Combination of Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE) with sonographic and demographic characteristics in preoperative prediction of recurrence or progression of endometrial cancer.

OBJECTIVE: To evaluate the ability of demographic and sonographic variables and the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE) classification to predict preoperatively tumor recurrence or progression in women with endometrial cancer. METHODS: The study included 339 women with histologically confirmed endometrial cancer who underwent expert transvaginal ultrasound in a single center before surgery as part of the prospective International Endometrial Tumor Analysis 4 study or who were evaluated using the same protocol. The tumors were classified according to histotype, FIGO (International Federation of Gynecology and Obstetrics) grade and FIGO stage. In addition, molecular analysis was performed for classification into the four ProMisE subtypes: polymerase-ϵ exonuclease domain mutations (POLE EDM), mismatch repair proteins deficiency (MMR-D), protein 53 wild type (p53 wt) and protein 53 abnormal (p53 abn). Demographic and preoperative sonographic characteristics, tumor recurrence or progression and survival were compared between the ProMisE subgroups. Cox regression analysis was used to identify prognostic factors associated with recurrence or progression, using univariable models to study crude associations and multivariable models to study adjusted associations. Logistic regression and receiver-operating-characteristics (ROC)-curve analysis were used to assess the predictive ability of the preoperative prognostic factors regarding recurrence or progression of cancer within 3 years after surgery, and to compare their predictive ability to that of the European Society for Medical Oncology (ESMO) preoperative (based on depth of myometrial invasion, histotype and grade) and postoperative (based on histotype, grade, surgical stage and lymphovascular space invasion) risk classifications. In a separate subanalysis, cases were stratified according to ProMisE p53 abn status (present vs absent) and sonographic tumor size (anteroposterior (AP) diameter < 2 cm vs ≥ 2 cm). RESULTS: Median follow-up time from surgery was 58 months (interquartile range, 48-71 months; range, 0-102 months). Recurrence or progression of cancer occurred in 51/339 (15%) women, comprising 14% of those with MMR-D, 8% of those with POLE EDM, 9% of those with p53 wt and 45% of those with p53 abn ProMisE subtype. On multivariable analysis, age, waist circumference, ProMisE subtype and tumor extension and AP diameter on ultrasound were associated with tumor recurrence or progression. A multivariable model comprising ProMisE subtype, age, waist circumference and sonographic tumor extension and size (area under the ROC curve (AUC), 0.89 (95% CI, 0.85-0.93)) had comparable ability to predict tumor recurrence/progression to that of a multivariable model comprising histotype, grade, age, waist circumference and sonographic tumor extension and size (AUC, 0.88 (95% CI, 0.83-0.92)), and better predictive ability than both the preoperative (AUC, 0.74 (95% CI, 0.67-0.82); P < 0.01) and postoperative (AUC, 0.79 (95% CI, 0.72-0.86); P < 0.01) ESMO risk classifications. Women with a combination of non-p53 abn subtype and tumor size < 2 cm (164/339 (48%)) had a very low risk (1.8%) of tumor recurrence or progression. CONCLUSIONS: The combination of demographic characteristics, sonographic findings and ProMisE subtype had better preoperative predictive ability for tumor recurrence or progression than did the ESMO classification, supporting their use in the preoperative risk stratification of women with endometrial cancer. The combination of p53 status with ultrasound tumor size has the potential to identify preoperatively a large group of women with a very low risk of recurrence or progression. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. - Legal Statement: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Ultrasound-based risk model for preoperative prediction of lymph-node metastases in women with endometrial cancer: model-development study.

