An Update on the Role of MRI in Treatment Stratification of Patients with Cervical Cancer.

Cervical cancer is the fourth most common cancer in women worldwide and the most common gynaecological malignancy. The FIGO staging system is the most commonly utilised classification system for cervical cancer worldwide. Prior to the most recent update in the FIGO staging in 2018, the staging was dependent upon clinical assessment alone. Concordance between the surgical and clinical FIGO staging decreases rapidly as the tumour becomes more advanced. MRI now plays a central role in patients diagnosed with cervical cancer and enables accurate staging, which is essential to determining the most appropriate treatment. MRI is the best imaging option for the assessment of tumour size, location, and parametrial and sidewall invasion. Notably, the presence of parametrial invasion precludes surgical options, and the patient will be triaged to chemoradiotherapy. As imaging is intrinsic to the new 2018 FIGO staging system, nodal metastases have been included within the classification as stage IIIC disease. The presence of lymph node metastases within the pelvis or abdomen is associated with a poorer prognosis, which previously could not be included in the staging classification as these could not be reliably detected on clinical examination. MRI findings corresponding to the 2018 revised FIGO staging of cervical cancers and their impact on treatment selection will be described.

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.

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.

Resolving a QTL complex for height, heading, and grain yield on chromosome 3A in bread wheat.

Crop height (Ht), heading date (Hd), and grain yield (GY) are inter-related in wheat. Independent manipulation of each is important for adaptation and performance. Validated quantitative trait loci (QTLs) for all three co-locate on chromosome 3A in the Avalon×Cadenza population, with increased Ht, Hd, and GY contributed by Cadenza. We asked if these are linked or pleiotropic effects using recombinant lines, and showed that Ht and Hd effects are independent. The Chinese Spring equivalent to the newly defined Ht interval contained a gene cluster involved in cell wall growth and displaying high levels of differential transcript expression. The Hd locus is larger and rearranged compared with the reference genome, but FT2 (Flowering Locus T2) is of particular interest. The Hd effect acted independently of photoperiod and vernalization, but did exhibit seasonal genotype×environment interaction. Recombinants were phenotyped for GY in replicated field experiments. GY was most associated with Cadenza alleles for later Hd, supporting physiological studies using the same lines proposing that 'late' alleles at this locus increase spike fertility and grain number (GN). The work has uncoupled height from heading and yield, and shown that one of very few validated GY QTLs in wheat is probably mediated by phenological variation.

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.

Epirubicin, Cisplatin, and Capecitabine for Primary Platinum-Resistant or Platinum-Refractory Epithelial Ovarian Cancer: Results of a Retrospective, Single-Institution Study.

OBJECTIVE: Primary platinum-resistant epithelial ovarian cancer (EOC) is an area of unmet medical need. There is limited evidence from small studies that platinum-based combinations can overcome "resistance" in a proportion of patients. We investigated the efficacy and toxicity of platinum-based combination chemotherapy in the platinum-resistant and platinum-refractory setting. METHODS: Epirubicin, cisplatin, and capecitabine (ECX) combination chemotherapy was used at our institution for the treatment of relapsed EOC. From the institutional database, we identified all patients with primary platinum-refractory or platinum-resistant relapse treated with ECX as second-line therapy between 2001 and 2012. We extracted demographic, clinical, treatment, and toxicity data and outcomes. We used logistic and Cox regression models to identify predictors of response and survival respectively. RESULTS: Thirty-four 34 patients (8 refractory, 26 resistant) were treated with ECX. Response Evaluation Criteria In Solid Tumors (RECIST) response rate was 45%, median progression-free survival (PFS) was 6.4 months, and overall survival (OS) was 10.6 months. Platinum-resistant patients had better outcomes than did platinum-refractory patients (response rate, 54% vs 0%, P = 0.047; PFS 7.2 vs 1.8 months, P < 0.0001; OS 14.4 vs 3 months, P < 0.001). In regression models, time to progression after first-line treatment and platinum-refractory status were the strongest predictors of response and PFS or OS, respectively. Patients with time to progression after first-line treatment longer than 3 months showed PFS and OS of 7.9 and 14.7 months, respectively. Toxicity was manageable, with only 13% of cycles administered at reduced doses. CONCLUSIONS: Epirubicin, cisplatin, and capecitabine seems to be active in platinum-resistant relapsed EOC with manageable toxicity. Further prospective investigation of platinum-anthracycline combinations is warranted in patients who relapse 3 to 6 months after first-line platinum-taxane treatment.