Exosomal microRNAs as tumor markers in epithelial ovarian cancer.

Specific microRNAs (miRNAs) are packaged in exosomes that regulate processes in tumor development and progression. The current study focuses on the influence of exosomal miRNAs in the pathogenesis of epithelial ovarian cancer (EOC). MiRNA profiles were determined in exosomes from plasma of 106 EOC patients, eight ovarian cystadenoma patients, and 29 healthy women by TaqMan real-time PCR-based miRNA array cards containing 48 different miRNAs. In cell culture experiments, the impact of miR-200b and miR-320 was determined on proliferation and apoptosis of ovarian cancer cell lines. We report that miR-21 (P = 0.0001), miR-100 (P = 0.034), miR-200b (P = 0.008), and miR-320 (P = 0.034) are significantly enriched, whereas miR-16 (P = 0.009), miR-93 (P = 0.014), miR-126 (P = 0.012), and miR-223 (P = 0.029) are underrepresented in exosomes from plasma of EOC patients as compared to those of healthy women. The levels of exosomal miR-23a (P = 0.009, 0.008) and miR-92a (P = 009, 0.034) were lower in ovarian cystadenoma patients than in EOC patients and healthy women, respectively. The exosomal levels of miR-200b correlated with the tumor marker CA125 (P = 0.002) and patient overall survival (P = 0.019). MiR-200b influenced cell proliferation (P = 0.0001) and apoptosis (P < 0.008). Our findings reveal specific exosomal miRNA patterns in EOC and ovarian cystadenoma patients, which are indicative of a role of these miRNAs in the pathogenesis of EOC.

Evaluation of hepatic cystic lesions.

Hepatic cysts are increasingly found as a mere coincidence on abdominal imaging techniques, such as ultrasonography (USG), computed tomography (CT) and magnetic resonance imaging (MRI). These cysts often present a diagnostic challenge. Therefore, we performed a review of the recent literature and developed an evidence-based diagnostic algorithm to guide clinicians in characterising these lesions. Simple cysts are the most common cystic liver disease, and diagnosis is based on typical USG characteristics. Serodiagnostic tests and microbubble contrast-enhanced ultrasound (CEUS) are invaluable in differentiating complicated cysts, echinococcosis and cystadenoma/cystadenocarcinoma when USG, CT and MRI show ambiguous findings. Therefore, serodiagnostic tests and CEUS reduce the need for invasive procedures. Polycystic liver disease (PLD) is arbitrarily defined as the presence of > 20 liver cysts and can present as two distinct genetic disorders: autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (PCLD). Although genetic testing for ADPKD and PCLD is possible, it is rarely performed because it does not affect the therapeutic management of PLD. USG screening of the liver and both kidneys combined with extensive family history taking are the cornerstone of diagnostic decision making in PLD. In conclusion, an amalgamation of these recent advances results in a diagnostic algorithm that facilitates evidence-based clinical decision making.

Hepatobiliary cystadenoma and cystadenocarcinoma: a single center experience.

AIMS AND BACKGROUND: Hepatobiliary cystadenoma and cystadenocarcinoma are rare cystic lesions of the liver. The aim of the study was to discuss the clinical features, diagnostic methods and surgical treatment of hepatobiliary cystadenoma and cystadenocarcinoma in our hospital. METHODS: Six patients with hepatobiliary cystadenomas and four with hepatobiliary cystadenocarcinomas were evaluated. We collected detailed clinical data, and all patients were followed. RESULTS: Three patients of the 6 with cystadenomas and 2 patients of the 4 with cystadenocarcinomas had marked elevation of CA19-9 (average, 707.0 U/ml and 1078.5 U/ml, respectively). CT scan with contrast revealed typical lesions in all 10 cases, i.e., cyst-occupying lesions with separations in the liver. All patients with hepatobiliary cystadenoma were treated by partial hepatectomy. None of them recurred at a mean follow-up of 40 months. Three patients with hepatobiliary cystadenocarcinoma underwent hepatectomy, without recurrence or metastasis at a mean follow-up of 32 months. CONCLUSIONS: Tumor markers (CA19-9) and imaging findings may be helpful for an early diagnosis. Complete resection is still the best choice. Even for hepatobiliary cystadenocarcinoma, considering the low malignant grade, we suggest that for the best prognosis radical excision should be attempted.