OBJECTIVE: To develop a preoperative risk model, using endometrial biopsy results and clinical and ultrasound variables, to predict the individual risk of lymph-node metastases in women with endometrial cancer. METHODS: A mixed-effects logistic regression model for prediction of lymph-node metastases was developed in 1501 prospectively included women with endometrial cancer undergoing transvaginal ultrasound examination before surgery, from 16 European centers. Missing data, including missing lymph-node status, were imputed. Discrimination, calibration and clinical utility of the model were evaluated using leave-center-out cross validation. The predictive performance of the model was compared with that of risk classification from endometrial biopsy alone (high-risk defined as endometrioid cancer Grade 3/non-endometrioid cancer) or combined endometrial biopsy and ultrasound (high-risk defined as endometrioid cancer Grade 3/non-endometrioid cancer/deep myometrial invasion/cervical stromal invasion/extrauterine spread). RESULTS: Lymphadenectomy was performed in 691 women, of whom 127 had lymph-node metastases. The model for prediction of lymph-node metastases included the predictors age, duration of abnormal bleeding, endometrial biopsy result, tumor extension and tumor size according to ultrasound and undefined tumor with an unmeasurable endometrium. The model's area under the curve was 0.73 (95% CI, 0.68-0.78), the calibration slope was 1.06 (95% CI, 0.79-1.34) and the calibration intercept was 0.06 (95% CI, -0.15 to 0.27). Using a risk threshold for lymph-node metastases of 5% compared with 20%, the model had, respectively, a sensitivity of 98% vs 48% and specificity of 11% vs 80%. The model had higher sensitivity and specificity than did classification as high-risk, according to endometrial biopsy alone (50% vs 35% and 80% vs 77%, respectively) or combined endometrial biopsy and ultrasound (80% vs 75% and 53% vs 52%, respectively). The model's clinical utility was higher than that of endometrial biopsy alone or combined endometrial biopsy and ultrasound at any given risk threshold. CONCLUSIONS: Based on endometrial biopsy results and clinical and ultrasound characteristics, the individual risk of lymph-node metastases in women with endometrial cancer can be estimated reliably before surgery. The model is superior to risk classification by endometrial biopsy alone or in combination with ultrasound. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Transvaginal ultrasound assessment of myometrial and cervical stromal invasion in women with endometrial cancer: interobserver reproducibility among ultrasound experts and gynecologists.

OBJECTIVES: To assess interobserver reproducibility among ultrasound experts and gynecologists in the prediction by transvaginal ultrasound of deep myometrial and cervical stromal invasion in women with endometrial cancer. METHODS: Sonographic videoclips of the uterine corpus and cervix of 53 women with endometrial cancer, examined preoperatively by the same ultrasound expert, were integrated into a digitalized survey. Nine ultrasound experts and nine gynecologists evaluated presence or absence of deep myometrial and cervical stromal invasion. Histopathology from hysterectomy specimens was used as the gold standard. RESULTS: Compared with gynecologists, ultrasound experts showed higher sensitivity, specificity and agreement with histopathology in the assessment of cervical stromal invasion (42% (95% CI, 31-53%) vs 57% (95% CI, 45-68%), P < 0.01; 83% (95% CI, 78-86%) vs 87% (95% CI, 83-90%), P = 0.02; and kappa, 0.45 (95% CI, 0.40-0.49) vs 0.58 (95% CI, 0.53-0.62), P < 0.001, respectively) but not of deep myometrial invasion (73% (95% CI, 66-79%) vs 73% (95% CI, 66-79%), P = 1.0; 70% (95% CI, 65-75%) vs 69% (95% CI, 63-74%), P = 0.68; and kappa, 0.48 (95% CI, 0.44-0.53) vs 0.52 (95% CI, 0.48-0.57), P = 0.11, respectively). Though interobserver reproducibility (in the context of test proportions 'good' and 'very good', according to kappa) regarding deep myometrial invasion did not differ between the groups (experts, 34% vs gynecologists, 22%, P = 0.13), ultrasound experts assessed cervical stromal invasion with significantly greater interobserver reproducibility than did gynecologists (53% vs 14%, P < 0.001). CONCLUSION: Preoperative ultrasound assessment of deep myometrial and cervical stromal invasion in endometrial cancer is best performed by ultrasound experts, as, compared with gynecologists, they showed a greater degree of agreement with histopathology and greater interobserver reproducibility in the assessment of cervical stromal invasion.

Influence of a 60-hour fast on insulin-mediated splanchnic and peripheral glucose metabolism in humans.

