Integrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer.

High grade serous ovarian carcinoma (HGSOC) is a highly heterogeneous disease that typically presents at an advanced, metastatic state. The multi-scale complexity of HGSOC is a major obstacle to predicting response to neoadjuvant chemotherapy (NACT) and understanding critical determinants of response. Here we present a framework to predict the response of HGSOC patients to NACT integrating baseline clinical, blood-based, and radiomic biomarkers extracted from all primary and metastatic lesions. We use an ensemble machine learning model trained to predict the change in total disease volume using data obtained at diagnosis (n = 72). The model is validated in an internal hold-out cohort (n = 20) and an independent external patient cohort (n = 42). In the external cohort the integrated radiomics model reduces the prediction error by 8% with respect to the clinical model, achieving an AUC of 0.78 for RECIST 1.1 classification compared to 0.47 for the clinical model. Our results emphasize the value of including radiomics data in integrative models of treatment response and provide methods for developing new biomarker-based clinical trials of NACT in HGSOC.

Magnetization transfer imaging of ovarian cancer: initial experiences of correlation with tissue cellularity and changes following neoadjuvant chemotherapy.

Objectives: To investigate the relationship between magnetization transfer (MT) imaging and tissue macromolecules in high-grade serous ovarian cancer (HGSOC) and whether MT ratio (MTR) changes following neoadjuvant chemotherapy (NACT). Methods: This was a prospective observational study. 12 HGSOC patients were imaged before treatment. MTR was compared to quantified tissue histology and immunohistochemistry. For a subset of patients (n = 5), MT imaging was repeated after NACT. The Shapiro-Wilk test was used to assess for normality of data and Spearman's rank-order or Pearson's correlation tests were then used to compare MTR with tissue quantifications. The Wilcoxon signed-rank test was used to assess for changes in MTR after treatment. Results: Treatment-naïve tumour MTR was 21.9 ± 3.1% (mean ± S.D.). MTR had a positive correlation with cellularity, rho = 0.56 (p < 0.05) and a negative correlation with tumour volume, ρ = -0.72 (p = 0.01). MTR did not correlate with the extracellular proteins, collagen IV or laminin (p = 0.40 and p = 0.90). For those patients imaged before and after NACT, an increase in MTR was observed in each case with mean MTR 20.6 ± 3.1% (median 21.1) pre-treatment and 25.6 ± 3.4% (median 26.5) post-treatment (p = 0.06). Conclusion: In treatment-naïve HGSOC, MTR is associated with cellularity, possibly reflecting intracellular macromolecular concentration. MT may also detect the HGSOC response to NACT, however larger studies are required to validate this finding. Advances in knowledge: MTR in HGSOC is influenced by cellularity. This may be applied to assess for cell changes following treatment.

Clinically Interpretable Radiomics-Based Prediction of Histopathologic Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma.

Background: Pathological response to neoadjuvant treatment for patients with high-grade serous ovarian carcinoma (HGSOC) is assessed using the chemotherapy response score (CRS) for omental tumor deposits. The main limitation of CRS is that it requires surgical sampling after initial neoadjuvant chemotherapy (NACT) treatment. Earlier and non-invasive response predictors could improve patient stratification. We developed computed tomography (CT) radiomic measures to predict neoadjuvant response before NACT using CRS as a gold standard. Methods: Omental CT-based radiomics models, yielding a simplified fully interpretable radiomic signature, were developed using Elastic Net logistic regression and compared to predictions based on omental tumor volume alone. Models were developed on a single institution cohort of neoadjuvant-treated HGSOC (n = 61; 41% complete response to NCT) and tested on an external test cohort (n = 48; 21% complete response). Results: The performance of the comprehensive radiomics models and the fully interpretable radiomics model was significantly higher than volume-based predictions of response in both the discovery and external test sets when assessed using G-mean (geometric mean of sensitivity and specificity) and NPV, indicating high generalizability and reliability in identifying non-responders when using radiomics. The performance of a fully interpretable model was similar to that of comprehensive radiomics models. Conclusions: CT-based radiomics allows for predicting response to NACT in a timely manner and without the need for abdominal surgery. Adding pre-NACT radiomics to volumetry improved model performance for predictions of response to NACT in HGSOC and was robust to external testing. A radiomic signature based on five robust predictive features provides improved clinical interpretability and may thus facilitate clinical acceptance and application.