A combined blood based gene expression and plasma protein abundance signature for diagnosis of epithelial ovarian cancer--a study of the OVCAD consortium.

BACKGROUND: The immune system is a key player in fighting cancer. Thus, we sought to identify a molecular 'immune response signature' indicating the presence of epithelial ovarian cancer (EOC) and to combine this with a serum protein biomarker panel to increase the specificity and sensitivity for earlier detection of EOC. METHODS: Comparing the expression of 32,000 genes in a leukocytes fraction from 44 EOC patients and 19 controls, three uncorrelated shrunken centroid models were selected, comprised of 7, 14, and 6 genes. A second selection step using RT-qPCR data and significance analysis of microarrays yielded 13 genes (AP2A1, B4GALT1, C1orf63, CCR2, CFP, DIS3, NEAT1, NOXA1, OSM, PAPOLG, PRIC285, ZNF419, and BC037918) which were finally used in 343 samples (90 healthy, six cystadenoma, eight low malignant potential tumor, 19 FIGO I/II, and 220 FIGO III/IV EOC patients). Using new 65 controls and 224 EOC patients (thereof 14 FIGO I/II) the abundances of six plasma proteins (MIF, prolactin, CA125, leptin, osteopondin, and IGF2) was determined and used in combination with the expression values from the 13 genes for diagnosis of EOC. RESULTS: Combined diagnostic models using either each five gene expression and plasma protein abundance values or 13 gene expression and six plasma protein abundance values can discriminate controls from patients with EOC with Receiver Operator Characteristics Area Under the Curve values of 0.998 and bootstrap .632+ validated classification errors of 3.1% and 2.8%, respectively. The sensitivities were 97.8% and 95.6%, respectively, at a set specificity of 99.6%. CONCLUSIONS: The combination of gene expression and plasma protein based blood derived biomarkers in one diagnostic model increases the sensitivity and the specificity significantly. Such a diagnostic test may allow earlier diagnosis of epithelial ovarian cancer.

A new approach for identifying patients with ovarian epithelial neoplasms based on high-resolution mass spectrometry.

We investigated the serum profiles of patients with ovarian neoplasm using high-performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS) to obtain serum "fingerprints" for use in identifying patients with these neoplasms. We used HPLC-HRMS to analyze serum samples from patients with ovarian neoplasms and control subjects. Serum samples from 145 patients were analyzed, including 85 with ovarian epithelial neoplasms. We also compared the results of this serum-fingerprinting approach with the results of the CA-125 test and imaging. Fingerprinting successfully permitted the separation of control patients and patients with ovarian neoplasms. The sensitivity and specificity of the test were between 96% and 100%. When the results of this test were concordant with the results of the CA-125 test, 99% of serum samples were correctly classified as being from a patient with an ovarian neoplasm or with no ovarian neoplasm. We found that a metabolite of molecular weight 472 is the main metabolite in the separation of patients with ovarian neoplasms from control subjects. HPLC-HRMS serum profiling could become a screening test for ovarian neoplasms.

[Adnexal tumor and pregnancy: diagnosis and treatment]. / Tumor anexial y embarazo: diagnóstico y tratamiento.

