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.

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.

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.

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.

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.

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.

Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma.

Only limited information is available on the role of complement activation in malignant pleural mesothelioma (MPM). Thus, we investigated the circulating and tissue levels of the complement component 4d (C4d) in MPM. Plasma samples from 55 MPM patients, 21 healthy volunteers (HV) and 14 patients with non-malignant pleural diseases (NMPD) were measured by ELISA for C4d levels. Tissue specimens from 32 patients were analyzed by C4d immunohistochemistry. Tumor volumetry was measured in 20 patients. We found no C4d labeling on tumor cells, but on ectopic lymphoid structures within the tumor stroma. Plasma C4d levels did not significantly differ between MPM, HV or NMPD. Late-stage MPM patients had higher plasma C4d levels compared to early-stage (p = 0.079). High circulating C4d was associated with a higher tumor volume (p = 0.047). Plasma C4d levels following induction chemotherapy were significantly higher in patients with stable/progressive disease compared to those with partial/major response (p = 0.005). Strikingly, patients with low C4d levels at diagnosis had a significantly better overall survival, confirmed in a multivariate cox regression model (hazard ratio 0.263, p = 0.01). Our findings suggest that circulating plasma C4d is a promising new prognostic biomarker in patients with MPM and, moreover, helps to select patients for surgery following induction chemotherapy.

Phase I study of a chloroquine-gemcitabine combination in patients with metastatic or unresectable pancreatic cancer.

PURPOSE: Following a previously published pre-clinical validation, this phase I study evaluated the safety, maximum tolerated dose, anti-tumour activity and immune status of a gemcitabine-chloroquine combination as a first- or late-line treatment in patients with metastatic or unresectable pancreatic cancer. METHODS: In this 3 + 3 dose escalation study, patients received a single weekly standard dose of intravenous gemcitabine, followed by single weekly oral intake of 100, 200 or 300 mg of chloroquine. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. Immune status was evaluated by RT-PCR to measure the relative expression of immune-related genes in peripheral blood mononuclear cells (PBMCs). RESULTS: Overall, nine patients [median age 72 years; interquartile range (IQR), 68-78 years] were treated. No dose-limiting toxicities as defined in the protocol were observed. Three patients experienced partial response, and two patients had stable disease. The median time to progression was 4 months (95% CI 0.8-7.2), and the median overall survival was 7.6 months (95% CI 5.3-9.9). Among 86 assayed immune genes, three were significantly differentially expressed in PBMCs from responding versus non-responding patients: interferon-gamma receptor-1, toll-like receptor 2, and beta-2 microglobulin. CONCLUSIONS: The addition of chloroquine to gemcitabine was well tolerated and showed promising effects on the clinical response to the anti-cancer chemotherapy. Based on these initial results, the efficacy of the gemcitabine-chloroquine combination should be further assessed.

Quantification of aortic valve calcification on contrast-enhanced CT of patients prior to transcatheter aortic valve implantation.

AIMS: The aim of the study was to develop a formula enabling the quantification of aortic valve calcification (AVC) on contrast-enhanced CT of patients undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Two hundred and seventeen (217) consecutive patients with severe aortic valve stenosis undergoing non-enhanced electrocardiography-gated CT angiography (NECT) and contrast-enhanced electrocardiography-gated CT angiography (CECT) prior to TAVI were subdivided into a training cohort (n=145) and a validation cohort (n=72). Aortic valve calcification (AVC) was semi-automatically segmented on CECT (AVC.

Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy.

BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced melanoma. We developed and validated a clinical prediction scale for response to anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma treated with pembrolizumab (2 or 10 mg kg-1 Q2W or Q3W) or nivolumab (3 mg kg-1 Q2W) at four cancer centres between 2011 to 2013 served as the setting for the present cohort study. Variables with significant association to response on a univariate analysis were entered into a forward stepwise logistic regression model and were given a score based on ORs to calculate a clinical prediction scale. RESULTS: The developed clinical prediction scale included elevated LDH (1 point), age <65 years (1 point), female sex (1 point), history of ipilimumab treatment (2 points) and the presence of liver metastasis (2 points). The scale had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80) in predicting response to therapy. The predictive performance of the score was maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a large cohort of patients, we developed and validated a simple five-factor prediction scale for the clinical activity of PD-1 antibodies in advanced melanoma patients. This scale can be used to stratify patients participating in clinical trials.

Computed tomography-based three-dimensional visualisation of bone corridors and trajectories for screws in open reduction and internal fixation of symphysis diastasis: a retrospective radiological study.

