Endocannabinoid system expression in ovarian epithelial tumors according to the dualistic model of ovarian carcinogenesis.

OBJECTIVE: Our study aimed to confirm the expression of the endocannabinoid system in the human epithelial ovarian tumors, assessing the immunohistochemical expression of Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase in benign, borderline and malignant tumors. MATERIALS AND METHODS: Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase immunohistochemical expression was determined in 118 epithelial ovarian tumors sequentially treated during the last decade in our department: 36 benign, 34 borderline and 48 malignant neoplasms. Cannabinoid Receptor type 1 and Fatty Acid Amide Hydrolase expression resulted predominantly weak-moderate in the benign and borderline forms. RESULTS: concerning malignant tumors, Cannabinoid Receptor Type 1 expression resulted predominantly moderate-strong in Type I tumors and negative-weak in Type II tumors. Fatty Acid Amide Hydrolase expression resulted, instead, independent by the tumor types. Furthermore, there was no significant difference in the Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase expression relatively to the tumoral stages. CONCLUSIONS: The present study confirmed a variable expression of the endocannabinoid system in human ovarian tumors. Cannabinoid Receptor Type 1 expression was significantly different in malignant epithelial ovarian tumors according to dualistic model of ovarian carcinogenesis. Thus, in the most aggressive types II ovarian tumors, Cannabinoid Receptor Type 1 expression resulted predominantly negative or weak.

Ovarian fibrosarcoma: case report and latest trends in diagnostic and therapeutic management.

The authors describe a rare case of primary ovarian fibrosarcoma and the latest trends in diagnosis and therapy. The rarity of this dis-ease and the scarce number of reported cases pose serious problems in differentiating it from other fibrous forms. A 58-year-old woman presented intermittent pelvic pain and a demarcated, mobile, and solid lump in the right adnexa. Diagnostic imaging revealed a solid- cystic inhomogeneous mass occupying the right adnexa and the CA125 level was elevated. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy and infracolic omentectomy. Histological findings with immunomarkers led to the final diagnosis of low-grade malignant mesenchymal neoplasm derived from the ovarian stroma compatible with fibrosarcoma. Twenty-four months follow-up showed no recurrence of disease. Ovarian fibrosarcoma is very uncommon neoplasm with a poor prognosis. Despite the efforts of several authors in reporting morphological, histological, and immunohistochemical features of this neoplasm, nowadays, the diagnosis, treatment, and prognosis are unresolved issues. The present case highlights the important role of immunohistochemistry to define histological type and differential diagnosis. As demonstrated by the authors' experience, they believe that surgery is curative in the early stages with low immunohistochemical positivity for ki67 and that chemotherapy should be reserved in advanced stages with regimens in use for the treatment of sarcomas.

Role of the association of high-risk HPV identified by real-time PCR in cervical preneoplastic lesions.

OBJECTIVE: To evaluate the effects of infection in multiple types of high-risk human papilloma virus (HPV) in cervical preneoplastic lesions in patients undergoing colposcopy following a diagnosis of atypical squamous cells of unknown significance (ASCUS) and low-grade squamous intraepithelial (LSIL) cytology. MATERIALS AND METHODS: Between 2009 and 2010, 2,500 patients were recruited with a mean age of 35 +/- 5 years. Screening for cervical cancer was performed and in case of ASCUS and LSIL the patients underwent colposcopy. The tests for the detection and typing of viral DNA (HPV - DNA test) were performed on cervical swab with real-time PCR amplification. RESULTS: The prevalence of infection was 70% (1579/2256) in the patients recruited. In relation to the degree of preneoplastic lesions some high-risk HPV viral genotypes were identified: HPV 16 (319/1466), HPV 18 (164/1466), HPV 45 (76/1466), HPV 31 (215/1466), HPV 52 (145/1466), HPV 58 (55/1466) HPV 56 (79/1466), HPV 51 (110/1466), HPV 6(138/1466), HPV 11 (88/1466), HPV 42 (34/1466), HPV 53 (43/1466). In case of high-grade lesions of CIN (CIN2 and CIN3) a greater HPV co-infection was detected and in particular the association from 16 to 18 (70%), 16-33 (18%) and 16 to 52 (12%). CONCLUSIONS: Infection caused by the simultaneous presence of multiple HPV genotypes appears to be associated with a significantly increased risk of high-grade lesions of CIN or invasive cancer than the presence of single viral infections. The infection with multiple HPV types is a significant risk factor for high-grade lesions of CIN in women undergoing colposcopy for ASCUS cytology/LSIL. The use of real-time PCR has shown the ability not only to identify the different types of HPV, but also to monitor quantitatively the same over time, and during the study phase, to evaluate the sensitivity and specificity of the method in comparison with other techniques.