BACKGROUND: The finding of adnexal masses during pregnancy is an exceptional event. Its reported incidence is less than 5% and most cases resolve spontaneously as the pregnancy progresses. OBJECTIVE: Describe a case series of patients with adnexal mass and pregnancy. MATERIAL AND METHODS: We retrospectively reviewed the medical records of patients who had diagnosis of pregnancy and adnexal over a period of five years. RESULTS: The incidence was 0.22%. The mean age was 26 +/- 7.3 years, mean gestational age was 17 +/- 6.6 weeks. The diagnosis was established by ultrasound (USG) in 95% of cases, 48% had cystic characteristics, the mean diameter of the tumor was 99 +/- 42 mm. Cistectomy was performed during pregnancy or trans-cesarean section in 30% and 58% of patients respectably. The mean tumor size was 118 mm (range 2 a 40 mm), weight 1,370 g (range 10 a 5,800 g). The most frequent histological diagnosis were serous cyst (40%), mature teratoma (28%), mucinous (6%), malignancy (4%). There were not complications related to the surgical procedure. CONCLUSIONS: The USG constitute a safe method for the diagnosis, but the image method with the highest positive predictive value is the MRI. Tumor markers (CA-125, AFP, GCH-B,DHL, ACE), are not useful during pregnancy. If the tumor doesn't achieve surgical criteria the recommended follow up is clinical observation and USG. If surgery is decided, it should be performed between 16 a 23 weeks of pregnancy, and it's recommended to send the tumor to histological diagnosis, in case of malignancy the surgery will continue according to the tumor stage. The time and delivery route will be decided by the obstetrician.

[Various acute phase reactants in different types of proliferative diseases of the uterine appendages].

The authors examined serum in patients with ovarian cancer (OC; a disseminated process), ovarian cystadenoma (OCA), or external endometriosis (EM) before treatment and in apparently healthy females (a control) for the content of some acute-phase proteins and cytokines to clarify the specific features of changes in their concentrations in relation to the type of the proliferative process. It was shown that in OC, there were significant reductions in the levels of alpha2-macroglobulin (MG), plasmin (PL), alpha1-antitrypsin (AT) and statistically significantly increases in the content of lactoferrin (LF), interleukin (IL)-6, IL-8, Ig, and the regulatory transport complex of P--M. In M, the concentrations of AT were lower and those of IL-6, IL-8, and PL-MG were higher (to a lesser degree than those in OC). In OCA, the levels of MG and IgA were increased; those of IL-8 and PL-MG were decreased. The concentrations of interferon and IgM were unchanged in all groups. The findings suggest that difefrent proliferative processes initially provoke a number of changes of varying magnitude and even directions in the serum levels of inflammation reactants, which should be borne in mind when conducting clinical tests in the intraoperative and, probably, postoperative periods.

Is there an indication for initial conservative management of pancreatic cystic lesions?

BACKGROUND: The management of small pancreatic cystic lesions presents a clinical challenge. METHODS: We reviewed our experience with 78 patients who presented with a cystic pancreatic lesion who underwent operative management between 1995 and 2005. Data on cyst characteristics were analyzed in the context of pathologic findings following resection. RESULTS: Among 78 patients, there were 55 (71%) females; median age 63 years. Patients presented with: an incidental finding (48%), pain (40%), acute pancreatitis (4%), other (8%). Operations were distal pancreatectomy (n = 47), pancreaticoduodenectomy (n = 16), and other (n = 15). Most patients had a non-malignant lesion (n = 65, 83%) (mucinous cystadenoma (n = 29), serous cystadenoma (n = 15), IPMN without invasion (n = 8), pseudocyst (n = 8), other benign (n = 5)). Malignant lesions (adenocarcinoma, neuroendocrine tumor, and other) were found in 13 patients (17%). The risk of malignancy increased with size: <3 cm (n = 25), 4%; 3-5 cm (n = 23), 13%; and >5 cm (n = 30), 30%. Pre-operative cyst fluid cytology was performed in 41 patients. The negative predictive value (NPV) of cytology for malignancy was 88% and the positive predictive value (PPV) was 80%. The NPV of CA 19-9 for malignancy was 90%; the PPV was 50%. CONCLUSIONS: Initial conservative management of small cystic pancreatic lesions may be indicated in selected patients.

Serum and tissue LDH levels in patients with breast/gynaecological cancer and benign diseases.

BACKGROUND: Lactate dehydrogenase A (LDHA) is involved in anaerobic glycolysis. In cancer patients, serum total lactate dehydrogenase (LDH) levels are often increased, and the gene for one of its isoenzymes, LDHA, is up-regulated. These features have been linked to poor prognosis in several studies. METHODS: We investigated comparatively the total serum LDH activity and tissue isoenzyme LDH5 and hypoxia-inducible factor 1alpha (HIF1alpha) levels in patients with breast (n = 18) and gynaecological (n = 23) malignancies and benign diseases (n =54). RESULTS: The serum LDH levels were significantly higher in patients with endometrial adenocarcinoma (349 +/- 100 IU/l) and ovarian cystadenocarcinomas (383 +/- 116 IU/l) compared to healthy controls (256 +/- 68 IU/l) (p values 0.01 and 0.006, respectively). This difference did not reach significance in patients with breast cancer (328 +/- 169 IU/l; p = 0.17)). Uterine leiomyoma patients showed intermediate LDH levels (310 +/- 81 IU/l), while patients with breast fibroadenomas and ovarian cystadenomas had LDH serum levels close to carcinomas (308 +/- 60 and 348 +/- 135 IU/l, respectively). LDH5 isoenzyme was strongly expressed in cancer cells, exhibiting a mixed cytoplasmic/nuclear subcellular pattern. Interestingly, a high LDH5 content in tissue sections was not invariably accompanied by high LDH serum levels. High HIF1alpha tissue expression was linked to high tissue LDH5 expression. CONCLUSION: Serum and tissue LDH is up-regulated in gynaecologic and breast malignancies and in a subset of benign conditions such as fibro- and cystadenomas. The release of LDH, however, in the bloodstream is partly related to the LDHA gene up-regulation.

Concentrations of follicle stimulating hormone are increased in ovarian tumor fluid: implications for the management of ovarian cancer.

PURPOSE OF INVESTIGATION: Significant progress has been made in recent years in the understanding of the mechanisms postulated by the gonadotropin theory of ovarian carcinogenesis. In the present study we compare FSH concentrations between serum and fluid from cysts or the rectouterine pouch of patients with epithelial tumors and non-neoplastic lesions. METHODS: We enrolled 277 patients. They were divided into five groups: I (n = 44)--ovarian cancer patients, II (n = 16)--borderline tumors, III (n = 40)--benign epithelial cystadenomas, IV (n = 137)--non-neoplastic lesions and V (n = 22)--admitted for "second-look" laparoscopy. RESULTS: There were any significant differences between FSH concentrations in serum and tumor fluid in patients with ovarian cancer (36.46 vs 28.11 mIU/ml) and borderline epithelial tumors (31.5 vs 22.7 mIU/ml). For benign cystadenomas the respective concentrations were 28.96 mIU/ml in serum and 6.93 mIU/ml in tumor fluid in these groups p < 0.0000001. The same highly significant differences were found in non-neoplastic lesions (24.97 vs 4.77 mIU/ml), p < 0.0000001. Patients who underwent "second-look" laparoscopy demonstrated significant differences (p < 0.05) as FSH concentration in serum and peritoneal fluid when neoplastic cells were not disclosed, but the difference was not significant (p = 0.752) when fluid from the rectouterine pouch was positive for carcinoma cells. CONCLUSIONS: The results of our study can reflect an ineffective tumor: blood barrier and easy diffusion of gonadotropins into the tumor tissue. Local reduction of FSH levels through administration of GnRH analogs may in some clinical situations produce clear therapeutic benefits for the management of ovarian malignancies.

Pre-operative differentiation of pediatric ovarian tumors: morphological scoring system and tumor markers.

OBJECTIVE: To investigate the importance of morphological scoring systems in differentiation of ovarian tumors in childhood. METHODS: Morphological assessment using DePriest's index was performed for all patients with histopathological confirmation of ovarian tumor, with evaluation of tumor markers, from January 1997. RESULTS: Fifty-three girls (age range 13 months to 19 years) were surgically treated for 59 ovarian tumors, including six bilateral. All lesions with cystic appearance on ultrasonography were benign, 23 of 35 semisolid, and four of ten solid tumors were also benign. Stage of malignant disease was as follows: stage I, ten; stage II, two; stage III, six. Sensitivity, positive predictive value and accuracy by DePriest's and Ueland's indexes for benign tumors (score <7) were: 0.88, 0.79; 0.89; and 0.94, 0.84; 0.93; respectively. Elevated levels of tumor markers were observed in 17 patients, including four patients with endocrine manifestations. In 24 patients ovaries were successfully preserved, including two patients with foci of immature teratoma in a dermoid cyst. CONCLUSION: Ultrasonographic assessment with morphological analysis recommended by DePriest and Ueland is a very useful procedure for differentiating benign from malignant ovarian tumors in children. Tumor markers and endocrinological investigation are also useful for preoperative evaluation.

