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Objectives: Results after trans-arterial radioembolisation (TARE) for intrahepatic cholangiocarcinoma (iCC) depend on the architecture of the tumour. This latter can be quantified through computed tomography (CT) texture analysis. The aims of the present study were to analyse relationships between CT textural features prior to TARE and objective response (OR), progression-free survival (PFS), and overall survival (OS). Methods: Texture analysis was retrospectively applied to 55 pre-TARE CT scans of iCCs, focusing attention on the histogram-based features and the grey-level co-occurrence matrix (GLCM). Texture features were harmonised using the ComBat procedure. Objective response was assessed using the Response Evaluation Criteria In Solid Tumours 1.1. The least absolute shrinkage and selection operator (LASSO) method was applied to select the most useful textural features related to OR. Results: Of the 55 patients, 53 had post-TARE imaging available, showing OR in 56.6% of cases. Texture analysis showed that iCCs showing OR after TARE had a higher uptake of iodine contrast in the arterial phase (higher mean histogram values, p< 0.001) and more homogeneous distribution (lower kurtosis, p= 0.043; GLCM contrast, p= 0.004; GLCM dissimilarity, p= 0.005, and higher GLCM homogeneity, p= 0.005; and GLCM correlation p= 0.030) at the pre-TARE CT scan. A favourable radiomic signature was calculated and observed in 15 of the 55 patients. The median PFS of these 15 patients was 12.1months and that of the remaining 40 patients was 5.1months (p= 0.008). Conclusions: Texture analysis of pre-TARE CT scans can quantify vascularisation and homogeneity of iCC architecture, providing clinical information useful in identifying ideal TARE candidates. Key Points: • Hypervascular tumours with a more homogeneous uptake of iodine contrast in the arterial phase were those most likely to be effectively treated by TARE. • The arterial phase was observed to be the best acquisition phase for providing information regarding the “sensitivity” of the tumour to TARE. • Patients with favourable radiomic signature showed a median progression-free survival of 12.1months versus 5.1months of patients with an unfavourable signature (p = 0.008).

Objectives: To evaluate the inter-observer reliability of modified Response Evaluation Criteria In Solid Tumours (mRECIST) of patients with hepatocellular carcinoma (HCC) undergoing neo-adjuvant treatments before liver transplant (LT). The agreement of tumor number, size, transplant criteria, and the radiological-pathological concordance were also assessed. Methods: A total of 180 radiological studies before/after neo-adjuvant therapies performed on 90 patients prior to LT were reviewed from three expert centers. Kappa-statistic and intraclass correlation (ICC) were evaluated on mRECIST and on tumoral features. Complete radiological response (CR) was compared with complete pathological response (CPR). Results: Before neo-adjuvant therapies, the agreement on tumor number, size, and transplant criteria ranged from moderate (defined as ICC of 0.41–0.60) to almost perfect (ICC of 0.81–0.99), being higher with magnetic resonance imaging (MRI) than CT (0.657–0.899 and 0.422–0.776, respectively). After neo-adjuvant therapies, the agreement decreased, as ICCs ranged between 0.518 and 0.663 with MRI and between 0.508 and 0.677 with CT. Concordant mRECIST pairs were 201 of 270 reviews (76.3%) with a kappa of 0.648 indicating substantial agreement. When the three observers completely agreed on CR, the positive predictive value for CPR was 51.6%. The negative predictive value was 94.2% with a kappa of 0.512 indicating fair agreement between radiology and pathology. Conclusions: mRECIST agreement was substantial among the three observers involved. The agreement on tumor number, size, and transplant criteria ranged from moderate to almost perfect, with the highest ICCs obtained with MRI before neo-adjuvant therapies. Finally, the predictive value of mRECIST in the diagnosis of CPR was only fair. Key Points: • The review of 180 radiological exams of patients with hepatocellular carcinoma before and after neo-adjuvant therapies showed that the concordance among three different raters on mRECIST diagnosis was substantial. • The inter-observer reliability on fulfilment of transplant criteria slightly decreased when evaluated through CT and after loco-regional therapies. • The radiological diagnosis of complete response after neo-adjuvant therapies was predictive of complete pathological response in only 51.6% of cases.

BackgroundPhosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.MethodsThe BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants.FindingsBetween Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [

Objective: To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme. Patients and Methods: Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results: A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged ≥75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received ≥2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7–6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus. Conclusion: The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients. © 2018 The Authors BJU International

Purpose To investigate the short- and long-term outcomes of liver first approach (LFA) in patients with synchronous colorectal liver metastases (CRLM), evaluating the predictive factors of survival. Methods Sixty-two out of 301 patients presenting with synchronous CRLM underwent LFA between 2007 and 2016. All patients underwent neoadjuvant chemotherapy. After neoadjuvant treatment patients were re-evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). Liver resection was scheduled after 4–6 weeks. Changes in non-tumoral parenchyma and the tumor response according to the Tumor Regression Grade score (TRG) were assessed on surgical specimens. Primary tumor resection was scheduled 4–8 weeks following hepatectomy. Results Five patients out of 62 (8.1%) showed “Progressive Disease” at re-evaluation after neoadjuvant chemotherapy, 22 (35.5%) showed “Stable Disease” and 35 (56.5%) “Partial Response”; of these latter, 29 (82%) showed histopathologic downstaging. The 5-year survival (OS) rate was 55%, while the 5-year disease-free survival (DFS) rate was 16%. RECIST criteria, T-stage, N-stage and TRG were independently associated with OS. Bilobar presentation of disease, RECIST criteria, R1 margin and TRG were independently associated with DFS. Patients with response to neoadjuvant chemotherapy had better survival than those with stable or progressive disease (radiological response 5-y OS: 65% vs. 50%; 5-y DFS: 20% vs. 10%; pathological response 5-y OS: 75% vs. 56%; 5-y DFS: 45% vs. 11%). Conclusions LFA is an oncologically safe strategy. Selection is a critical point, and the best results in terms of OS and DFS are observed in patients having radiological and pathological response to neoadjuvant chemotherapy.

Background Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments. Material and methods Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT. Results Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin. Conclusion Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.

Sorafenib is an effective anti-angiogenic treatment for hepatocellular carcinoma (HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients, avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume (viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume, density or perfusion. Perfusion computed tomography and Dynamic Contrast-Enhanced-UltraSound can measure the vascularization of HCC lesions and help predict tumor response to anti-angiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable, reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue, allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib.

BACKGROUND: In this paper the clinical value of PET for early prediction of tumor response to erlotinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen is evaluated. The aim was to compare the early metabolic treatment response using European Organization for Research and Treatment of Cancer (EORTC) 1999 recommendations and PET Response Criteria in Solid Tumors (PERCIST), and the standard treatment response using Response Evaluation Criteria in Solid Tumors (RECIST). METHODS: Twenty patients with stage IV NSCLCwere enrolled prospectively. PET/CT studies were performed before, then 48 hours, and 45 days after the initiation of erlotinib treatment. The lesion with the highest uptake in each patient was evaluated according to EORTC1999 recommendations, PERCIST and RECIST to assess metabolic and anatomic response. Response classifications were compared statistically using Wilcoxon signed-rank test. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier Test. RESULTS: At 48 hours, the Kaplan-Meier analysis showed that EORTC proved to be a significant prognostic factor for predicting DFS and OS. At 45 days, there was a significant difference in response evaluation between RECIST and metabolic classifications. RECIST and PERCIST were significant prognostic factors for predicting DFS and OS. EORTC was not able to discriminate responder from non-responder patients. CONCLUSIONS: This study shows that, according to the EORTC protocol, the PET exam is able to provide early identification of patients who benefit from Erlotinib treatment. Used at the end of therapy, PERCIST could be considered an appropriate metabolic evaluation method to discriminate responders from non-responders.