The role of hypertension, body mass index, and serum leptin levels in patients with endometrial hyperplasia during premenopausal period.

OBJECTIVES: to investigate whether body mass index (BMI), hypertension (HTN), diabetes, age, and physical activity can be considered risk factors for endometrial simple hyperplasia in premenopausal women. Furthermore this study was undertaken to determine whether serum concentration of leptin in patients with BMI>or= 30 kg / m2 with endometrial hyperplasia deviate from values in patients with normal endometrium. MATERIALS AND METHODS: The authors enrolled 167 hyperplasia cases and 282 controls. Demographic characteristics and data on age, diabetes, hypertension, BMI, physical activity, and anthropometric parameters were collected. Leptin concentration in serum was measured with immunoenzymatic test kit from IBL. Univariable and multivariable analysis were performed to verify the association among age, HTN, BMI, physical activity, diabetes, and the presence of uterine hyperplasia. Furthermore the authors evaluated the correlation between BMI and leptin level (with Pearson's linear correlation) in women with simple hyperplasia and in controls. RESULTS: The prevalence of hyperplasia found was 34.4%. The following factors were independently associated with increased risk of endometrial hyperplasia: HTN (odds ratio 3.19, 95% confidence interval 1.20-8.48, p<0.020) and BMI>or=30 Kg/m2 (odds ratio 6.43, 95% confidence interval 3.92-10.53, p<0.000). Mean leptin concentration in serum was higher in patients who had endometrial hyperplasia than in controls (p<0.005) and the leptin levels depended on BMI. CONCLUSIONS: The following are risk factors for endometrial hyperplasia in premenopausal women: BMI>or=30 kg/m2 and HTN (blood pressure>or=130/85 or in therapy). Leptin appears to participate in proliferative processes of the endometrium, depending on BMI. Current guidelines may need to be reconsidered.

[Thyroid carcinoma: evaluation of prognostic factors]. / Carcinoma della tiroide: valutazione dei fattori prognostici.

Between 1990 and 1997, 36 thyroid cancer patients were observed at the III Department of Surgical Oncology, Regina Elena Cancer Institute in Rome. There were 31 (86.1%) women and 5 (13.9%) men, with a mean age of 47.7 years (range 17-72). Diagnostic data consisted of: papillary carcinoma in 25 patients, follicular carcinoma in 9 and Hürthle cell carcinoma in 1. Twenty patients were less than 45 years old (15 papillary and 5 follicular carcinoma) and 16 were more than 45 years old (10 papillary and 4 follicular carcinoma, 1 Hürthle cell carcinoma and 1 with undifferentiated cancer). We performed total thyroidectomy in 32 cases and isthmectomy in 3 (2 papillary carcinoma, T1, < 45 years, 1 follicular carcinoma with minimal invasion). At the time of diagnosis, 6 patients with papillary carcinoma showed signs of local metastasis. No patients exhibited distant diffusion. A follow-up was performed at mean 41 months (2-84 months). Two patients with follicular carcinomas had been treated with radioiodine and showed disease progression with distant metastasis. Our results coincide with the literature on this topic. Total thyroidectomy is preferred, in low-risk patients as well, because subsequent radioiodine treatment and disease relapse monitoring are facilitated. Lateral cervical lymphadenectomy was performed only in cases when there was clinical evidence of metastasis and recurrent disease at this level has never been observed.

