IDegLira fixed-ratio combination in the real world: a retrospective observational single-center Italian experience.

OBJECTIVE: An improvement of type 2 diabetes treatment is represented by the recent availability of a fixed-ratio combination of slow insulin degludec and GLP-1 RA liraglutide (IDegLira), which shows encouraging clinical trial results. This work represents a real-world evidence study to evaluate if the obtained clinical results are also confirmed in the clinical practice, in an Italian type 2 diabetes patients' population. PATIENTS AND METHODS: This retrospective observational study was conducted in the Diabetology Service of the Umbria local sanitary agency (USL Umbria 1) in Perugia. The study investigated all diabetic patients >18 years, who underwent anti-diabetic treatment with basal insulin with or without the concomitant consumption of one or more oral anti-diabetic agent (BOT group) or GLP-1 RA or rapid-acting insulin bolus (BB group), with unsatisfactory glycemic control for either hypoglycemic episodes or weight gain. The observation period was February 2018 to April 2019. RESULTS: IDegLira results to be effective in reducing HbA1c and fasting plasma glucose, especially among GLP-1 RA and BOT subgroup. In BOT group, a statistical difference was noted from the first month of treatment, also for post-prandial glycemia. Obtained results were achieved at a moderate dose of IDegLira reported during the study, which also represents a significant reduction of the amount of basal insulin in BB patients. CONCLUSIONS: Obtained results suggest that in a real-world setting, the switch to IDegLira treatment is a valid option for patients with unsatisfactory glycemic control, or who experienced side effects such as weight gain and hypoglycemia of other insulin therapies.

Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer.

BACKGROUND AND AIM: Capecitabine is an orally bioavailable prodrug that is converted to 5-fluorouracil through several enzymatic steps, the last of which is mediated by thymidine phosphorylase (TP). TP has been reported to be expressed at higher levels in cancer tissue compared with normal counterpart. The present study aimed at evaluating the potential relationship between TP expression and benefit from capecitabine in patients with metastatic breast cancer (BC). METHODS: Immunohistochemistry for TP and other biological markers was carried out on paraffin-embedded cancer tissues of 61 patients with BC treated with at least three cycles of capecitabine as single agent for metastatic disease. All patients had received capecitabine 1000 mg/m(2) b.i.d. days 1-14 every 21 days. The following variables were analyzed as potential determinants of benefit from capecitabine: TP expression, estrogen receptor (ER) and progesterone receptor status, human epidermal growth factor receptor-2 (HER-2) status, MIB-1 expression, performance status at the beginning of capecitabine treatment, stage at diagnosis, grade, presence of visceral metastases at the beginning of capecitabine treatment, and previous chemotherapy. RESULTS: Overall, median time to progression (TTP) was 6.5 months (range 1.4-33). On multivariate analysis, ER status [hazard ratio (HR) for progression = 0.31; 95% confidence interval (CI) = 0.15-0.64; P = 0.002], presence of visceral metastases at the beginning of capecitabine treatment (HR = 2.30; 95% CI = 1.21-4.39; P = 0.01), and capecitabine as first- or second-line treatment (HR = 2.28; 95% CI = 1.21-4.32; P = 0.01) independently predicted TTP. TP was highly expressed in 34 of 61 cases (55.7%). In the subgroup of patients with TP-expressing tumor, TTP was significantly longer in patients who received anthracyclines and taxanes before capecitabine (median TTP 7.5 versus 3.3 months, P = 0.01, log-rank test). Similarly, patients with a TP-positive tumor showed a longer TTP if they received taxanes before capecitabine than patients with TP-positive tumor who did not receive this treatment (7.3 versus 3.4 months, P = 0.03). CONCLUSIONS: These data provide further evidence that TP expression in BC could represent a biomarker of sensitivity to capecitabine treatment. Prospective studies with translational approach are desirable to confirm the predictive and prognostic role of TP.

Thymidine phosphorylase expression is associated with time to progression in patients receiving low-dose, docetaxel-modulated capecitabine for metastatic breast cancer.

