Endometrial Cancer: Analysing Patterns of Recurrence and Real-Life Outcome Data Using the 2020 ESGO-ESTRO-ESP Risk Stratification System.

AIMS: To evaluate patterns of recurrence and explore the prognostic differences between the 2018 FIGO staging system and the 2020 ESGO-ESTRO-ESP risk stratification system of endometrial cancer with an emphasis on early-stage disease. BACKGROUND: The incidence of endometrial cancer has risen by around 60% since the 90's. It is projected that by 2035 endometrial cancer will be the sixth most common cause of cancer-related death amongst females. METHODS: This was a retrospective cohort study which included patients treated between 2010 and 2017. Primary endpoints were overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meyer survival analysis was used to assess OS and RFS across different risk groups. Cox proportional hazards regression was used to evaluate prognostic risk factors implicated in recurrence. Different recurrence patterns across the subgroups were analysed with Pearson's chi-square test. RESULTS: The study included 692 patients with a recurrence rate of 14.9%. The median time to recurrence was 17.1 months (IQR:8.8-28.4). The mean OS varied between 97.2 months in the low-risk group to 63.1 months in the high-risk group (p < 0.001). Mean RFS was 96.1 in the low-risk group and 58.9 in the high-risk group (p < 0.001). RFS was predicted by the following factors; high risk group (OR=3.87; p = 0.041), LVSI (OR=2.54, p = 0.005), carcinosarcoma (OR=2.20, p = 0.021) and serous subtype (OR=1.91, p = 0.01). Logistic regression was used to evaluate risk factors for loco-regional and distant recurrence. Patients in the low-risk group were less likely to have distant recurrence (OR=0.08, p = 0.004). Similarly, negative LVSI and Grade 1 cancers were associated with decreased risk of distant recurrence (OR=0.34, p = 0.006 and OR=0.33, p = 0.007, respectively). There were no significant risk factors for loco-regional recurrence. CONCLUSIONS: The 2020 ESGO-ESTRO-ESP risk stratification provides accurate estimates of recurrence risk and survival. Those treated in line with current guidance have significantly better outcomes.

Laparoscopic and Robotic Surgery for Endometrial and Cervical Cancer.

Minimally invasive surgery (MIS) has many benefits, in the form of reduced postoperative morbidity, improved recovery and reduced inpatient stay. It is imperative, however, when new techniques are adopted, in the context of treating oncology patients, that the oncological efficacy and safety are established rigorously rather than assumed based on first principles. Here we have attempted to provide a comprehensive review of all the contentious and topical themes surrounding the use of MIS in the treatment of endometrial and cervix cancer following a thorough review of the literature. On the topic of endometrial cancer, we cover the role of laparoscopy in both early and advanced disease, together with the role and unique benefits of robotic surgery. The surgical challenge of patients with a raised body mass index and the frail and elderly are discussed and finally the role of sentinel lymph node assessment. For cervical cancer, the role of MIS for staging and primary treatment is covered, together with the interesting and highly specialist topics of fertility-sparing treatment, ovarian transposition and the live birth rate associated with this. We end with a discussion on the evidence surrounding the role of adjuvant hysterectomy following radical chemoradiation and pelvic exenteration for recurrent cervical cancer. MIS is the standard of care for endometrial cancer. The future of MIS for cervix cancer, however, remains uncertain. Current recommendations, based on the available evidence, are that the open approach should be considered the gold standard for the surgical management of early cervical cancer and that MIS should only be adopted in the context of research. Careful counselling of patients on the current evidence, discussing in detail the risks and benefits to enable them to make an informed choice, remains paramount.

Use of surgical sealant in debulking surgery for advanced ovarian carcinoma--case report.

Haemostatic sealants are frequently used in gynaecological surgery. Several commercial products are available with similar mechanisms of action and chemical structure. We report the use of Floseal in a laparotomy for ovarian cancer to achieve haemostasis. This is the first reported case with the successful use of Floseal in gynaecological oncology.

Liver resection for metastases arising from recurrent granulosa cell tumour of the ovary--a case series.

Ovarian granulosa cell tumours (GCT) occur rarely and represent 2-3% of all ovarian tumours. Regarded as tumours with low malignant potential and renowned for late recurrences, these tumours occasionally metastasize to the liver. We present our experience with three patients who underwent secondary cytoreductive surgery including liver resection for recurrence of the disease resulting in greatly improved quality of life and disease-free interval.

Use of serum progesterone measurements to reduce need for follow-up in women with pregnancies of unknown location.

