Immunohistochemical biomarkers are prognostic relevant in addition to the ESMO-ESGO-ESTRO risk classification in endometrial cancer.

OBJECTIVE: Pre-operative immunohistochemical (IHC) biomarkers are not incorporated in endometrial cancer (EC) risk classification. We aim to investigate the added prognostic relevance of IHC biomarkers to the ESMO-ESGO-ESTRO risk classification and lymph node (LN) status in EC. METHODS: Retrospective multicenter study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), analyzing pre-operative IHC expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER) and progesterone receptor (PR), and relate to ESMO-ESGO-ESTRO risk groups, LN status and outcome. RESULTS: A total of 763 EC patients were included with a median follow-up of 5.5-years. Abnormal IHC expression was present for p53 in 112 (14.7%), L1CAM in 79 (10.4%), ER- in 76 (10.0%), and PR- in 138 (18.1%) patients. Abnormal expression of p53/L1CAM/ER/PR was significantly related with higher risk classification groups, and combined associated with the worst outcome within the 'high and advanced/metastatic' risk group. In multivariate analysis p53-abn, ER/PR- and ESMO-ESGO-ESTRO 'high and advanced/metastatic' were independently associated with reduced disease-specific survival (DSS). Patients with abnormal IHC expression and lymph node metastasis (LNM) had the worst outcome. Patients with LNM and normal IHC expression had comparable outcome with patients without LNM and abnormal IHC expression. CONCLUSION: The use of pre-operative IHC biomarkers has important prognostic relevance in addition to the ESMO-ESGO-ESTRO risk classification and in addition to LN status. For daily clinical practice, p53/L1CAM/ER/PR expression could serve as indicator for surgical staging and refine selective adjuvant treatment by incorporation into the ESMO-ESGO-ESTRO risk classification.

The role of hormonal therapy in patients with uterine carcinoma.

OBJECTIVE: The aim of the study was to describe the role of hormonal therapy in the treatment of malignant uterine tumors, indications, the effect of the treatment and to verify its safety in our study cohort. We also present an overview of recent studies on that topic. DESIGN: Unicentric retrospective observational study and review of recent literature. SETTING: Department of Obstetrics and Gynecology, Masaryk University, University Hospital Brno. METHODS: The results of recent relevant studies and reviews published in English until December 2017 were used for the review. The publications were searched using the PubMed server. All patients diagnosed in our oncogynecological center between 2010 and 2016 and who were treated hormonally - either in primary therapy or in relapse settings, were included in our study. We were interested in age, BMI, stage of disease, histological type and grade of tumor, occurrence of adverse effects, duration of survival, reasons for choosing hormonal therapy. Medroxyprogesterone-acetate or megestrol-acetate was used in the treatment. RESULTS: Between 2010 and 2016, 415 malignant tumors of the uterus were diagnosed in our oncology center. Recurrence of the disease occurred in 31 patients (8%), on average 16 months after primary treatment. Primary hormonal therapy was used in only 19 patients (5%), mostly because of contraindications of another treatment due to high age, comorbidities or obesity. Median age of patients was 83 years, mean BMI 41, median survival of patients who died was 8 months. Five patients (16%) were treated hormonally for the recurrence. Median survival from diagnosis of recurrence was 20 months. One patient (4%) experienced partial pulmonary embolism. CONCLUSION: Hormonal therapy plays an irreplaceable role in uterine cancer patients, especially in primary non-operable patients, in treatment of a relapse, or in a fertility-sparing procedure. This treatment option is safe, with minimal adverse effects.

[Current FIGO staging classification for cancer of ovary, fallopian tube and peritoneum]. / Novinky ve FIGO stagingu karcinomu ovaria, tuby a peritonea.

INTRODUCTION: Pelvic high-grade serous carcinomas (HGSCs) include carcinoma of ovary, fallopian tube, and peritoneum. Five-year survival, irrespective of the stage, is between 35-40%. Most patients are diagnosed in advanced stages of the disease. The new revised and expanded dualistic model of ovarian carcinogenesis shows that type II tumors are composed for the most part of high-grade serous ovarian carcinoma, carcinosarcoma, undifferentiated carcinoma and can be further subdivided into morphologic and molecular subtypes. Many type II carcinomas develop from STIC predominantly in the distal portion of the fallopian tube and it is very likely the point of the origin of a significant subset of the pelvic high-grade serous carcinomas. OBJECTIVE: To provide an overview of major changes in our understanding of the origin of ovarian cancer, that led to the revision of FIGO (International Federation of Gynecology and Obstetrics) classification and its unification for the ovary, fallopian tube and peritoneum. We summarize the new classification, main changes compared to the former one and their clinical impact. METHODS: For this review, we have used the results of studies and review articles on the subject published in English up to October 2016. They were identified through a search of literature using PubMed, MEDLINE-Ovid, Scopus and Cochrane Library with the keywords ("serous tubal intraepithelial carcinoma" or "high-grade serous ovarian carcinoma" or "FIGO ovarian cancer staging 2014"). We retrieved and assessed potentially relevant studies, and checked the reference lists of all papers of interest to identify additional relevant publications. CONCLUSION: The origin of most cases of pelvic HGSC (carcinoma of ovary, the fallopian tube, and peritoneum) is expected in the fallopian tube epithelium. The main changes in the revised FIGO classification for extrauterine pelvic serous carcinomas were subdivision of stages IC, III and IV and elimination of the stage IIC, based on new knowledge and prognostic data. A prerequisite for the proper treatment of patients is to perform adequate surgical and pathological staging, including determining the grade of carcinoma. These factors, coupled with appropriately performed operation with zero postoperative residuum (R0), are the most important prognostic factors for patients with carcinoma of the ovary, fallopian tube, and peritoneum.

