Patterns of radiological response to tebentafusp in patients with metastatic uveal melanoma.

Metastatic uveal melanoma (mUM) is a rare type of melanoma with poor outcomes. The first systemic treatment to significantly prolong overall survival (OS) in patients with mUM was tebentafusp, a bispecific protein that can redirect T-cells to gp-100 positive cells. However, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the clinical impact of tebentafusp. As metabolic response assessed by PET Response Criteria in Solid Tumors (PERCIST) has been reported to better correlate with clinical outcome, we here compared the patterns of radiological and morphological responses in HLA-A*02:01-positive patients with mUM treated with tebentafusp. In the 19 enrolled patients, RECIST showed an overall response rate (ORR) of 10%, median progression-free survival of 2.8 months (95% CI 2.5-8.4), and median OS (mOS) of 18.8 months. In 10 patients, where both RECIST and PERCIST evaluation was available, the ORR was 10% for both; however, the PFS was longer for PERCIST compared to RECIST, 3.1 and 2.4 months, respectively. A poor agreement between the criteria was observed at all assessments (Cohen's kappa ≤0), yet they differed significantly only at the first on-treatment imaging ( P  = 0.037). Elevated baseline LDH and age were associated with an increased risk for RECIST progression, while lymphocyte decrease after the first infusions correlated to reduced risk of RECIST progression. Detectable ctDNA at baseline did not correlate with progression. Early response to tebentafusp may be incompletely captured by conventional imaging, leading to a need to consider both tumor morphology and metabolism.

How Does Target Lesion Selection Affect RECIST? A Computer Simulation Study.

OBJECTIVES: Response Evaluation Criteria in Solid Tumors (RECIST) is grounded on the assumption that target lesion selection is objective and representative of the change in total tumor burden (TTB) during therapy. A computer simulation model was designed to challenge this assumption, focusing on a particular aspect of subjectivity: target lesion selection. MATERIALS AND METHODS: Disagreement among readers and the disagreement between individual reader measurements and TTB were analyzed as a function of the total number of lesions, affected organs, and lesion growth. RESULTS: Disagreement rises when the number of lesions increases, when lesions are concentrated on a few organs, and when lesion growth borders the thresholds of progressive disease and partial response. There is an intrinsic methodological error in the estimation of TTB via RECIST 1.1, which depends on the number of lesions and their distributions. For example, for a fixed number of lesions at 5 and 15, distributed over a maximum of 4 organs, the error rates are observed to be 7.8% and 17.3%, respectively. CONCLUSIONS: Our results demonstrate that RECIST can deliver an accurate estimate of TTB in localized disease, but fails in cases of distal metastases and multiple organ involvement. This is worsened by the "selection of the largest lesions," which introduces a bias that makes it hardly possible to perform an accurate estimate of the TTB. Including more (if not all) lesions in the quantitative analysis of tumor burden is desirable.

Early Postoperative Serum Phosphate Drop Predicts Sufficient Hypertrophy After Liver Surgery.

OBJECTIVE: The aim of this study was to assess the impact of postoperative hypophosphatemia on liver regeneration after major liver surgery in the scenario of Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) and living liver donation (LLD). BACKGROUND: Hypophosphatemia has been described to reflect the metabolic demands of regenerating hepatocytes. Both ALPPS and LLD are characterized by an exceptionally strong liver regeneration and may be of particular interest in the context of posthepatectomy hypophosphatemia. METHODS: Serum phosphate changes within the first 7 postoperative days after ALPPS (n=61) and LLD (n=54) were prospectively assessed and correlated with standardized volumetry after 1 week. In a translational approach, postoperative phosphate changes were investigated in mice and in vitro . RESULTS: After ALPPS stage 1 and LLD, serum phosphate levels significantly dropped from a preoperative median of 1.08 mmol/L [interquartile range (IQR) 0.92-1.23] and 1.07 mmol/L (IQR 0.91-1.21) to a postoperative median nadir of 0.68 and 0.52 mmol/L, respectively. A pronounced phosphate drop correlated well with increased liver hypertrophy ( P <0.001). Patients with a low drop of phosphate showed a higher incidence of posthepatectomy liver failure after ALPPS (7% vs 31%, P =0.041). Like in humans, phosphate drop correlated significantly with degree of hypertrophy in murine ALPPS and hepatectomy models ( P <0.001). Blocking phosphate transporter (Slc20a1) inhibited cellular phosphate uptake and hepatocyte proliferation in vitro. CONCLUSION: Phosphate drop after hepatectomy is a direct surrogate marker for liver hypertrophy. Perioperative implementation of serum phosphate analysis has the potential to detect patients with insufficient regenerative capacity at an early stage.