Serum mesothelin in epithelial ovarian carcinoma: a new screening marker and prognostic factor.

UNLABELLED: The aim of this study was to determine the relationship between mesothelin and clinical pathological characteristics and whether mesothelin can be used as a biomarker for the detection and prognosis of epithelial ovarian carcinoma, or not. PATIENTS AND METHODS: Pre-operative mesothelin and CA125 levels from normal populations, patients with benign ovarian tumors and patients with ovarian carcinomas were measured. The histopathological characteristics and serum meosthelin, and CA125 levels influencing clinical outcome were evaluated comparatively. RESULTS: Mesothelin levels were higher in cancer patients than in those with benign ovarian tumors or in normal populations. Mesothelin, also significantly increased from early to advanced stages. Elevated mesothelin before therapy and advanced stage, revealed poorer overall survival (OS) for cancer patients. Elevated mesothelin before therapy also revealed poorer OS in cancer patients with optimal debulking surgery and in advanced-stage cancer patients. CONCLUSION: Mesothelin might be a new tumor marker for the differential diagnosis of epithelial ovarian carcinoma and a prognostic factorfor the outcome of epithelial ovarian carcinoma patients.

Potential markers that complement expression of CA125 in epithelial ovarian cancer.

BACKGROUND: When ovarian carcinoma is diagnosed in stage I, up to 90% of patients can be cured with surgery and currently available chemotherapy. At present, less than 25% of cases are diagnosed at this stage. To increase the fraction of ovarian cancers detected at an early stage, screening strategies have been devised that utilize a rising serum CA125 level to trigger the performance of transvaginal sonography. One limitation of CA125 as an initial step in such a screening strategy is that up to 20% of ovarian cancers lack expression of the antigen. Serum tumor markers that can be detected in ovarian cancers that lack CA125 expression might improve the sensitivity for early detection. METHODS: From 296 ovarian cancers, 65 (22%) were found to have weak or absent CA125 expression on immunoperoxidase staining. Tissue expression of CA125 was compared to serum CA125 levels. Using immunoperoxidase staining of tissue arrays, we have assessed expression of 10 potential serum tumor markers in the 65 epithelial ovarian cancers with little or no CA125 expression and in ovarian cystadenomas, tumors of low malignant potential, normal ovaries, and 16 other normal tissues. RESULTS: Low or absent expression of CA125 in surgical specimens of epithelial ovarian cancer was associated with low levels of serum CA125 in pre-operative serum specimens. In ovarian cancers that lacked CA125, all specimens (100%) expressed human kallikrein 10 (HK10), human kallikrein 6 (HK6), osteopontin (OPN), and claudin 3. A smaller fraction of CA125-deficient ovarian cancers expressed DF3 (95%), vascular endothelial growth factor (VEGF) (81%), MUC1 (62%), mesothelin (MES) (34%), HE4 (32%), and CA19-9 (29%). When reactivity with normal tissues was considered, however, MES and HE4 showed the greatest specificity. Differential expression was also found for HK10, OPN, DF3, and MUC1. CONCLUSIONS: At the level of tissue expression, each of 10 potential serum markers could be detected in 29-100% of ovarian cancers that had low or absent expression of CA125. Several markers exhibited more intense expression in cancers than in normal organs. Further investigation is needed to demonstrate complementary expression of markers in serum.

Giant multilocular cystadenoma of the prostate responsive to GnRH antagonists.

Giant multilocular cystadenoma of the prostate is a rare, benign, but locally recurrent, tumor that is usually treated by surgery. We report a case initially treated by surgical resection and followed by evaluation of serum prostate-specific antigen values. After evidence of biochemical failure, pathologic recurrence was confirmed and treated by the gonadotropin-releasing hormone antagonist Lupron, with excellent results. The patient was stable without biochemical or radiologic evidence of progression during the last 2.5 years. This result offers a new treatment option for patients with this rare tumor.