[Postoperative administration of octreotide to reduce lymphorrhea, lymphocele, lymphedema and lymphatic ascites after lymphadenectomy in gynecological malignancies]. / Vliv pooperacního podání oktreotidu na redukci lymforey a následne vzniku lymfocyst, lymfedému a lymfatického ascitu po lymfadenektomii u gynekologických malignit.

INTRODUCTION: Octreotide is a synthetic analogue of natural somatostatin. Octreotide effect on lymphorrhea reduction in gynecological malignancies has only been assessed in case studies. DESIGN: Original work. SETTING: Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Faculty of Medicine, Masaryk University and University Hospital Brno. METHODS: In 2014 there was a prospective, randomized, one-institution study. Patients underwent surgery including pelvic or pelvic and paraaortic lymphadenectomy for cervical, uterine and ovarian cancer. The informed consent was signed. Octreotide was evaluated in relation to diagnosis, surgery (laparoscopy versus laparotomy), pelvic and/or paraaortic lymphadenectomy, number of removed lymph nodes and their positivity, neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant radiotherapy, albumin, BMI, number of days with drains postoperatively, number of days in hospital, blood loss during surgery, time of surgery, total number of drains placed into abdominal cavity. In follow up period, within 1 year after surgery, we searched for lymphocele, lymph-edema of lower extremities and lymphatic ascites in relation to lymphorrhea. RESULTS: 44 patients (9 cervical, 19 endometrial and 16 ovarian cancer) were enrolled in two statistically comparable randomized groups. "Octreotide group", which paradoxically showed lymphorrhea of 4082 ml on average, (without 1992 ml, p = 0.001), needed drainage for more days (p = 0.001). The diagnosis had no influence on lymphorrhea in both groups (p = 0.966). The neoadjuvant chemotherapy was administered (p = 0.026), the more lymph nodes were removed (p = 0.018), the more days the drainage was in place (p < 0.001), the bigger the lymphorrhea; no relationship between lymphorrhea and age (p = 0.631), albumin level (p = 0.584), BMI ( p= 0.966) or number of positive nodes (p = 0.259), length of surgery (p = 0.206), blood loss (p = 0.494). Nor lymphedema (p = 0.404), nor lymphocele (p = 0.086), correlated with postoperative lymphorrhea. Lymphatic ascites was associated with lymphorrhea (p = 0.048). CONCLUSION: Octreotide did not reduce lymphorrhea and the incidence of lymphocele, lymphedema of lower extremities and lymphatic ascites within one year of follow-up period after surgery. According to our results, we do not recommend to administer the octreotide in oncogynecological patients after pelvic and/or paraaortic lymphadenectomy.

Molecular testing of endometrial carcinoma in real-world clinical practice.

BACKGROUND: Molecular classification has brought significant changes in the management of endometrial cancer (EC). In this article, we aim to analyze our first experience with an implementation of molecular testing into daily clinical practice. MATERIALS AND METHODS: In all newly diagnosed EC, the status of mismatch repair (MMR) and p53 proteins has been evaluated immunohistochemically as a part of the routine histopathological examination since May 2021. In tumors that do not meet clinical criteria for a low risk and those with MMR deficiency or p53 mutation, the molecular genetic testing of the POLE gene is performed as well. Recommendations for adjuvant treatment or follow-up are subsequently made based on the risk of recurrence. Genetic counselling is proposed to all patients with MMR-deficient tumors or family history of cancer. RESULTS: A total of 85 patients with newly diagnosed EC between May 2021 and May 2022 were enrolled in the analysis. The median age was 66 years. The results of molecular testing were as follows: 22 (26%) MMR-deficient, 8 (9%) p53-mutated and none POLE-ultramutated of those 40 tumors with performed POLE sequencing. A total of 46 (51%) patient had a low risk, 2 (2%) intermediate, 14 (16%) high-intermediate and 20 (24%) patients had a high risk of recurrence. Advanced or metastatic diseases were diagnosed in 6 (7%) patients. The median time between surgery and multidisciplinary tumor board decision was 21 days (8-36). A total of 76 (90%) patients underwent the whole treatment plan according to the recurrence risk. At the time of analysis, the results of genetic testing were available in 18 patients and revealed 4 (22%) carriers of a pathogenic variant in any of the genes associated with Lynch syndrome. CONCLUSION: Molecular testing combining immunohistochemical analyses of MMR and p53 proteins in all newly diagnosed EC patients with sequencing analysis of POLE in those with non-low-risk disease is feasible and does not prolong the time needed for treatment decision.