A brief period of starvation (2-3) depletes the hepatic glycogen stores but results in only a limited reduction of the muscle glycogen depots. In this situation insulin resistance contributes to the glucose intolerance, but it is not known which tissue or tissues are responsible for the decreased insulin sensitivity. The present study was therefore undertaken to examine the influence of a 60-h fast on insulin sensitivity in splanchnic and peripheral tissues in normal humans. Euglycemic (95 mg/dl) 1-mU insulin and hyperglycemic (215-225 mg/dl) glucose clamp studies were conducted for 2 h in overnight (12 h) and prolonged (60 h) fasted nonobese subjects. Splanchnic exchange of glucose and gluconeogenic precursors was measured using the hepatic vein catheter technique. During the euglycemic clamp, insulin infusion resulted in similar steady state insulin levels in 60-h and 12-h fasted subjects (73 +/- 7 vs. 74 +/- 5 microU/ml). Total glucose disposal was reduced by 45% after 60 h of fasting (4.0 +/- 0.3 vs. 7.6 +/- 1.1 mg/kg per min, P less than 0.05) and the splanchnic glucose balance reverted from a net release in the basal state (12 h fast, -1.7 +/- 0.2, and 60-h fast, -0.9 +/- 0.1 mg/kg per min, P less than 0.01) to a net uptake during the clamps that was similar after 60 h and 12 h of fasting (0.6 +/- 0.1 vs. 0.6 +/- 0.2 mg/kg per min). During the hyperglycemic clamp, insulin levels rose rapidly in all subjects. In the 12-h fasted group this rise was followed by a further gradual one, reaching significantly higher values than in 60-h fasted subjects during the second hour (67 +/- 15 vs. 25 +/- 2 microU/ml, P less than 0.05). Total glucose disposal was lower, though not significantly so, after the 60-h fast (2.6 +/- 0.4 vs. 5.4 +/- 1.3 mg/kg per min, 0.05 less than P less than 0.10), and as with the euglycemic clamp, the splanchnic glucose balance was altered from a basal net release to a net uptake during the clamp (1.3 +/- 0.2 vs. 1.1 +/- 0.2 mg/kg per min). After an overnight fast, splanchnic lactate uptake fell and the arterial lactate concentration rose in response to both hyperglycemia and hyperinsulinemia, whereas these variables were unchanged in the 60-h fasted subjects during both types of clamp studies.

Gut exchange of glucose and lactate in basal state and after oral glucose ingestion in postoperative patients.

Glucose uptake by the intestine and its conversion into 3-carbon compounds in the human intestine in the basal state and after an oral glucose load are not understood. Consequently, we studied the arterial and portal venous concentration differences (A-PV) for glucose and glucogenic substrates in the basal state and 3 h after the ingestion of a 100-g glucose load with the catheter technique. Five patients were studied 3-11 days after surgery for gallbladder disease or cancer of the colon or liver. A-PV for glucose in the basal state was 0.12 +/- 0.02 mM (P less than 0.01), indicating net glucose uptake by extrahepatic splanchnic tissues. No net exchange of lactate or pyruvate was detected, but there was release of alanine and uptake of glutamine. After glucose ingestion, glucose was released by the gut, reflecting absorption of the load (mean A-PV for glucose -2.10 +/- 0.04 mM, P less than 0.01). The arterial glucose concentration rose gradually from 4.6 +/- 0.1 mM before glucose ingestion to a plateau at 9.5 +/- 0.7 mM from 90 to 180 min. Glucose ingestion was accompanied by net lactate and alanine release (A-PV -0.16 +/- 0.06 mM and -48 +/- 7 microM, respectively), whereas A-PV for pyruvate did not change. We conclude that, in postoperative patients, there is a significant net glucose uptake by the gastrointestinal tract in the basal state. Glucose ingestion is accompanied by a small release of lactate and alanine from the intestine. However, the estimated net gut formation of lactate and alanine can play only a minor role in the disposal of an oral glucose load.

Effects of captopril on hepatic venous pressure and blood flow in patients with liver cirrhosis.

To examine the possible contribution of the renin-angiotensin-aldosterone system to portal hypertension in patients with cirrhosis of the liver, seven such patients were studied with the hepatic venous catheterization technique, in the basal state, and after the intake of 12.5 to 25 mg of captopril. Hepatic venous wedge pressure was 22 +/- 2 mm Hg in the basal state and fell to 19 to 20 mm Hg at 45 to 90 minutes after the administration of captopril (P less than 0.05 to 0.01). Wedge to free hepatic venous pressure difference (basal 14 +/- 2 mm Hg) remained unchanged after captopril, and estimated hepatic blood flow was unaltered. Small but significant reductions in arterial blood pressures were seen after the administration of captopril. Aldosterone concentrations decreased whereas renin activity tended to increase after captopril. It is concluded that captopril inhibits the renin-angiotensin system in patients with cirrhosis of the liver, but fails significantly to decrease portal venous pressure. Captopril is thus unlikely to favorably influence the incidence of bleeding in these patients.

