Prognostic value of clinical and radiomic parameters in patients with liver metastases from uveal melanoma.

Approximately every second patient with uveal melanoma develops distant metastases, with the liver as the predominant target organ. While the median survival after diagnosis of distant metastases is limited to a year, yet-to-be-defined subgroups of patients experience a more favorable outcome. Therefore, prognostic biomarkers could help identify distinct risk groups to guide patient counseling, therapeutic decision-making, and stratification of study populations. To this end, we retrospectively analyzed a cohort of 101 patients with newly diagnosed hepatic metastases from uveal melanoma by using Cox-Lasso regression machine learning, adapted to a high-dimensional input parameter space. We show that substantial binary risk stratification can be performed, based on (i) clinical and laboratory parameters, (ii) measures of quantitative overall hepatic tumor burden, and (iii) radiomic parameters. Yet, combining two or all three domains failed to improve prognostic separation of patients. Additionally, we identified highly relevant clinical parameters (including lactate dehydrogenase, thrombocyte counts, aspartate transaminase, and the metastasis-free interval) at first diagnosis of metastatic disease as predictors for time-to-treatment failure and overall survival. Taken together, the risk stratification models, built by our machine-learning algorithm, identified a comparable and independent prognostic value of clinical, radiological, and radiomic parameters in uveal melanoma patients with hepatic metastases.

Deep learning-based assessment of body composition and liver tumour burden for survival modelling in advanced colorectal cancer.

BACKGROUND: Personalized therapy planning remains a significant challenge in advanced colorectal cancer care, despite extensive research on prognostic and predictive markers. A strong correlation of sarcopenia or overall body composition and survival has been described. Here, we explore whether automated assessment of body composition and liver metastases from standard of care CT images can add to clinical parameters in personalized survival risk prognostication. METHODS: We retrospectively analysed clinical imaging data from 85 patients (50.6% female, mean age 58.9 SD 12.2 years) with colorectal cancer and synchronous liver metastases. Pretrained deep learning models were used to assess body composition and liver metastasis geometry from abdominal CT images before the initiation of systemic treatment. Abdominal muscle-to-bone ratio (MBR) was calculated by dividing abdominal muscle volume by abdominal bone volume. MBR was compared with body mass index (BMI), abdominal muscle volume, and abdominal muscle volume divided by height squared. Differences in overall survival based on body composition and liver metastasis parameters were compared using Kaplan-Meier survival curves. Results were correlated with clinical and biomarker data to develop a machine learning model for survival risk prognostication. RESULTS: The MBR, unlike abdominal muscle volume or BMI, was significantly associated with overall survival (HR 0.39, 95% CI: 0.19-0.80, P = 0.009). The MBR (P = 0.022), liver metastasis surface area (P = 0.01) and primary tumour sidedness (P = 0.007) were independently associated with overall survival in multivariate analysis. Body composition parameters did not correlate with KRAS mutational status or primary tumour sidedness. A prediction model based on MBR, liver metastasis surface area and primary tumour sidedness achieved a concordance index of 0.69. CONCLUSIONS: Automated segmentation enables to extract prognostic parameters from routine imaging data for personalized survival modelling in advanced colorectal cancer patients.

Is there a connection between immunohistochemical markers and grading of lung cancer with apparent diffusion coefficient (ADC) and standardised uptake values (SUV) of hybrid 18F-FDG-PET/MRI?

INTRODUCTION: To correlate tumour grading and prognostic immunohistochemical markers of lung cancer with simultaneously acquired standardised uptake values (SUV) and apparent diffusion coefficient (ADC) derived from hybrid PET/MRI. METHODS: In this retrospective study, 55 consecutive patients (mean age 62.5 ± 9.2 years) with therapy-naïve, histologically proven lung cancer were included. All patients underwent whole-body PET/MRI using 18F-flourdeoxyglucose (18F-FDG) as a radiotracer. Diffusion-weighted imaging of the chest (DWI, b-values: 0, 500, 1000 s/mm2 ) was performed simultaneously with PET acquisition. Histopathological tumour grading was available in 43/55 patients. In 15/55 patients, immunohistochemical markers, that is, phospho-AKT Ser473 (pAKTS473), phosphorylated extracellular signal-regulated kinase (pERK), phosphatase and tensin homolog (PTEN), and human epidermal growth factor receptor 2 (erbB2) were available. RESULTS: The average SUVmax, SUVmean, ADCmin and ADCmean in lung cancer primaries were 12.6 ± 5.9, 7.7 ± 4.6, 569.9 ± 96.1 s/mm2 and 825.8 ± 93.2 s/mm2 , respectively. We found a significant inverse correlation between the ADCmin and SUVmax (r = -0.58, P < 0.001) as well as between the ADCmin and SUVmean (r = -0.44, P < 0.001). Tumour grading showed a significant positive correlation with SUVmax and SUVmean (R = 0.34 and R = 0.31, both P < 0.05) and a significant inverse correlation with ADCmin and ADCmean (r = -0.30 and r = -0.40, both P < 0.05). In addition, erbB2 showed a significant inverse correlation with SUVmax and SUVmean (r = -0.50 and r = -0.49, both P < 0.05). The other immunohistochemical markers did not show any significant correlation. CONCLUSION: 18F-FDG-PET/MRI showed weak to moderate correlations between SUV, ADC, tumour grading and erbB2-expression of lung cancer. Hence, 18F-FDG-PET/MRI may, to some extent, offer complementary information to the histopathology of lung cancer, for the evaluation of tumour aggressiveness and treatment response.