Placental MRI: Identification of radiological features to predict placental attachment disease regardless of reader expertise.

PURPOSE: To compare the accuracy of placental MRI in reporting placental adhesive disease in readers with different expertise and to identify the most reliable MRI features that predict placental pathology regardless of reader expertise. METHODS: Retrospective analysis of 27 placental MRI studies by six radiologists with different expertise levels; specificity, sensitivity, and accuracy were used to quantify the predictive performance of eight radiological features previously described in the literature. Histopathological evaluation was used as a diagnostic gold standard when available and the presence of the radiological features was decided by consensus. Features with higher sensitivity and specificity were identified and the optimal cut-off was calculated to obtain the resulting accuracy. RESULTS: The accuracy for seniors with expertise was non-statistically higher (0.83) compared to senior with no expertise (SWE) (0.65) and juniors (0.74) with SWE having tendency to over-estimate the severity of abnormality (26% vs 17%), whilst junior underestimated the degree of placental infiltration when compared to seniors with expertise (18.5% vs 0%, p = 0.006). Dark bands was the criteria with the highest sensitivity (95%) and high specificity (74%), followed by myometrial thinning (89%-76%) and uterine bulging (86%-81%). These three features demonstrated substantial (K) agreement. Using these features with optimal diagnostic cut-off, the accuracy increased to 0.91 for both the seniors and SWE and to 0.93 for the juniors. CONCLUSION: Placental MRI is most accurately interpreted by experienced radiologists; however, less experienced readers can obtain an accurate diagnosis relying on set criteria that are easier to be identified.

MRI of the endometrium - from normal appearances to rare pathology.

MRI was recently included as a standard pre-operative diagnostic tool for patients with endometrial cancer. MR findings allow a better risk assessment and ultimately guides the surgical planning. Therefore, it is vital that the radiological interpretation is as accurate as possible. This requires essential knowledge regarding the appropriate MRI protocol, as well as different appearances of the endometrium, ranging from normal peri- and post-menopausal changes, benign findings (e.g. endometrial hyperplasia, polyp, changes due to exogenous hormones) to common and rare endometrium-related malignancies. Furthermore, this review will emphasize the role of MRI in staging endometrial cancer patients and highlight pitfalls that could result in the underestimation or overestimation of the disease extent.

MRI findings in-between leiomyoma and leiomyosarcoma: a Rad-Path correlation of degenerated leiomyomas and variants.

Leiomyomas are the most common benign tumors of the uterus. On the opposite side, leiomyosarcomas are rare malignant uterine tumors that account for a significant proportion of uterine cancer deaths. Especially when large and degenerated, leiomyomas and leiomyoma variants can have overlapping imaging characteristics with those of leiomyosarcomas. Although not always possible, it is paramount to be able to differentiate between leiomyomas and leiomyosarcomas on imaging, as the therapeutic management can differ. This pictorial review aims to familiarize radiologists with imaging features of leiomyomas and various types of leiomyoma degeneration and variants, together with their pathology correlates.

Serous borderline ovarian tumours: an extensive review on MR imaging features.

Serous borderline ovarian tumours (SBOTs) are an intermediate group of neoplasms, which have features between benign and malignant ovarian tumours and for which, fertility-sparing surgery can be offered. MRI in imaging of SBOTs is, therefore, crucial in raising the possibility of the diagnosis, in order to present the patient with the most appropriate treatment options. There are characteristic MRI features that SBOTs demonstrate. In addition, recent advanced techniques, and further classification into subtypes within the borderline group have been developed. The aim of this article is to review the MRI features of SBOT and provide the reporter with an awareness of the imaging tips and tricks in the differential diagnosis of SBOT.

Diagnostic interpretation of non-contrast qualitative MR imaging features for characterisation of uterine leiomyosarcoma.

