Increased oxidized LDL cholesterol levels in peritoneal fluid of women with advanced-stage endometriosis

Summary Introduction: Proinflammatory and prooxidative environment in the peritoneal cavity may be involved in the pathogenesis of endometriosis. Imbalance between reactive oxygen species levels and the antioxidant capacity leads to oxidation of low-density lipoproteins (LDL). The importance of oxidized LDL (Ox-LDL) in the development of atherosclerosis is well recognized. Aim: The aim of our study was to evaluate for the presence of ox-LDL in the peritoneal fluid (PF) of women with and without endometriosis. Material and Methods: A total of 60 women who underwent laparoscopy were divided into groups: endometriosis sufferers with minimal to mild (n 20) and moderate to severe (n 20) stages, and the reference group (n 20) with functional follicle ovarian cysts. Oxidized LDL levels were determined in the PF using enzyme immunoassay. Results: Oxidized LDL levels were detectable in all peritoneal fluid samples. Significantly increased levels of ox-LDL were observed in PF of women with stage III/IV endometriosis compared to the reference group (p=0.03). However, peritoneal fluid ox-LDL concentrations did not differ significantly between patients with minimal/mild and women with moderate/severe stage of the disease (p=0.2). No significant difference in the PF ox-LDL concentrations was also found between women with stage I/II endometriosis and patients with follicle cysts (p=0.3). Conclusions: Increased peritoneal fluid ox-LDL levels observed in women with advanced-stage endometriosis suggest the important role of oxidative stress in the pathogenesis of the disease

Evaluation of the intracellular expression of interleukin 17 in patients with ovarian cancer

Knowledge of the role of interleukin 17 (IL-17) has led to the identification of new subpopulation of T helper lymphocytes – Th17 and T cytotoxic lymphocytes secreting IL-17 (Tc17). An increasing amount of attention is paid to their role in anti-tumor immunity. Aim: The aim of this study was to evaluate the percentage of peripheral blood, peritoneal fluid and cancer tissue CD4+ and CD8+ T lymphocytes producing IL-17 in patients with ovarian cancer. Material and Methods: Forty patients operated due to advanced ovarian carcinoma and twenty-four patients with functional follicle ovarian cysts were recruited. Peripheral blood, peritoneal fluid and cancer tissue mononuclear cells from ovarian cancer patients were stimulated for 4 hours ex vivo with phorbol myristate acetate (PMA) (50ng/ml) and ionomycin(1μg/ml). The percentage of CD4+ and CD8+ T cells producing IL-17 was measured using flow cytometry. Results: CD4+ and CD8+ T lymphocytes producing IL-17 were detected in the peripheral blood, peritoneal fluid and cancer tissue of ovarian cancer patients. The percentage of CD4+ T cells producing IL-17 was higher in the peripheral blood, peritoneal fluid and cancer tissue when compared to CD8+/IL17+ T cells. The percentage of CD4+/IL-17+ was significantly higher in cancer tissue compared to T cells derived form peripheral blood. There was no difference in the percentage of CD4+/IL-17 + T cells between peripheral blood and peritoneal fluid and peritoneal fluid and cancer tissue of ovarian cancer patients. There was no difference in the percentage of CD8+/IL-17+ T lymphocytes in the peripheral blood, peritoneal fluid and cancer tissue in patients suffering from ovarian cancer. Conclusions: Increased percentage of CD4+/IL-17+ and CD8+/IL-17+ T cells in cancer tissue indicates that these cells are accumulated in ovarian cancer microenvironment