Improved survival in metastatic breast cancer: results from a 20-year study involving 1033 women treated at a single comprehensive cancer center.

PURPOSE: Diagnosis and treatment of breast cancer have changed profoundly over the past 25 years. The outcome improved dramatically and was well quantified for early stage breast cancer (EBC). However, progress in the treatment of metastatic disease has been less convincingly demonstrated. We have studied survival data of patients with metastatic breast cancer (MBC) from a large academic cancer center over a period of 20 years. METHODS: Data from 1033 consecutive MBC patients who were treated at the Department of Medical Oncology of the West German Cancer Center from January 1990 to December 2009 were retrospectively analyzed for overall survival (OS) and risk factors. Patients were grouped in 5-year cohorts, and survival parameters of each cohort were compared before and after adjustment for risk factors. RESULTS: Overall survival of patients with MBC treated at specialized center has significantly improved from 1990 to 2010 (hazard ratio 0.7, 95%CI 0.58-0.84). The increments in OS have become less profound over time (median OS 1990-1994: 24.2 months, 1995-1999: 29.6 months, 2000-2004: 36.5 months, 2005-2009: 37.8 months). CONCLUSION: Survival of patients with MBC has improved between 1990 and 2004, but less from 2005 to 2009. Either this suggests an unnoticed shift in the patient population, or a lesser impact of therapeutic innovations introduced in the most recent period.

Prospective comparison of 18F-FDG PET/MRI and 18F-FDG PET/CT for thoracic staging of non-small cell lung cancer.

OBJECTIVES: To compare the diagnostic performance of 18F-FDG PET/MRI and 18F-FDG PET/CT for primary and locoregional lymph node staging in non-small cell lung cancer (NSCLC). METHODS: In this prospective study, a total of 84 patients (51 men, 33 women, mean age 62.5 ± 9.1 years) with histopathologically confirmed NSCLC underwent 18F-FDG PET/CT followed by 18F-FDG PET/MRI in a single injection protocol. Two readers independently assessed T and N staging in separate sessions according to the seventh edition of the American Joint Committee on Cancer staging manual for 18F-FDG PET/CT and 18F-FDG PET/MRI, respectively. Histopathology as a reference standard was available for N staging in all 84 patients and for T staging in 39 patients. Differences in staging accuracy were assessed by McNemars chi2 test. The maximum standardized uptake value (SUVmax) and longitudinal diameters of primary tumors were correlated using Pearson's coefficients. RESULTS: T stage was categorized concordantly in 18F-FDG PET/MRI and 18F-FDG PET/CT in 38 of 39 (97.4%) patients. Herein, 18F-FDG PET/CT and 18F-FDG PET/MRI correctly determined the T stage in 92.3 and 89.7% of patients, respectively. N stage was categorized concordantly in 83 of 84 patients (98.8%). 18F-FDG PET/CT correctly determined the N stage in 78 of 84 patients (92.9%), while 18F-FDG PET/MRI correctly determined the N stage in 77 of 84 patients (91.7%). Differences between 18F-FDG PET/CT and 18F-FDG PET/MRI in T and N staging accuracy were not statistically significant (p > 0.5, each). Tumor size and SUVmax measurements derived from both imaging modalities exhibited excellent correlation (r = 0.963 and r = 0.901, respectively). CONCLUSION: 18F-FDG PET/MRI and 18F-FDG PET/CT show an equivalently high diagnostic performance for T and N staging in patients suffering from NSCLC.

