Stereotactic body radiotherapy in patients with hepatocellular carcinoma in a multimodal treatment setting.

PURPOSE: Retrospective evaluation of stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 36 patients (45 lesions) treated between 2011 and 2017. Twenty-seven had previous treatments. Current treatment consisted of SBRT alone (n = 15) or selective transarterial chemoembolization (TACE) followed by SBRT to the same lesions (n = 21). Eight patients received additional local treatments to different lesions. Liver function was predominantly moderately restricted (Child A: 29, Child B: 6, Child C: 1). Treatment planning was based on 4D-computed tomography, dose/fractionation varied depending on location and size, most commonly 3 fractions of 12.5 Gy (65% isodose) and 5 fractions of 8 Gy (80% isodose). RESULTS: Median follow-up was 15 months. Local recurrence was observed in 3 lesions (7%), resulting in 1­and 2­year local control rates of 93%. The only significantly predicting factor was the use of abdominal compression. New hepatic lesions occurred in 19 patients (52%), 1­ and 2­year freedom-from-hepatic-failure (FFHF) was 39% and 32%, respectively. Only the number of treated lesions was predictive for FFHF. Sixteen patients have died, resulting in 1­ and 2­year overall survival (OS) of 64% and 41%, respectively, significantly impacted by the number of treated lesions and Child-Pugh class. Severe acute and late toxicity (≥grade 3) was observed in 3% and 8%, respectively. 6 patients (17%) received liver transplantation (OLT) after SBRT, of whom 5 showed pathological complete remission. CONCLUSION: SBRT (±TACE) in highly pretreated HCC is effective and associated with excellent LC and low toxicity. SBRT may be used as definitive or bridging treatment prior to OLT. Patients with multifocal lesions have significantly decreased 1­ and 2­year FFHF and OS.

Percutaneous CT fluoroscopy-guided core biopsy of pancreatic lesions: technical and clinical outcome of 104 procedures during a 10-year period.

Background In unclear pancreatic lesions, a tissue sample can confirm or exclude the suspected diagnosis and help to provide an optimal treatment strategy to each patient. To date only one small study reported on the outcome of computed tomography (CT) fluoroscopy-guided biopsies of the pancreas. Purpose To evaluate technical success and diagnostic rate of all CT fluoroscopy-guided core biopsies of the pancreas performed in a single university center during a 10-year period. Material and Methods In this retrospective study we included all patients who underwent a CT fluoroscopy-guided biopsy of a pancreatic mass at our comprehensive cancer center between 2005 and 2014. All interventions were performed under local anesthesia on a 16-row or 128-row CT scanner. Technical success and diagnostic rates as well as complications and effective patient radiation dose were analyzed. Results One hundred and one patients (54 women; mean age, 63.9 ± 12.6 years) underwent a total of 104 CT fluoroscopy-guided biopsies of the pancreas. Ninety-eight of 104 interventions (94.2%) could be performed with technical success and at least one tissue sample could be obtained. In 88 of these 98 samples, a definitive pathological diagnosis, consistent with clinical success could be achieved (89.8%). Overall 19 minor and three major complications occurred during the intra- or 30-day post-interventional period and all other interventions could be performed without complications; there was no death attributable to the intervention. Conclusion CT fluoroscopy-guided biopsy of pancreatic lesions is an effective procedure characterized by a low major complication and a high diagnostic rate.

Prevalence and distribution of calcified nodules in carotid arteries in correlation with clinical symptoms.

