Johannes M. Ludwig

The Role of Diffusion-Weighted Imaging (DWI) in Locoregional Therapy Outcome Prediction and Response Assessment for Hepatocellular Carcinoma (HCC): The New Era of Functional Imaging Biomarkers

Reliable response criteria are critical for the evaluation of therapeutic response in hepatocellular carcinoma (HCC). Current response assessment is mainly based on: (1) changes in size, which is at times unreliable and lag behind the result of therapy; and (2) contrast enhancement, which can be difficult to quantify in the presence of benign post-procedural changes and in tumors presenting with a heterogeneous pattern of enhancement. Given these challenges, functional magnetic resonance imaging (MRI) techniques, such as diffusion-weighted imaging (DWI) have been recently investigated, aiding specificity to locoregional therapy response assessment and outcome prediction. Briefly, DWI quantifies diffusion of water occurring naturally at a cellular level (Brownian movement), which is restricted in multiple neoplasms because of high cellularity. Disruption of cellular integrity secondary to therapy results in increased water diffusion across the injured membranes. This review will provide an overview of the current literature on DWI therapy response assessment and outcome prediction in HCC following treatment with locoregional therapies.

Hepatic intra-arterial injection of irinotecan drug eluting beads (DEBIRI) for patients with unresectable colorectal liver metastases: A systematic review

PURPOSE To systematically review the safety and efficacy of transarterial drug-eluting beads, irinotecan (DEBIRI) for the treatment of pretreated patients with unresectable colorectal liver metastases (CRLM). METHODS A systematic search of the current literature was conducted to extract publications reporting on the use of DEBIRI for CRLM. Data on the safety and efficacy was extracted and tabulated. Weighted average values (WAV) were calculated for each variable to provide a single value representing the pooled safety and efficacy data. RESULTS 13 studies (15 treatment arms) were evaluated, comprising a total of 850 patients. There were 6 prospective phase I/II trials, 5 retrospective trials and 2 randomized control trials. All papers involved patients previously treated with systemic chemotherapy. The weighted average all-grade toxicity rate was 35.2% (range; 6-100%). The high-grade WAV toxicity rate was 10.1% (range; 0-32%). Weighted average response rates were 56.2% and 51.1% according to RECIST (Response Evaluation Criteria in Solid Tumors) and modified RECIST/EASL (European Association for the Study of the Liver) response criteria respectively. The weighted average progression-free survival and overall survival were 8.1 months and 16.8 months, respectively. CONCLUSION Transarterial DEBIRI is safe and effective in the treatment of unresectable CRLM to the liver. Further studies are warranted to better define its role in the treatment algorithm of this patient subset.

Predictors and prognosticators for survival with Yttrium-90 radioembolization therapy for unresectable colorectal cancer liver metastasis

This critical review aims to explore predictive and prognostic biomarkers of Yttrium-90 (Y90) radioembolization therapy of colorectal liver metastases. A brief overview of established predictive and prognostic molecular and genetic biomarkers in colorectal cancer therapies will be discussed. A review of the literature on imaging modalities, genetic, metabolic and other molecular markers and the subsequent outcomes in post-Y90 treatment will be presented. How these biomarkers and future biomarker research can inform locoregional treatment decisions in the clinical setting of metastatic colorectal cancer lesions of the liver will be explored. There are opportunities for personalized cancer treatment in the setting of Y90 radioembolization. The ability to predict tumor response after Ytrium-90 radioembolization therapy can greatly impact clinical decision making and enhance treatment outcomes, therefore further research into the field is needed.

Immuno-thermal ablations – boosting the anticancer immune response

The use of immunomodulation to treat malignancies has seen a recent explosion in interest. The therapeutic appeal of these treatments is far reaching, and many new applications continue to evolve. In particular, immune modulating drugs have the potential to enhance the systemic anticancer immune effects induced by locoregional thermal ablation. The immune responses induced by ablation monotherapy are well documented, but independently they tend to be incapable of evoking a robust antitumor response. By adding immunomodulators to traditional ablative techniques, several researchers have sought to amplify the induced immune response and trigger systemic antitumor activity. This paper summarizes the work done in animal models to investigate the immune effects induced by the combination of ablative therapy and immunomodulation. Combination therapy with radiofrequency ablation, cryoablation, and microwave ablation are all reviewed, and special attention has been paid to the addition of checkpoint blockades.