Splanchnic metabolism of amino acids in healthy subjects: effect of 60 hours of fasting.

Brief starvation is accompanied by decreased circulating levels of most amino acids, which has been attributed to an increased splanchnic uptake of amino acids, primarily alanine, for gluconeogenesis. However, quantitative data on splanchnic exchange of amino acids and gluconeogenic precursors is lacking. Consequently, arterial concentrations and splanchnic exchange of whole blood amino acids, ketone bodies, glucose, and gluconeogenic precursors were measured in 16 prolonged fasted (60 to 64 hours) and 15 overnight fasted (12 to 14 hours) healthy, nonobese subjects. After the 60-hour fast net splanchnic glucose production decreased by 41% to 0.31 +/- 0.02 mumol/L (P less than .001), whereas the splanchnic uptake of gluconeogenic precursors increased and could account for the total glucose output. Net splanchnic uptake of taurine, threonine, serine, glycine, lysine, histidine, and arginine rose significantly in response to fasting (P less than .05 to .01) due to increased splanchnic fractional extraction. Although the splanchnic fractional extraction of alanine was augmented by 40% (P less than .001), net splanchnic uptake was not influenced by fasting. Total net splanchnic uptake of amino acids increased by 68%, from 231 +/- 44 mumol/min in the postabsorptive state to 388 +/- 63 mumol/min (mean +/- SEM) (P less than .05) in the 60-hour fasted state. However, only one half of this rise was accounted for by gluconeogenic amino acids.

Influence of vasoactive intestinal polypeptide (VIP) on splanchnic and central hemodynamics in healthy subjects.

The influence of VIP, a potent vasodilator, on central hemodynamics, splanchnic blood flow and glucose metabolism was studied in six healthy subjects. Teflon catheters were inserted into an artery, a femoral vein and a right-sided hepatic vein. A Swan-Ganz catheter was introduced percutaneously and its tip placed in the pulmonary artery. Determinations of cardiac output, systemic, pulmonary arterial and hepatic venous pressures as well as splanchnic blood flow were made in the basal state and at the end of two consecutive 45 min periods of VIP infusion at 5 and 10 ng/kg/min, respectively. Arterial blood samples for analysis of glucose, FFA, insulin and glucagon were drawn at timed intervals. VIP infusion at 5 ng/kg/min resulted in an increase in cardiac output (55%) and heart rate (25%) as well as a reduction in mean systemic arterial pressure (15%) and vascular resistance (45%). With the higher rate of VIP infusion heart rate tended to rise further while cardiac output and arterial pressure remained unchanged. At 15 min after the end of VIP infusion the above variables had returned to basal levels. Splanchnic blood flow and free hepatic venous pressure did not change significantly. Arterial concentrations of glucose, FFA, insulin and glucagon increased during VIP infusion. At 15 min after the end of infusion the glucose levels were still significantly higher than basal (20%). Net splanchnic glucose output did not change in response to VIP infusion. It is concluded that VIP exerts a potent vasodilatory effect resulting in augmented cardiac output and lowered systemic blood pressure and vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of insulin on peripheral uptake of branched chain amino acids in the 60-hour fasted state.

The influence of insulin on branched chain amino acid (BCAA) metabolism was investigated in healthy subjects faster for 60-64 h, using the euglycemic insulin clamp technique and hepatic venous catheterization. As compared to the postabsorptive state, fasting resulted in a 50-80% decrease in glucose disposal during the clamps, indicating insulin resistance. However, the arterial concentrations of BCAA, which were increased by 200-220% after the fast, decreased to a similar extent during hyperinsulinemia, regardless of the fasting situation. The splanchnic exchange of BCAA was unaltered both in response to fasting itself and to fasting and hyperinsulinemia. The results suggest that insulin resistance during fasting does not influence BCAA metabolism. Furthermore, the changes in BCAA concentrations after a prolonged fast are due to altered peripheral metabolism of BCAA.

Infusion of ornithine-alpha-ketoglutarate in healthy subjects: effects on protein metabolism.