INTRODUCTION: Typical stabilisation of pelvic open book injuries consists of plate fixation of the symphysis. No previous literature has been published about the evaluation of screw placement and their trajectory with four oblique 4.5 mm screws using a four-hole plate in symphysis diastasis. The aim of this study was to define insertion points and angles of trajectory for crossed screw placement regardless of any plate design based on an analysis of three-dimensional computed tomography data sets. METHODS: One hundred human pelvic CT data sets were collected. Unilateral and bilateral placements of crossed 4.5 mm screws were simulated. Primary outcome measure was successful simulated screw placement without cortical breach. Secondary outcome measures included the anatomical measurements of the screw positions. RESULTS: Simulated screw placement of two oblique screws on each side of the pubic symphysis without cortical breach was achieved in all (100 %) cases. There were a total of 400 screw simulations. Medial screws were longer, lateral screws had higher coronal angles, and the distance between both screws was higher on the right side (p < 0.001 each). The lengths of the right lateral, right medial, left lateral, and left medial screws were 44.9, 65.8, 45.4, and 67.4 mm, respectively. The sagittal angles to the dorsal surface area of the pubic rami were 10.5°, 11.1°, 9.0°, and 11.0°. The coronal angles to the vertical axis of the symphysis measured 39.5°, 16.0°, 33.8°, and 16.8°. The distances between these screws and the medial edge of the pubic crest were 33.5, 8.6, 29.5, and 7.3 mm. Furthermore, certain sex- and side-related differences were noted. CONCLUSIONS: This series provides results about the feasibility and a detailed anatomical description of crossed screw placement. This is of special interest in pelvic surgery for choosing the entry points, safe screw channel parameters, and trajectories.

Prognostic value of aortic regurgitation after TAVI in patients with chronic kidney disease.

BACKGROUND: Aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) for severe aortic valve stenosis results in major haemodynamic changes. Influence of post-implant AR and aortic valve calcification on outcome in patients with chronic kidney disease (CKD) is unclear. METHODS: Short-term outcome was defined as a combined 30-day endpoint, long-term outcome as survival. Post-implant AR was classified as none/mild or moderate/severe using transthoracic echocardiography. Aortic valve calcification was calculated by computed tomography. Logistic regression analyses were performed in patients with none/mild (estimated glomerular filtration rate [eGFR]≥30ml/min/1.73m(2)) and advanced (eGFR<30ml/min/1.73m(2)) CKD to evaluate predictors of outcome and post-implant AR. RESULTS: TAVI was performed in 546 consecutive patients. Moderate/severe post-implant AR was the only independent predictor of the 30-day endpoint in patients with advanced (OR 7.091, 95% CI 1.144-43.962, p=0.035), but not in patients with none/mild CKD. Similarly, moderate/severe AR predicted impaired survival only in patients with advanced CKD (p<0.001). NT-proBNP (OR 1.023 per 500ng/l increase, 95% CI 1.003-1.043; p=0.026) before intervention was the only independent predictor of the 30-day endpoint in patients with none/mild CKD. Aortic valve calcification was comparable in patients with none/mild versus advanced CKD and was an independent predictor of moderate/severe post-implant AR in the overall population as well as in the subgroups with none/mild or advanced CKD. CONCLUSIONS: Moderate/severe AR after TAVI predicts outcome in patients with advanced CKD, but not in patients with none/mild CKD. Aortic valve calcification is an important predictor of post-implant AR independent of kidney function.

Circulating activin A is a novel prognostic biomarker in malignant pleural mesothelioma - A multi-institutional study.

INTRODUCTION: The deregulation of activin expression is often observed in various malignancies. Previous studies indicate that activin A plays a protumourigenic role in malignant pleural mesothelioma (MPM). The aim of the study was to evaluate circulating activin A level as a biomarker in MPM. METHODS: Plasma samples were collected from 129 MPM patients in four institutions at the time of diagnosis or before surgical resection. Samples from 45 healthy individuals and from 16 patients with non-malignant pleural diseases served as controls. Circulating activin A was measured by enzyme-linked immunosorbent assay and correlated to clinicopathological variables. RESULTS: Plasma activin A level was significantly elevated in MPM patients (862 ± 83 pg/ml) when compared to healthy controls (391 ± 21 pg/ml; P < 0.0001). Patients with pleuritis or fibrosis only showed a modest increase (versus controls; 625 ± 95 pg/ml; P = 0.0067). Sarcomatoid (n = 10, 1629 ± 202 pg/ml, P = 0.0019) and biphasic (n = 23, 1164 ± 233 pg/ml, P = 0.0188) morphology were associated with high activin A levels when compared to epithelioid histology (n = 94, 712 ± 75 pg/ml). The tumour volume showed a positive correlation with increased circulating activin A levels. MPM patients with below median activin A levels had a significantly longer overall survival when compared to those with high activin A levels (median survival 735 versus 365 d, P < 0.0001). Importantly, circulating activin A levels were exclusively prognostic in epithelioid MPM. CONCLUSIONS: Our findings suggest that the measurement of circulating activin A may support the histological classification of MPM and at the same time help to identify epithelioid MPM patients with poor prognosis.