OBJECTIVE: To assess the value of non-contrast MRI features for characterisation of uterine leiomyosarcoma (LMS) and differentiation from atypical benign leiomyomas. METHODS: This study included 57 atypical leiomyomas and 16 LMS which were referred pre-operatively for management review to the specialist gynaeoncology multidisciplinary team meeting. Non-contrast MRIs were retrospectively reviewed by five independent readers (three senior, two junior) and a 5-level Likert score (1-low/5-high) was assigned to each mass for likelihood of LMS. Evaluation of qualitative and quantitative MRI features was done using uni- and multivariable regression analysis. Inter-reader reliability for the assessment of MRI features was calculated by using Cohen's κ values. RESULTS: In the univariate analysis, interruption of the endometrial interface and irregular tumour shape had the highest odds ratios (ORs) (64.00, p < 0.001 and 12.00, p = 0.002, respectively) for prediction of LMS. Likert score of the mass was significant in prediction (OR, 3.14; p < 0.001) with excellent reliability between readers (ICC 0.86; 95% CI, 0.76-0.92). The post-menopausal status, interruption of endometrial interface and thickened endometrial stripe were the most predictive independent variables in multivariable estimation of the risk of leiomyosarcoma with an accuracy of 0.88 (95%CI, 0.78-0.94). CONCLUSION: At any level of expertise as a radiologist reader, the loss of the normal endometrial stripe (either thickened or not seen) in a post-menopausal patient with a myometrial mass was highly likely to be LMS. ADVANCES IN KNOWLEDGE: This study demonstrates the potential utility of non-contrast MRI features in characterisation of LMS over atypical leiomyomas, and therefore influence on optimal management of these cases.

Ovary: MRI characterisation and O-RADS MRI.

Ultrasound has a high specificity for the diagnosis of a benign lesion in cases of classic appearing simple cyst, hemorrhagic cyst, endometrioma and dermoid. However, ultrasound can sometimes be limited for definitive characterisation and risk stratification of other types of lesions, including those with echogenic content that may appear solid, with or without blood flow. Frequently, MRI can be used to further characterise these types of lesions, due to its ability to distinguish solid tissue from non-tissue solid components such as fat, blood, or debris. Incorporating the MR imaging into the evaluation of adnexal lesions can improve diagnostic certainty and guide clinical management potentially avoiding inappropriate surgery for benign lesions and expediting appropriate treatment for malignant lesions, particularly in the females with sonographically indeterminate adnexal lesions.

Differentiating uterine sarcoma from leiomyoma: BET1T2ER Check!

Although rare, uterine sarcoma is a diagnosis that no one wants to miss. Often benign leiomyomas (fibroids) and uterine sarcomas can be differentiated due to the typical low T2 signal intensity contents and well-defined appearances of benign leiomyomas compared to the suspicious appearances of sarcomas presenting as large uterine masses with irregular outlines and intermediate T2 signal intensity together with possible features of secondary spread. The problem is when these benign lesions are atypical causing suspicious imaging features. This article provides a review of the current literature on imaging features of atypical fibroids and uterine sarcomas with an aide-memoire BET1T2ER Check! to help identify key features more suggestive of a uterine sarcoma.

Non-contrast MRI can accurately characterize adnexal masses: a retrospective study.

OBJECTIVE: To determine the accuracy of interpretation of a non-contrast MRI protocol in characterizing adnexal masses. METHODS AND MATERIALS: Two hundred ninety-one patients (350 adnexal masses) who underwent gynecological MRI at our institution between the 1st of January 2008 and the 31st of December 2018 were reviewed. A random subset (102 patients with 121 masses) was chosen to evaluate the reproducibility and repeatability of readers' assessments. Readers evaluated non-contrast MRI scans retrospectively, assigned a 5-point score for the risk of malignancy and gave a specific diagnosis. The reference standard for the diagnosis was histopathology or at least one-year imaging follow-up. Diagnostic accuracy of the non-contrast MRI score was calculated. Inter- and intra-reader agreement was analyzed with Cohen's kappa statistics. RESULTS: There were 53/350 (15.1%) malignant lesions in the whole cohort and 20/121 (16.5%) malignant lesions in the random subset. Good agreement between readers was found for the non-contrast MRI score (к = 0.73, 95% confidence interval [CI] 0.58-0.86) whilst the intra-reader agreement was excellent (к = 0.81, 95% CI 0.70-0.88). The non-contrast MRI score value of ≥ 4 was associated with malignancy with a sensitivity of 84.9%, a specificity of 95.9%, an accuracy of 94.2% and a positive likelihood ratio of 21 (area under the receiver operating curve 0.93, 95% CI 0.90-0.96). CONCLUSION: Adnexal mass characterization on MRI without the administration of contrast medium has a high accuracy and excellent inter- and intra-reader agreement. Our results suggest that non-contrast studies may offer a reasonable diagnostic alternative when the administration of intravenous contrast medium is not possible. KEY POINTS: • A non-contrast pelvic MRI protocol may allow the characterization of adnexal masses with high accuracy. • The non-contrast MRI score may be used in clinical practice for differentiating benign from malignant adnexal lesions when the lack of intravenous contrast medium precludes analysis with the O-RADS MRI score.