MET Expression in Advanced Non-Small-Cell Lung Cancer: Effect on Clinical Outcomes of Chemotherapy, Targeted Therapy, and Immunotherapy.

BACKGROUND: The receptor tyrosine kinase MET is implicated in malignant transformation, tumor progression, metastasis, and acquired treatment resistance. We conducted an analysis of the effect of MET expression and MET genomic aberrations on the outcome of patients with advanced or metastatic pulmonary adenocarcinomas prospectively enrolled in an institutional precision oncology program. PATIENTS AND METHODS: Standardized immunohistochemistry (IHC) analyses of MET and markers of pathway activation were available in 384 patients, and next-generation sequencing-based MET hotspot mutation analyses were available from 892 patients. Clinical data were retrieved with a median follow-up from initial diagnosis of 37 months. RESULTS: High MET expression, defined as MET IHC 3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%). High MET expression correlated with activation markers of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations. There was no association of MET expression with outcome during chemotherapy. High MET expression negatively affected the outcome during EGFR-targeting therapy but was associated with more favorable results with programmed death 1/programmed death ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1 expression or KRAS mutation. Two patients with MET exon 14 mutation and high PD-L1 expression failed to respond to pembrolizumab. CONCLUSION: MET expression affects the outcomes of targeted therapies in non-small-cell lung cancer, thus supporting the development of biomarker-informed combination strategies. The interaction of MET expression and MET mutation with immune checkpoint inhibitor therapy is novel and merits further investigation.

Hepatic arterial infusion chemotherapy for extensive liver metastases of breast cancer: efficacy, safety and prognostic parameters.

PURPOSE: Hepatic arterial infusion chemotherapy (HAIC) is an option for patients with liver-predominant metastatic breast cancer (LMBC), when no further systemic treatment is available. But systematic reports are limited. Here we conducted a retrospective analysis of LMBC patients treated at an expert center. METHODS: Individual patient data were retrieved from the clinical data base of the West German Cancer Center. Primary endpoints included hepatic response (RECIST), progression-free survival (PFS), overall survival (OS), and toxicity. A score based on LDH, AST, ALT and bilirubine was developed to estimate the hepatic metastasis load. RESULTS: Data from 70 consecutive patients were included. All patients were heavily pretreated (median 7 treatment lines for LMBC). HAIC protocols included mitomycin/5-FU (70%), mitomycin (14.3%), melphalan (12.9%) and 5-FU (7.1%), with selection based on patient characteristics. Partial hepatic remission was obtained as best response in 14 patients (20.0%), stable disease in 27 patients (38.6%), and progressive disease in 29 patients (41.4%). Median PFS and OS from initiation of HAIC were 2 (range 0-10) and 7 months (range 1-37). Mainly hepatic and hematopoietic HAIC-related toxicities were observed; there was no treatment-related death. The hepatic metastasis score effectively separated two prognostic groups: Patients with a score <3 had significantly superior PFS (15 vs 7 weeks, p = 0.017) and OS (12 vs 5 months, p = 0.002). CONCLUSION: HAIC offers a safe and effective salvage treatment strategy in heavily pretreated patients with LMBC and no further treatment options. The hepatic metastasis score may help to identify patients with sustained clinical benefit.

Curvature estimation from a volume-of-fluid indicator function for the simulation of surface tension and wetting with a free-surface lattice Boltzmann method.

The free surface lattice Boltzmann method (FSLBM) is a combination of the hydrodynamic lattice Boltzmann method with a volume-of-fluid (VOF) interface capturing technique for the simulation of incompressible free surface flows. Capillary effects are modeled by extracting the curvature of the interface from the VOF indicator function and imposing a pressure jump at the free boundary. However, obtaining accurate curvature estimates from a VOF description can introduce significant errors. This article reports numerical results for three different surface tension models in standard test cases and compares the according errors in the velocity field (spurious currents). Furthermore, the FSLBM is shown to be suited to simulate wetting effects at solid boundaries. To this end, a new method is developed to represent wetting boundary conditions in a least-squares curvature reconstruction technique. The main limitations of the current FSLBM are analyzed and are found to be caused by its simplified advection scheme. Possible improvements are suggested.

Effects of zeolite supplementation on parameters of intestinal barrier integrity, inflammation, redoxbiology and performance in aerobically trained subjects.