Implementing CT tumor volume and CT pleural thickness into future staging systems for malignant pleural mesothelioma.

OBJECTIVES: Tumor thickness and tumor volume measured by computed tomography (CT) were suggested as valuable prognosticator for patients' survival diagnosed with malignant pleural mesothelioma (MPM). The purpose was to assess the accuracy of CT scan based preoperatively measured tumor volume and thickness compared to actual tumor weight of resected MPM specimen and pathologically assessed tumor thickness, as well as an analysis of their impact on overall survival (OS). METHODS: Between 09/2013-08/2018, 74 patients were treated with induction chemotherapy followed by (extended) pleurectomy/decortication ((E)PD). In 53 patients, correlations were made between CT-measured volume and -tumor thickness (cTV and cTT) and actual tumor weight (pTW) based on the available values. Further cTV and pT/IMIG stage were correlated using Pearson correlation. Overall survival (OS) was calculated with Kaplan Meier analysis and tested with log rank test. For correlation with OS Kaplan-Meier curves were made and log rank test was performed for all measurements dichotomized at the median. RESULTS: Median pathological tumor volume (pTV) and pTW were 530 ml [130 ml - 1000 ml] and 485 mg [95 g - 982 g] respectively. Median (IQR) cTV was 77.2 ml (35.0-238.0), median cTT was 9.0 mm (6.2-13.7). Significant association was found between cTV and pTV (R = 0.47, p < 0.001) and between cTT and IMIG stage (p = 0,001) at univariate analysis. Multivariate regression analysis revealed, that only cTV correlates with pTV. Median follow-up time was 36.3 months with 30 patients dead at the time of the analysis. Median OS was 23.7 months. 1-year and 3-year survival were 90 and 26% respectively and only the cTV remained statistically associated with OS. CONCLUSION: Preoperatively assessed CT tumor volume and actual tumor volume showed a significant correlation. CT tumor volume may predict pathological tumor volume as a reflection of tumor burden, which supports the integration of CT tumor volume into future staging systems.

Lung Nodules in Melanoma Patients: Morphologic Criteria to Differentiate Non-Metastatic and Metastatic Lesions.

Lung nodules are frequent findings in chest computed tomography (CT) in patients with metastatic melanoma. In this study, we assessed the frequency and compared morphologic differences of metastases and benign nodules. We retrospectively evaluated 85 patients with melanoma (AJCC stage III or IV). Inclusion criteria were ≤20 lung nodules and follow-up using CT ≥183 days after baseline. Lung nodules were evaluated for size and morphology. Nodules with significant growth, nodule regression in line with RECIST assessment or histologic confirmation were judged to be metastases. A total of 438 lung nodules were evaluated, of which 68% were metastases. At least one metastasis was found in 78% of patients. A 10 mm diameter cut-off (used for RECIST) showed a specificity of 95% and a sensitivity of 20% for diagnosing metastases. Central location (n = 122) was more common in metastatic nodules (p = 0.009). Subsolid morphology (n = 53) was more frequent (p < 0.001), and calcifications (n = 13) were solely found in non-metastatic lung nodules (p < 0.001). Our data show that lung nodules are prevalent in about two-thirds of melanoma patients (AJCC stage III/IV) and the majority are metastases. Even though we found a few morphologic indicators for metastatic or non-metastatic lung nodules, morphology has limited value to predict the presence of lung metastases.

Development of a Prognostic AI-Monitor for Metastatic Urothelial Cancer Patients Receiving Immunotherapy.

