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

$\textbf{Background:}$ 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 $\textit{TP53}$ 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). $\textbf{Methods and Findings:}$ 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 $\textit{TP53}$ 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 $\textit{TP53}$ 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, $p$ 32 cm$^3$, 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. $\textbf{Conclusions:}$ 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.This work was supported by Cancer Research UK Grant numbers: A15601 (JDB), A11906 (NR), A20240 (NR), A18072 (JDB). JDB was supported by the National Institute for Health Research Cambridge Biomedical Research Centre. CAP was supported in part by the Academy of Medical Sciences, the Wellcome Trust, British Heart Foundation and Arthritis Research UK

Role of MRI in staging and follow-up of endometrial and cervical cancer:pitfalls and mimickers

Abstract MRI plays important roles in endometrial and cervical cancer assessment, from detection to recurrent disease evaluation. Endometrial cancer (EC) is the most common malignant tumor of the female genital tract in Western countries. EC patients are divided into risk categories based on histopathological tumor type, grade, and myometrial invasion depth. EC is surgically staged using the International Federation of Gynecology and Obstetrics (FIGO) system. Since FIGO (2009) stage correlates with prognosis, preoperative staging is essential for tailored treatment. MRI reveals myometrial invasion depth, which correlates with tumor grade and lymph node metastases, and thus correlates with prognosis. Cervical cancer (CC) is the second most common cancer, and the third leading cause of cancer-related death among females in developing countries. The FIGO Gynecologic Oncology Committee recently revised its CC staging guidelines, allowing staging based on imaging and pathological findings when available. The revised FIGO (2018) staging includes node involvement and thus enables both therapy selection and evaluation, prognosis estimation, and calculation of end results. MRI can accurately assess prognostic indicators, e.g., tumor size, parametrial invasion, pelvic sidewall, and lymph node invasion. Despite these important roles of MRI, radiologists still face challenges due to the technical and interpretation pitfalls of MRI during all phases of endometrial and cervical cancer evaluation. Awareness of mimics that can simulate both cancers is critical. With careful application, functional MRI with DWI and DCE sequences can help establish a correct diagnosis, although it is sometimes necessary to perform biopsy and histopathological analysis

Primary diaphragmatic closure following diaphragmatic resection and cardiophrenic lymph node dissection during interval debulking surgery for advanced ovarian malignancy

Highlights • Gaining trans-diaphragmatic access to thoracic cavity during de-bulking laparotomy. • Assessment and dissection of bulky cardiophrenic lymph nodes to achieve optimal cytoreduction. • Technique for primary closure of diaphragm following radical resection

The modified radical peri-partum caesarean hysterectomy (Soleymani-Alazzam-Collins (SAC) technique): a systematic, safe procedure for the management of severe placenta accreta spectrum (PAS)

OBJECTIVES: To describe a stepwise, systematic technique for radical caesarean hysterectomy for placenta accreta spectrum (PAS). To investigate outcomes for women with severe, invasive PAS, who were hysterectomised using this technique. STUDY DESIGN: A retrospective cohort study, undertaken at a large UK tertiary referral centre. Twenty-four cases of elective primary caesarean hysterectomy with a confirmed intrapartum diagnosis of severe percreta (FIGO grades 3b and c) were identified between 2011 and 2020. Sixteen had standard care (surgical technique dependant on surgeon's preference) and eight had the radical peri-partum hysterectomy using the SAC-technique as described. Non-parametric testing was used due to sample size. RESULTS: The SAC-technique resulted in significantly less blood loss (P=0.032), more transverse incisions (p=0.009) and less ICU admissions (p=0.046). There was no significant difference in theatre time. CONCLUSION: (s) The SAC-technique demonstrated a significant improvement in outcomes for women with severe PAS, without increasing surgical time

The Ten Year Experience of A Regional Specialist Gynaecology Cancer Genetics Clinic with Lynch Syndrome

Aims: To review the outcomes from a single institution experience of a regional referral practice in Lynch Syndrome (LS) Method: Service review. Surveillance was outpatient hysteroscopy, endometrial biopsy, CA 125 and TV ultrasound. Risk reducing surgery (RRS) was laparoscopic hysterectomy and bilateral salpingo-oophorectomy. Results: Since 2007 60 patients have had RRS and a further 7 patients are undergoing surveillance. There are 18 MLH-1, 17 MSH-2, 7 MSH-6 and 2 PMS-2 mutation carriers having risk reducing surgery with the balance having strong family history. The frequency of surgery is increasing with more referrals. The mean age for RRS is 45 years (range 32-62 yrs). 21 patients opted for surveillance, mean time period 3 years, with the longest screen being 11 years. Forty patients chose RRS, 25 within 6 months of the specialist clinic, 9 within 12 months (1 cancer at surgery aged 54 years), 6 within 24 months (1 cancer at surgery aged 48 years). There has been one ovarian cancer (stage 1A endometrioid) discovered at the time of removing an abnormal ovary at time of colorectal cancer surgery aged 41 years which precipitated diagnosis of LS. Three patients have had endometrial cancer detected at RRS, one stage 2 requiring adjuvant radiotherapy. Prior cancer in carriers include bowel and breast cancer. There have been no deaths. Conclusion: Centralised services provide excellent care for patients with cancer mutation

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

Vascular invasion in hepatocellular carcinoma:is there a correlation with MRI?

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the commonest malignancies worldwide. Prognosis is predicted by size at diagnosis, vascular invasion and tumour proliferation markers. This study investigates if MRI features of histologically proven HCCs correlate with vascular invasion. METHODS: Between 2006 and 2008, 18 consecutive patients, with a total of 27 HCCs, had comprehensive MRI studies performed at our institution within a median of 36 days of histology sampling. Each lesion was evaluated independently on MRI by 3 radiologists (blinded to both the radiology and histopathology reports) using a 5-point confidence scale for 23 specific imaging features. The mean of the rating scores across readers was calculated to determine interobserver consistency. The most consistent features were then used to examine the value of features in predicting vascular invasion, using a χ(2 )test for trend, having eliminated those features without sufficient variability. RESULTS: 22 of the 23 imaging features showed sufficient variability across lesions. None of these significantly correlated with the presence of vascular invasion, although a trend was identified with the presence of washout in the portal venous phase on MRI and the median size of lesions, which was greater with vascular invasion. CONCLUSION: This study suggests that no single MRI feature accurately predicts the presence of vascular invasion in HCCs, although a trend was seen with the presence of washout in the portal venous phase post gadolinium. Larger prospective studies are required to investigate this further

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