BACKGROUND: Zeolites are crystalline compounds with microporous structures of Si-tetrahedrons. In the gut, these silicates could act as adsorbents, ion-exchangers, catalysts, detergents or anti-diarrheic agents. This study evaluated whether zeolite supplementation affects biomarkers of intestinal wall permeability and parameters of oxidation and inflammation in aerobically trained individuals, and whether it could improve their performance. METHODS: In a randomized, double-blinded, placebo controlled trial, 52 endurance trained men and women, similar in body fat, non-smokers, 20-50 years, received 1.85 g of zeolite per day for 12 weeks. Stool samples for determination of intestinal wall integrity biomarkers were collected. From blood, markers of redox biology, inflammation, and DNA damage were determined at the beginning and the end of the study. In addition, VO2max and maximum performance were evaluated at baseline and after 12 weeks of treatment. For statistical analyses a 2-factor ANOVA was used. RESULTS: At baseline both groups showed slightly increased stool zonulin concentrations above normal. After 12 weeks with zeolite zonulin was significantly (p < 0.05) decreased in the supplemented group. IL-10 increased tendentially (p < 0.1) in the zeolite group. There were no significant changes observed in the other measured parameters. CONCLUSIONS: Twelve weeks of zeolite supplementation exerted beneficial effects on intestinal wall integrity as indicated via decreased concentrations of the tight junction modulator zonulin. This was accompanied by mild anti-inflammatory effects in this cohort of aerobically trained subjects. Further research is needed to explore mechanistic explanations for the observations in this study.

Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Probiotics are an upcoming group of nutraceuticals claiming positive effects on athlete's gut health, redox biology and immunity but there is lack of evidence to support these statements. METHODS: We conducted a randomized, double-blinded, placebo controlled trial to observe effects of probiotic supplementation on markers of intestinal barrier, oxidation and inflammation, at rest and after intense exercise. 23 trained men received multi-species probiotics (1010 CFU/day, Ecologic®Performance or OMNi-BiOTiC®POWER, n = 11) or placebo (n = 12) for 14 weeks and performed an intense cycle ergometry over 90 minutes at baseline and after 14 weeks. Zonulin and α1-antitrypsin were measured from feces to estimate gut leakage at baseline and at the end of treatment. Venous blood was collected at baseline and after 14 weeks, before and immediately post exercise, to determine carbonyl proteins (CP), malondialdehyde (MDA), total oxidation status of lipids (TOS), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Statistical analysis used multifactorial analysis of variance (ANOVA). Level of significance was set at p < 0.05, a trend at p < 0.1. RESULTS: Zonulin decreased with supplementation from values slightly above normal into normal ranges (<30 ng/ml) and was significantly lower after 14 weeks with probiotics compared to placebo (p = 0.019). We observed no influence on α1-antitrypsin (p > 0.1). CP increased significantly from pre to post exercise in both groups at baseline and in the placebo group after 14 weeks of treatment (p = 0.006). After 14 weeks, CP concentrations were tendentially lower with probiotics (p = 0.061). TOS was slightly increased above normal in both groups, at baseline and after 14 weeks of treatment. There was no effect of supplementation or exercise on TOS. At baseline, both groups showed considerably higher TNF-α concentrations than normal. After 14 weeks TNF-α was tendentially lower in the supplemented group (p = 0.054). IL-6 increased significantly from pre to post exercise in both groups (p = 0.001), but supplementation had no effect. MDA was not influenced, neither by supplementation nor by exercise. CONCLUSIONS: The probiotic treatment decreased Zonulin in feces, a marker indicating enhanced gut permeability. Moreover, probiotic supplementation beneficially affected TNF-α and exercise induced protein oxidation. These results demonstrate promising benefits for probiotic use in trained men. CLINICAL TRIAL REGISTRY: http://www.clinicaltrials.gov, identifier: NCT01474629.

Is there a glass transition in planar vortex systems?

The criteria for the existence of a glass transition in a planar vortex array with quenched disorder are studied. Applying a replica Bethe ansatz, we obtain for self-avoiding vortices the exact quenched average free energy and effective stiffness which is found to be in excellent agreement with recent numerical results for the related random bond dimer model [C. Zeng, P. L. Leath, and T. Hwa, Phys. Rev. Lett. 83, 4860 (1999)] Including a repulsive vortex interaction and a finite vortex persistence length xi, we find that for xi-->0 the system is at all temperatures in a glassy phase; a glass transition exists only for finite xi. Our results indicate that planar vortex arrays in superconducting films are glassy at presumably all temperatures.