Практические Рекомендации По Лекарственному Лечению Рака Коры Надпочечника
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The relationship between urine steroid metabolome and the course of adrenocortical cancer
Background: Adrenocortical cancer (ACC) is a rare aggressive and rapidly metastatic disease. Early diagnosis of the disease and its metastatic stage are important for the choice of treatment strategy. Evaluation of urine steroid profiles (USP) by gas chromatography-mass spectrometry (GC-MS) is a highly sensitive and specific biomarker instrument that allows for differentiation between benign and malignant tumor and obvious prospects for the diagnosis in patients with adrenal incidentalomas. In our previous study we have found no difference in urine excretion of tetrahydro-11-deoxycortisole (THS), 5-ene-pregnenes and 3,16,20-pregnenetriol/3,16,20-pregnenetriol ratio (3,16,20-dP3/3,16,20-dP3) in patients with metastatic ACC in early postoperative period, compared to pre-operative parameters. We did not account for the disease stage and primary tumor size in that study in ACC patients. Aim: To identify specific characteristics of urine steroid metabolome by GC-MS in ACC IIV stages patients before surgery in order to detect early signs of metastases and the relationship between adrenal steroidogenesis abnormalities and disease stages. Materials and methods: We performed a retrospective analysis of the data from the study of USP in 59 ACC stage I-IV patients with L. M. Weiss score 3, according to pathological examination of the surgical samples. The Cushing syndrome was diagnosed by immunochemistry assay in 28 (47.6%) of ACC patients. Tumor staging was done according to ENSAT based on the results of imaging and postoperative histological reports. ENSAT I was diagnosed in 8 patients, ENSAT II in 26, ENSAT III in 14, ENSAT IV in 11 ACC patients. The control group included 28 healthy donors. USP was assessed by GC-MS before surgery with a gas chromatography-mass-spectrometer Shimadzu GCMS-ТQ8050. Results: The first variant of urinary steroid metabolome abnormalities with increased excretion of dehydroepiandrosterone (DHEA) and THS was found in 10 (90.9%) of ENSAT IV ACC patients and in 20 (50%) of ENSAT II + III patients. The fourth USP variant was characterized by no difference in androgen and THS urinary excretion from that in healthy individuals and was found in ACC ENSAT I patients. Only in ACC ENSAT I patients, there was an increase of pregnanediol (P2) urinary excretion and of the P2/pregnanetriol (P3) ratio, compared to those in healthy donors. ROC-analysis demonstrated that ТНS 867 mcg/24 hours, 3,16,20-dP3 300 mcg/24 hours and 3,16,20-dP3/3,16,20-dP3 1.6 cut-offs had a sensitivity and specificity of 100% for preoperative identification of ENSAT IV ACC patients before surgery and for early diagnosis of ACC metastases. There were positive correlations between 16-oxo-androstenediol, THS, and progestogens, as well as a negative correlation between 3,16,20-dP3/3,16,20-dP3 ratio and the disease stage. Conclusion: Urinary excretion of THS, DHEA and its metabolites, P2, 5-ene-pregnenes, and 3,16,20-dP3/3,16,20-dP3 ratio determined by GC-MS are important biochemical markers of ACC stages and can be used as ACC metastases prognostic markers.