Lymphocyte activation markers in patients with ovarian cancer

Objectives: The aim of this study was to evaluate the phenotype and T cell activation markers: CD69, CD25 and HLA - DR in the peripheral blood and tumor tissue of ovarian cancer patients. Material and methods: The study group consisted of 26 patients operated due to ovarian cancer (FIGO IIb - IV). Mononuclear immune cells were isolated from peripheral blood and ovarian cancer tissue. To obtain peripheral blood lymphocytes, blood was collected into heparinized tubes and diluted 1:1 with PBS, then layered on Gradisol L and centrifuged 20 minutes at 2800 rpm. Mononuclear cells were washed twice with PBS and labeled with monoclonal antibodies. A small piece of tumor tissue (about 1cm3) was fragmented with a surgical blade. Minced tissue was suspended in PBS and layered on Gradisol L for mononuclear cells isolation. To assess the phenotype and activation status of peripheral blood and tumor infiltrating lymphocytes, we used FACS Canto cytometer and monoclonal antibodies conjugated with fluorochromes: anti-CD3-FITC, anti-CD4-PECy5, anti-CD8-APC, anti-CD25-PE, anti-CD69-PE-Cy7, anti-HLA-DR-PE-Cy7. Statistical analysis was performed using the Statistica 5.0 and Wilcoxon test. Results: In all cases we detected T helper CD3+CD4+ and cytotoxic CD3+CD8+ T lymphocytes in both blood samples and tumor tissues. We observed no statistically significant difference in the percentage of CD3+ CD4+ cells among the mononuclear cells present in peripheral blood and tumor tissue. The percentage of CD3+CD8+ cytotoxic T lymphocytes was higher among mononuclear cells isolated from the tumor tissue. The percentage of CD3+ lymphocytes expressing the very early activation marker CD69 was significantly higher among tumor infiltrating lymphocytes compared with peripheral blood lymphocytes. Similarly, the percentages of CD3+CD4+CD69+ T helper lymphocytes and CD3+CD8+CD69+ cytotoxic T lymphocytes were significantly higher on lymphocytes isolated from tumor tissue when compared to blood. The expression of an early activation marker – CD25 was significantly higher on the CD3+ and CD3+CD8+ peripheral blood lymphocytes compared to CD3+ and CD3+CD8+ tumor infiltrating lymphocytes. There were no statistically important differences between the percentages of, isolated from blood and tissue, CD3+CD4+ T helper lymphocytes. The expression of the late activation marker - HLA-DR was significantly higher on CD3+ lymphocytes isolated from tumor tissue compared with peripheral blood. Similarly, the percentages of CD3+CD4+ lymphocytes and CD3+CD8+ cytotoxic T cells expressing HLA-DR were significantly higher among tumor infiltrating lymphocytes when compared to peripheral blood ones. Conclusions: T cells obtained from ovarian cancer tissues are activated cells. The state of T cell activation may be the result of direct contact of these cells with tumor antigens. The low expression of CD25 may suggest abnormal clonal expansion of antigen-specific lymphocytes

Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial

Background: Ion channel inhibition may offer protection against coronavirus disease 2019 (COVID-19). Inflammation and reduced platelet count occur during COVID-19 but precise quantification of risk thresholds is unclear. The Recov ery-SIRIO study aimed to assess clinical effects of amiodarone and verapamil and to relate patient phenotypes to outcomes. Methods: RECOVERY-SIRIO is a multicenter open-label 1:1:1 investigator-initiated randomized trial with blinded event adjudication. A sample of 804 symptomatic hospitalized nonintensive-care COVID-19 patients, follow-up for 28 days was initially planned. Results: The trial was stopped when a total of 215 patients had been randomized to amiodarone (n = 71), verapamil (n = 72) or standard care alone (n = 72). At 15 days, the hazard ratio (hazard ratio [HR], 95% confidence interval [CI]) for clinical improvement was 0.77 (0.52–1.14) with amiodarone and 0.97 (0.81–1.17) with verapamil as compared to usual care. Clinically relevant associations were found between mortality or lack of clinical improvement and higher peak C-reactive protein (CRP) levels or nadir platelet count at 7, 10 and 15 days. Mortality rate increased by 73% every 5 mg/dL increment in peak CRP (HR 1.73, 95% CI 1.27–2.37) and was two-fold higher for every decrement of 100 units in nadir platelet count (HR 2.19, 95% CI 1.37–3.51). By cluster analysis, thresholds of 5 mg/dL for peak CRP and 187 × 103/mcL for nadir platelet count identified the phenogroup at greatest risk of dying. Conclusions: In this randomized trial, neither amiodarone nor verapamil were found to significantly accelerate short-term clinical improvement. Peak CRP and nadir platelet counts were associated with increased mortality both in isolation and by cluster analysis