PURPOSE: Calcified nodules ("CN") are responsible for up to 5% of coronary-infarcts and, therefore, classified as minor criteria of "vulnerable" atherosclerotic plaque. We sought to evaluate prevalence and distribution of CN in carotid arteries in correlation with clinical symptoms. METHODS: 178 consecutive patients with unilateral ischemic stroke and carotid plaques ≥2 mm by duplex ultrasound underwent a carotid-black-blood-3T-MRI with fat-saturated pre- and post-contrast T1w-, PDw-, T2w- and TOF images using dedicated surface-coils. CN were defined as distinct calcification with an irregular, protruding, and convex luminal surface. Prevalence of CN was determined in common carotid artery ("CCA") and internal carotid artery ("ICA") in consensus by two reviewers blinded to clinical information. RESULTS: Thirty seven CN in 28 arteries of 26 patients were identified. Prevalence of CN in CCA compared to ICA was slightly higher (59 vs. 41%), but nearly similar in 66 arteries with ≥30% compared to 290 arteries with <30% stenosis (9.1 vs. 7.6%) and in the artery ipsilateral versus contralateral to stroke (7.9 vs. 7.9%; P values n.s.). Prevalence of CN was significantly higher in 40 symptomatic arteries with ≥30% stenosis compared to asymptomatic 26 arteries (15.6 vs. 0%; P = 0.04). There was a significantly higher prevalence of hypercholesterolemia and hypertension in patients with CN (57.7 vs. 36.0 and 88.5 vs. 66.7%; P values <0.05). CONCLUSION: CN were found in 7.9% of arteries with carotid-plaques ≥2 mm by duplex-ultrasound; prevalence was significantly higher in symptomatic arteries with ≥30% stenosis compared to asymptomatic with <30% stenosis, suggesting that CN play a role in pathogenesis of ischemic stroke in a small subset of patients.

Reducing tumor growth and angiogenesis using a triple therapy measured with Contrast-enhanced ultrasound (CEUS).

BACKGROUND: To evaluate the in vivo response by detecting the anti-angiogenic and invasion-inhibiting effects of a triple-combination-therapy in an experimental-small-animal-squamous-cell-carcinoma-model using the "flash-replenishment" (FR) method to assess tissue hemodynamics via contrast-enhanced-ultrasound (CEUS). METHODS: Human hypopharynx-carcinoma-cells were subcutaneously injected into the left flank of 22-female-athymic-nude-rats. After seven days of subcutaneous tumor growth, FR-measurements were performed on each rat. Treatment-group and control-group were treated every day for a period of one week, with the treatment-group receiving solvents containing a triple therapy of Upamostat®, Celecoxib® and Ilomastat® and the control-group solvents only. On day seven, follow-up measurements were performed using the same measurement protocol to assess the effects of the triple therapy. VueBox® was used to quantify the kinetic parameters and additional immunohistochemistry analyses were performed for comparison with and validation of the CEUS results against established methods (Proliferation/Ki-67, vascularization/CD31, apoptosis/caspase3). RESULTS: Compared to the control-group, the treatment-group that received the triple-therapy resulted in a reduction of tumor growth by 48.6% in size. Likewise, the immunohistochemistry results showed significant decreases in tumor proliferation and vascularization in the treatment-group in comparison to the control-group of 26%(p ≤ 0.05) and 32.2%(p ≤ 0.05) respectively. Correspondingly, between the baseline and follow-up measurements, the therapy-group was associated with a significant(p ≤ 0.01) decrease in the relative-Blood-Volume(rBV) in both the whole tumor(wt) and hypervascular tumor(ht) areas (p ≤ 0.01), while the control-group was associated with a significant (p ≤ 0.01) increase of the rBV in the wt area and a non-significant increase (p ≤ 0.16) in the ht area. The mean-transit-time (mTT) of the wt and the ht areas showed a significant increase (p ≤ 0.01) in the follow-up measurements in the therapy group. CONCLUSION: The triple-therapy is feasible and effective in reducing both tumor growth and vascularization. In particular, compared with the placebo-group, the triple-therapy-group resulted in a reduction in tumor growth of 48.6% in size when assessed by CEUS and a significant reduction in the number of vessels in the tumor of 32% as assessed by immunohistochemistry. As the immunohistochemistry supports the CEUS findings, CEUS using the "flash replenishment"(FR) method appears to provide a useful assessment of the anti-angiogenic and invasion-inhibiting effects of a triple combination therapy.

Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: The European Network on Radioembolization with Yttrium-90 resin microspheres study group (ENRY) conducted a retrospective study to evaluate the outcomes among elderly (≥ 70 years) and younger patients (<70 years) with unresectable hepatocellular carcinoma (HCC) who received radioembolization at 8 European centers. METHODS: Patients with confirmed diagnosis of unresectable HCC who either progressed following resection or locoregional treatment and/or who were considered poor candidates for chemoembolization were evaluated by a multidisciplinary team for radioembolization with (90)Y-resin microspheres (SIR-Spheres; Sirtex Medical). The survival outcome and all adverse events were compared between the two age groups. RESULTS: Between 2003 and 2009, 128 elderly and 197 younger patients received radioembolization. Patients in both groups had similar demographic characteristics. Many elderly and younger patients alike had multinodular, BCLC stage C disease, invading both lobes (p = 0.648). Elderly patients had a lower tumor burden, a smaller median target liver volume (p = 0.016) and appeared more likely to receive segmental treatment (p = 0.054). Radioembolization was equally well tolerated in both cohorts and common procedure-related adverse events were predominantly grade 1-2 and of short duration. No significant differences in survival between the groups were found (p = 0.942) with similar median survival in patients with early, intermediate or advanced BCLC stage disease. CONCLUSIONS: Radioembolization appears to be as well-tolerated and effective for the elderly as it is for younger patients with unresectable HCC. Age alone should not be a discriminating factor for the management of HCC patients.

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.

Prediction of 90Y Radioembolization Outcome from Pretherapeutic Factors with Random Survival Forests.

Our objective was to predict the outcome of 90Y radioembolization in patients with intrahepatic tumors from pretherapeutic baseline parameters and to identify predictive variables using a machine-learning approach based on random survival forests. Methods: In this retrospective study, 366 patients with primary (n = 92) or secondary (n = 274) liver tumors who had received 90Y radioembolization were analyzed. A random survival forest was trained to predict individual risk from baseline values of cholinesterase, bilirubin, type of primary tumor, age at radioembolization, hepatic tumor burden, presence of extrahepatic disease, and sex. The predictive importance of each baseline parameter was determined using the minimal-depth concept, and the partial dependency of predicted risk on the continuous variables bilirubin level and cholinesterase level was determined. Results: Median overall survival was 11.4 mo (95% confidence interval, 9.7-14.2 mo), with 228 deaths occurring during the observation period. The random-survival-forest analysis identified baseline cholinesterase and bilirubin as the most important variables (forest-averaged lowest minimal depth, 1.2 and 1.5, respectively), followed by the type of primary tumor (1.7), age (2.4), tumor burden (2.8), and presence of extrahepatic disease (3.5). Sex had the highest forest-averaged minimal depth (5.5), indicating little predictive value. Baseline bilirubin levels above 1.5 mg/dL were associated with a steep increase in predicted mortality. Similarly, cholinesterase levels below 7.5 U predicted a strong increase in mortality. The trained random survival forest achieved a concordance index of 0.657, with an SE of 0.02, comparable to the concordance index of 0.652 and SE of 0.02 for a previously published Cox proportional hazards model. Conclusion: Random survival forests are a simple and straightforward machine-learning approach for prediction of overall survival. The predictive performance of the trained model was similar to a previously published Cox regression model. The model has revealed a strong predictive value for baseline cholinesterase and bilirubin levels with a highly nonlinear influence for each parameter.

Reduced Periprocedural Analgesia After Replacement of Water for Injection with Glucose 5% Solution as the Infusion Medium for 90Y-Resin Microspheres.

The primary aim of our study was to compare the need for periinterventional on-demand analgesia when water for injection (WFI) was replaced with glucose 5% (G5) for 90Y-resin microsphere administration. METHODS: Forty-one patients who received 77 radioembolization procedures with G5 (2014-2015) were retrospectively matched with 41 patients (77 radioembolization procedures) who received radioembolization with WFI (2011-2014) at our center. The need for on-demand pain medication was chosen as an objective and accessible measure of periprocedural pain experienced by patients. RESULTS: Patients were well matched according to sex, age, tumor type and involvement, and prior antiangiogenic therapies. Periinterventional analgesic requirements were significantly lower for radioembolization procedures performed with G5 than WFI: 5 of 77 (6.5%) versus 29 of 77 (37.7%), P ≤ 0,001, respectively. Early stasis (defined as slowed antegrade flow, before total vascular stasis) occurred in 12 of 154 (7.8%) radioembolization procedures overall and was not different (P ≤ 0.229) between the 2 groups (4/77 [5.2%] vs. 8/77 [10.4%]). CONCLUSION: Slow pulsatile administration of 90Y-resin microspheres with WFI is associated with a low rate of stasis. Replacement of WFI with G5 significantly reduces the need for periprocedural analgesia. These data favor the use G5 for 90Y-resin microsphere implantation in daily practice.