Hyperhomocyst(e)inemia and a common methylenetetrahydrofolate reductase mutation (Ala223Val MTHFR) in patients with inherited thrombophilic coagulation defects.

To assess whether certain abnormalities of the sulfated amino acid metabolism are associated with the occurrence of thromboembolic events in patients with inherited thrombophilic conditions, the levels of homocyst(e)ine, before or after methionine load, and the presence of the Ala223Val substitution in the 5,10-methylenetetrahydrofolate reductase (MTHFR) were evaluated in 119 subjects with a congenital single thrombophilic condition (type I deficiency of antithrombin n = 10, protein C n = 24, protein S n = 16; activated protein C resistance due to factor V Leiden mutation n = 69). Sixty-three subjects had experienced at least one documented thrombotic event, while the remaining 56 subjects were still free from any thrombotic symptom. Our results show that (1) high homocyst(e)ine levels, either in fasting condition or after methionine load, were not more frequent in subjects with inherited thrombophilic alterations (14.4%) than in normal control subjects (10% by definition) and (2) the frequency of hyperhomocyst(e)inemia was similar in thrombophilic subjects, who already have (14.3%) or have not (14.6%) experienced thrombotic events. As regards the MTHFR mutation, the homozygous condition was present in 23.2% of the thrombophilic patients versus 17.5% in the control subjects, a nonsignificant difference. The mutation was slightly more frequent in those thrombophilic subjects who had suffered a thrombotic episode (25.5%) versus those with no thrombosis (20.8%), with odds ratios of 1.61 (confidence interval (CI) = 0.58-4.52) and 1.24 (CI = 0.42-3.43), respectively. These differences were also nonsignificant. It is concluded that in subjects with inherited thrombophilias, a condition of hyperhomocyst(e)inemia "per se" is not a factor increasing the risk of thrombosis. The risk enhancement conferred by the MTHFR mutation, if any, seems to be slight or limited, and its significance could be ascertained only in a large multicenter trial.

Comparison of new rapid methods for D-dimer measurement to exclude deep vein thrombosis in symptomatic outpatients.

Eighty-seven outpatients consecutively admitted to the emergency unit of our hospital with clinically suspected first deep vein thrombosis (DVT) of a leg had D-dimer levels measured by the following recently introduced fast methods: VIDAS (bioMerieux), LPIA (Mitsubishi), Nephelotex (Biopool), Nycocard (Nycomed) and Instant.I.A. (Diagnostica Stago). A latex agglutination test (Minutex, Biopool) was also performed and a classical ELISA (Gold EIA, Agen) used as reference. Venography was performed in all patients, with DVT diagnosed in 42 (37 proximal). All the new methods can be adopted in emergency situations, since they are suited for individual tests, are rapid and the reagents ready to use. All the methods proved to have a good interassay reproducibility. The new D-dimer and latex agglutination tests showed negative (88-96%) and positive (63-81%) predictive values similar to those of ELISA (92% and 71%, respectively), though the still wide confidence intervals suggest larger patient population series be investigated. As regards clinical application, the use of these tests to rule out DVT should be tested in prospective clinical follow-up trials where anticoagulation is withheld in subjects with negative non-invasive reliable vascular tests and normal D-dimer levels.

[Deep venous thrombosis. Evaluation of a non-invasive diagnostic procedure based on compression ultrasonography and measurement of D-dimer plasma levels]. / Trombosi venosa profonda. Validazione di una procedura diagnostica non invasiva basata su ultrasonografia con compressione associata a dosaggio dei D-dimeri plasmatici.

BACKGROUND: Clinical diagnosis of deep venous thrombosis (DVT) of the leg is unreliable. An accurate diagnosis is important for therapeutic decision since anticoagulant treatment, though potentially dangerous, is useless in case of a false positive diagnosis, whereas a false negative diagnosis may lead to withdrawal of an extremely necessary anticoagulation. Contrast venography is still recognized as the gold standard method for the diagnosis of DVT, but in recent years a variety of accurate non-invasive methods has been developed. The ultrasound compression sonography (CUS) is considered a simple non invasive test highly sensitive and specific for proximal DVT in symptomatic outpatients, though non adequately sensitive and specific for isolated calf DVT. Plasma D-dimer levels (DD, fibrin degradation products) have a high negative predictive value for DVT. The aim of this study, performed in outpatients with suspected leg DVT, was to validate, versus venography, a non-invasive, easy to perform and fast diagnostic procedure based on a combination of CUS and D-dimer test. End points of the procedure were: confirmation or exclusion of proximal DVT; suspicion of isolated calf DVT in which case the test would be repeated in a few days to detect any possible proximalization of thrombosis. MATERIALS AND METHODS: Sixty-eight consecutive outpatients, 37 male, with clinically suspected first episode of leg DVT were eligible and examined with CUS, DD test and venography. RESULTS: The results showed that the diagnostic procedure under examination has a high sensibility and specificity for DVT. CONCLUSIONS: It can thus be recommended as routine diagnostic procedure in symptomatic outpatients with suspected DVT reserving venography special cases only.

Role of surgery in the treatment of recurrent esophageal cancer.

Neoplastic recurrence is the most common cause of death after surgery for esophageal cancer. The Authors review the therapeutic options evaluating in terms of palliation of dysphagia and complication and mortality rates. Prognostic factors and mechanisms determining the recurrence are also reviewed. A strategy for a rational approach in the management of recurrent esophageal cancer emerges from both the literature and their own experience. Notwithstanding the small life span of these patients, the treatment of esophageal obstruction is mandatory. The therapeutic options that be considered are: palliative resection, surgical bypass, laser therapy, intubation, radiotherapy. The site of obstruction, the presence of metastasis, the general status can lead to the optimal choice. In terms of palliation of dysphagia the surgical approach seems to obtain the best results, even if high complication and mortality rates have been reported. Bypass is the second surgical choice when applicable. The other non-surgical modalities have been administered in large series of patients with good results. Combination therapies can obtain better results.

Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study.

The occurrence of a "rebound hypercoagulable state" in patients after dicontinuation of oral anticoagulants is still a matter of debate and no definite recommendation can be made on the best procedure for anticoagulant withdrawal. The present study investigated the changes in the levels of markers of activated blood coagulation in 32 patients (pts) in whom warfarin treatment (for venous thromboembolic disease) was randomly withdrawn abruptly (n = 17, group A) or gradually (n = 15, group B: 2/3 of initial dose the 1st week, 1/3 the 2nd weeks and nothing from the 3rd week on). Blood was sampled at baseline, once a week for the first three weeks and after 2 months. At the 1st week group A had significantly higher F1+2 and TAT values (p < 0.001); at the 2nd week F1+2 levels remained higher (p < 0.05) though INR values were not different from those of group B. After baseline, higher than normal F1+2 levels were recorded in 32/66 (48%) controls in group A vs 15/60 (25%) in group B (p < 0.01); at the 2nd week, 10/17 (59%) patients in group A vs 1/15 (7%) in group B still had higher than normal F1+2 levels (p < 0.01). The values of areas under curve (AUC) and maximum concentrations of all variables were not statistically different in the two groups; however, very high levels were observed in a few cases of group A. Thrombotic events (one DVT recurrence and one thrombophlebitis in a varicose vein) occurred in 2 pts of group A, both with high F1+2 and TAT AUC values.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute effects of defibrotide, an experimental antithrombotic agent, on fibrinolysis and blood prostanoids in man.