SW43-DOX ± loading onto drug-eluting bead, a potential new targeted drug delivery platform for systemic and locoregional cancer treatment – An in vitro evaluation

Treatment of unresectable primary cancer and their distant metastases, with the liver representing one of the most frequent location, is still plagued by insufficient treatment success and poor survival rates. The Sigma‐2 receptor is preferentially expressed on many tumor cells making it an appealing target for therapy. Thus, we developed a potential targeted drug conjugate consisting of the Sigma‐2 receptor ligand SW43 and Doxorubicin (SW43‐DOX) for systemic cancer therapy and for locoregional treatment of primary and secondary liver malignancies when loaded onto drug‐eluting bead (DEB) which was compared in vitro to the treatment with Doxorubicin alone.

Targeted Yttrium 89-Doxorubicin Drug-Eluting Bead—A Safety and Feasibility Pilot Study in a Rabbit Liver Cancer Model

The purpose of this article is to evaluate feasibility and safety of the cancer targeting (radio)-chemoembolization drug-eluting bead (TRCE-DEB) concept drug SW43-DOX-L-NETA(89Y) DEB for the intra-arterial treatment of VX2 rabbit liver tumors. The treatment compound comprises of the sigma-2 receptor ligand SW43 for cancer targeting, doxorubicin (DOX), and 89yttrium (89Y) as nonradioactive surrogate for therapeutic (yttrium-90, lutetium-177) and imaging (yttrium-86) radioisotopes via the chelator L-NETA. Ten New Zealand white rabbits with VX2 tumor allografts were used. SW43-DOX-89Y was synthesized, loaded onto DEB (100 μL; 100-300 μm), and administered intra-arterially in six rabbits at increasing doses (0.2-1.0 mg/kg). As controls, two rabbits each received either doxorubicin IV (0.3 mg/kg) or no treatment. Consecutive serum analysis for safety and histopathological evaluation after sacrifice were performed. One-Way ANOVA incl. Bonferroni Post-Hoc test was performed to compare groups. Targeted compound synthesis, loading onto DEB, and intra-arterial administration were feasible and successful in all cases. Serum liver enzyme levels increased in a dose dependent manner within 24 h and normalized within 3 days for 0.2/0.6 mg/kg SW43-DOX-89Y loaded onto DEB. The two rabbits treated with 1 mg/kg SW43-DOX-89Y had to be euthanized after 3/24 h due to worsening general condition. Histopathological necrosis increased over time in a dose depended manner with 95-100% tumor necrosis 3-7 days post treatment (0.6 mg/kg). SW43-DOX-89Y loaded onto DEB can be formulated and safely administered at a concentration of 0.6 mg/kg. Loading with radioactive isotopes (e.g., 86yttrium/90yttrium/177lutetium) to synthesize the targeted radio-chemoembolization drug-eluting bead (TRCE-DEB) concept drug is feasible.

Infiltrative Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis Treated With a Single High-Dose Y90 Radioembolization and Subsequent Liver Transplantation Without a Recurrence

Background Infiltrative hepatocellular carcinoma with macrovascular invasion is a relatively rare presentation and usually fatal disease. Methods Both patients exceeded Milan and University of California-San Francisco (UCSF) criteria, and per Barcelona Clinic Liver Cancer group guidelines, they were enrolled in a prospective open-label radioembolization phase II trial that gave them optimized lobar doses of Yttrium-90 as solely the first-line therapy without concomitant or additional pharmacological or locoregional therapies. Results Three months after radioembolization, the patients demonstrated no residual viable disease on surveillance imaging. The patients were then followed up with serial imaging for 2 years in 3-month intervals, without documenting recurrence or extrahepatic disease. Finally, both patients underwent transplantation and after more than 20 months of imaging surveillance, no locoregional or systemic recurrence have been observed. Conclusions We present, to our knowledge, the first 2 reports of transplantation after successfully downstaging infiltrative disease with portal vein tumoral thrombosis, which traditionally poses as a relative contraindication for resection or transplantation.

Establishment of human metastatic colorectal cancer model in rabbit liver: A pilot study.

