatment ADC values of hepatic CRC metastases and response to systemic chemotherapy. Overall, five eligible studies were identified. The following data were extracted: authors, year of publication, study design, number of patients, mean value ADC and standard-deviation, measure method, b-values, and Tesla-strength. The methodological quality of every study was checked according to the Quality Assessment of Diagnostic Studies-2 instrument. The meta-analysis was undertaken by employing RevMan 5.3 software. DerSimonian and Laird random-effects models with inverse-variance weights were used to account for heterogeneity. Mean ADC values including 95% confidence intervals were calculated. RESULTS: Five studies (n = 114 patients) were included. The pretreatment mean ADC in the responder group was 1.15 × 10-3 mm2/s (1.03, 1.28) and 1.37 × 10-3 mm2/s (1.3, 1.44) in the nonresponder group. An ADC baseline threshold of 1.2 × 10-3 mm2/s, below which no nonresponder was found, can distinguish both groups. CONCLUSION: The results indicate ADC can serve as a predictor of response to chemotherapy for CRC patients.

Interstitial Brachytherapy for Limited (<4 cm) and Large (≥4 cm) Hepatic Metastases from Rare and Less Common Cancers.

BACKGROUND/AIM: Interstitial brachytherapy (iBT) seems to achieve higher local tumor control rates for lesions limited in size. The objective was to evaluate the efficacy and safety of iBT in the treatment of limited and large liver metastases from rare or less common cancers (RLCC). PATIENTS AND METHODS: A total of 194 unresectable liver metastases categorized as limited (<4 cm, n=153, subgroup A) and large lesions (≥4 cm, n=41, subgroup B) were treated. Clinical and image-based follow-up was conducted every 3 months after iBT. RESULTS: Cumulative local recurrence (CLR) rate was 9.8% (19 recurrences; A: n=16; B: n=3). No significant difference in CLR was noted between subgroup A and B (A:10.5%, B:7.3%, p=0.339). Median follow-up was 6.2 months (range=2.2-92.9 months). Complication assessment revealed 5 severe adverse events (grade 3: 4.3%, grade 4 and 5: 0%) with 4 events in A and 1 event in B. CONCLUSION: IBT is a feasible, effective, and safe minimally invasive treatment for small and large liver metastases from RLCC.

Efficacy and safety of percutaneous computed tomography-guided high-dose-rate interstitial brachytherapy in treatment of oligometastatic lymph node metastases of retroperitoneal space.

PURPOSE: To assess efficacy, safety, and outcome of computed tomography (CT)-guided high-dose-rate (HDR) interstitial brachytherapy in patients with oligometastatic lymph node metastases of the retroperitoneal space. MATERIAL AND METHODS: 24 patients with a total of 47 retroperitoneal lymph node metastases from different primary tumors were treated with CT-guided interstitial brachytherapy using an 192Ir source (single fraction irradiation). Every three months after treatment, clinical and imaging follow-up were conducted to evaluate local control and safety. RESULTS: Median follow-up was 9.6 months (range, 2.9-39.0 months). Local tumor control rate was 95.7%. The median diameter of the gross tumor volume was 2.2 cm (range, 1-8.6 cm), treated with a median D100 (minimal enclosing tumor dose) of 14.9 Gy (range, 4.5-20.6 Gy). One severe adverse event (grade three) was recorded.Cumulative median progression-free survival was 4.2 months (range, 1.4-23.7 months), and cumulative median overall survival after interstitial brachytherapy was 15.9 months (range, 3.8-39.0 months). CONCLUSIONS: CT-guided HDR interstitial brachytherapy is a safe and feasible method for local ablation of oligometastatic lymph node metastases of the retroperitoneal space, and might provide a well-tolerated additional therapeutic option in the multidisciplinary management of selected patients.

Radioablation of Hepatic Metastases from Renal Cell Carcinoma With Image-guided Interstitial Brachytherapy.

BACKGROUND/AIM: High-dose-rate interstitial brachytherapy (iBT) has been shown to provide high tumor control rates in the treatment of primary or secondary malignancies at various sites. The objective of this study was to evaluate the efficacy and safety of image-guided iBT in patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: A total of 14 patients with a cumulative number of 54 unresectable RCC liver metastases after treatment with computed tomography (CT)- or open magnetic resonance imaging (MRI)-guided iBT using an iridium-192 source (single fraction irradiation) were included in this retrospective study. RESULTS: Local tumor control rate was 92.6% during a median follow-up of 10.2 months (range=2.4-73.6 months). Median progression-free survival after iBT was 3.4 months (range=1.0-27.8 months). Median overall survival was 51.2 months (range=10.2-81.5 months). No severe adverse events (grade 3 or more) were recorded. CONCLUSION: Image-guided iBT is a safe and feasible treatment in patients with mRCC.

Efficacy and safety of CT-guided high-dose-rate interstitial brachytherapy in primary and secondary malignancies of the pancreas.

