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Diffusion kurtosis MRI as a predictive biomarker of response to neoadjuvant chemotherapy in high grade serous ovarian cancer.

ABSTRACT: This study assessed the feasibility of using diffusion kurtosis imaging (DKI) as a measure of tissue heterogeneity and proliferation to predict the response of high grade serous ovarian cancer (HGSOC) to neoadjuvant chemotherapy (NACT). Seventeen patients with HGSOC were imaged at 3 T and had biopsy samples taken prior to any treatment. The patients were divided into two groups: responders and non-responders based on Response Evaluation Criteria In Solid Tumours (RECIST) criteria. The following imaging metrics were calculated: apparent diffusion coefficient (ADC), apparent diffusion (D_app) and apparent kurtosis (K_app). Tumour cellularity and proliferation were quantified using histology and Ki-67 immunohistochemistry. Mean K_app before therapy was higher in responders compared to non-responders: 0.69 ± 0.13 versus 0.51 ± 0.11 respectively, P = 0.02. Tumour cellularity correlated positively with K_app (rho = 0.50, P = 0.04) and negatively with both ADC (rho = -0.72, P = 0.001) and D_app (rho = -0.80, P < 0.001). Ki-67 expression correlated with K_app (rho = 0.53, P = 0.03) but not with ADC or D_app. In conclusion, K_app was found to be a potential predictive biomarker of NACT response in HGSOC, which suggests that DKI is a promising clinical tool for use oncology and radiology that should be evaluated further in future larger studies.

SUBMITTER: Deen SS

PROVIDER: S-EPMC6656714 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Diffusion kurtosis MRI as a predictive biomarker of response to neoadjuvant chemotherapy in high grade serous ovarian cancer.

Deen Surrin S SS Priest Andrew N AN McLean Mary A MA Gill Andrew B AB Brodie Cara C Crawford Robin R Latimer John J Baldwin Peter P Earl Helena M HM Parkinson Christine C Smith Sarah S Hodgkin Charlotte C Patterson Ilse I Addley Helen H Freeman Susan S Moyle Penny P Jimenez-Linan Mercedes M Graves Martin J MJ Sala Evis E Brenton James D JD Gallagher Ferdia A FA

Scientific reports 20190724 1

This study assessed the feasibility of using diffusion kurtosis imaging (DKI) as a measure of tissue heterogeneity and proliferation to predict the response of high grade serous ovarian cancer (HGSOC) to neoadjuvant chemotherapy (NACT). Seventeen patients with HGSOC were imaged at 3 T and had biopsy samples taken prior to any treatment. The patients were divided into two groups: responders and non-responders based on Response Evaluation Criteria In Solid Tumours (RECIST) criteria. The following ...[more]

PMID: 31341212

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Project description:BackgroundHigh grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in which patients have still yet to respond meaningfully to clinically available immunotherapies. Hence, novel immune targets are urgently needed. Our past work has identified that mast cells are significantly upregulated at the mRNA level in HGSOC patient tumors following neoadjuvant chemotherapy (NACT) exposure. Therefore, in this current investigation we sought to characterize intratumoral mast cell phenotypic changes as a result of NACT exposure and determine how these adaptations are associated with patient clinical outcomes.MethodsHematologic immunohistochemistry was employed to determine mast cell levels in 36 matched pre- and post-NACT HGSOC patient tumors. Fluorescent Immunohistochemistry was utilized to identify Tryptase+(carboxypeptidase A3 (CPA3) + mast cells as well as histamine levels in 29 and 20, respectively, matched pre- and post-NACT HGSOC patient tumors. Finally, human immortalized mast cells, LUVA were stimulated with carboplatin and paclitaxel and genomic changes were analyzed by quantitative PCR.ResultsHematologic labeled intratumoral mast cells were significantly upregulated in the intraepithelial and stromal regions of the tumor, post-NACT. Lower levels of pre-NACT mast cells were significantly associated with an improved progression-free survival (PFS). Histamine, a marker of mast cell degranulation was similarly upregulated in post-NACT exposed tumors. Through the characterization of mast cell specific proteases Tryptase and CPA3, it was found that Tryptase+/ CPA3 + mast cells were significantly upregulated both in the intraepithelial and stromal compartments of the tumor, while Tryptase + cells were significantly upregulated in the stromal regions of the tumor. Lower post-NACT treated levels with Tryptase+/ CPA3 + cells were significantly associated with improved overall survival (OS) and PFS while higher Tryptase + mast cells were associated with improved OS. Finally, following chemotherapy exposure mast cell activating factors AREG and CCL2 were significantly upregulated while TGFB1, an inhibitor of mast cell activation was downregulated in LUVA cells.ConclusionsEnhanced mast cell numbers, as well as activation and degranulation are a consequence of NACT exposure. Post-NACT mast cells displayed differing associations with survival outcomes that was dependent upon granule classification. Ultimately, mast cells represent a clinically relevant putative HGSOC immune target.

Project description:BackgroundA validated prognostic index for the outcome of patients with advanced high-grade serous ovarian cancer (HGSOC) undergoing neoadjuvant chemotherapy (NACT) remains elusive. To address this need, we developed an ovarian neoadjuvant chemotherapy prognostic index (ONCPI) to improve predictive accuracy.MethodsWe encompassed an analysis of the clinicopathological characteristics of patients with advanced HGSOC who were administered platinum-based NACT. Blood inflammatory composite markers were calculated and converted into binary values using optimal cutoffs. Omental hematoxylin and eosin (H&E) stained slides were selected for the assessment of chemotherapy response score (CRS), which served as a measure of NACT efficacy. Logistic regression analysis and Cox proportional hazards regression model were utilized to construct a prognostic index.ResultsMultivariate logistic analysis showed that both CRS and neutrophil-to-lymphocyte ratio (NLR) independently influenced the response to platinum-based chemotherapy. Meanwhile, Kaplan-Meier and Cox regression analysis revealed that CRS score was significantly correlated with progression-free survival (PFS) and overall survival (OS), and patients with high NLR showed poor OS. We further developed an ovarian neoadjuvant chemotherapy prognostic index (ONCPI) based on the CRS and NLR. The area under the curve (AUC) value of ONCPI was 0.771 (P < 0.001, 95% CI: 0.656-0.887) for the prediction of platinum resistance. This AUC value surpasses that of the individual NLR and CRS, which were 0.670 (P = 0.018, 95% CI: 0.547-0.793) and 0.714 (P = 0.003, 95% CI: 0.590-0.839), respectively. Moreover, survival analysis suggested that patients with ONCPI of 0 and 1 were significantly associated with improved PFS and OS.ConclusionsThe ONCPI emerges as a significant prognostic marker for predicting NACT outcome in advanced HGSOC patients and holds promise for integration into clinical practice and risk-stratified trial design.

Dataset Information

Diffusion kurtosis MRI as a predictive biomarker of response to neoadjuvant chemotherapy in high grade serous ovarian cancer.

Publications

Diffusion kurtosis MRI as a predictive biomarker of response to neoadjuvant chemotherapy in high grade serous ovarian cancer.

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