Pancreatic neuroendocrine neoplasms — management guidelines (recommended by the Polish Network of Neuroendocrine Tumours)

W niniejszej publikacji przedstawiono zaktualizowane zalecenia dotyczące diagnostyczno-terapeutycznego postępowania w nowo­tworach neuroendokrynnych trzustki (PNEN) zaproponowane przez Polską Sieć Guzów Neuroendokrynnych. Zawierają one nowe dane uzyskane w latach 2013–2016, które albo potwierdziły wcześniejsze wytyczne, albo doprowadziły do zmian lub utworzenia dodatkowych zaleceń. W diagnostyce duże znaczenie mają badania biochemiczne, obrazowe (anatomiczne i czynnościowe), jak również rozpoznanie histopatologiczne, które determinuje postępowanie z chorymi na PNEN i musi być potwierdzone badaniem immunohistochemicznym. Terapia PNEN wymaga współpracy wielodyscyplinarnej grupy doświadczonych specjalistów zajmujących się nowotworami neuroendokrynnymi. Leczenie chirurgiczne jest podstawową metodą postępowania w wielu przypadkach. Dalsza terapia wymaga wielokierunkowego działania, dlatego omówiono zasady bioterapii, leczenia radioizotopowego, celowanego leczenia molekularnego oraz chemioterapii.This article presents updated diagnostic and therapeutic guidelines for the management of pancreatic neuroendocrine tumours (PNEN), proposed by the Polish Network of Neuroendocrine Tumours. The guidelines contain new data received in the years 2013–2016, which confirm previous recommendations, and have led to modification of previous guidelines or have resulted in the formulation of new guidelines. Biochemical and imaging (anatomical and functional) tests are of great importance in diagnostics, as well as histopathological diagnosis to determine the management of PNEN patients, but they must be confirmed by an immunohistochemical examination. PNEN therapy requires collaboration among the members a multidisciplinary team of specialists experienced in the management of these neoplasms. Surgery is the basic form of treatment in many cases. Further therapy requires a multidirectional procedure; therefore, the rules of biotherapy, peptide receptor radionuclide therapy, molecular targeted therapy, and chemotherapy are discussed

Colorectal neuroendocrine neoplasms — management guidelines (recommended by the Polish Network of Neuroendocrine Tumours)

Nowotwory/guzy neuroendokrynne (NEN/NET) jelita grubego są rozpoznawane coraz częściej, szczególnie guzy odbytnicy. To zjawisko jest najprawdopodobniej związane z powszechnym wykonywaniem kolonoskopii przesiewowych. Coraz więcej przemawia za tym, że NEN odbytnicy i okrężnicy to dwie odrębne choroby. Nowotwory neuroendokrynne odbytnicy są najczęściej zmianami niewielkich roz­miarów, cechują się niskim lub umiarkowanym stopniem złośliwości histologicznej, dobrym rokowaniem i większość z nich kwalifikuje się do leczenia endoskopowego. Natomiast NEN okrężnicy to często nowotwory agresywne, niskozróżnicowane, o złej lub niepewnej prognozie, wymagające operacji. Zasady postępowania z tymi chorymi stale się zmieniają. Opierając się na najnowszym piśmiennictwie oraz ustaleniach wypracowanych na spotkaniu roboczym Polskiej Sieci Guzów Neuroendokrynnych (grudzień 2016 r.) w pracy uzupełniono i uaktualniono dane i wytyczne postępowania dotyczące NEN jelita grubego, opublikowane w Endokrynologii Polskiej 2013; 64: 494–504.Neuroendocrine neoplasms/tumours (NENs/NETs) of the large intestine are detected increasingly often, especially rectal tumours, which is probably associated with the widespread use of screening colonoscopy. There is a growing body of evidence supporting the thesis that the NENs of the rectum and the NENs of the colon are two different diseases. Rectal NENs are usually small lesions, of low to moderate histological malignancy, associated with good prognosis, and most may be treated endoscopically. NENs of the colon, however, are often aggressive, poorly differentiated, associated with a poor or uncer­tain prognosis, and require surgical treatment. The management guidelines regarding these groups of patients are constantly changing. On the basis of the recent literature data and conclusions reached by the working meeting of the Polish Network of Neuroendocrine Tumours (December 2016), this study completes and updates the data and management guidelines regarding colorectal NENs published in Endokrynologia Polska 2013; 64: 358–368.

Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours)

Postęp w diagnostyce i leczeniu nowotworów neuroendokrynnych (NEN), opublikowanie wyników nowych randomizowanych badań klinicznych oraz powstanie nowych zaleceń ENETS skłoniło ekspertów skupionych w Polskiej Sieci Guzów Neuroendokrynnych do uaktualnienia opublikowanych w 2013 roku zaleceń dotyczących postępowania w nowotworach neuroendokrynnych. W niniejszym artykule przedstawiono zalecenia ogólne postępowania w NEN będące wynikiem ustaleń ekspertów uczestniczących w III Konferencji Okrągłego Stołu pt. „Diagnostyka i leczenie nowotworów neuroendokrynnych układu pokarmowego: rekomendacje polskie w świetle aktualnych zaleceń europejskich”, która odbyła się w Żelechowie koło Warszawy w grudniu 2016 roku. Korzystając z bogatego doświadczenia ośrodków zajmujących się tymi nowotworami, mamy nadzieję, że udało nam się wypracować najbardziej optymalny sposób postępowania u chorych z NEN, uwzględniający najnowsze osiągnięcia medycyny, który będzie mógł być skutecznie realizowany w naszym kraju. W kolejnych częściach tego opracowania przedstawiono zasady postępowania w: NEN żołądka i dwunastnicy (z uwzględnieniem gastrinoma), trzustki; jelita cienkiego i wyrostka robaczkowego oraz jelita grubego.Progress in the diagnostics and therapy of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN), the published results of new randomised clinical trials, and the new guidelines issued by the European Neuroendocrine Tumour Society (ENETS) have led the Polish Network of Neuroendocrine Tumours to update the 2013 guidelines regarding management of these neoplasms. We present the general recommendations for the management of NENs, developed by experts during the Third Round Table Conference — Diagnostics and therapy of gastro-entero-pancreatic neuroendocrine neoplasms: Polish recommendations in view of current European recommenda­tions, which took place in December 2016 in Żelechów near Warsaw. Drawing from the extensive experience of centres dealing with this type of neoplasms, we hope that we have managed to develop the optimal management system, applying the most recent achievements in the field of medicine, for these patients, and that it can be implemented effectively in Poland. These management guidelines have been arranged in the following order: gastric and duodenal NENs (including gastrinoma); pancreatic NENs; NENs of the small intestine and appendix, and colorectal NENs

Gastroduodenal neuroendocrine neoplasms, including gastrinoma — management guidelines (recommended by the Polish Network of Neuroendocrine Tumours)

W niniejszej pracy przedstawiono uaktualnione zalecenia grupy ekspertów Polskiej Sieci Guzów Neuroendokrynnych dotyczące zasad postępowania w nowotworach neuroendokrynnych żołądka i dwunastnicy z uwzględnieniem gastrinoma. Omówiono epidemiologię, patogenezę i obraz kliniczny tych nowotworów. Przedstawiono zalecenia dotyczące zasad postępowania diagnostycznego, z uwzględ­nieniem diagnostyki biochemicznej, histopatologicznej oraz lokalizacyjnej. Przedstawiono także zasady postępowania terapeutycznego, w tym leczenie endoskopowe i chirurgiczne, oraz omówiono możliwości leczenia farmakologicznego i radioizotopowego. Przedstawiono także zalecenia odnośnie do monitorowania chorych z NEN żołądka, dwunastnicy z uwzględnieniem gastrinoma.This paper presents the updated Polish Neuroendocrine Tumour Network expert panel recommendations on the management of neuroendocrine neoplasms (NENs) of the stomach and duodenum, including gastrinoma. The recommendations discuss the epidemiology, pathogenesis, and clinical presentation of these tumours as well as their diagnosis, including biochemical, histopathological, and localisation diagnoses. The principles of treatment are discussed, including endoscopic, surgical, pharmacological, and radionuclide treatments. Finally, there are also recommendations on patient monitoring