The relationship between urine steroid metabolome and the course of adrenocortical cancer
Background: Adrenocortical cancer (ACC) is a rare aggressive and rapidly metastatic disease. Early diagnosis of the disease and its metastatic stage are important for the choice of treatment strategy. Evaluation of urine steroid profiles (USP) by gas chromatography-mass spectrometry (GC-MS) is a highly sensitive and specific biomarker instrument that allows for differentiation between benign and malignant tumor and obvious prospects for the diagnosis in patients with adrenal incidentalomas. In our previous study we have found no difference in urine excretion of tetrahydro-11-deoxycortisole (THS), 5-ene-pregnenes and 3,16,20-pregnenetriol/3,16,20-pregnenetriol ratio (3,16,20-dP3/3,16,20-dP3) in patients with metastatic ACC in early postoperative period, compared to pre-operative parameters. We did not account for the disease stage and primary tumor size in that study in ACC patients. Aim: To identify specific characteristics of urine steroid metabolome by GC-MS in ACC IIV stages patients before surgery in order to detect early signs of metastases and the relationship between adrenal steroidogenesis abnormalities and disease stages. Materials and methods: We performed a retrospective analysis of the data from the study of USP in 59 ACC stage I-IV patients with L. M. Weiss score 3, according to pathological examination of the surgical samples. The Cushing syndrome was diagnosed by immunochemistry assay in 28 (47.6%) of ACC patients. Tumor staging was done according to ENSAT based on the results of imaging and postoperative histological reports. ENSAT I was diagnosed in 8 patients, ENSAT II in 26, ENSAT III in 14, ENSAT IV in 11 ACC patients. The control group included 28 healthy donors. USP was assessed by GC-MS before surgery with a gas chromatography-mass-spectrometer Shimadzu GCMS-ТQ8050. Results: The first variant of urinary steroid metabolome abnormalities with increased excretion of dehydroepiandrosterone (DHEA) and THS was found in 10 (90.9%) of ENSAT IV ACC patients and in 20 (50%) of ENSAT II + III patients. The fourth USP variant was characterized by no difference in androgen and THS urinary excretion from that in healthy individuals and was found in ACC ENSAT I patients. Only in ACC ENSAT I patients, there was an increase of pregnanediol (P2) urinary excretion and of the P2/pregnanetriol (P3) ratio, compared to those in healthy donors. ROC-analysis demonstrated that ТНS 867 mcg/24 hours, 3,16,20-dP3 300 mcg/24 hours and 3,16,20-dP3/3,16,20-dP3 1.6 cut-offs had a sensitivity and specificity of 100% for preoperative identification of ENSAT IV ACC patients before surgery and for early diagnosis of ACC metastases. There were positive correlations between 16-oxo-androstenediol, THS, and progestogens, as well as a negative correlation between 3,16,20-dP3/3,16,20-dP3 ratio and the disease stage. Conclusion: Urinary excretion of THS, DHEA and its metabolites, P2, 5-ene-pregnenes, and 3,16,20-dP3/3,16,20-dP3 ratio determined by GC-MS are important biochemical markers of ACC stages and can be used as ACC metastases prognostic markers.
Biomarkers for assessment of the polychemotherapy results in patients with adrenocortical cancer based on gas chromatography-mass spectrometry studies of urine steroid profiles
Background: The effectiveness of polychemotherapy (PCT) for adrenocortical cancer (ACC) is assessed by imaging tests with the RECIST 1.1 criteria. However, the presence of subclinical tumor foci does not allow for an objective measurement of the true tumor burden. As shown previously, postoperative assessment of the steroid metabolome by gas chromatography-mass spectrometry (GCMS) in ACC patients makes it possible to identify early signs of adrenal steroidogenesis abnormalities and of the recurrence of adrenocortical carcinoma. Aim: To identify biomarkers of response to PCT by GCMS study of the urine steroid profile in ACC patients after surgical resection of the tumor. Materials and methods: Urine steroid profiles were studied by GCMS (Shimadzu GCMS-TQ8050 gas chromatography-mass spectrometer) in 30 ACC patients (stages II, III and IV) after surgery and first line (combination of etoposide, doxorubicin and cisplatin with daily mitotane) and second line (gemcitabine combined with capecitabine and mitotane) PCT. The control group included 25 patients with hormonally inactive adenomas. Results: The response to PCT according to RECIST 1.1 criteria was obtained in 23 patients (Group 1, responders) and in 7 patients ACC progressed under PCT (Group 2, non-responders). In the responders, the urinary excretion of etiocholanolone, pregnanediol and pregnanetriol was lower than in the control group. The non-responders had higher urinary excretion of androgens, progestogens and tetrahydro-11-deoxycortisol (THS), compared to the responders and the control group. The patients with ACC progression under PCT had an increase in 3β,16,20-pregnenetriol (3β,16,20-dP3) levels and a decrease of the 3α,16,20-dP3/3β,16,20-dP3 ratio, compared to those in the PCT responders. The threshold values for urinary excretion of dehydroepiandrosterone (DHEA, ≤ 469 mcg/24h; AUC = 1.0), THS (≤ 223 mcg/24h; AUC = 1.0), and 3β,16,20-dP3 (≤ 130 mcg/24h; AUC = 0.986), as well as the 3α,16,20-dP3/3β,16,20-dP3 ratio (≥ 2.13; AUC = 1.0) had 100% sensitivity and specificity for the assessment of the PCT effectiveness. Conclusion: Different urine steroid profiles were obtained by GCMS in the ACC patients after PCT with and without treatment response. The 100% sensitivity and specificity of the threshold values for urinary excretion of DHEA, THS, 3β,16,20-dP3 and the 3α,16,20-dP3/3β,16,20-dP3 ratio for the assessment of PCT results indicate the potential to use these parameters as biomarkers of response or progression of the disease in the monitoring of PCT effects in ACC patients.
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