BACKGROUND: Preclinical data have indicated a synergistic interaction between docetaxel and capecitabine by means of taxane-induced up-regulation of thymidine phosphorylase (TP). On the basis of such premises, we conducted a phase II trial to determine the activity and tolerability of weekly docetaxel plus capecitabine in patients with metastatic breast cancer (MBC). Furthermore, we explored the relationship between TP tumor expression and benefit from this regimen. PATIENTS AND METHODS: Patients received docetaxel 36 mg/m(2) i.v. on days 1, 8, and 15 and capecitabine orally 625 mg/m(2) b.i.d. from days 8 to 21. Cycles were repeated every 4 weeks. In the correlative study, we evaluated the TP expression by immunohistochemistry and the TP messenger RNA expression by real-time RT-PCR in the primary tumor. RESULTS: Forty-seven women were enrolled. In the intention-to-treat analysis, objective responses were achieved in 24 patients (51%). Fourteen additional patients (30%) had stable disease. The median time to progression (TTP) was 6 months (range 1-44 months). Median survival was 17 months (range 1-48 months). Overall, the treatment was well tolerated. The most common clinical adverse events (all grades) were alopecia (55%), nail changes (53%), fatigue/asthenia (51%), nausea/vomiting (51%), neutropenia (49%), and neuropathy (49%). A significantly higher TTP was observed in patients with TP-positive tumors (log-rank test, P = 0.009). Interestingly, a subgroup analysis confirmed this TTP benefit in patients with TP-positive tumors obtaining a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3). CONCLUSIONS: This study indicates that a regimen with low doses of capecitabine plus weekly docetaxel is active against MBC. The correlative analysis provides preliminary evidence that TP expression may be a predictive marker for therapeutic benefit.

Expression of periostin in human breast cancer.

BACKGROUND: Periostin is a secreted adhesion protein, normally expressed in mesenchime-derived cells. Aberrant expression of the periostin gene in epithelial tumours seems to play a role in angiogenesis and metastases. AIMS: To investigate periostin expression in a consecutive series of breast carcinomas and correlate it with established biological and prognostic factors. METHODS: A consecutive series of 206 breast carcinomas was investigated by immunohistochemistry with a specific antiperiostin antibody. Immunohistochemical expression of oestrogen and progesterone receptors, Ki-67 (MIB-1), HER-2/neu, VEGF-A, VEGFR-1 and VEGFR-2 was analysed. Periostin expression was also investigated in MCF-7 and MDA-468 cell lines by immunohistochemistry, western blot and quantitative RT-PCR. Localisation of periostin was investigated in MCF-7 cells by the green fluorescent protein (GFP) approach. RESULTS: Periostin was highly expressed in carcinoma cells, but not in normal breast tissues. The pattern of expression was mainly cytoplasmic. However, in 12% of cases a nuclear reactivity was observed. Nuclear periostin significantly correlated with tumour size, and with expression of oestrogen receptor, progesterone receptor, VEGF-A, VEGFR-1 and VEGFR-2. A nuclear localisation of periostin was also observed in MCF-7 and MDA-468 cell lines. In MCF-7 cells the nuclear localisation of periostin was also shown by transfection of a vector expressing a GFP-periostin chimeric protein. CONCLUSIONS: Results indicate that the aberrant gene expression of periostin in breast cancer cells is associated with an abnormal nuclear localisation of the protein. The nuclear localisation of periostin in breast cancer may induce significant biological effects.

Four primary malignancies successively occurred in a BRCA2 mutation carrier: a case report.

Carriers of BRCA2 germline mutation have a significantly increased lifetime risk of breast and ovarian cancer compared to non carriers. Several other carcinomas seem to be associated with BRCA2 mutations: pancreas, prostate, larynx, gallbladder, bile duct cancer, and malignant melanoma. We described a case of a 67-year-old BRCA2 mutation carrier of Caucasian, non-Jewish, ethnic origin who successively developed 4 primary malignancies in 30 months: breast ductal carcinoma, chronic lymphatic leukemia, ovarian serous papillary carcinoma, and endocervical adenocarcinoma. This is the first case of 4 primary malignancies in a BRCA mutation carrier, also occurred in such a short observation period. Chronic lymphatic leukemia and endocervical adenocarcinoma have not been yet associated to BRCA2 germline mutation.

