Clinical Areas

Clinical areas


  • Pneumonia Open or Close

    Pneumonia is a lung infection that can potentially be serious. If it occurs in the context of a hospital, it is called nosocomial pneumonia (NP); otherwise it is a community-acquired pneumonia (CAP). The incidence of pneumonia is estimated to be between 1.5‰ and 14.0‰. This incidence is more frequent in children < 5 years and adults > 65 years.

    Typically, cough, bloody or purulent sputum appear, associated with chest pain and shortness of breath, with high fever, chills and a general ill feeling. Quickly, the picture can worsen and lead to severe sepsis, septic shock or acute respiratory distress syndrome.

    The first dose of antibiotics should be given as soon as possible. In severe sepsis or septic shock, the time to the first dose is strongly associated with a reduction in mortality. Between 7% and 12% of patients who are admitted into hospital for pneumonia are readmitted within 30 days.

    The mortality rate of out-hospital patients is < 1%, and 4-18% for in-hospital patients. The rate can reach 50% in intensive care unit (ICU) patients

    Blood tests can provide information about the inflammatory state, the associated organ damage, and the severity of the disease (National Clinical Guideline Centre).

    • Pro-adrenomedullin, prohormone forms of atrial natriuretic peptide, cortisol, procalcitonin (PCT), copeptin, and C-reactive protein (CRP) are identified biomarkers able to predict mortality.
    • Serial testing of PCT levels may be a successful strategy to monitor the clinical course, adjust the duration of antibiotic therapy and identify non-responders in severe infections.
    • Near-to-patient CRP testing may help to reduce antibiotic prescription in patients with non-severe pneumonia.

    As a lung endothelial cell response to inflammation, blood endocan has been investigated in the context of pneumonia. Kao et al showed that CAP patients,

    • when admitted to emergency room, had higher plasma concentrations of endocan than controls [2.03 ± 1.88 ng/mL (n=82), 0.91 ± 0.38 ng/mL (n=82), p < 0.001].
    • following antibiotic treatment, plasma endocan normalizes [1.04 ± 0.72 ng/mL (n=82); p < 0.001].
    • plasma endocan correlates with the clinical severity scores: PSI (r = 0.554, p < 0.001), CURB-65 (r = 0.510, p < 0.001), and APACHE II (r = 0.447, p < 0.001).

    Significance

    • Plasma endocan may play a role in the diagnosis and clinical assessment of CAP, which could potentially guide the development of treatment strategies.
  • Respiratory failure Open or Close

    Respiratory failure or acute respiratory distress syndrome (ARDS) is defined as an acute hypoxemia (PaO2/FiO2 < 300) and the presence of bilateral pulmonary infiltrates on chest radiograph not due to congestive heart failure or fluid overload (ARDS Definition Task Force).

    In most Western countries, the incidence of ARDS is estimated between 1.5 to 75 cases per 100,000. The major cause of ARDS is pneumonia in 55 to 75% of cases. Other causes are extrapulmonary, mainly severe sepsis, polytrauma or surgery.

    ARDS develops from 1 to 7 days after patients enter the healthcare system.

    Despite improved care and therapies, the morbidity and mortality of ARDS remain high. Death occurs in 30 to 40% of cases. Furthermore, only 34% of survivors are well enough to be discharged directly home, while remaining patients require complementary care for cognitive abnormalities, weakness, depression, or post-traumatic stress disorder.

    Over the past 10 years, the idea has gradually gained ground that care procedures for patients with ARDS, especially those including ventilator management, could be an aggravating factor of this disease, with an increase in mortality as a direct consequence. This subsequently led to the development of protective lung ventilation strategies for patients, which are now widely used in intensive care units (ICUs).

    The effectiveness of such protective lung ventilation strategies, proven by randomised clinical trials, led to the idea that the early application of such strategies could prevent the onset or, at least, reduce the severity of ARDS in high-risk patients. Such a preventive approach has been the subject of many current clinical studies concerning not only ventilatory strategies, but also certain drug treatments. There are thus many significant clinical needs in this respect.