Neuroendocrine neoplasms of the small intestine and appendix — management guidelines (recommended by the Polish Network of Neuroendocrine Tumours)

W pracy przedstawiono uaktualnione polskie zalecenia postępowania z chorymi na nowotwory neuroendokrynne (NEN) jelita cienkiego i wyrostka robaczkowego. Jelito cienkie, a w szczególności jelito kręte, należą do najczęstszych lokalizacji tych nowotworów. Większość z nich to nowotwory wysokozróżnicowane i wolno rosnące; rzadko są to raki neuroendokrynne. Ich objawy mogą być nietypowe, a rozpoznanie opóźnione albo przypadkowe. Zapalenie wyrostka robaczkowego jest najczęściej pierwszą manifestacją NEN o tym umiej­scowieniu. Typowe objawy zespołu rakowiaka występują u około 20–30% pacjentów z NEN jelita cienkiego z przerzutami odległymi. Jedną z głównych przyczyn zgonu u pacjentów z zespołem rakowiaka są choroby serca — rakowiakowa choroba serca. W diagnostyce laboratoryjnej najbardziej przydatne jest oznaczenie stężenia chromograniny A, badanie stężenia kwasu 5-hydroksyindolooctowego jest pomocne w diagnostyce zespołu rakowiaka. W obrazowaniu stosuje się ultrasonografię, tomografię komputerową, rezonans magnetyczny, kolonoskopię, wideoendoskopię kapsułkową, enteroskopię dwubalonową, scyntygrafię receptorów somatostatynowych. Szczegółowe badanie histologiczne jest kluczowe dla właściwego rozpoznania i leczenia chorych z NEN jelita cienkiego i wyrostka robaczkowego. Leczeniem z wyboru jest postępowanie chirurgiczne, radykalne lub paliatywne. W leczeniu farmakologicznym czynnych i nieczyn­nych hormonalnie NEN jelita cienkiego i wyrostka robaczkowego podstawowe znaczenie mają długodziałające analogi somatostatyny. U chorych z NET jelita cienkiego w okresie uogólnienia z progresją w trakcie leczenia SSA, z wysoką ekspresją receptorów somatostatynowych należy rozważyć w pierwszej kolejności leczenie radioizotopowe, a następnie terapie celowane — ewerolimus. Po wyczerpaniu powyższych dostępnych terapii w wybranych przypadkach można rozważyć chemioterapię. Przedstawiono także zalecenia odnośnie do monitorowania chorych.This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20–30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his­tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio­isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered

Neuroendocrine neoplasms of the small intestine and the appendix - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours).

This study presents the revised Polish guidelines regarding the management of patients suffering from neuroendocrine neoplasms (NENs) of the small intestine and appendix. The small intestine, especially the ileum, is the most common location for these neoplasms. Most are well differentiated and slow growing. Their symptoms may be atypical, which can result in delayed or accidental diagnosis. Appendicitis is usually the first manifestation of NEN in this location. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of patients suffering from small intestinal NENs with distant metastases. The main cause of death in patients with carcinoid syndrome is carcinoid heart disease. The most useful laboratory test is the determination of chromogranin A, while concentration of 5-hydroxyindoleacetic acid is helpful in the diagnostics of carcinoid syndrome. For visualisation, ultrasound, computed tomography, magnetic resonance imaging, colonoscopy, video capsule endoscopy, double-balloon enteroscopy, and somatostatin receptor scintigraphy may be used. A detailed his-tological report is crucial for the proper diagnostics and therapy of NENs of the small intestine and appendix. The treatment of choice is surgical management, either radical or palliative. The pharmacological treatment of the hormonally active and non-active small intestinal NENs as well as NENs of the appendix is based on long-acting somatostatin analogues. In patients with generalised NENs of the small intestine in progress during the SSA treatment, with good expression of somatostatin receptors, the first-line treatment should be radio-isotope therapy, while targeted therapies, such as everolimus, should be considered afterwards. When the above therapies are exhausted, in certain cases chemotherapy may be considered