[An abdominal Burkitt's lymphoma in acute phase. Case report]. / Il linfoma di Burkitt a localizzazione addominale con presentazione acuta. Caso clinico.

Burkitt's lymphoma is a highly malignant, aggressive and rapidly growing B-cell neoplasm, which has low long-term survival rates. Abdomen is the most frequent onset site of nonendemic Burkitt's lymphoma. The rapidity of volumetric doubling of this neoplasm frequently justifies an abdominal acute presentation, that may mime other less rare diseases. Symptoms are often misleading and make diagnosis difficult. The aim of this work is to report a case of a 13-year-old boy affected by terminal ileum Burkitt's lymphoma with hepatic metastasis, which initially was mistaken for acute appendicitis complicated by hepatic abscesses and, following a second surgical operation, for terminal-ileum inflammatory bowel disease. The rapidity of growth of this neoplasm justifies the finding, during the second surgical operation, of a mass that was not clinically manifested during first operation, carried out only a week ago. Clinical signs and instrumental investigations were not diagnostic, as well as the literature reports. The role of surgery remains controversial, and is usually limited to collection of specimens for histological diagnosis or to management of acute complications, as in our case report. Mostly treatment protocols are based on chemotherapy, because of the high sensibility of this neoplasm.

Nuclear alterations of cells and atypical metaplastic cells in cervical smears are predictive criteria of high-grade cervical intraepithelial neoplasia.

Diagnoses based on the screening of cervical smears show low interobserver reproducibility and are frequently discordant with the final histological diagnosis. The aim of this study was to identify which of the cytomorphologic criteria used in the screening of cervical smears were most predictive of the histopathological grades of cervical intraepithelial neoplasia. The abnormal cervical smears of 206 women were reviewed blindly according to 22 pre-established cytomorphological criteria. Colposcopic evaluation was carried out in all cases. The marked presence of several nuclear criteria frequently found together in the same smear was associated with high grade intraepithelial neoplasia regardless of the presence of any other criteria. On the other hand, when the nuclear criteria were less evident, the cluster of criteria related to metaplastic cells was predictive of a diagnosis of high-grade intraepithelial neoplasia. Focusing on selected cytological criteria can aggregate predictive value to cervical smear diagnoses.

Meal intake similarly reduces circulating concentrations of octanoyl and total ghrelin in humans.

UNLABELLED: ABSTRACT. Several data show that meal intake and nutritional status regulate circulating ghrelin concentrations in humans. Ghrelin mainly circulates in two different forms: octanoyl and des-octanoyl ghrelin. Most circulating ghrelin is des-octanoyl ghrelin which is considered inactive because it lacks endocrine activity. However, recent evidence suggests that des-octanoyl ghrelin exerts biological activity such as stimulation of adipogenesis, cardiovascular effects and control of cell growth. In healthy humans, although the total ghrelin concentration is known to peak before meals and to be reduced by food intake, no data are available about the octanoyl ghrelin response in the absorptive state. Therefore, after an overnight fast, we compared the effects of a mixed meal ingestion (meal study) or of additional 240 min fasting (control study) on plasma concentrations of octanoyl and total ghrelin in 6 healthy subjects (body mass index: 23 +/- 0.7). At baseline, octanoyl-ghrelin accounted for 3.15 +/- 0.2% of total circulating ghrelin without differences between the two sessions. A similar ratio was maintained in the absorptive state with no differences between the studies and basal values. Compared with control, meal intake significantly suppressed (nadir at 90 min) octanoyl and total ghrelin by 38 +/- 3 and 40 +/- 3% of basal values, respectively. In the meal study, multivariate analysis of variance showed that serum insulin best predicted plasma octanoyl-ghrelin concentrations accounting for 97% of its variation (r2 = -0.97,p = 0.0016). IN CONCLUSION: in healthy humans, octanoyl-ghrelin represents about 3-4% of total circula-ting ghrelin and this ratio is closely maintained in post-absorptive and absorptive states.