Ultrasound-guided targeted biopsies of CT-based radiomic tumour habitats: technical development and initial experience in metastatic ovarian cancer.

PURPOSE: To develop a precision tissue sampling technique that uses computed tomography (CT)-based radiomic tumour habitats for ultrasound (US)-guided targeted biopsies that can be integrated in the clinical workflow of patients with high-grade serous ovarian cancer (HGSOC). METHODS: Six patients with suspected HGSOC scheduled for US-guided biopsy before starting neoadjuvant chemotherapy were included in this prospective study from September 2019 to February 2020. The tumour segmentation was performed manually on the pre-biopsy contrast-enhanced CT scan. Spatial radiomic maps were used to identify tumour areas with similar or distinct radiomic patterns, and tumour habitats were identified using the Gaussian mixture modelling. CT images with superimposed habitat maps were co-registered with US images by means of a landmark-based rigid registration method for US-guided targeted biopsies. The dice similarity coefficient (DSC) was used to assess the tumour-specific CT/US fusion accuracy. RESULTS: We successfully co-registered CT-based radiomic tumour habitats with US images in all patients. The median time between CT scan and biopsy was 21 days (range 7-30 days). The median DSC for tumour-specific CT/US fusion accuracy was 0.53 (range 0.79 to 0.37). The CT/US fusion accuracy was high for the larger pelvic tumours (DSC: 0.76-0.79) while it was lower for the smaller omental metastases (DSC: 0.37-0.53). CONCLUSION: We developed a precision tissue sampling technique that uses radiomic habitats to guide in vivo biopsies using CT/US fusion and that can be seamlessly integrated in the clinical routine for patients with HGSOC. KEY POINTS: • We developed a prevision tissue sampling technique that co-registers CT-based radiomics-based tumour habitats with US images. • The CT/US fusion accuracy was high for the larger pelvic tumours (DSC: 0.76-0.79) while it was lower for the smaller omental metastases (DSC: 0.37-0.53).

Integrative radiogenomics for virtual biopsy and treatment monitoring in ovarian cancer.

BACKGROUND: Ovarian cancer survival rates have not changed in the last 20 years. The majority of cases are High-grade serous ovarian carcinomas (HGSOCs), which are typically diagnosed at an advanced stage with multiple metastatic lesions. Taking biopsies of all sites of disease is infeasible, which challenges the implementation of stratification tools based on molecular profiling. MAIN BODY: In this review, we describe how these challenges might be overcome by integrating quantitative features extracted from medical imaging with the analysis of paired genomic profiles, a combined approach called radiogenomics, to generate virtual biopsies. Radiomic studies have been used to model different imaging phenotypes, and some radiomic signatures have been associated with paired molecular profiles to monitor spatiotemporal changes in the heterogeneity of tumours. We describe different strategies to integrate radiogenomic information in a global and local manner, the latter by targeted sampling of tumour habitats, defined as regions with distinct radiomic phenotypes. CONCLUSION: Linking radiomics and biological correlates in a targeted manner could potentially improve the clinical management of ovarian cancer. Radiogenomic signatures could be used to monitor tumours during the course of therapy, offering additional information for clinical decision making. In summary, radiogenomics may pave the way to virtual biopsies and treatment monitoring tools for integrative tumour analysis.