    In clinical practice, such preventive strategies mean being able to predict with good probability the patient at risk. Yet clinical research in this area is hampered by the inability to predict the onset or worsening of ARDS, leading to increase considerably the size of cohorts of patients to be included in a study.

    Endocan, is an anti-inflammatory molecule produced by pulmonary endothelial cells and released into the circulation in response to inflammation. Blood endocan levels increase during pneumonia, severe sepsis or polytrauma, and this increase associates with no ARDS occurence and reciprocally:

    • Mikkelsen et al observed that low blood endocan at ICU admission in severe polytrauma patients were found in those who develop ARDS within 72h.
    • Palud et al obtained identical results in a cohort of septic shock patients where low blood endocan at ICU admission (< 3.55 ng / mL) are observed in patients who ARDS occurs 48-72h later.
    • Ioakeimidou et al confirmed among 175 septic patients, those who develop ARDS during ICU stay exhibited the lowest blood endocan at admission. Moreover the authors suggest that endocan can be usefull to monitor sepsis worsening or improvement during ICU stay.

    All these studies points out an interesting decisional value for low blood endocan (present cutoff < 3.55 ng/mL with PPV > 80%). Basically, a low blood endocan can be interpreted as an unsufficient lung protection against inflammation, and thus requires anti-inflammatory strategies starting before occurence of ARDS. 

    This concept has been yet confirmed for the systemic inflammatory response syndrome (SIRS) event following cardiovascular surgery (Stoppelkamp et al), and digestive graft versus host disease following bone marrow allograft (Lindas et al).

    Significance

    Application of endocan in ICU admission can have many advantages:

    • It early identifies patients at high risk of ARDS, who could benefit from specific preventive therapeutic strategies.
    • It increases the chances of patient survival or quality of life by acting when the pathophysiological processes are still reversible.
    • It reduces ICU costs (e.g., reduced ventilation times, length of stay) and post-resuscitation care (e.g., shorter duration of rehabilitation).
  • Hepatocellular carcinoma Open or Close

    Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide and one of the leading causes of death in patients with cirrhosis. The incidence of HCC in the United States has doubled over the past 2 decades and is anticipated to continue increasing over the next 20 years owing to the growing number of patients with advanced hepatitis C virus and/or nonalcoholic steatohepatitis.

    Only 46% of HCC cases are diagnosed at an early stage and most do not receive curative therapy.

    Patients with an ultrasound mass of 1 cm or larger or an AFP level > 20 ng/mL should be evaluated with CT or dynamic contrast-enhanced MRI. Liver biopsy is usually reserved for patients with undetermined lesions on cross-sectional imaging, corresponding to 1/3 of patients with HCC (Singal et al).

    Tests for HCC biomarkers might increase rates of early tumor detection. The use of AFP in combination with ultrasound increased the sensitivity of early detection of HCC from 32% to 63%. New biomarkers, including AFPL3, des carboxy prothrombin, GP73, and osteopontin, are being evaluated for early HCC detection.

    Liver resection may be considered the primary treatment modality in patients with HCC in the absence of or well compensated cirrhosis. However, resection is usually contraindicated in patients with advanced liver disease, replaced by locoregional therapies (Dhir et al).

    Endocan is a circulating biomarker overexpressed by tumor endothelial cells in response to angiogenic factors. Several authors described association between endocan expression in HCC and tumor agressiveness

    • Nault et al assessed the prognostic value of serum endocan, in 295 patients with alcoholic cirrhosis among them 58 with early HCC, and 67 with advanced HCC. High levels of serum endocan (>5 ng/mL) were independently associated with death [HR, 2.84; 95% confidence interval (CI,) 1.18-6.84; P = 0.02], and with greater risk of tumor recurrence (P = 0.025) in patients treated by radiofrequency ablation.
    • Ziol et al assessed the expression of endocan in 150 needle biopsy HCC samples obtained just before percutaneous ablation. Endocan expression by HCC stromal endothelial cells was observed in 58 patients (40%) and was associated with higher serum AFP levels, larger tumor, and predicts independently early recurrence as well as serum bilirubin, or serum AFP.
    • Calderaro J et al. assessed correlations between endocan expression and satellite nodules and microvascular invasion in 182 surgically resected HCC. Endocan was expressed in stromal endothelial cells from 54% HCC. The others cases were strictly negative. The endocan positive HCC correlates with microvascular invasion (p=0.0073), and the presence of satellite nodules (p<0.0001).
    • Villa E et al identified fast growing HCC by the five-gene risk signature (ROC AUC=0.961 (p<0.0001)) from HCC biopsies. Interestingly, all these genes have roles in endothelial cell migration, angiogenesis and blood vessel morphogenesis, among which endocan is one of the strongest expressed genes.

    Significance

    • Both transcriptomic and proteomic endocan signatures can convergently predict the growth rate of HCC in individual patient.
    • Decisional tree for HCC treatment might benefit from endocan evaluation in blood, biopsy, and resected tumor.
    • Tissue and serum endocan is an easily assessable prognostic biomarker of overall survival in alcoholic cirrhosis with and without hepatocellular carcinoma.
  • Lung cancer Open or Close

    Lung cancer arises from the cells of the respiratory epithelium and can be divided into two broad categories. Small cell lung cancer (SCLC) is a highly malignant tumor derived from cells exhibiting neuroendocrine characteristics and accounts for 15% of lung cancer cases. Non–small cell lung cancer (NSCLC), which accounts for the remaining 85% of cases, is further divided into 3 major pathologic subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma by itself accounts for 38% of all lung cancer cases, with squamous cell carcinoma accounting for 20% and large cell carcinoma accounting for 3%.

    With an estimated 239,320 new cases of lung cancer in the United States in 2010, lung cancer is the leading cause of cancer death in the US (161,250 in 2010) and around the world. The median age at diagnosis for cancer of the lung and bronchus as 71 years.

    Surgery, radiotherapy, chemotherapy, and targeted therapies are all used to treat lung cancer. Lung cancer is associated with good prognosis if diagnosed at an early stage, when surgery is most effective. However, for advanced disease, where surgery is contraindicated, targeted therapies that block signalling pathways associated with tumour growth and suppression can be proposed. Among them, therapies targeting tumor angiogenesis, such as anti-VEGF antibodies (bevacizumab), are a major step in the treatment of NSCLC.

    Endocan : a marker of tumor endothelium in carcinomas. Endocan is a proteoglycan produced and secreted specifically by endothelial cells in response to angiogenic factors like VEGF or FGF-2 (Scherpereel et al). Endocan is exclusively expressed at the tumor endothelium in various carcinomas from kidney, colon or liver. 

    Endocan in lung cancer Several studies made on more than 200 patients pointed out that endocan secretion rates are higher.

    • Borczuk et al first found esm1 gene overexpressed, and belonging to the bad prognosis gene profile.
    • Grigoriu et al demonstrated a specific endocan expression at the tumor vessels of NSCLC, where endocan and VEGF mRNA correlate. Grigoriu et al also found that serum endocan levels, as well as tumor, node, and metastasis status, were correlated with both survival and time to tumor progression. Using a cutoff value of 1.3 ng/mL, median survival was 6 months (95% CI: 1-11 months, p = 0.016) for the high endocan group [endocan median: 3.78 ng/mL (1.62-4.99 ng/mL)], versus 33 months (95% CI: 9-56 months) for the low endocan group [endocan median: 1 ng/mL (0.55-1.2 ng/mL). Similar results were obtained when considering the time to tumor progression.
    • Wallyn et al designed a pilot study including a group of 24 patients with stage IIIB-IV non-squamous NSCLC who had a chemotherapy combined with bevacizumab (bevacizumab group), and a second group  who had a similar chemotherapy but without bevacizumab (control group, n = 32). Endocan was evaluated with CT-scan before (T0) and after 1 cycle (T1). An initial high endocan level appeared as a marker of bad prognosis (overall survival) (HR=1.469 [1.120-1.925]; p=0.005) using a cut-off value of 0.72 ng/mL (HR=2.276 [1.074-4.82]; p=0.032). Moreover, in the bevacizumab group, a significant decrease of endocan level between T0 and T1 was a marker of good prognosis (HR=0.141 [0.022-0.889]; p=0.037).

    Significance

    • Endocan appears to have a significant prognostic value both in terms of survival and in terms of response to anti-angiogenic therapies
  • Gastric cancer Open or Close

    Gastric cancer (GC) grows from the gastric mucosa. According to Globocan 2012, there were about 952 000 new cases of GC in the world, making it the 5th most common malignancy.

    Helicobacter pylori has been identified as a carcinogen, accounting for 60–70% of GC globally and eradication is a potential preventive measure.

    The curative treatment is based on the partial or total gastrectomy with lymph node dissection. Adjuvant chemotherapy can be proposed. The 5-year survival is 60 to 80% in the absence of lymph node involvement and 15% if the nodes are invaded.

    Endocan is an endothelial cell specific molecule produced and secreted in response to angiogenic factors such as VEGF or FGF-2. Endocan is exclusively overexpressed at the tumor endothelium in various solid tumors like lung, renal, colon cancer, and hepatocellular carcinoma (HCC). In lung cancer, and HCC, blood levels are associated with poor prognosis.

    In GC, endocan is also expressed by intra-tumor vessels. However, endocan was also detected within the tumoral cells. Such a detection in tumoral cells is only found in severe forms of glioblastoma (Maurage et al).

    • Liu et al found a tumoral cell expression in 67/159 GC (42%).
    • Zhang et al showed 44/53 GC positive for endocan, among them 16 strongly positive.
    • The latest study, from Zhao et al, found a tumoral cell endocan expression in 64/255 patients (25%).

    The compiled data indicate a prevalence of 37% CG (175/467) positive for tumor cell expression of endocan.

    A marker of tumor aggressiveness

    • Liu et al showed that endocan positive (+) GC is associated with the presence of microvascular invasion (p = 0.0057) and poor prognosis (p = 0.012), but not with TNM stage or histologic type.
    • In the series of Zhao et al, endocan+ GC is associated with poor prognosis (p = 0.017), but not with gender, histological type, or TNM stage.

    The association between endocan+ GC and poor prognosis is similar to that found in HCC where endocan+ biopsies also exhibit criteria of tumor aggressiveness: microvascular invasion, satellite nodules, early recurrent, reduced survival.

    Increased blood endocan in GC An increase of circulating endocan rate in GC has also been demonstrated in 2 studies (Lv et al, Sun et al). The values of sensitivity and specificity varies from 74% to 98% and from 51% to 89% respectively. Nevertheless, they appear above the diagnostic values of CEA and CA19-9. The relationship between positivity and histological elevation of circulating endocan is not established.

    Endocan is involved in human gastric cell proliferation. Specific inhibition of endocan by siRNA in the human MGC-803 cell line, inhibits cellular proliferation (Zhao et al). These data support the protumoral role of endocan previously identified.

    • Overexpressed in human cell lines, endocan induces the development of tumor xenografts or accelerates their growth (Scherpereel et al).
    • The angiogenic switch accompanying the passage from a tumor dormancy status to tumor progression is associated with overexpression of 5 genes including endocan (Almog et al).
    • Furthermore, the variable malignancy of tumor clones correlates with the expression level of the endocan gene (Satchi-Feinaro et al).

    The mechanisms of action are still not fully known.

    • A first mechanism of action involves the participation of the glycan chain of endocan as comitogenic factor (Béchard et al, Scherpereel et al).
    • A 2nd mechanism refers to the anti-inflammatory action of endocan which leads to inhibition of the stromal inflammatory response (Béchard et al, Yassine et al).

    Significance

    • Endocan overexpression in GC tissue and in blood from GC patients appears to be a valuable prognostic marker defining a subset of particularly aggressive GC, which may benefit from a differentiated therapeutic strategy
  • Diabetic proliferative retinopathy Open or Close

    The blood vessels supplying the retina may sustain injury as a result of underlying disease such as diabetes and age. The vascular pathologic features can be categorized as proliferation, such as proliferative diabetic retinopathy (PRD), or a combination of proliferation and leakage, as seen in neovascular age-related macular degeneration (AMD). The World Health Organization has identified PRD and AMD as priority eye diseases for the prevention of vision loss in developed countries. The pathologic transformations of the retinal vasculature are associated with increased expression of vascular endothelial growth factor A (VEGF). Furthermore, its inhibition is associated with functional and anatomic improvements in the affected eye.

    Despite uniform treatment of AMD patients, 10–15% do not show any treatment benefit and continue to lose vision. Another 30-40% gain initially, but subsequently loses vision. To date, it is unclear why this happens. However, Predictors of treatment outcomes remain necessary to help in deciding for the best treatment out of several options for an individual patient.

    High amounts of endocan are associated with filopodia of endothelial tip cells involved angiogenesis guidance and motility. Endocan up-regulates endothelial cell migration. Endocan is also found on tip cells in developing mouse retinas or oxygen-induced experimental retinopathy (Strasser et al, Recchia et al, Del Toro et al).

    Shalwala et al revealed an elevation of vitreous endocan levels in PDR. Vitreous endocan from 24 PDR patients had a mean level of 1.92 ng/mL, while 26 non-diabetic patients had a mean of 0.78 ng/mL (p<0.001). Serum endocan concentrations did not differ significantly between the PDR (1.67 ng/mL) and non-diabetic (1.71 ng/mL) groups (p=0.72).

    A more recent study refined the value of vitreous endocan. Abu el Asrar et al compared vitreous biomarkers of angiogenesis including soluble VE-cadherin, soluble endoglin, VEGF, and endocan in 44 PDR versus 29 non-diabetic patients. All these biomarkers are higher in PDR patients than in non-diabetic patients, but only endocan is able to distinguish active PDR (n=23) from inactive PDR (n=21) (p<0.001).

    Significance

    • Vitreous endocan is released locally by endothelial cells, and relates to endothelial cell activation by VEGF.
    • Endocan is an easily measurable vitreous angiogenic biomarker, and a potential option for refining indication and guiding anti-angiogenic therapy.
  • Preeclampsia Open or Close

    Preeclampsia is a condition of pregnancy characterized by high blood pressure occurring at the end of the second quarter (after 20 weeks of gestation). It is estimated that about 5% of pregnancies are accompanied by preeclampsia. Each year in France, 40,000 women are affected by this disease. In most cases, monitoring avoids the serious complications. But in 10% cases, a severe form occurs. The only way to save the mother is then to extract the fetus and placenta, whatever the fetus already viable or not.

    High blood pressure > 140 mm Hg and proteinuria > 300 mg / 24h define clinically preeclampsia, and are the first warning signs. These manifestations can be accompanied by symptoms such as violent headache, visual disturbances, abdominal pain, vomiting or oliguria. Massive edema may appear and be accompanied by a sudden weight gain.

    Rapid development in the 3rd trimester of pregnancy. After the appearance of the first symptoms, preeclampsia can progress rapidly and requires care. It can cause serious complications in 10% cases and then engages the vital prognosis of the mother and her fetus. These complications are eclampsia, cerebral hemorrhage, renal failure, placental abruption, HELLP syndrome, characterized by an increase in the destruction of red blood cells in the liver (hemolysis), an elevated liver enzymes, and a thrombopenia, which increases the risk of bleeding.

    The origin of the disease is a placental dysfunction. It becomes clinically symptomatic in the second part of the pregnancy, a period in which fetal growth requires considerable blood flow. Imperfect placenta allows the continuation of the pregnancy, but an increased release of placental factors in maternal blood is observed. The consequences in the mother are numerous: action on maternal blood vessels, resulting in increased blood pressure, abnormal blood clotting, production of inflammatory molecules (C-reactive protein, TNF) or deficient immunological tolerance to the fetus.

    The management of preeclampsia requires hospitalization allowing an extremely regular monitoring of the mother. The issue of the treatment is to prolong the pregnancy as long as possible in order to free the child for an acceptable period of its development.

    To find early markers of preeclampsia

    Early administration of low dose aspirin before 16 weeks of pregnancy reduces by 2 to 4 the risk of preeclampsia. After this period, it is no longer effective. If the routine use of aspirin to pregnant women in early pregnancy does not seem possible, its use in women at risk may be appropriate.

    But if doctors had very early markers of the disease, to learn from the first weeks of pregnancy if a woman will develop the disease or not, that strategy would take its meaning. Therefore discover such markers is one of the major challenges of the coming years, to strengthen the monitoring of women and prevent further complications.

    Currently, several markers detectable from 20 weeks of pregnancy are investigating: placental growth factor, soluble endoglin or soluble receptor of VEGF. But the aim should be to identify more early markers, detectable before 16 weeks of pregnancy.

    Endocan: a very early marker of endothelial dysfunction in preeclampsia

    Shuitmaker et al showed that pregnant women with low plasma endocan levels at 12-16 weeks gestation predicted an increased risk of early severe preeclampsia. Indeed, the plasma endocan rates between the 12th and 16th week of gestation differ between groups: 1.86 ng / mL ± 0.86 ng / mL in normal pregnancy group (n = 23), 0.41 ± 0.36 ng / mL in the early preeclampsia (n = 11, p <0.01).

    Significance

    • The decrease of plasma endocan levels between the 12th and 16th week of amenorrhea in women who will develop preeclampsia early, gives endocan prognostic value which can determine the risk in pregnant woman develop early preeclampsia from the 12th week.
  • Cirrhosis Open or Close

    Alcoholic liver disease (ALD) is one of the major chronic liver diseases worldwide. ALD encompasses a range of disorders including simple steatosis, inflammation, fibrosis, and cirrhosis. The prognosis of ALD is variable, with nearly 100% survival in mild cases as compared to high short-term mortality among the most severe cases. Various predictive models have been developed to aid in the assessment of prognosis and to guide treatment, including Maddrey's discriminant function, the model for end-stage liver disease, the Glasgow score, the ABIC score, and the Lille model.

    Liver biopsy is the « gold standard » method used to estimate the prognosis and helps in decision making regarding therapy; however, this procedure is invasive, painful, with rare but serious complications. To overcome liver biopsy, several non invasive methods have been developed: transient elastography (FibroScan, Echosens, Paris, France), LiverMultiscan, a MRI-based marker (Perspectum Diagnostics, Oxford, UK), and FibroTest, a serum surrogate fibrosis marker (Biopredictive, Paris, France).

    Interestingly, in a french series of 170 patients with alcoholic cirrhosis without HCC, the mean level of circulating endocan (mean ± SD, 4.8 ± 3.1 ng/mL) is higher than no cirrhotic control population (0.77 ± 0.18 ng/mL) (Nault et al).

    • Serum endocan >5 ng/mL is associated with strong risk of death.
    • In multivariate analysis, high serum endocan (> 5 ng/mL) is independently associated with death, but not with HCC.

    Two recent japonese series confirmed the French report. In this series, serum endocan levels were found somewhat higher in LC patients, than in healthy subjects (Toshikuni et al, Ozaki et al).

    However, a recent turkish series obtained controversial results showing lower endocan levels in chronic liver diseases, mainly refering to an unusual normal value of 8.95 ± 15.05 ng/mL (mean ± SD, Tok et al).