Effects of whole-body vibration exercise on the endocrine system of healthy men.

Whole-body vibration is reported to increase muscle performance, bone mineral density and stimulate the secretion of lipolytic and protein anabolic hormones, such as GH and testosterone, that might be used for the treatment of obesity. To date, as no controlled trial has examined the effects of vibration exercise on the human endocrine system, we performed a randomized controlled study, to establish whether the circulating concentrations of glucose and hormones (insulin, glucagon, cortisol, epinephrine, norepinephrine, GH, IGF-1, free and total testosterone) are affected by vibration in 10 healthy men [age 39 +/- 3, body mass index (BMI) of 23.5 +/- 0.5 kg/m2, mean +/- SEM]. Volunteers were studied on two occasions before and after standing for 25 min on a ground plate in the absence (control) or in the presence (vibration) of 30 Hz whole body vibration. Vibration slightly reduced plasma glucose (30 min: vibration 4.59 +/- 0.21, control 4.74 +/- 0.22 mM, p=0.049) and increased plasma norepinephrine concentrations (60 min: vibration 1.29 +/- 0.18, control 1.01 +/- 0.07 nM, p=0.038), but did not change the circulating concentrations of other hormones. These results demonstrate that vibration exercise transiently reduces plasma glucose, possibly by increasing glucose utilization by contracting muscles. Since hormonal responses, with the exception of norepinephrine, are not affected by acute vibration exposure, this type of exercise is not expected to reduce fat mass in obese subjects.

Lack of correlation between immunohistochemical expression of E2F-1, thymidylate synthase expression and clinical response to 5-fluorouracil in advanced colorectal cancer.

BACKGROUND: The level of the enzyme thymidylate synthase (TS) is known to inversely correlate with the clinical activity of 5-fluorouracil (FU) in advanced colorectal cancer patients. Since the correlation is not very strong, we have retrospectively analyzed the expression of E2F-1 in tumor samples or metastases from 25 patients with advanced colorectal cancer, homogeneously treated with an FU-based regimen. E2F-1 is a transcription factor regulating the expression of TS along with other crucial DNA synthesis related enzymes. MATERIALS AND METHODS: E2F-1 expression was analyzed by immunohistochemistry using the anti-E2F-1 monoclonal antibody KH95, scoring 2000 cells/case. Expression of TS was evaluated by immunohistochemistry using a rabbit anti-human polyclonal antibody. RESULTS: The level of E2F-1 expression did not correlate with TS expression, although a trend for correlation between E2F-1 level and maximal tumor shrinkage was observed (r = 0.42; P = 0.054). CONCLUSIONS: In spite of previous reports demonstrating that E2F-1 quantified by rt-PCR and western blot correlates with TS and could be used as a predictor to select colorectal cancer patients more likely to respond to FU treatment, our data suggest that, under these experimental conditions, immunohistochemistry cannot be used for such selection.

Circulating ghrelin levels of visceral obese men are not modified by a short-term treatment with very low doses of GH replacement.

Ghrelin, the endogenous ligand for the GH secretagogue-receptor (GHS-R), in addition to its GH-releasing action, has orexigenic and adipogenic properties. These characteristics make ghrelin a potential hormone involved in the pathogenesis of obesity. Ghrelin levels are decreased in obese humans and it is unknown whether this decrease is responsible for the blunted GH secretion reported in visceral obesity. Since only few data are available on the potential feedback regulation by GH on systemic ghrelin concentrations, it remains to be established whether the correction of circulating GH concentrations in obese individuals affects ghrelin concentrations. To answer this question, we measured plasma ghrelin levels after a week of administration of low doses of recombinant human GH (rhGH) in a randomized, double-blind, placebo (PL)-controlled trial. This study was originally designed to evaluate the effects of GH replacement on lipid kinetics in visceral obese men. Six adult men with abdominal/visceral obesity (age 42+/-3 yr, body weight 107 +/- 10 kg, BMI 33 +/- 1 kg/m2, waist circumference 111 +/- 3 cm, mean +/- SE) were evaluated in the basal state (BS) and after one week of treatment with subcutaneous bedtime injections of either PL, 2.5 (GH2.5) or 3.3 (GH3.3) pg/kg/die of rhGH. In comparison to BS either PL, GH2.5 or GH3.3 did not significantly modify circulating ghrelin concentrations (p = 0.77). In contrast, a significant increase of serum GH (p = 0.0028), IGF-I (p = 0.0033) and whole body rate of lipolysis (p = 0.038, GH2.5; p = 0.009, GH3.3) occurred, in comparison to BS or PL, after GH2.5 and GH3.3, without differences between the two treatments. These data demonstrate that in abdominal/visceral obese men a short-term treatment with very low doses of rhGH replacement, sufficient to augment the rate of lipolysis, do not modify circulating ghrelin levels.

