Tumour microenvironment characterisation to stratify patients for hyperthermic intraperitoneal chemotherapy in high-grade serous ovarian cancer (OVHIPEC-1).

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial. METHODS: Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models. RESULTS: While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence. CONCLUSION: Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation. CLINICAL TRIAL REGISTRATION: NCT00426257.

Is routine admission to a critical care setting following hyperthermic intraperitoneal chemotherapy for ovarian cancer necessary?

INTRODUCTION: Hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly being used in patients with stage III ovarian cancer undergoing interval cytoreductive surgery (CRS). It is uncertain whether routine postoperative admission to a critical care setting after CRS-HIPEC is necessary. This study aims to estimate the incidence of patients requiring critical care, and to create a prediction model to identify patients who may forego admission to a critical care setting. METHODS: We analyzed 154 patients with primary ovarian cancer undergoing interval CRS-HIPEC at two Dutch centers between 2007 and 2021. Patients were routinely admitted to a critical care setting for 12-24 h. Patients that received critical support as defined by pre-specified definitions were retrospectively identified. Logistic regression analysis with backward selection was used to predict the need for critical care and the model was validated using bootstrapping. RESULTS: Thirty-eight percent of patients received postoperative critical care, consisting mainly of hemodynamic interventions. Independent predictors of critical care were blood loss, norepinephrine dose during surgery, and age (bootstrapped AUC = 0.76). Using a probability cut-off of 20%, one-third of patients are defined as low-risk for requiring critical care, with a negative predictive value of 0.88. CONCLUSIONS: The majority of patients,primarily undergoing low to intermediate complexity surgeries, did not receive critical care interventions after CRS-HIPEC. Selective admission to a critical care setting may be warranted and its feasibility and safety needs to be evaluated prospectively. Our prediction model can help identify patients in whom admission to a critical care setting may be omitted. Hospital costs and burden on critical care units will benefit from patient selection.

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.

BACKGROUND: The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up. METHODS: In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18-76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0-2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed. FINDINGS: Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4-12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5-13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6-12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0-18·5]; hazard ratio [HR] 0·63 [95% CI 0·48-0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0-39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6-55·1]; HR 0·70 [95% CI 0·53-0·92], stratified log-rank p=0·011). INTERPRETATION: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding).

Translational and pharmacological principles of hyperthermic intraperitoneal chemotherapy for ovarian cancer.

The long-term survival of advanced-stage ovarian cancer patients remains poor, despite extensive cytoreductive surgery, chemotherapy, and the recent addition of poly (ADP-ribose) polymerase inhibitors (PARPi). Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown survival benefit by specifically targeting peritoneal metastases, the primary site of disease recurrence. Different aspects of how HIPEC exerts its effect remain poorly understood. Improved understanding of the effects of hyperthermia on ovarian cancer cells, the synergy of hyperthermia with intraperitoneal chemotherapy, and the pharmacological and pharmacokinetic properties of intraperitoneally administered cisplatin may help identify ways to optimize the efficacy of HIPEC. This review provides an overview of these translational and pharmacological principles of HIPEC and aims to expose knowledge gaps that may direct further research to optimize the HIPEC procedure and ultimately improve survival for women with advanced ovarian cancer.

Large primary vaginal stone in a woman with multiple sclerosis.

Vaginal stones are rare and therefore a delay in accurate diagnosis often occurs. We present a 54-year old woman with multiple sclerosis who was diagnosed with a primary vaginal stone. Initially, she presented with recurring urinary tract infections (UTI) and macroscopic haematuria to the urologist. A cystoscopy showed no abnormalities. Because of persistent bleeding, she was referred to the gynaecologist, and on gynaecological examination, a vaginal stone was revealed. Stone formation was likely to be the result of urinary pooling due to incontinence, which was caused by a neurogenic bladder. Other contributing factors were prolonged recumbency, threads of an intrauterine device and a UTI. The presence of a vesicovaginal fistula was excluded by testing with methylene blue. The stone was surgically removed and composed of 70% struvite and 30% apatite. The patient was treated for decubitus ulcerations of the vaginal wall with estriol (Synapause-E3). Follow-up was uneventful.

Peri-operative care pathways: re-engineering care to achieve the 'triple aim'.

Elective surgical pathways offer a particular opportunity to plan radical change in the way care is delivered, based on patient need rather than provider convenience. Peri-operative pathway redesign enables improved patient experience of care (including quality and satisfaction), population/public health, and healthcare value (outcome per unit of currency). Among physicians with the skills to work within peri-operative medicine, anaesthetists are well positioned to lead the re-engineering of such pathways. Re-engineered pre-operative pathways open up opportunities for intervention before surgery including shared decision-making, comorbidity management and collaborative behavioural change. Individualised, risk-adapted, intra-operative interventions will drive more reliable and consistent care. Risk-adapted postoperative care, particularly around transitions of care, has a significant role in improving value through peri-operative medicine. Improved integration with primary care providers offers the potential for minimising errors around transitions of care before and after surgery, as well as maximising opportunities for population health interventions, including lifestyle modification (e.g. activity/exercise, smoking and/or alcohol cessation), pain management and sleep medicine. Systematic data collection focused on quality improvement is essential to drive continuous clinical improvement and will be enabled by technological development in predictive analytics, systems modelling and artificial intelligence.

Influence of transducer frequency and imaging modality on the intraoperative assessment of myocardial perfusion with transesophageal echocardiography.

OBJECTIVE: To determine factors that improve intraoperative myocardial perfusion assessment with conventional ultrasound imaging and intravenous ultrasound agents. DESIGN: Prospective cohort study with repeated interventions on each patient. SETTING: Single university hospital. PARTICIPANTS: Fourteen patients scheduled for elective coronary artery bypass graft surgery. INTERVENTIONS: Myocardial perfusion was evaluated with contrast transesophageal echocardiography during conventional imaging after central venous injections of the contrast agent Optison (0.3 mL) before cardiopulmonary bypass. Eight patients received the injection during continuous sampling at each of 4 transducer frequency settings (3.5, 5.0, 6.0, 7.0 MHz). In another 6 patients, injections were administered during continuous and intermittent sampling (electrocardiogram-gated) at 3.5 and 5.0 MHz. Generalized estimating equations were used to compare mean responses, with p < or = 0.05 considered significant. MEASUREMENTS AND MAIN RESULTS: All recorded images were analyzed with off-line videodensitometry. Background-corrected peak pixel intensity (PPI(corr)) and rate of change in pixel intensity (PPI(corr)/T(PPI)) were determined for each injection. PPI(corr) was greater at 3.5 MHz than at 5.0, 6.0, and 7.0 MHz (p < 0.001). PPI(corr)/T(PPI) was greater at 3.5 MHz than at 5.0 (p < 0.001), 6.0 (p = 0.003), and 7.0 MHz (p < 0.001). PPI(corr) was greater for gated than for nongated sampling conditions at 3.5 (p < 0.05) and 5.0 MHz (p < 0.05). CONCLUSION: To optimize myocardial contrast opacification, intraoperative transesophageal echocardiography should be performed with intermittent sampling at a transducer frequency close to the intrinsic frequency of the contrast agent.

Changes in regional myocardial function after coronary artery bypass graft surgery are predicted by intraoperative low-dose dobutamine echocardiography.

BACKGROUND: Left ventricular dysfunction is often reversed after coronary artery bypass graft (CABG) surgery; however, this change is not easily predicted. The authors hypothesized that functional changes after a low dose of dobutamine (5 microgram. kg-1. min-1) intraoperatively would predict functional changes when complete revascularization was achieved. METHODS: The authors analyzed 560 segments in 40 patients scheduled for elective CABG surgery for regional wall motion (1-5 scoring system) at four stages: baseline (after induction and intubation), with administration of low-dose dobutamine before cardiopulmonary bypass, after separation from cardiopulmonary bypass (early), and after administration of protamine (late). Two independent observers scored the myocardial regions according to a 16-segment model in multiple imaging planes. For each segment, the response to dobutamine was dichotomized as improved or not improved from baseline and analyzed with logistic regression. The influence of covariates (ejection fraction, myocardial infarction, diabetes mellitus, and beta blockers) was also determined with logistic regression models. P < 0.05 was considered significant. RESULTS: Changes in myocardial function after low-dose dobutamine were highly predictive for early (P < 0.0001) and late (P < 0.0001) changes in myocardial function from baseline regional scores. The overall odds ratio for early and late improvement increased by 20.7 and 34.6, respectively, when improvement was observed after low-dose dobutamine was administered. The overall positive predictive value of improved regional wall motion after CABG did not vary with left ventricular ejection fraction, a history of myocardial infarction, or beta blocker use, and it varied little with diabetic status (range, 0.86-0.96) if regional wall motion improved with low-dose dobutamine before CABG. The overall negative predictive value was 0.70; however, the range varied with diabetic status (i.e., lowest in diabetic patients and highest in nondiabetic patients). CONCLUSION: Intraoperative low-dose dobutamine is a reliable method to predict myocardial functional reserve and to determine functional recovery expected after coronary revascularization.

Fenoldopam: a new parenteral antihypertensive: consensus roundtable on the management of perioperative hypertension and hypertensive crises.

A panel of clinicians from anesthesiology, surgery, nephrology, hypertension, cardiology, and pharmacology was convened to discuss pharmacologic therapeutics in the management of hypertensive crisis and perioperative hypertension. The panel discussed the advantages and limitations of currently available parenteral drugs, and assessed the potential use of fenoldopam mesylate, a drug in clinical development since 1981, and recently approved by the U.S. Food and Drug Administration (FDA). Fenoldopam is a dopamine receptor (DA1 selective) agonist that is a systemic and renal vasodilator. It was concluded that fenoldopam offers significant advantages as a parenterally administered agent for the management of blood pressure in both hypertensive emergencies and in the perioperative setting.

Assessing flow during minimally invasive coronary artery bypass: an Allen's test equivalent.

The use of a provocative test to elicit selective regional myocardial dysfunction (detected with intraoperative TEE) as a method to infer adequacy of regional myocardial perfusion following MIDCAB is described. We liken the similarity of this technique to the originally described "Allens test" for determination of collateral blood flow adequacy.