    Significance

    • Endocan is an anti-inflammatory molecule which limits the leukocyte diapedesis through binding to LFA-1. Endocan is produced specifically by non sinusoidal endothelial cells.
    • In the context of ALD, serum endocan may be immunosuppressive, may favour infection and/or may reflect the risk of infection during the course of ALD.
    • Serum endocan is an easily assessable prognostic biomarker, and an option for refining the prognosis in addition to the classical Child-Pugh score, and possibly for guiding treatment.
  • Pituitary adenoma Open or Close

    Prevalence of pituitary adenomas is estimated to be 2.87–3.90/100,000. While histologically benign, 1/3 of all pituitary adenomas invade the cavernous and sphenoid sinuses, and/or recur following surgical ablation.

    To reduce the rate of recurrence, postoperative treatments may be proposed, such as somatostatin or dopamine analogs in growth hormone (GH) and prolactin adenomas, radiotherapy in nonfunctioning adenomas, and recently temozolomide therapy in carcinomas or aggressive tumors with multiple recurrences.

    To date, there is no histological consensus marker predictive of recurrence. Angiogenic factors are candidate markers, among them endocan represents one emerging candidate for predicting recurrence.

    Cornelius et al found:

    • in normal pituitaries (n=18), no endocan expression in vessels but sporadic expression in isolated endocrine cells;
    • in adenoma tissues,
      • an endothelial endocan expression in 52/107 cases;
      • a subset of pituitary tumoral cell endocan expression (30%: in 32/107), involving from 1% to 100% of the tumor cells, more often observed in ACTH adenomas (38%: 8/21) than in nonfunctioning adenomas (25%: 8/32) or GH adenomas (15%: 7/48). No IR was observed in prolactinoma (0%: 0/6).
    • A positive association between endothelial endocan expression and recurrence (p = 0.0009), tumor size (p = 0.0012), and average mitosis count (p = 0.02).
    • No association between tumoral cell endocan expression and tumor size, mitosis count and Ki-67.

    Matano et al found:

    • endocan expression in all vascular endothelial cells, but in very few tumor cells;
    • a correlation between % endocan relative to CD34 and Knosp grade (Spearman’s r-value = 0.651, p<0.0001);
    • the % endocan relative to CD34 (2.0 to 73.1%) did not differ significantly between GH-omas (23.5 ± 21.18 %), NF-omas (33.47 ± 17.61 %), PRL-omas (25.83 ± 12.22 %), ACTH-omas (16.25 ± 12.61 %), and TSH-omas (56.0 %; Kruskal–Wallis test, p = 0.661).

    Miao et al found in 66 pituitary adenomas:

    • endocan mostly expressed in tumor cells and a few vascular endothelial cells;
    • positive correlation of endocan expression in tumor cells with Knosp tumor grade (p<0.001, Spearman’s r = 0.616). In comparison, endocan expression in endothelial cells was unrelated to Knosp tumor grades (p<0.05, Spearman’s r = 0.208).

    Cai et al found:

    • endocan expression in the majority of tumor vessels.
    • Tumor expression of endocan is sporadic
    • endocan-microvessel density of bromocriptine-resistant prolactinomas was significantly higher than that of bromocriptine-sensitive prolactinomas [47.9 ± 11.6 (n = 8), vs 13.1 ± 2.8 (n = 17), p = 0.0006], indicating that endocan is a bromocriptine resistance-related gene.

    Endocan silencing in GH3 and MMQ cells induces:

    • suppression of viability,
    • increased sensitivity to bromocriptine treatment.
    • down-regulation of angiogenesis-associated genes (VEGFR2, FGF2).

    Significance

    • The immunolabeling of endocan in endothelial cells and in TCs may be a relevant marker of aggressive behavior in pituitary tumors.
    • Endocan is a bromocriptine resistance-related gene able to promote angiogenesis and tumor cells growth of prolactinomas.