Rationale and objectives To develop a human metastatic colorectal cancer (mCRC) model in a rabbit liver. Materials and methods Immunosuppression in 4 adult New Zealand White rabbits weighing 3.5 to 4.5 kg was induced with daily subcutaneous injection of 15 mg/kg Cyclosporine A (CsA). On day 3 open mini-laparotomy was performed and 0.2 ml (1.8x105 cells) suspension of HCT-116 and HT-29 human CRC cells were injected into the left and right medial lobe respectively. On day 10 the CsA dose was reduced to 10 mg/kg daily maintenance dose. Rabbits were weighed weekly, closely monitored for CsA side effects (weight loss, gingival hyperplasia and gut modification). Rabbits were sacrificed 5, 6, 7, and 8 weeks after cells injection. Liver tumors were collected for histopathology and immunohistochemical analysis. Results HT-29 Tumor growth was observed in 3 rabbits (75%). Tumors measured 3, 4 and 6 mm after 5, 6 and 8 weeks respectively. Microscopically, tumors contained hyperchromatic, pleomorphic cells that stained for monoclonal carcinoembryonic antigen (CEA), polyclonal CEA, cytokeratin 20, vascular markers (CD31, CD34), and vascular endothelial growth factor (VEGF) by immunohistochemistry, supporting involvement by the poorly differentiated HT-29 colorectal cancer cell line. No gross tumor growth or microscopic viability was observed from HCT-116 cell injection. CsA extra-hepatic manifestations included minimal gum hyperplasia and decrease in gut motility in 3 rabbits (75%), which was treated with Azithromycin 15 mg/kg and Cisapride 0.5 mg/kg every 12 hours, respectively. Conclusion We successfully developed a human metastatic colon cancer model in immunosuppressed rabbit liver using HT-29 cells.

Radiofrequency ablation versus resection for hepatocellular carcinoma in patients with Child–Pugh A liver cirrhosis: a meta-analysis

AIM To evaluate whether radiofrequency ablation (RFA) or surgical resection (RES) has superior overall survival (OS) and disease-free survival (DFS) in patients with hepatocellular carcinoma and Child-Pugh class A liver cirrhosis. MATERIALS AND METHODS Meta-analysis was used to compare 1-, 3-, and 5-year OS and DFS between RFA and RES. Those studies meeting inclusion criteria and published prior to 1 June 2015 were included. The odds ratio (OR) was used as the treatment effect measure. A priori defined sensitivity analyses of study subgroups was performed. RESULTS Fifteen studies were included in this analysis. Subgroup analyses based on predetermined patient characteristics were performed to minimise bias. No difference in 1-year OS, 3-year OS, and 3-year DFS was found in analyses limited to studies where patients were equally eligible for both therapies. There was also not a significant difference in OS and DFS between RFA and RES when studies were limited to those with only solitary tumours or tumours <3 cm. CONCLUSION The data suggest the equivalence of RFA and RES in patients with solitary tumours <3 cm and good liver status based on Child-Pugh score.

Survival Rates after Thermal Ablation versus Stereotactic Radiation Therapy for Stage 1 Non–Small Cell Lung Cancer: A National Cancer Database Study

Purpose To compare survival rates of thermal ablation and stereotactic radiation therapy (SRT) for stage 1 non-small cell lung cancer (NSCLC). Materials and Methods In this retrospective study, patients with stage 1 NSCLC treated by thermal ablation (TA) or SRT were identified in the 2004-2013 National Cancer Database. Patients who underwent TA and SRT were one-to-one propensity matched to undergo thermal ablation. Outcomes were overall survival and unplanned hospital readmission within 30 days after treatment. Results This study included 28 834 patients (TA, 1102 patients; SRT, 27 732 patients). Patients treated with TA had more comorbidities (Charlson comorbidity index of 1 vs ≥2, 32.8% [362 of 1102] vs 19.7% [217 of 1102], respectively) compared with SRT (Charlson comorbidity index of 1 vs ≥2, 26.9% [7448 of 27 732] vs 15.3% [4251 of 27 732], respectively; P , .001) and smaller tumor size (mean tumor size, TA vs SRT: 19 mm vs 22 mm, respectively; P , .001). In the propensity score-matched cohort with balanced distribution of potential confounders, there was no significant difference in overall survival between TA and SRT at a mean follow-up of 52.4 months (survival difference, P = .69). Overall survival rates were comparable between TA and SRT (1 year, 85.4% vs 86.3%, respectively, P = .76; 2 years, 65.2% vs 64.5%, respectively, P = .43; 3 years, 47.8% vs 45.9%, respectively, P = .32; 5 years, 24.6% vs 26.1%, respectively, P = .81). Unplanned hospital readmission rates were higher for patients who underwent TA versus those who underwent SRT (3.7% [40 of 1070] vs 0.2% [two of 1070], respectively; P , .001). Conclusion Regarding overall survival, thermal ablation was noninferior to stereotactic radiation therapy for primary treatment of stage 1 non-small cell lung cancer.