Independent validation of CT radiomics models in colorectal liver metastases: predicting local tumour progression after ablation.

OBJECTIVES: Independent internal and external validation of three previously published CT-based radiomics models to predict local tumor progression (LTP) after thermal ablation of colorectal liver metastases (CRLM). MATERIALS AND METHODS: Patients with CRLM treated with thermal ablation were collected from two institutions to collect a new independent internal and external validation cohort. Ablation zones (AZ) were delineated on portal venous phase CT 2-8 weeks post-ablation. Radiomics features were extracted from the AZ and a 10 mm peri-ablational rim (PAR) of liver parenchyma around the AZ. Three previously published prediction models (clinical, radiomics, combined) were tested without retraining. LTP was defined as new tumor foci appearing next to the AZ up to 24 months post-ablation. RESULTS: The internal cohort included 39 patients with 68 CRLM and the external cohort 52 patients with 78 CRLM. 34/146 CRLM developed LTP after a median follow-up of 24 months (range 5-139). The median time to LTP was 8 months (range 2-22). The combined clinical-radiomics model yielded a c-statistic of 0.47 (95%CI 0.30-0.64) in the internal cohort and 0.50 (95%CI 0.38-0.62) in the external cohort, compared to 0.78 (95%CI 0.65-0.87) in the previously published original cohort. The radiomics model yielded c-statistics of 0.46 (95%CI 0.29-0.63) and 0.39 (95%CI 0.28-0.52), and the clinical model 0.51 (95%CI 0.34-0.68) and 0.51 (95%CI 0.39-0.63) in the internal and external cohort, respectively. CONCLUSION: The previously published results for prediction of LTP after thermal ablation of CRLM using clinical and radiomics models were not reproducible in independent internal and external validation. CLINICAL RELEVANCE STATEMENT: Local tumour progression after thermal ablation of CRLM cannot yet be predicted with the use of CT radiomics of the ablation zone and peri-ablational rim. These results underline the importance of validation of radiomics results to test for reproducibility in independent cohorts. KEY POINTS: • Previous research suggests CT radiomics models have the potential to predict local tumour progression after thermal ablation in colorectal liver metastases, but independent validation is lacking. • In internal and external validation, the previously published models were not able to predict local tumour progression after ablation. • Radiomics prediction models should be investigated in independent validation cohorts to check for reproducibility.

Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer.

Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.

Genomic characteristics of trastuzumab-resistant Her2-positive metastatic breast cancer.

PURPOSE: Resistance to trastuzumab therapy is linked to phosphoinositol 3-kinase (PI3K) pathway activation. One key downstream effector and regulator of this pathway is the mechanistic target of rapamycin (mTOR). In 2011, a phase I/II study evaluated the combination of trastuzumab and everolimus (a mTOR inhibitor) for treatment of Her2-positive metastatic breast cancer (MBC) for patients who had progressed on trastuzumab-based therapy. METHODS: We retrospectively analyzed GeneChip microarray data from 22 of 47 patients included in the study. RESULTS: Using an unbiased approach, we found that mutations in BRAF, EGFR and KIT are significantly more common in this heavily treated population when compared with the cohort of invasive breast carcinoma patients in The Cancer Genome Atlas (TCGA). Furthermore, 10 out of 22 patients had PIK3CA mutations (45.4%) but PI3KCA status was not predictive of PFS in our cohort. Finally, the use of OncoScantm has allowed us to detected mutations in five genes that have not been shown to be mutated in TCGA subset of Her-2 overexpressing breast cancer: CTNNB1, HRAS, KRAS, NF2 and SMARCB1. CONCLUSION: Mutational burden in heavily treated trastuzumab-resistant Her2-positive metastatic breast cancer is highly variable and not directly correlated with outcome. Activation of the MAPK/ERK pathway through mutations in EGFR, BRAF or KIT may mediate resistance to trastuzumab.

Neurocysticercotic Calcifications and Hippocampal Sclerosis: A Case-Control Study.

OBJECTIVE: The exact role of calcified neurocysticercotic lesions (CNLs) in epilepsy is yet unknown and controversial. Although the relationship between CNLs, epilepsy and mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) has already been addressed, to our knowledge, no study has actually provided strong statistical evidence, nor reported the ODDS ratio for these associations. Therefore, we designed this case-control study to assess the likelihood of having MTLE-HS versus other forms of epilepsy in the presence of CNLs. METHODS: In this case-control study we included 119 consecutive patients with epilepsy and 106 disease controls (headache) with previous CT scans. We subdivided cases into MTLE-HS and other epilepsies. We used brain CT scans to define presence or absence of CNLs. After exploratory analyses, we used logistic regression to analyze the association between CNLs, epilepsy subgroups and disease controls. RESULTS: CNLs were found in 31.09% of cases and in 11.32% of controls (p<0.001). The initial analysis comparing epilepsy versus controls revealed a significant association between CNLs and epilepsy (OR = 5.32; 95%CI = 2.43-11.54; p<0.001). However, when we compared MTLE-HS versus other epilepsies versus controls we confirmed that CNLs were associated with MTLE-HS (OR = 11.27, 95%CI = 4.73-26.85; p<0.001) but other epilepsies were not. We found no difference in the CNLs load and no difference in the location of the CNLs when we compared patients with MTLE-HS, other epilepsies and disease controls. SIGNIFICANCE: The inclusion of controls allowed us to estimate the likelihood of having epilepsy in the presence of CNLs. We found that patients with CNLs were 11 times more likely to have MTLE-HS; however, the presence of CNLs did not change the odds of having other types of epilepsy. These findings raise the possibility of neurocysticercosis playing a role in the pathophysiology of MTLE-HS and need further confirmation in other series.