Elly Brockbank

Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma

PURPOSE To develop and validate a histopathologic scoring system for measuring response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIC to IV tubo-ovarian high-grade serous carcinoma. PATIENTS AND METHODS A six-tier histopathologic scoring system was proposed and applied to a test cohort (TC) of 62 patients treated with neoadjuvant chemotherapy and interval debulking surgery. Adnexal and omental sections were independently scored by three pathologists. On the basis of TC results, a three-tier chemotherapy response score (CRS) system was developed and applied to an independent validation cohort of 71 patients. RESULTS The initial system showed moderate interobserver reproducibility and prognostic stratification of TC patients when applied to the omentum but not to the adnexa. Condensed to a three-tier score, the system was highly reproducible (kappa, 0.75). When adjusted for age, stage, and debulking status, the score predicted progression-free survival (PFS; score 2 v 3; median PFS, 11.3 v 32.1 months; adjusted hazard ratio, 6.13; 95% CI, 2.13 to 17.68; P < .001). The three-tier CRS system applied to omental samples from the validation cohort showed high reproducibility (kappa, 0.67) and predicted PFS (CRS 1 and 2 v 3: median, 12 v 18 months; adjusted hazard ratio, 3.60; 95% CI, 1.69 to 7.66; P < .001). CRS 3 also predicted sensitivity to first-line platinum therapy (94.3% negative predictive value for progression < 6 months). A Web site was established to train pathologists to use the CRS system. CONCLUSION The CRS system is reproducible and shows prognostic significance for high-grade serous carcinoma. Implementation in international pathology reporting has been proposed by the International Collaboration on Cancer Reporting, and the system could potentially have an impact on patient care and research.

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response. Experimental Design: We obtained pre- and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response. Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4+ T cells showed enhanced IFNγ production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8+ T-cell and CD45RO+ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3+ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- versus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025–36. ©2016 AACR.

Copy number signatures and mutational processes in ovarian carcinoma

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.The authors identify copy number signatures from shallow whole-genome sequencing of high-grade serous ovarian cancer (HGSOC) cases. HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in genomic aberration.

A Case of Stage 4B Seromucinous Ovarian Borderline Tumor With Endometriosis and Review of the Literature.

Ovarian mucinous borderline tumors are traditionally divided into 2 morphologic groups: endocervical type, also known as seromucinous, and intestinal type. We present a case of stage 4B seromucinous ovarian borderline tumor with endometriosis and review the literature. At the time of writing, this is believed to be the first case of a seromucinous borderline tumor reported at such an advanced stage.

The management of pregnancy after trachelectomy for early cervical cancer

Cervical cancer continues to affect many women in the UK with over half under the age of 45 years at the time of diagnosis; with a trend towards starting families later in life this raises fertility concerns. While the standard treatment for stage IA2 or IB1 cervical cancer is a radical hysterectomy, radical trachelectomy has been shown to have equivalent 5‐year survival and is a surgical option if there is a wish to preserve fertility. Although trachelectomies are performed by gynaecological oncologists, the management of any subsequent pregnancies falls under the remit of obstetricians who therefore require a sound knowledge of the procedure and potential obstetric sequelae. Pregnancies following trachelectomy are high risk because of the increased rate of mid‐trimester miscarriage and preterm delivery, often as a consequence of preterm prelabour rupture of membranes. Delivery is by caesarean section, traditionally by classical section as a permanent isthmic suture is placed at the time of trachelectomy, but nowadays a transverse incision may be used to reduce morbidity and the implications on future fertility.

Haemorrhagic shock due to spontaneous splenic rupture in a patient subsequently diagnosed with advanced ovarian cancer.

Epithelial ovarian cancer (EOC) is the second most common gynaecological cancer and affects mainly postmenopausal women. The majority of women with ovarian cancer (70–80%) present with advanced stage disease and have a poor prognosis, with 5-year survival not exceeding 40–50% (Berrino et al. 2007). The majority of patients are presented with non-specific symptoms; including abdominal distension, bloating, altered bowel habit, cachexia, weight loss and occasionally shortness of breath. These symptoms are mainly related to disseminated disease, large volume of ascites and pleural effusions, which are common features in advanced ovarian cancer. In this report we describe the case of a woman who was presented to Accident and Emergency (A&E) with haemorrhagic shock due to atraumatic spontaneous splenic rupture. She had a concurrent diagnosis of advanced EOC that is postulated to be the underlying cause of her initial presentation. Atraumatic splenic rupture (ASR) is a very rare event occurring in association with malignant and benign conditions. This is the first report of ASR causing life-threatening haemorrhagic shock in a patient with advanced EOC.