Infusion of ornithine-alpha-ketoglutarate (Ornicetil) has been suggested to improve nitrogen balance in trauma patients. Whether this anticatabolic effect is localised to the liver or to skeletal muscle is as yet unknown. Consequently, the splanchnic and leg exchange of amino acids, urea and ammonia were measured in seven healthy non-obese subjects in the basal state and during infusion of ornithine-alpha-ketoglutarate at a rate of 28 mg/min for 150 min. The results demonstrate a six-fold rise in arterial ornithine and an increased uptake by both splanchnic and leg tissues during infusion. The splanchnic uptake of threonine and lysine also increased, while no other alterations were seen in leg amino acid exchange. The arterial urea concentration decreased slightly (-6%, P<0.01) during the infusion in spite of an unchanged urea production from the liver. The ammonia concentration fell by 20% (P<0.05), while glycerol and ketone body concentrations did not change significantly. It is concluded that intravenous infusion of ornithine-alpha-ketoglutarate in healthy subjects does not significantly influence hepatic or skeletal muscle protein metabolism.

Influence of beta blockade on branched chain amino acid concentrations in cirrhosis.

Cirrhosis of the liver is typically accompanied by low plasma levels of the three branched chain amino acids (BCAA). These patients also demonstrate increased concentrations of several hormones such as insulin, glucagon and catecholamines. Catecholamines have been shown to influence the plasma levels of amino acids in healthy subjects and diabetics. In the present study, amino acid concentrations were investigated before and up to 3 hours after beta blockade (Inderal, 40-80 mg, n = 10) or fasting (n = 8) in cirrhotic patients. In the basal state the patients had low levels of all three BCAA, as compared with healthy subjects. Norepinephrine was more than 3 times as high in the patients (3.65 +/- 0.6 vs. 0.84 +/- 0.08 nmol/l, p < 0.01) while epinephrine was only slightly raised (0.43 +/- 0.1 vs. 0.25 +/- 0.06 nmol/l, NS). Significant correlations were observed between the concentrations of norepinephrine and individual as well as the sum of the three BCAA (r = 0.43-0.62, p < 0.05-0.001), while no correlation was observed between the BCAAs and epinephrine or insulin. Three hours after beta blockade the concentrations of leucine (basal: 74 +/- 6, 180 min: 89 +/- 6 mumol/l, p < 0.05) and valine (basal: 110 +/- 10, 180 min: 132 +/- 11 mumol/l, p < 0.01) had increased significantly. A similar tendency was observed for isoleucine. No changes were observed after prolonged fasting. The results suggest that catecholamines, primarily norepinephrine, might contribute to the low levels of BCAA in cirrhotics.

The influence of a long-acting somatostatin analogue on splanchnic haemodynamics and metabolism in healthy subjects and patients with liver cirrhosis.

The influence of a long-acting somatostatin octapeptide analogue (SMS 201-995) on splanchnic circulation and metabolism has been studied in healthy subjects and in patients with liver cirrhosis. In healthy subjects doses of 5, 10, 50, or 100 micrograms SMS and in the cirrhotic patients 25 micrograms SMS were infused intravenously during 1 h. Measurements were obtained before, during, and for 1 h after SMS infusion. SMS infusion in healthy subjects resulted in a 25-35% reduction in hepatic blood flow. This effect was largely independent of the dose used. Splanchnic oxygen uptake was unchanged before and during SMS infusion. Insulin and glucagon levels fell markedly in response to SMS administration, and the blood concentration and splanchnic output of glucose decreased transiently. Patients with liver cirrhosis responded to SMS infusion similarly to the healthy subjects. Hepatic blood flow decreased by 25-35% and remained suppressed for at least 1 h after infusion. Wedge hepatic venous pressure was 18 +/- 2 mm Hg in the basal state and decreased progressively during and after SMS infusion (60 min after infusion, 15 +/- 2 mm Hg; P less than 0.01). The marked hyperinsulinaemia and hyperglucagonaemia seen in the basal state decreased significantly during SMS administration. As in the case of the controls, blood concentration and splanchnic output of glucose fell transiently during and after SMS infusion. It is concluded that SMS exerts a marked and prolonged suppressive effect on hepatic blood flow in both healthy subjects and patients with liver cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)