PURPOSE: To evaluate efficacy and safety of CT-guided iBT in patients with primary and secondary malignancies of the pancreas. MATERIAL AND METHODS: 13 patients with 13 lesions of the pancreatic corpus and tail were included: 8 secondary malignancies (metastatic lesions = ML) and 5 primary malignancies, including 3 primary tumors (PT) and 2 isolated locoregional recurrences (ILR) after surgical resection were treated with image-guided iBT using a 192iridium source (single fraction irradiation). Every 3 months after treatment clinical and imaging follow-up were conducted to evaluate efficacy. Peri- and postinterventional complications were assessed descriptively. RESULTS: The median diameter of the gross tumor volume (GTV) was 3 cm (range 1-6.5 cm), treated with a median D100 (minimal enclosing tumor dose) of 15.3 Gy (range 9.2-25.4 Gy). Local tumor control (LTC) was 92.3% within a median follow-up period of 6.7 months (range 3.2-55.7 months). Cumulative median progression free survival (PFS) was 6.2 months (range 2.8-25.7 months; PFS of primary and secondary malignancies was 5.8 and 6.2 months, respectively). Cumulative median over all survival (OS) after iBT was 16.2 months (range 3.3-55.7 months; OS of primary and secondary malignancies was 7.4 months and 45.6 months, respectively). 1 patient developed mild acute pancreatits post iBT, spontanously resolved within 1 week. No severe adverse events (grade 3+) were recorded. CONCLUSION: Image-guided iBT is a safe and particularly effective treatment in patients with primary and secondary malignancies of the pancreas and might provide a well-tolerated additional therapeutic option in the multidisciplinary management of selected patients.

Image-guided interstitial high-dose-rate brachytherapy in the treatment of metastatic esophageal squamous cell carcinoma.

PURPOSE: To evaluate the efficacy of computed tomography (CT)- and magnetic resonance imaging (MRI)-guided interstitial high-dose-rate brachytherapy (HDR IBT = IBT) in patients with metastatic esophageal squamous cell carcinoma. MATERIAL AND METHODS: Eleven patients with 21 unresectable metastases of histologically proven esophageal squamous cell carcinoma were included in this retrospective study. Fourteen visceral and 7 lung metastases were treated with image-guided (CT or open MRI guidance) IBT using a 192Iridium source (single fraction irradiation). Clinical and imaging follow-up were performed every 3 months after treatment. Primary endpoint was local tumor control (LTC) and safety. Furthermore, we analyzed safety, progression-free survival (PFS), and overall survival (OS). RESULTS: The median diameter of the target lesions was 2.2 cm (range: 0.7-6.8 cm), treated with a median D100 of 20.1 Gy (range: 10-25 Gy). During a median follow-up of 6.3 months (range: 3-21.8 months), three patients displayed local recurrences, resulting in LTC of 85.7%. Median PFS was 3.4 months and median OS after IBT was 13.7 months. No severe adverse events (grade 3+) requiring hospitalization or invasive intervention were recorded. CONCLUSIONS: Image-guided IBT is a safe and effective treatment in patients with metastasized esophageal squamous cell carcinoma.

Image-guided Interstitial Brachytherapy in the Management of Metastasized Anal Squamous Cell Carcinoma.

BACKGROUND/AIM: Interstitial brachytherapy (IBT) has been shown to provide high tumor control rates in metastatic colorectal carcinoma. Our aim was to evaluate efficacy and safety of IBT in patients with metastatic anal squamous cell carcinoma (mASCC). PATIENTS AND METHODS: Seven patients with a total of 38 unresectable ASCC metastases (28 liver, nine lung, one nodal metastases) were treated with computed tomographic or open magnetic resonance imaging-guided IBT using an iridium-192 source. Clinical and image-based follow-up were performed every 3 months after treatment. RESULTS: Local tumor control rate was 97.4% during a median follow-up of 15.2 months. Median progression-free survival was 3.3 months (range=2.5-32.6 months). Median overall survival after IBT was 25.2 months (range=6.5-51.0 months). No severe adverse events (grade 3 or more) were recorded. CONCLUSION: Image-guided IBT is a safe and particularly effective treatment in patients with mASCC and might provide a well-tolerated therapeutic option in a multidisciplinary setting.

sarA negatively regulates Staphylococcus epidermidis biofilm formation by modulating expression of 1 MDa extracellular matrix binding protein and autolysis-dependent release of eDNA.

Biofilm formation is essential for Staphylococcus epidermidis pathogenicity in implant-associated infections. Nonetheless, large proportions of invasive Staphylococcus epidermidis isolates fail to form a biofilm in vitro. We here tested the hypothesis that this apparent paradox is related to the existence of superimposed regulatory systems suppressing a multicellular biofilm life style in vitro. Transposon mutagenesis of clinical significant but biofilm-negative S. epidermidis 1585 was used to isolate a biofilm positive mutant carrying a Tn917 insertion in sarA, chief regulator of staphylococcal virulence. Genetic analysis revealed that inactivation of sarA induced biofilm formation via overexpression of the giant 1 MDa extracellular matrix binding protein (Embp), serving as an intercellular adhesin. In addition to Embp, increased extracellular DNA (eDNA) release significantly contributed to biofilm formation in mutant 1585ΔsarA. Increased eDNA amounts indirectly resulted from upregulation of metalloprotease SepA, leading to boosted processing of autolysin AtlE, in turn inducing augmented autolysis and release of eDNA. Hence, this study identifies sarA as a negative regulator of Embp- and eDNA-dependent biofilm formation. Given the importance of SarA as a positive regulator of polysaccharide mediated cell aggregation, the regulator enables S. epidermidis to switch between mechanisms of biofilm formation, ensuring S. epidermidis adaptation to hostile environments.