[Somatostatin analogues in the treatment of carcinoid]. / Analoga somatostatinu v lécbe karcinoidu.

The patient--born in 1960, was first diagnosed in 1981 as having malignant carcinoid of the right lung. The disease relapsed in 2002 in a form of distant dissemination. According to tumor histology--atypical carcinoid--this patient was initially treated with palliative systemic chemotherapy, specifically with cisplatin and etoposid. His disease stabilized after administration of 4 cycles of chemotherapy. The treatment was accompanied by protracted toxicity with marked alteration of his general conditions after the 4th cycle. Upon request of his relatives, the patient was referred to Masaryk Memorial Cancer Institute to receive supportive care. His general conditions then stabilized but intermittent episodic abdominal discomfort with occasional vomiting persisted. Due to positive octreoscan, the patient was given somatostatin analogues with a very good and long-term clinical effect. The symptoms disappeared, except a persisting ocular disorder due to periorbital infiltration. The patient state improved allowing further outpatient care. When somatostatin analogues were discontinued, serum chromogranin A rose rapidly and was accompanied by new appearance of symptoms. After re-administering somatostatin analogues the symptoms disappeared and the concentration of serum chromogranin A decreased. The patient has been still (with two 5,5 years interruptions) treated with somatostatin analogues with very good tolerance and clinical effect--at present there are no symptoms of the disease and, according to imaging methods, long-term stabilization continues. This case study illustrates the necessity of cautious and individual approach to the choice of treatment strategy in patients with malignant carcinoid.

Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer.

OBJECTIVES: Development and metastases of colorectal cancer (CRC) are characterized by multiple genetic alterations. MicroRNAs (miRNAs) are endogenously expressed regulatory noncoding RNAs. Previous, mainly preclinical studies showed altered expression levels of several miRNAs in CRC. METHODS: In our study, the expression levels of miR-21, miR-31, miR-143 and miR-145 in 29 primary colorectal carcinomas and 6 non-tumor adjacent tissue specimens were examined by real-time polymerase chain reaction. miRNA expression levels were also correlated with commonly used clinicopath-ologic features of CRC. RESULTS: Expression levels of analyzed miRNAs significantly differed among tumors and adjacent non-tumor tissues: miR-21 (p = 0.0001) and miR-31 (p = 0.0006) were upregulated, and miR-143 (p = 0.011) and miR-145 (p = 0.003) were downregulated in tumors. For the first time, a high expression of miR-21 was associated with lymph node positivity (p = 0.025) and the development of distant metastases (p = 0.009) in CRC patients. Thus, expression of miR-21 correlated with CRC clinical stage (p = 0.032). Furthermore, tumors >50 mm in maximal tumor diameter were characterized by lower expression of miR-143 (p = 0.006) and miR-145 (p = 0.003). We found no correlation between analyzed miRNAs and serum levels of carcinoembryonic antigen. CONCLUSION: Our results suggest possible roles of miR-21, miR-31, miR-143 and miR-145 in CRC.

The ACAT inhibitor VULM1457 significantly reduced production and secretion of adrenomedullin (AM) and down-regulated AM receptors on human hepatoblastic cells.

Acyl-CoA:cholesterol acyltransferase (ACAT) is an important enzyme in the pathways of cholesterol esterification. It has been shown that new ACAT inhibitor 1-(2,6-diisopropyl-phenyl)-3-[4-(4'-nitrophenylthio)phenyl] urea (VULM1457) significantly reduced atherogenic activity in animal experimental atherosclerosis. Proliferative hormone adrenomedullin (AM) has been shown to be released in response to hypoxia, however, its role in cellular protection has remained elusive. The effect of increased local production of AM in cells and resultant down-regulation of AM receptors has not been investigated yet. We hypothesized that increased expression of AM in hypoxic cells was the result of excessive AM production with resultant AM receptor down-regulation, surface-membrane protein degradation and that the new specific ACAT inhibitor would reduce AM induction in hypoxia and thus proliferation of cells. In order to investigate specific cellular AM signaling and protection induced by VULM1457, we characterized specific surface-membrane [125I]AM receptors expressed on cells, evaluated AM secretion (RIA assays), AM mRNA expression in cultured cells (RT-PCR analysis) and proliferation (incorporation of [3H]thymidine) in control, hypoxic and metabolically stressed human hepatoblastoma cell lines exposed to gradually increasing concentrations of VULM1457. The new ACAT inhibitor VULM1457 in concentration 0.03 and 0.1 micromol/l significantly down-regulated specific AM receptors on HepG2 cells, reduced AM secretion of HepG2 cells exposed to hypoxia. These results suggest that VULM1457, as new member of ACAT family of inhibitors could negatively regulate cell proliferation induced by AM, which may correlate with down-regulation of membrane-bound AM receptors on HepG2 cells, and moreover, with the induction and expression of AM in hypoxia.