Treatment of isolated ascending aortic aneurysm by off-pump epiaortic wrapping is safe and durable.

OBJECTIVES: Isolated ascending aortic aneurysm (iAA) is usually treated by open graft repair requiring sternotomy, cardiopulmonary bypass (CPB) and cardioplegia. This approach carries significant mortality in older patients or those presenting with comorbidities. We report an original series of patients presenting with iAA and treated with epiaortic wrapping by using a synthetic mesh. This less invasive aortic repair technique allows reducing the aortic diameter to a predefined value and is performed without CPB. METHODS: Data from patients presenting with an iAA and treated with the wrapping technique (WT) by polypropylene/polyester mesh from November 2006 to July 2015 were collected. The end-points that were analysed included maximal aortic transverse diameter, perioperative mortality and morbidity, survival, freedom from reinterventions and aortic valve function during follow-up. The maximal aneurysm transverse diameter was analysed based on contrast-enhanced computed tomography (CTA) or magnetic resonance (MR) performed preoperatively, and during the follow-up. RESULTS: The off-pump WT was used in 33 cases with no perioperative mortality. The median radiological follow-up was 33.47 (range: 1-106) months. Overall, the WT achieved a 30% diameter reduction. The mean preoperative and postoperative ascending aortic transverse diameter was 5.5 cm [standard deviation (SD): 0.6] and 3.7 cm (SD: 0.30), respectively (P = 0.001). In addition, CTA or MR follow-up showed stable diameters at the level of the aortic root and the distal ascending aorta. No death occurred during the follow-up. At 5 years, the estimated freedom rate from reinterventions of the aortic root and ascending aorta was 94%. CONCLUSIONS: This series shows that the WT with a polypropylene/polyester mesh allows safe off-pump treatment of patients with iAA. Mid- and long-term results are promising. This technique could be an attractive alternative, especially for patients unfit for aortic surgery with CPB and cardioplegia.

A New Prognostic Score Supporting Treatment Allocation for Multimodality Therapy for Malignant Pleural Mesothelioma: A Review of 12 Years' Experience.

INTRODUCTION: Treatment of malignant pleural mesothelioma (MPM) remains a clinical challenge. The aim of this study was to identify selection factors for allocation of MPM patients to multimodal therapy based on survival data from 12 years of experience. METHODS: Eligible patients had MPM of all histological subtypes with clinical stage T1-3 N0-2 M0. Induction chemotherapy consisted of cisplatin/gemcitabine (cis/gem) or cisplatin/pemetrexed (cis/pem), followed by extrapleural pneumonectomy (EPP). Multivariate analysis was performed to assess independent prognosticators for overall survival (OS). A Multimodality Prognostic Score was developed based on clinical variables available before surgery. RESULTS: From May 1999 to August 2011, 186 MPM patients were intended to be treated with induction chemotherapy followed by EPP. Hematologic toxicity was significantly less frequent after cis/pem compared to cis/gem, but there was no difference in response or OS between the regimens. One hundred and twenty-eight patients underwent EPP with a 30-day mortality of 4.7%. Fifty-two percent of the patients received adjuvant radiotherapy. The median OS of patients undergoing EPP was significantly longer with 22 months (95% confidence interval: 20-24) when compared to 11 months (9-12) for patients treated without EPP. A prognostic score was defined considering tumor volume, histology, C-reactive protein level, and response to chemotherapy that identified patient groups not benefitting from multimodality treatment which was confirmed in an independent cohort. CONCLUSION: Patients receiving induction chemotherapy followed by EPP for MPM of all histological subtypes and irrespective of nodal status showed a median survival of 22 months. A prognostic score is proposed to help patient allocation for surgery after validation in an independent cohort.