OBJECTIVE: To assess the efficacy of a progesterone-based algorithm for the management of women with pregnancies of unknown location (PULs) and explore the feasibility of developing a single-visit strategy in those with a low risk of requiring medical intervention. METHODS: All clinically stable women in whom pregnancy could not be identified on ultrasound scan were managed by a pre-defined protocol based on measurement of serum progesterone and beta-human chorionic gonadotropin (beta-hCG). Intervention in the form of surgery or medical treatment with methotrexate was offered to all women with persistent or worsening symptoms and non-declining serum beta-hCG. Decision-tree analysis was used to develop a protocol for the management of women with resolving pregnancies who are at low risk of requiring medical intervention. RESULTS: 1110 women were included in the data analysis: normal intrauterine pregnancy was diagnosed in 248 (22.3%; 95% CI, 19.9-24.8) women. 761 (68.6%; 95% CI, 65.8-71.3) abnormal pregnancies resolved spontaneously on expectant management, while the remaining 101 (9.1%; 95% CI, 7.4-10.8) women with abnormal pregnancies required some form of medical intervention. Intervention rates in patients presenting with initial serum progesterone levels of

Intraoperative haemostasis with new fibrin surgical sealant (Quixil) in gynaecological oncology.

We evaluated the effectiveness and safety of Quixil in gynaecological oncology with a prospective observational study over 11 months in a gynaecological oncology centre. Quixil was opportunistically used when conventional haemostatic techniques failed, in 35 laparotomies and four laparoscopies. A total of 26 operations were performed for malignant disease and 13 for benign indications. Demographic, intraoperative and postoperative data were collected. Haemostasis was accomplished within 5 min from sealant application. No hypersensitivity reactions were noted. Bowel recovery and postoperative pain were usual. In the laparotomy group, the mean hospital stay was 11 days and mean operating time, 164 min. In the laparoscopy group, the mean hospital stay was 3 days and mean operating time 165 min. In both groups, the incidence of complications and recurrence rates were in line with the expected population rates of these treated patients. We conclude that Quixil is an efficient, safe and effective haemostatic agent, which has a role to play in gynaecological surgery for benign and malignant disease.

Dexamethasone inhibits leukocyte emigration in rat mesenteric post-capillary venules: an intravital microscopy study.

The effect of subcutaneous administration of dexamethasone (DEX) on interleukin-1beta(IL-1beta, 20 ng i.p., - 2 h) and platelet-activating factor (PAF, 100 nM in superfusion) -induced leukocyte interaction with the endothelium of rat mesenteric post-capillary venules was studied. DEX produced a dose-dependent inhibition of IL-1beta-induced leukocyte extravasation in the rat mesenteric vascular bed, with a calculated ED5o of 40 microg/kg and a maximal effect of 80-100% inhibition at 0.1 mg/kg. IL-1beta-induced cell adhesion to post-capillary venules was only partially inhibited by the steroid, with a calculated ED50 of 480 microg/kg and a maximal effect of 40-60% inhibition. Furthermore, the steroid inhibited leukocyte emigration, but not adhesion, caused by superfusion of the mesenteric vascular bed with PAF. A doubling of leukocyte emigration time (from 226 to 552 s) was observed after treatment of rats with DEX. Administration for 5 days of a dose of 10 microg/kg DEX (which was inactive when given as a single injection) resulted again in a selective inhibition of IL-1beta-induced leukocyte emigration, without effect on cell adhesion. These data demonstrate a preferential susceptibility of the leukocyte emigration process to the inhibitory action of DEX.

The chemical, genetic and immunological basis of idiosyncratic drug-induced liver injury.

Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug-induced liver injury (iDILI), a phenomenon that occurs with many drugs including ß-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.

Comparison of transvaginal color Doppler imaging and color Doppler energy for assessment of intraovarian blood flow.

OBJECTIVE: To investigate any systematic differences in the analysis of blood flow velocity waveforms derived by color Doppler imaging and color Doppler energy examination of corpora lutea and adnexal tumors, to test whether the accuracy for diagnosing ovarian malignancy differs between end points derived by color Doppler imaging and color Doppler energy, and to compare the reproducibility of flow velocity waveform analysis obtained by both methods. METHODS: Fifty-six asymptomatic women with presumed corpora lutea and 67 women with known adnexal masses were included in the study. They all were examined using transvaginal sonography with color Doppler imaging and color Doppler energy. Pulsed Doppler sonography was used to obtain flow velocity waveforms to determine the pulsatility index (PI), resistance index (RI), peak systolic velocity, and time-averaged maximum velocity. The tumors were classified retrospectively according to histologic criteria. RESULTS: There were 52 women with benign, three with borderline, and 12 with malignant ovarian tumors. Repeated-measures analysis of variance revealed no systematic differences in the values of all four measurements performed under color Doppler imaging and color Doppler energy for all cases of corpora lutea and adnexal tumors (PI: P=.153, RI: P=.197, peak systolic velocity: P=.355, time-averaged maximum velocity: P=.159). All cases of borderline and malignant tumors had detectable pulsatile blood flow with color Doppler imaging and color Doppler energy. Forty-two (80.8%) of the benign tumors had flow detectable with color Doppler imaging, compared with 40 (76.9%) with color Doppler energy (P=.480). Analysis of receiver operating characteristic curves showed a marginal but nonsignificant improvement in diagnostic performance with color Doppler energy compared with color Doppler imaging for all four measurements (PI: P=.182, RI: P=.178, peak systolic velocity: P=.254, time-averaged maximum velocity: P=.238). The intraclass correlation coefficients for all four measurements were superior with color Doppler imaging compared with color Doppler energy. CONCLUSION: Flow velocity waveform analysis and diagnostic accuracy for ovarian malignancy are not significantly different between color Doppler imaging and color Doppler energy. Examinations with color Doppler imaging appear to be more reproducible than those with color Doppler energy.

Analysis of the protection afforded by annexin 1 in ischaemia-reperfusion injury: focus on neutrophil recruitment.

Ischaemia-reperfusion injury underlies many of the most important cardiovascular diseases such as myocardial infarction, thrombotic stroke, embolic vascular occlusions and peripheral vascular insufficiency. Neutrophils feature prominently in this inflammatory component of post-ischaemic injury. Experimental therapies, shown to reduce neutrophil-mediated ischaemia-reperfusion injury include neutrophil depletion, direct inhibitors of neutrophil activators, antibodies against neutrophil adhesion molecules and the endothelial adhesion molecules. However, aside from these approaches, it is increasingly recognised that glucocorticoids are potent inhibitors of neutrophil-mediated injury. The anti-inflammatory actions of glucocorticoid include the activation of classical cytoplasmic receptors leading to changes in gene transcription as well as the induction of regulatory proteins, such as annexin 1. Annexin 1 is a potent inhibitor of neutrophil extravasation in vivo. Administration of the annexin 1 or peptides derived from its N-terminal domain, reduce neutrophil extravasation in models of acute inflammation. In addition, as reviewed by this article, annexin 1 protects against ischaemia-reperfusion in the heart and mesenteric microcirculation, as well as in multiple organ failure associated with splanchnic ischaemia-reperfusion. Such findings would suggest annexin 1 is a novel anti-inflammatory agent with a potential for the treatment of cardiovascular pathologies associated with neutrophil activation and recruitment.

A comparison of intratumoural indices of blood flow velocity and impedance for the diagnosis of ovarian cancer.

The aim was to assess the value of blood flow velocity indices in an ultrasound-based test to discriminate between malignant and benign adnexal tumours. Fifty-one women (35 premenopausal and 16 postmenopausal) with persistent adnexal masses were scanned prior to surgery using transvaginal sonography with colour Doppler imaging. Intratumoural flow velocity waveforms obtained by pulsed Doppler sonography were used to determine the time averaged maximum velocity (TAMXV), peak systolic velocity (PSV), pulsatility index (PI) and resistance index (RI). The tumours were classified by histologic criteria (42 benign, 1 borderline and 8 malignant tumours). Two of the malignant and the single borderline tumour were stage I, five were stage III and one was stage IV. Detectable blood flow signals were found in all malignant and borderline tumours and in 33 of 42 (78.6%) of the benign tumours. TAMXV was the best parameter for discrimination of benign and malignant adnexal pathology and at a cut-off value of TAMXV > or = 12 cm/s to indicate malignancy, the sensitivity and specificity were 88.9% and 81.0%, respectively. At the same sensitivity level, this gave a better specificity than the PI < or = 0.90 (specificity 61.9%, P = 0.036), RI < or = 0.60 (specificity 54.8%, P = 0.010) and PSV > or = 16 cm/s (specificity 71.4%, P = 0.121). Discrimination between benign and malignant tumours was improved further by using two criteria rather than one. When the two criteria of a TAMXV of > or = 12 cm/s and a PI < or = 1.0 were applied simultaneously, the tumours could be characterised with a sensitivity of 88.9% and a specificity of 88.1%. Therefore, intratumoural PSV and TAMXV could be used to discriminate between benign and malignant adnexal tumours better than values for PI and RI. The best discrimination was achieved by using a combination of cut-off values for velocity and impedance parameters as two criteria to define malignancy.