Metabolic response to exercise.

At the beginning, the survival of humans was strictly related to their physical capacity. There was the need to resist predators and to provide food and water for life. Achieving these goals required a prompt and efficient energy system capable of sustaining either high intensity or maintaining prolonged physical activity. Energy for skeletal muscle contraction is supplied by anaerobic and aerobic metabolic pathways. The former can allow short bursts of intense physical activity (60-90 sec) and utilizes as energetic source the phosphocreatine shuttle and anaerobic glycolysis. The aerobic system is the most efficient ATP source for skeletal muscle. The oxidative phosporylation of carbohydrates, fats and, to a minor extent, proteins, can sustain physical activity for many hours. Carbohydrates are the most efficient fuel for working muscle and their contribution to total fuel oxidation is positively related to the intensity of exercise. The first metabolic pathways of carbohydrate metabolism to be involved are skeletal muscle glycogenolysis and glycolysis. Later circulating glucose, formed through activated gluconeogenesis, becomes an important energetic source. Among glucose metabolites, lactate plays a primary role as either direct or indirect (gluconeogenesis) energy source for contracting skeletal muscle. Fat oxidation plays a primary role during either low-moderate intensity exercise or protracted physical activity (over 90-120 min). Severe muscle glycogen depletion results in increased rates of muscle proteolysis and branched chain amino acid oxidation. Endurance training ameliorates physical performance by improving cardiopulmonary efficiency and optimizing skeletal muscle supply and oxidation of substrates.

Diabetes and exercise.

Physical activity has acute and chronic effects on glucose, lipid and protein metabolism. Long-term effects of regular exercise are particularly advantageous for Type 2 diabetic patients. Regular aerobic exercise reduces visceral fat mass and body weight without decreasing lean body mass, ameliorates insulin sensitivity, glucose and BP control, lipid profile and reduces the cardiovascular risk. For these reasons, regular aerobic physical activity must be considered as an essential component of the cure of Type 2 diabetes mellitus. In this regard, individual behavioral strategies have been documented to be effective in motivating sedentary Type 2 diabetic subjects to the adoption and the maintenance of regular physical activity. In Type 1 diabetic subjects, the lack of the physiological inhibition of insulin secretion during exercise results in a potential risk of hypoglycemia. On the other hand, exercise-induced activation of counter-regulatory hormones might trigger an acute metabolic derangement in severe insulin-deficient subjects. Thus, diabetic patients, before starting exercise sessions, must be carefully educated about the consequences of physical activity on their blood glucose and the appropriate modifications of diet and insulin therapy.

APE/Ref-1 is controlled by both redox and cAMP-dependent mechanisms in rat thyroid cells.

APE/Ref-1 is a multifunctional protein possessing both redox and DNA repair functions. Through its redox activity, APE/Ref-1 controls the DNA-binding function of several transcriptional regulators (AP1, NF-kappaB, p53, Pax proteins). We have previously shown that APE/Ref-1 upregulates the transcriptional activity of the thyroid-specific transcription factor Pax8. In thyroid cells, APE/Ref-1 can be detected both in the nuclear and cytoplasmatic compartments. In this study regulatory mechanisms acting on APE/Ref-1 were revealed using the FRTL-5 cell line. TSH induces both cytoplasm-to-nucleus translocation and neosynthesis of APE/Ref-1 protein. Interestingly, only neosynthesis is dependent on cAMP signalling. In contrast, the cytoplasm-to-nucleus translocation is dependent on redox-mediated mechanisms. Based upon the data shown in this study and in others, a bimodal control of APE/Ref-1 by TSH can be delineated.