Biliary cystadenoma with elevated CA 19.9.

We report a case of a large biliary cystadenoma occupying the entire peritoneal cavity, manifesting as an abdominal swelling for years and an elevation of CA 19.9 serum levels. Serum CA 19.9 levels fell to normal values after surgical excision. Recognition and management of this rare hepatic lesion is discussed.

Diagnostic value of serum VEGF in women with ovarian tumors.

BACKGROUND: Angiogenesis is necessary for growth and invasiveness of malignant tumors. Vascular endothelial growth factor (VEGF) is considered to play a key role in tumor angiogenesis. Few data are available with regard to serum levels of VEGF in patients with ovarian tumors. We investigated the diagnostic value of serum VEGF in patients with ovarian neoplasms. MATERIALS AND METHODS: 61 patients with ovarian neoplasms (41 ovarian carcinomas, 20 cystadenomas) and 20 healthy women were included into the study. VEGF serum concentrations were determined by a commercially available ELISA. RESULTS: Statistical analysis revealed significant differences in VEGF serum values of ovarian cancer patients vs. healthy controls or patients with cystadenomas. No difference could be seen between serum levels of healthy controls and women with benign ovarian tumors. For ovarian cancer patients vs. normal controls a sensitivity of 71% and a specificity of 65% resulted. The sensitivity and specificity of cancer patients vs. patients with benign neoplasms were 71% and 65%, respectively. CONCLUSION: Our results suggest that VEGF has potential as a serum marker with diagnostic relevance in ovarian neoplasms.

Soluble adhesion molecules in serum and cyst fluid from patients with cystic tumours of the ovary.

The potential of the soluble forms of the adhesion molecules ICAM-1 (sICAM-1), CD44std (sCD44std) and E-cadherin (sE-cadherin) was tested for the diagnosis of benign and malignant cystic epithelial tumours of the ovary. Concentrations of sICAM-1, sCD44 std and sE-cadherin were measured by enzyme-linked immunosorbent assay (ELISA) in the serum and cyst fluid obtained from 23 patients with luteal cysts, 29 with cystadenomas, nine with dermoid cysts, five with borderline tumours and 11 with carcinomas. Serum concentrations of sICAM-1, but not of sCD44std and sE-cadherin, were constantly elevated compared with normal controls. Cyst fluid concentrations of sICAM-1, sCD44std and sE-cadherin were elevated in borderline and malignant tumours compared with cystadenomas (P = 0.034, 0.006 and 0.001, respectively). In conclusion, our results suggest that serum concentrations of adhesion molecules have no diagnostic value in ovarian tumours, whereas cyst fluid concentrations may facilitate distinction between benign lesions and borderline or malignant tumours.

CA 19-9 production by a cystadenoma with mesenchymal stroma of the common hepatic duct: a case report.

A case of a CA 19-9 producing cystadenoma with mesenchymal stroma originating from the common hepatic duct is presented, with a review of the literature. The findings of ultrasound and CT scans and the endoscopic retrograde cholangiopancreatography picture allowed the establishment of a confident pre-operative diagnosis. Although there was an elevation of CA 19-9 serum levels, the resected specimen did not show any malignant focus at pathologic examination. After surgical excision, CA 19-9 serum levels returned to normal.

[The dynamic indices of lipid peroxidation and of the antioxidant system under the influence of surgical treatment in ovarian cystoma]. / Dynamika pokaznykiv perekysnoho okyslennia lipidiv ta antyoksydantnoï systemy pid vplyvom khirurhichnoho likuvannia kistomy iaiechnyka.

The state of the lipids peroxide oxidation (LPO) and antioxidant system (AOS) was studied up in 22 patients with ovarian cystoma [correction of cyst]. According to the level of retinoli acetas, acidum ascorbinicum, tocopheroli acetas, the reduced glutation superoxiddysmutase (SOD) activity. The LPO activation and vitamins level lowering in the patients blood plasma were established. The operative intervention conduction caused the LPO activation and the AOS factors level lowering, observed during 7-8 days after the operation.