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

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 (Dapp) and apparent kurtosis (Kapp). Tumour cellularity and proliferation were quantified using histology and Ki-67 immunohistochemistry. Mean Kapp 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 Kapp (rho = 0.50, P = 0.04) and negatively with both ADC (rho = -0.72, P = 0.001) and Dapp (rho = -0.80, P < 0.001). Ki-67 expression correlated with Kapp (rho = 0.53, P = 0.03) but not with ADC or Dapp. In conclusion, Kapp 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.

Recurrent ovarian immature teratoma in a 12-year-old girl: Implications for management.

Immature teratomas (IT) are rare and recurrences uncommon. A 12-year-old female with grade 3 (high-grade) ovarian IT underwent surgical resection but experienced early recurrences; the first was treated with surgery but the second was metastatic and managed with chemotherapy, resulting in growing-teratoma-syndrome and need for further surgery. She now remains well in uneventful clinical follow-up. We believe chemotherapy could be reserved for very carefully selected recurrent IT cases, which may alter the natural history of disease.

Sodium MRI with 3D-cones as a measure of tumour cellularity in high grade serous ovarian cancer.

The aim of this study was to assess the feasibility of rapid sodium MRI (23Na-MRI) for the imaging of peritoneal cancer deposits in high grade serous ovarian cancer (HGSOC) and to evaluate the relationship of 23Na-MRI with tumour cellularity. 23Na-MRI was performed at 3 T on twelve HGSOC patients using a 3D-cones acquisition technique. Tumour biopsies specimens were collected after imaging and cellularity was measured from histology. Total 23Na-MRI scan time for each patient was approximately 11 min. At an isotropic resolution of 5.6 mm, signal-to-noise ratios (SNRs) of 82.2 ± 15.3 and 15.1 ± 7.1 (mean ± standard deviation) were achieved for imaging of tumour tissue sodium concentration (TSC) and intracellular weighted sodium concentration (IWS) respectively. Tumour TSC and IWS concentrations were: 56.8 ± 19.1 mM and 30.8 ± 9.2 mM respectively and skeletal muscle TSC and IWS concentrations were 33.2 ± 16.3 mM and 20.5 ± 9.9 mM respectively. There were significant sodium concentration differences between cancer and skeletal muscle, Wilcoxon signed-rank test, P < 0.001 for TSC and P = 0.01 for IWS imaging. Tumour cellularity displayed a strong negative correlation with TSC, Spearman's rho = -0.92, P < 0.001, but did not correlate with IWS. This study demonstrates that 23Na-MRI using 3D-cones can rapidly assess sodium concentration in peritoneal deposits of HGSOC and that TSC may serve as a biomarker of tumour cellularity.

Feasibility of Quantitative Magnetic Resonance Fingerprinting in Ovarian Tumors for T1 and T2 Mapping in a PET/MR Setting.

Multiparametric magnetic resonance imaging (MRI) can be used to characterize many cancer subtypes including ovarian cancer. Quantitative mapping of MRI relaxation values, such as T 1 and T 2 mapping, is promising for improving tumor assessment beyond conventional qualitative T 1- and T 2-weighted images. However, quantitative MRI relaxation mapping methods often involve long scan times due to sequentially measuring many parameters. Magnetic resonance fingerprinting (MRF) is a new method that enables fast quantitative MRI by exploiting the transient signals caused by the variation of pseudorandom sequence parameters. These transient signals are then matched to a simulated dictionary of T 1 and T 2 values to create quantitative maps. The ability of MRF to simultaneously measure multiple parameters, could represent a new approach to characterizing cancer and assessing treatment response. This feasibility study investigates MRF for simultaneous T 1, T 2, and relative proton density (rPD) mapping using ovarian cancer as a model system.

Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study.

BACKGROUND: Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). METHODS AND FINDINGS: We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%-22%) compared to 0.7% (IQR 0.3%-2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28-54) compared with a median time to nadir of 84 d (IQR 42-116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07-0.67, p = 0.008). Conversely, a decrease in TP53MAF of ≤60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%-92%) and 88% specificity (95% CI 64%-99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort. CONCLUSIONS: In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment.