Microenvironment inflammatory infiltrate drives growth speed and outcome of hepatocellular carcinoma: a prospective clinical study

In HCC, tumor microenvironment, heavily influenced by the underlying chronic liver disease, etiology and stage of the tissue damage, affects tumor progression and determines the high heterogeneity of the tumor. Aim of this study was to identify the circulating and tissue components of the microenvironment immune-mediated response affecting the aggressiveness and the ensuing clinical outcome. We analyzed the baseline paired HCC and the surrounding tissue biopsies from a prospective cohort of 132 patients at the first diagnosis of HCC for immunolocalization of PD-1/PD-L1, FoxP3, E-cadherin, CLEC2 and for a panel of 82 microRNA associated with regulation of angiogenesis, cell proliferation, cell signaling, immune control and autophagy. Original microarray data were also explored. Serum samples were analyzed for a panel of 19 cytokines. Data were associated with biochemical data, histopathology and survival. Patients with a more aggressive disease and shorter survival, who we named fast-growing accordingly to the tumor doubling time, at presentation had significantly higher AFP levels, TGF-β1 and Cyphra 21-1 levels. Transcriptomic analysis evidenced a significant downregulation of CLEC2 and upregulation of several metalloproteinases. A marked local upregulation of both PD-1 and PD-L1, a concomitant FoxP3-positive lymphocytic infiltrate, a loss of E-cadherin, gain of epithelial-mesenchymal transition (EMT) phenotype and extreme poor differentiation at histology were also present. Upregulated microRNA in fast-growing HCCs are associated with TGF-β signaling, angiogenesis and inflammation. Our data show that fast HCCs are characterized not only by redundant neo-angiogenesis but also by unique features of distinctively immunosuppressed microenvironment, prominent EMT, and clear-cut activation of TGFβ1 signaling in a general background of long-standing and permanent inflammatory state

[Effect of GnRH analogues on bone density in the vertebral column and the femur].

The objective of this study was to evaluate the effect on vertebral and femural bone density of the gonadotropin-releasing hormone (GnRH) analog administration. The changes in mineral bone density after 6 months discontinuation of the GnRH analog treatment were also measured. Forty-three premenopausal women with regular cycles and suffering from uterine myomatosis have been selected for the study. Twenty-eight women (group A) were treated with Goserelin 3.2 mg given as a depot every 28 days for 6 months. Fifteen women were treated with 10 mg of medroxyprogesterone acetate (MPA) from day 16 to day 25 of each month for 6 months. Vertebral and femural bone density was measured (by Hologic QDR-X 1000) just before the start of the study, at 6 months of treatment and at 12 months (after 6 months of discontinuation treatment). Significant loss of vertebral bone density was demonstrated in women treated with GnRH analog. After six months of treatment discontinuation bone mineral density did not recover the pretreatment values. Bone femural density showed a not significant decrease in the GnRH analog group. In our experience, the treatment with GnRH analog in premenopausal women induces a reduction in lumbar bone density that is not reversible after the treatment withdrawal; for this reason it would be safe to add at the GnRH analog a therapy which can prevent the bone loss

Evaluation of the body composition and fat distribution in long-term users of hormone replacement therapy

The aim of the study was to evaluate the body composition and fat distribution in long-term users of hormonal replacement therapy (HRT). 18 healthy menopausal women, long-term users of HRT (transdermal estradiol 50 microg continuously administered and 10 mg/day of medroxyprogesterone acetate for 12 days/month) and 18 healthy menopausal women, who had never used HRT were included in the study. Age, menopausal age, parity, weight and height (body mass index, weight/height2), and lifestyle habits were similar. Waist and hip circumference, body composition and waist/hip ratio were measured and the results were analyzed. No significant difference was demonstrated in fat and water percentage, and waist/hip ratio. Nevertheless, the waist circumference of long-term HRT users was significantly lower than that of non-users. In conclusion, abdominal fat in long-term HRT users is lower than that of non-users of similar age, menopausal age and body mass index

The Neogene-Quaternary geodynamic evolution of the central Calabrian Arc: A case study from the western Catanzaro Trough basin

The Catanzaro Trough is a Neogene-Quaternary basin developed in the central Calabrian Arc, between the Serre and the Sila Massifs, and filled by up to 2000 m of continental to marine deposits. It extends from the Sant’Eufemia Basin (SE Tyrrhenian Sea), offshore, to the Catanzaro Basin, onshore. Here, onshore structural data have been integrated with structural features interpreted using marine geophysical data to infer the main tectonic processes that have controlled the geodynamic evolution of the western portion of the Catanzaro Trough, since Upper Miocene to present. The data show a complex tectonostratigraphic architecture of the basin, which is mainly controlled by the activity of NW–SE and NE–SW trending fault systems. In particular, during late Miocene, the NW-SE oriented faults system was characterized by left lateral kinematics. The same structural regime produces secondary fault systems represented by E-W and NE-SW oriented faults. The ca. E-W lineaments show extensional kinematics, which may have played an important role during the opening of the WNW–ESE paleo-strait; whereas the NE-SW oriented system represents the conjugate faults of the NW-SE oriented structural system, showing a right lateral component of motion. During the Piacenzian-Lower Pleistocene, structural field and geophysical data show a switch from left-lateral to right-lateral kinematics of the NW-SE oriented faults, due to a change of the stress field. This new structural regime influenced the kinematics of the NE-SW faults system, which registered left lateral movement. Since Middle Pleistocene, the study area experienced an extensional phase, WNW-ESE oriented, controlled mainly by NE-SW and, subordinately, N-S oriented normal faults. This type of faulting splits obliquely the western Catanzaro Trough, producing up-faulted and down-faulted blocks, arranged as graben-type system (i.e Lamezia Basin). The multidisciplinary approach adopted, allowed us to constrain the structural setting of the central Calabria segment. The joined onshore with offshore structural data analysis allowed us to image a more faithful geodynamic evolution of the Calabrian Arc, included in the wider geodynamic framework of the Mediterranean region Moreover, our results show the close correlation between the NE-SW and N-S normal fault systems and evidence of deformed Quaternary deposits. These findings are relevant to seismic hazard understanding in an area which is historically considered at the highest risk of earthquake and tsunami and where are present important infrastructures and cities

[Hormone substitution therapy. Side-effects and compliance of various therapeutic regimens].

The aim of this study is to evaluate the tolerability and long-term compliance of four Estrogen Progestin treatments (HRT) for menopause. One hundred and ten symptomatic menopausal women were divided into four groups according to therapeutic regimens: A) Estradiol (E2) transdermal treatment 50 micrograms (TTS 50) continuously administered (cont.) plus Medroxyprogesterone Acetate (MPA) 10 mg/die for twelve days a month: 35 women. B) Conjugated Equine Estrogens (CEE) 0.625 mg/die cont. plus MPA for twelve days a month: 25 women. C) Estradiol transdermal 50 micrograms (cont.) plus MPA 2.5 mg/die cont.: 26 women. D) CEE 0.625 mg/die cont. plus MPA 2.5 mg/die cont.: 24 women. Menopausal symptoms were significantly reduced with all treatments. During the first year group C and D patients showed irregular bleeding (group C: 46%, group D: 61%). After 24 months the bleeding frequency was reduced (group C: 11%, group D: 13%). Mastodynia was the more frequent side-effect in particular among women who were utilizing cont.comb. regimens. The total percentage of drop out (D.O.) after 2 years was more than 30% (Group A: 31%, Group B: 33%, Group C: 39%, Group D: 35%). The most frequent reasons for abandoning HRT (79% of all DO) were not linked to therapy side-effects. 19% of DO switched to other hormonal regimens

Hysteroscopic findings in postmenopausal abnormal uterine bleeding: a comparison between HRT users and non-users

The aim of our study was to investigate hysteroscopic findings in a sample of 410 menopausal women (hormonal replacement therapy, HRT users n = 219 and HRT non-users n = 191) and to evaluate the relationship between the presence of intrauterine disease, the use of HRT and the presence of AUB. Two hundred and nineteen women on HRT underwent standard office hysteroscopy by means of the Hamou hysteroscope (in 94 cases for abnormal uterine bleeding (AUB) and in 125 cases for periodic endometrium monitoring). One hundred and ninety-one women who had never received HRT were submitted to office hysteroscopy (154 for AUB and 37 for other reasons). Intrauterine diseases are more frequent in patients who do not use HRT (P = 0.02). Endometrial polyps is a frequent disease present in 30% of the sample (23.7% of HRT users and 30.8% of HRT non-users). Myomas were present in 8.7% of all patients examined (6.8% of HRT users and 11% of HRT non-users). Irregular bleeding in menopause is often associated with endouterine abnormalities: in symptomatic patients the frequency of endouterine diseases was 41% while in asymptomatic patients was 28% (P = 0.003). In patients taking HRT (n = 219) endouterine disease is demonstrated in 37% with AUB and in 26% without AUB (P = 0.07). Benign intrauterine diseases (endometrial polyps and submucous myomas) are more frequent in postmenopausal women who do not use HRT. In patients taking HRT irregular bleeding is associated with intrauterine diseases; however, the absence of AUB does not exclude the presence of endometrial polyps or myomas. Copyright 2002 Published by Elsevier Science Ireland Ltd