Background: Immune checkpoint inhibitor efficacy in advanced cancer patients remains difficult to predict. Imaging is the only technique available that can non-invasively provide whole body information of a patient's response to treatment. We hypothesize that quantitative whole-body prognostic information can be extracted by leveraging artificial intelligence (AI) for treatment monitoring, superior and complementary to the current response evaluation methods. Methods: To test this, a cohort of 74 stage-IV urothelial cancer patients (37 in the discovery set, 37 in the independent test, 1087 CTs), who received anti-PD1 or anti-PDL1 were retrospectively collected. We designed an AI system [named prognostic AI-monitor (PAM)] able to identify morphological changes in chest and abdominal CT scans acquired during follow-up, and link them to survival. Results: Our findings showed significant performance of PAM in the independent test set to predict 1-year overall survival from the date of image acquisition, with an average area under the curve (AUC) of 0.73 (p < 0.001) for abdominal imaging, and 0.67 AUC (p < 0.001) for chest imaging. Subanalysis revealed higher accuracy of abdominal imaging around and in the first 6 months of treatment, reaching an AUC of 0.82 (p < 0.001). Similar accuracy was found by chest imaging, 5-11 months after start of treatment. Univariate comparison with current monitoring methods (laboratory results and radiological assessments) revealed higher or similar prognostic performance. In multivariate analysis, PAM remained significant against all other methods (p < 0.001), suggesting its complementary value in current clinical settings. Conclusions: Our study demonstrates that a comprehensive AI-based method such as PAM, can provide prognostic information in advanced urothelial cancer patients receiving immunotherapy, leveraging morphological changes not only in tumor lesions, but also tumor spread, and side-effects. Further investigations should focus beyond anatomical imaging. Prospective studies are warranted to test and validate our findings.

Prognostic Value of Deep Learning-Mediated Treatment Monitoring in Lung Cancer Patients Receiving Immunotherapy.

BACKGROUND: Checkpoint inhibitors provided sustained clinical benefit to metastatic lung cancer patients. Nonetheless, prognostic markers in metastatic settings are still under research. Imaging offers distinctive advantages, providing whole-body information non-invasively, while routinely available in most clinics. We hypothesized that more prognostic information can be extracted by employing artificial intelligence (AI) for treatment monitoring, superior to 2D tumor growth criteria. METHODS: A cohort of 152 stage-IV non-small-cell lung cancer patients (NSCLC) (73 discovery, 79 test, 903CTs), who received nivolumab were retrospectively collected. We trained a neural network to identify morphological changes on chest CT acquired during patients' follow-ups. A classifier was employed to link imaging features learned by the network with overall survival. RESULTS: Our results showed significant performance in the independent test set to predict 1-year overall survival from the date of image acquisition, with an average area under the curve (AUC) of 0.69 (p < 0.01), up to AUC 0.75 (p < 0.01) in the first 3 to 5 months of treatment, and 0.67 AUC (p = 0.01) for durable clinical benefit (6 months progression-free survival). We found the AI-derived survival score to be independent of clinical, radiological, PDL1, and histopathological factors. Visual analysis of AI-generated prognostic heatmaps revealed relative prognostic importance of morphological nodal changes in the mediastinum, supraclavicular, and hilar regions, lung and bone metastases, as well as pleural effusions, atelectasis, and consolidations. CONCLUSIONS: Our results demonstrate that deep learning can quantify tumor- and non-tumor-related morphological changes important for prognostication on serial imaging. Further investigation should focus on the implementation of this technique beyond thoracic imaging.

Combination of HAI-FUDR and Systemic Gemcitabine and Cisplatin in Unresectable Cholangiocarcinoma: A Dose Finding Single Center Study.