Defibrotide is a polynucleotide extracted from mammalian lung, which shows antithrombotic and anti-ischaemic activity in animals, probably related to stimulation of fibrinolysis and/or enhancement of prostacyclin production. The effect of a single infusion of defibrotide on fibrinolysis and the levels of certain prostanoids in man has been investigated in a cross-over double-blind placebo-controlled study. Evaluation of changes in fibrinolysis was difficult because of the spontaneous activation observed after placebo. However, the fast-acting plasminogen activator inhibitor was decreased only at end of the defibrotide infusion, suggesting a moderate profibrinolytic effect superimposed on the spontaneous activation. There was a marked and prolonged elevation of the plasma level of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin. In collagen stimulated whole blood, both 6-keto-PGF1 alpha and prostaglandin E2 production were also greatly increased, with no consistent indication of inhibition of thromboxane B2. It is suggested that defibrotide stimulates prostacyclin and prostaglandin E2 production by leucocytes or via platelet/leukocyte interactions. The effects observed here should be useful in guiding subsequent clinical trials.

Effects of iloprost (ZK 36374), a prostacyclin derivative, on platelet function after ischaemic exercise in patients with stable angina pectoris.

The effect of a chemically stable prostacyclin analogue (Iloprost) on platelet function was investigated in a controlled study in patients with angiographically confirmed stable angina pectoris after ischaemic exercise. In placebo experiments, ADP platelet aggregation was increased after exercise only when measured in whole blood and not in PRP. While plasma thromboxane B2 levels were unchanged, those of 6-keto PGF1 alpha were significantly although transiently increased after exercise. Iloprost displayed a potent antiaggregating activity in PRP and also reversed platelet hyperaggregation occurring in whole blood determinations after exercise. Plasma thromboxane B2 levels were significantly reduced but occasionally a rebound increase occurred 30 min. after end of the infusion. In contrast plasma level of 6-keto PGF1 alpha did not change after Iloprost and its recorded post-exercise increase was counteracted, thus suggesting a negative feed-back mechanism between Iloprost and natural prostacyclin. The data also suggest that degradation of the analogue is probably accomplished through pathways different from those of PGI2.

Blood coagulation changes in homocystinuria: effects of pyridoxine and other specific therapy.

The aim of this study was to investigate the blood coagulation changes in three patients with homocystinuria, in baseline condition and during therapy. At baseline, antithrombin III activity and factor VII levels were reduced in all three patients; antithrombin III protein and protein C antigen were also slightly lowered in one patient, and factor X in another. beta-Thromboglobulin, a measure of platelet activation, was increased in one case. During pyridoxine treatment, antithrombin III activity was rapidly restored to normal; factor VII increased and beta-thromboglobulin decreased. These data suggest that, in addition to platelet activation, abnormalities of blood clotting, and particularly reduction of antithrombin III, may play a role in the thrombotic tendency associated with homocystinuria. The nature of these clotting alterations is still uncertain, but their improvement during active metabolic treatment suggests that the defect in amino acid transsulfuration of homocystinuria may directly affect synthesis or activity of some liver-dependent clotting factors.

A proposed TNM classification for malignant primary liver tumours.

On the basis of 211 hepatic resections and reresections, a study was made to evaluate the possibility of compiling a checklist for primary liver tumours according to the TNM classification. This would aid the surgeon in planning therapy and provide a useful guide for prognosis and late results.

Our experience with resection of primary and secondary liver tumours.

The authors retrospectively analyse the results achieved in recent years by surgical treatment of 103 malignant primary or secondary liver cancers: (Three patients have been operated on twice at different times for recurrence.) 23 hepatic resections were performed for benign lesions. The operative mortality is very low, the incidence of postoperative complications is minimal, and the survival up to 8 years is rather satisfactory. In all cases we used Ton That Tung's surgical technique, that is, "finger fracture with intraparenchymal ligature of the vasculobiliary pedicles."

Platelet aggregation related to age in diabetes mellitus.

Platelet aggregation induced by ADP and collagen was studied in 174 diabetic patients before entering a controlled clinical trial. The clinical characteristics have been precisely defined. The degree of retinal abnormality was assessed by fundus angiofluorography in every patient. Most patients had background retinopathy; the remainder were normal. All results were computer analysed. The only significant relationship observed was between platelet sensitivity to ADP which increases regularly in relation to age in both insulin- and non-insulin-treated diabetic patients with or without background retinopathy. Spontaneous platelet aggregation was observed in 13 subjects and was not correlated to the existence of a neuropathy or any other clinical characteristics.