BACKGROUND: Unresectable cholangiocarcinoma has a poor prognosis and treatment options are limited. Combined systemic and intrahepatic chemotherapy may improve local control and enable downsizing. The aim of this study was to determine the maximum tolerated dose (MTD) of intravenous gemcitabine combined with intravenous cisplatin and hepatic arterial infusion (HAI) with floxuridine (FUDR) in patients with unresectable intrahepatic or hilar cholangiocarcinoma. METHODS: Twelve patients were treated within a 3 + 3 dose escalation algorithm with 600, 800, or 1,000 mg/m2 gemcitabine and predefined doses of cisplatin 25 mg/m2 on days 1 and 8, q21, for 4 cycles, and FUDR 0.2 mg/kg on days 1-14 as continuous HAI, q28, for 3 cycles. Safety and toxicity as well as resectability rates after 3 months and preliminary survival data are reported. RESULTS: The determined MTD for gemcitabine was 800 mg/m2. Dose limiting toxicities were neutropenic fever and biliary tract infections. In total, 27% of the patients showed partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, the 3-year overall survival rate was 33%, median overall survival 23.9 months (range 1-49), and median progression-free survival 10.1 months (range 2-40). CONCLUSIONS: Intravenous gemcitabine/cisplatin plus HAI-FUDR is feasible and appears effective for disease control. Larger prospective studies evaluating this triplet combination are warranted.

Outcome of Patients With Severe Aortic Stenosis and Normal Coronary Arteries Undergoing Transcatheter Aortic Valve Implantation.

Coronary artery disease and severe aortic stenosis (AS) often coexist. This study sought to investigate the impact of normal coronary arteries as negative risk marker in patients undergoing transcatheter aortic valve implantation (TAVI). Consecutive patients with severe AS undergoing TAVI were dichotomized according to the presence or absence of normal coronary arteries, defined as absence of coronary lesions with diameter stenosis ≥30% in vessels ≥1.5 mm in diameter on coronary angiogram in patients without prior coronary revascularization. The primary end point was 1-year mortality. Out of 987 patients with severe AS undergoing TAVI, 258 (26%) patients had normal coronary arteries. These patients were younger, more likely women, and had lower EuroSCORE II and STS risk scores. Although mortality at 30 days was similar in the normal coronary artery and the coronary atherosclerosis groups (3.1% vs 5.6%, p = 0.11), it was lower in those with normal coronary arteries at 1 year (8.9% vs 17%, p = 0.003). In multivariable analysis, the presence of normal coronary arteries on coronary angiogram independently predicted 1-year mortality (adjusted HR 0.57, 95% CI 0.37 to 0.90, p = 0.02). In conclusion, this study defined normal coronary arteries as negative risk marker in patients with severe AS undergoing TAVI.

Accuracy of Conventional and Machine Learning Enhanced Chest Radiography for the Assessment of COVID-19 Pneumonia: Intra-Individual Comparison with CT.

PURPOSE: To evaluate diagnostic accuracy of conventional radiography (CXR) and machine learning enhanced CXR (mlCXR) for the detection and quantification of disease-extent in COVID-19 patients compared to chest-CT. METHODS: Real-time polymerase chain reaction (rt-PCR)-confirmed COVID-19-patients undergoing CXR from March to April 2020 together with COVID-19 negative patients as control group were retrospectively included. Two independent readers assessed CXR and mlCXR images for presence, disease extent and type (consolidation vs. ground-glass opacities (GGOs) of COVID-19-pneumonia. Further, readers had to assign confidence levels to their diagnosis. CT obtained ≤ 36 h from acquisition of CXR served as standard of reference. Inter-reader agreement, sensitivity for detection and disease extent of COVID-19-pneumonia compared to CT was calculated. McNemar test was used to test for significant differences. RESULTS: Sixty patients (21 females; median age 61 years, range 38-81 years) were included. Inter-reader agreement improved from good to excellent when mlCXR instead of CXR was used (k = 0.831 vs. k = 0.742). Sensitivity for pneumonia detection improved from 79.5% to 92.3%, however, on the cost of specificity 100% vs. 71.4% (p = 0.031). Overall, sensitivity for the detection of consolidation was higher than for GGO (37.5% vs. 70.4%; respectively). No differences could be found in disease extent estimation between mlCXR and CXR, even though the detection of GGO could be improved. Diagnostic confidence was better on mlCXR compared to CXR (p = 0.013). CONCLUSION: In line with the current literature, the sensitivity for detection and quantification of COVID-19-pneumonia was moderate with CXR and could be improved when mlCXR was used for image interpretation.

Patterns of organizing pneumonia and microinfarcts as surrogate for endothelial disruption and microangiopathic thromboembolic events in patients with coronavirus disease 2019.

BACKGROUND: To evaluate chest-computed-tomography (CT) scans in coronavirus-disease-2019 (COVID-19) patients for signs of organizing pneumonia (OP) and microinfarction as surrogate for microscopic thromboembolic events. METHODS: Real-time polymerase-chain-reaction (RT-PCR)-confirmed COVID-19 patients undergoing chest-CT (non-enhanced, enhanced, pulmonary-angiography [CT-PA]) from March-April 2020 were retrospectively included (COVID-19-cohort). As control-groups served 175 patients from 2020 (cohort-2020) and 157 patients from 2019 (cohort-2019) undergoing CT-PA for pulmonary embolism (PE) during the respective time frame at our institution. Two independent readers assessed for presence and location of PE in all three cohorts. In COVID-19 patients additionally parenchymal changes typical of COVID-19 pneumonia, infarct pneumonia and OP were assessed. Inter-reader agreement and prevalence of PE in different cohorts were calculated. RESULTS: From 68 COVID-19 patients (42 female [61.8%], median age 59 years [range 32-89]) undergoing chest-CT 38 obtained CT-PA. Inter-reader-agreement was good (k = 0.781). On CT-PA, 13.2% of COVID-19 patients presented with PE whereas in the control-groups prevalence of PE was 9.1% and 8.9%, respectively (p = 0.452). Up to 50% of COVID-19 patients showed changes typical for OP. 21.1% of COVID-19 patients suspected with PE showed subpleural wedge-shaped consolidation resembling infarct pneumonia, while only 13.2% showed visible filling defects of the pulmonary artery branches on CT-PA. CONCLUSION: Despite the reported hypercoagulability in critically ill patients with COVID-19, we did not encounter higher prevalence of PE in our patient cohort compared to the control cohorts. However, patients with suspected PE showed a higher prevalence of lung changes, resembling patterns of infarct pneumonia or OP and CT-signs of pulmonary-artery hypertension.

Multimodality imaging derived energy loss index and outcome after transcatheter aortic valve replacement.

AIMS: To assess whether the combination of transthoracic echocardiography (TTE) and multidetector computed tomography (MDCT) data affects the grading of aortic stenosis (AS) severity under consideration of the energy loss index (ELI) in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: Multimodality imaging was performed in 197 patients with symptomatic severe AS undergoing TAVR at the University Hospital Zurich, Switzerland. Fusion aortic valve area index (fusion AVAi) assessed by integrating MDCT derived planimetric left ventricular outflow tract area into the continuity equation was significantly larger as compared to conventional AVAi (0.41 ± 0.1 vs. 0.51 ± 0.1 cm2/m2; P < 0.01). A total of 62 patients (31.4%) were reclassified from severe to moderate AS with fusion AVAi being >0.6 cm2/m2. ELI was obtained for conventional AVAi and fusion AVAi based on sinotubular junction area determined by TTE (ELILTL 0.47 ± 0.1 cm2/m2; fusion ELILTL 0.60 ± 0.1 cm2/m2) and MDCT (ELIMDCT 0.48 ± 0.1 cm2/m2; fusion ELIMDCT 0.61 ± 0.05 cm2/m2). When ELI was calculated with fusion AVAi the effective orifice area was >0.6 cm2/m2 in 85 patients (43.1%). Survival rate 3 years after TAVR was higher in patients reclassified to moderate AS according to multimodality imaging derived ELI (78.8% vs. 67%; P = 0.01). CONCLUSION: Multimodality imaging derived ELI reclassifies AS severity in 43% undergoing TAVR and predicts mid-term outcome.

Flat chest projection in the detection and visualization of rib fractures: A cross-sectional study comparing curved and multiplanar reformation of computed tomography images in different reader groups.

BACKGROUND: Rib fractures are common and potentially life-threatening. Fast and correct detection as well as comprehensive visual overview of rib fractures are of clinical and forensic importance. This study compared two computed tomography (CT) reformation methods, curved planar reformation (CPR) with conventional multiplanar reformation (MPR), regarding detection of rib fractures in different readers. METHODS: Twelve postmortem CT datasets were retrospectively assessed for rib fractures using CPR and MPR. After defining the gold-standard regarding side, level, localization, and quantity of fractures, four reader groups per two readers consisting of radiologists, trauma surgeons, forensic pathologists, and laypersons, were evaluated for sensitivity, proportion of false positives, time to fracture detection, and subjective preference. RESULTS: Overall sensitivity for fracture detection did not vary significantly between both methods. However, it was significantly higher in trauma surgeons and laypersons when reading CPR compared to MPR (70.7% vs. 62.0%, p=0.038 and 33.7% vs. 22.1%, p=0.003 respectively). It was significantly lower in radiologists (63.8% vs. 76.8%, p=0.001). Forensic pathologists performed similarly with both methods (53.6% vs. 56.5%, p=0.549). All non-radiologists preferred the use of CPR (75%). All readers found CPR to provide better visual overview (100%). CONCLUSION: CPR may increase rib fracture detection rates of non-radiologists (i.e. trauma surgeons and laypersons) and provides a better visual overview. However, radiologists achieve higher fracture detection rates when allowed to work with the software tools they are more experienced with. The overall sensitivity was improvable and better visualization methods are warranted in order to avoid misdiagnosis and medicolegal errors regarding rib fracture detection.

Volumetric assessment of solid pulmonary nodules on ultralow-dose CT: a phantom study.

BACKGROUND: To reduce the radiation exposure from chest computed tomography (CT), ultralow-dose CT (ULDCT) protocols performed at sub-millisievert levels were previously tested for the evaluation of pulmonary nodules (PNs). The purpose of our study was to investigate the effect of ULDCT and iterative image reconstruction on volumetric measurements of solid PNs. METHODS: CT datasets of an anthropomorphic chest phantom containing solid microspheres were obtained with a third-generation dual-source CT at standard dose, 1/8th, 1/20th and 1/70th of standard dose [CT volume dose index (CTDIvol): 0.03-2.03 mGy]. Semi-automated volumetric measurements were performed on CT datasets reconstructed with filtered back projection (FBP) and advanced modelled iterative reconstruction (ADMIRE), at strength level 3 and 5. Absolute percentage error (APE) evaluated measurement accuracy related to the effective volume. Scan repetition differences were evaluated using Bland-Altman analysis. Two-way analysis of variance (ANOVA) assessed influence of different scan parameters on APE. Proportional differences (PDs) tested the effect of dose settings and reconstruction algorithms on volumetric measurements, as compared to the standard protocol (standard dose-FBP). RESULTS: Bland-Altman analysis revealed small mean interscan differences of APE with narrow limits of agreement (-0.1%±4.3% to -0.3%±3.8%). Dose settings (P<0.001), reconstruction algorithms (P<0.001), nodule diameters (P<0.001) and nodule density (P=0.011) had statistically significant influence on APE. Post-hoc Bonferroni tests showed slightly higher APE when scanning with 1/70th of standard dose [mean difference: 3.4%, 95% confidence interval (CI): 2.5-4.3%; P<0.001], and for image reconstruction with ADMIRE5 (mean difference: 1.8%, 95% CI: 1.0-2.5%; P<0.001). No significant differences for scanning with 1/20th of standard dose (P=0.42), and image reconstruction with ADMIRE3 (P=0.19) were found. Scanning with 1/70th of standard dose and image reconstruction with FBP showed the widest range of PDs (-16.8% to 23.4%) compared to standard dose-FBP. CONCLUSIONS: Our phantom study showed no significant difference between nodule volume measurements on standard dose CT (CTDIvol: 2 mGy) and ULDCT with 1/20th of standard dose (CTDIvol: 0.10 mGy).

Erratum to the impact of slice-reduced computed tomography on histogram based densitometry assessment of lung fibrosis in patients with systemic sclerosis.

[This corrects the article DOI: 10.21037/jtd.2018.04.39.].

Radiogenomics: bridging imaging and genomics.

From diagnostics to prognosis to response prediction, new applications for radiomics are rapidly being developed. One of the fastest evolving branches involves linking imaging phenotypes to the tumor genetic profile, a field commonly referred to as "radiogenomics." In this review, a general outline of radiogenomic literature concerning prominent mutations across different tumor sites will be provided. The field of radiogenomics originates from image processing techniques developed decades ago; however, many technical and clinical challenges still need to be addressed. Nevertheless, increasingly accurate and robust radiogenomic models are being presented and the future appears to be bright.

Pre-procedural CT angiography inferior vena cava measurements: a predictor of mortality in patients undergoing transcatheter aortic valve implantation.

OBJECTIVES: To assess the value of pre-procedural computed tomography angiography (CTA) measurements of the suprahepatic inferior vena cava (IVC) to detect elevated central venous pressure (CVP) assessed by right heart catheterisation (RHC), and to predict post-procedural 1-year mortality in a cohort of patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: We retrospectively evaluated 408 consecutive patients undergoing CTA before TAVI between January 2011 and December 2014. Two hundred and five patients were included in the RHC cohort, who underwent RHC and CTA within ≤1 day prior to TAVI. Two hundred and three patients not fulfilling this requirement were included in the validation cohort. Measurements of the IVC were performed between diaphragm and right atrium on axial slices. Receiver operating characteristic (ROC) analyses, Kaplan-Meier analyses and Cox regression analyses were performed. RESULTS: In the RHC cohort, ROC curve analyses for IVC area measurements indicated an AUC of 0.77 (p < 0.001) to detect CVP ≥10mmHg and an area under the ROC curve (AUC) of 0.72 (p < 0.001) to predict 1-year mortality. An IVC area cut-off of ≥665 mm2 predicted 1-year mortality with a specificity of 84% and a sensitivity of 63%. Kaplan-Meier analysis showed that patients with an IVC area ≥665 mm2 had a significantly higher post-procedural 1-year mortality (38% versus 7%, log-rank p < 0.001) with a hazard ratio of 5.5 (95% CI, 2.2-13.6; p < 0.001). Applying this cut-off value to the validation cohort confirmed a significantly higher 1-year mortality after TAVI (34% versus 11%; log-rank p = 0.004) for patients with an IVC area ≥665 mm2. CONCLUSIONS: Pre-procedural enlargement of the suprahepatic IVC is a predictor of post-procedural 1-year mortality in patients evaluated for TAVI. KEY POINTS: • IVC measurements are moderate predictors of an elevated CVP in TAVI patients. • Pre-procedural IVC enlargement is a predictor of 1-year mortality after TAVI. • IVC enlargement is associated with right heart dysfunction in TAVI patients.

Peripheral Blood TCR Repertoire Profiling May Facilitate Patient Stratification for Immunotherapy against Melanoma.

Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4; however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment peripheral blood mononuclear cells from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA). A receiver operating characteristic curve determined the optimal threshold for a dichotomized analysis according to objective responses as defined by RECIST1.1. Correlations between treatment outcome, clinical variables, and DE50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE50 values were predictive of a longer progression-free survival and good responses to PD-1 blockade, but, on the other hand, predicted a poor response to CTLA4 inhibition. Multivariate logistic regression models identified DE50 as the only independent predictive factor for response to anti-CTLA4 therapy (P = 0.03) and anti-PD1 therapy (P = 0.001). Fisher exact tests confirmed the association of low DE50 with response in the anti-CTLA4 (P = 0.041) and the anti-PD1 cohort (P = 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCR-based method, could help predict responses to anti-PD1 and anti-CTLA4 therapies.

The impact of slice-reduced computed tomography on histogram-based densitometry assessment of lung fibrosis in patients with systemic sclerosis.

Background: To evaluate usability of slice-reduced sequential computed tomography (CT) compared to standard high-resolution CT (HRCT) in patients with systemic sclerosis (SSc) for qualitative and quantitative assessment of interstitial lung disease (ILD) with respect to (I) detection of lung parenchymal abnormalities, (II) qualitative and semiquantitative visual assessment, (III) quantification of ILD by histograms and (IV) accuracy for the 20%-cut off discrimination. Methods: From standard chest HRCT of 60 SSc patients sequential 9-slice-computed tomography (reduced HRCT) was retrospectively reconstructed. ILD was assessed by visual scoring and quantitative histogram parameters. Results from standard and reduced HRCT were compared using non-parametric tests and analysed by univariate linear regression analyses. Results: With respect to the detection of parenchymal abnormalities, only the detection of intrapulmonary bronchiectasis was significantly lower in reduced HRCT compared to standard HRCT (P=0.039). No differences were found comparing visual scores for fibrosis severity and extension from standard and reduced HRCT (P=0.051-0.073). All scores correlated significantly (P<0.001) to histogram parameters derived from both, standard and reduced HRCT. Significant higher values of kurtosis and skewness for reduced HRCT were found (both P<0.001). In contrast to standard HRCT histogram parameters from reduced HRCT showed significant discrimination at cut-off 20% fibrosis (sensitivity 88% kurtosis and skewness; specificity 81% kurtosis and 86% skewness; cut-off kurtosis ≤26, cut-off skewness ≤4; both P<0.001). Conclusions: Reduced HRCT is a robust method to assess lung fibrosis in SSc with minimal radiation dose with no difference in scoring assessment of lung fibrosis severity and extension in comparison to standard HRCT. In contrast to standard HRCT histogram parameters derived from the approach of reduced HRCT could discriminate at a threshold of 20% lung fibrosis with high sensitivity and specificity. Hence it might be used to detect early disease progression of lung fibrosis in context of monitoring and treatment of SSc patients.

Impact of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) on growth of colorectal liver metastases.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy induces an unprecedented liver hypertrophy and enables resection of otherwise unresectable liver tumors. The effect of associating liver partition and portal vein ligation for staged hepatectomy on tumor proliferation, however, remains a concern. This study investigated the impact of associating liver partition and portal vein ligation for staged hepatectomy on growth of colorectal metastases in mice and in humans. METHODS: The effect of associating liver partition and portal vein ligation for staged hepatectomy and 90% portal vein ligation on colorectal liver and lung metastases was investigated in mice. In vivo tumor progression was assessed by magnetic resonance imaging, histology, and survival experiments. The effects of associating liver partition and portal vein ligation for staged hepatectomy, portal vein ligation, and control sera on cultures of several colorectal cancer cell lines (MC38 and CT26) were tested in vitro. Additionally, the international associating liver partition and portal vein ligation for staged hepatectomy registry enabled us to identify patients with remaining tumor in the future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy stage 1. RESULTS: Two and 3 weeks after associating liver partition and portal vein ligation for staged hepatectomy stage 1, portal vein ligation, or sham surgery, liver magnetic resonance images showed similar numbers (P=.14/0.82), sizes (P=.45/0.98), and growth kinetics (P=.58/0.68) of intrahepatic tumor. Tumor growth was not different between the associating liver partition and portal vein ligation for staged hepatectomy and portal vein ligation groups after completion of stage 2. Median survival after tumor cell injection was similar after sham surgery (36 days; 95% confidence interval; 27-57 days), completion of associating liver partition and portal vein ligation for staged hepatectomy (42 days; 95% confidence interval; 35-49 days), and portal vein ligation (39 days; 95% confidence interval; 34-43 days, P=.237). Progression of pulmonary metastases and in vitro cell proliferation were comparable among groups. Observations in humans failed to identify any accelerated tumor growth in the future liver remnant within the regenerative phase after associating liver partition and portal vein ligation for staged hepatectomy stage 1. CONCLUSION: The accelerated regeneration process associated with associating liver partition and portal vein ligation for staged hepatectomy does not appear to enhance growth of colorectal metastases.