Radiation-induced angiosarcoma of the breast: case report and self-criticism of therapeutic approach.

Angiosarcoma (AS) of the breast is a rare and highly aggressive vascular cancer. It presents as a primitive or radioinduced form. The case of a 46-year-old woman who underwent quadrantectomy of the breast plus axillary lymph node dissection and radiotherapy postoperatively (QUART) for ductal infiltrant carcinoma is reported in the following. Ten years later, the patient underwent mastectomy with immediate reconstruction, for local recurrence that was diagnosed as an AS of the breast at final pathological examination. She did not receive any adjuvant treatment due to local post-operative complications related to breast reconstruction. We criticize our therapeutic approach and we recommend more attention about local recurrence suggesting that tru-cut needle biopsy of local recurrence of the breast after QUART, should be the correct diagnostic approach.

Endometrial histologic changes in post-menopausal breast cancer patients using tamoxifen.

OBJECTIVE: The aim of this study was to evaluate the effect of tamoxifen on the endometrium of post-menopausal women with breast cancer and to examine the relationship between ultrasonography, hysteroscopy and histopathologic changes. METHOD: Included in this longitudinal study were 303 post-menopausal women taking 20 mg daily of tamoxifen. Hysteroscopy was performed in 83 patients with an endometrial thickness of only >or=5 mm and 34 with vaginal bleeding also. Forty-five asymptomatic patients (control group) underwent hysteroscopies. RESULT: The most frequent outcome in patients with endometrial thickness of only >or=5 mm was an atrophic endometrium in an empty cavity (79.5%) whereas simple hyperplasia (35.3%) was found in women with vaginal bleeding. Carcinoma was diagnosed in seven cases (5.9%). In the control group, no endometrial cancer was found. CONCLUSION: This study suggests that patients with a thickness >5 mm should be offered a whole hysteroscopic evaluation, whenever bleeding is reported.

A polymorphism in endostatin, an angiogenesis inhibitor, predisposes for the development of prostatic adenocarcinoma.

We have performed association studies between a novel coding single nucleotide polymorphism (D104N) in endostatin, one of the most potent inhibitors of angiogenesis, and prostate cancer. We observed that heterozygous N104 individuals have a 2.5 times increased chance of developing prostate cancer as compared with homozygous D104 subjects (odds ratio, 2.4; 95% confidence interval, 1.4-4.16). Modeling of the endostatin mutant showed that the N104 protein is stable. These results together with the observation that residue 104 is evolutionary conserved lead us to propose that: (a) the DNA segment containing this residue might contain a novel interaction site to a yet unknown receptor; and (b) the presence of N104 impairs the function of endostatin.

[Papillary lesions of the breast: diagnostic imaging and contribution of percutaneous needle biopsy with 14G needle]. / Lesioni papillari della mammella: diagnosi per immagini ed apporto dell'agobiopsia percutanea con ago da 14 gauge.

PURPOSE: To evaluate the presence of suggestive mammographic, US, color-Doppler, RM findings of 33 PLB and to show the accuracy of the large-core biopsy in evaluating these lesions. MATERIAL AND METHODS: A retrospective review of imaging-guided large-core biopsy of 860 consecutive lesions revealed that PLB were diagnosed in 31/33 cases and 3 were suspicious papillary lesions. Surgical correlation was available for all these lesions. Mammography and US were performed in all patients, Color-Doppler in 13/33 and MR in 10/33. RESULTS: Histological findings by percutaneous biopsy demonstrated 26 (79%) benign, 3 (9%) atypical, and 4 (12%) malignant lesions. Histological findings after surgery confirmed the diagnosis for benign and malignant lesions, while of the 3 atypical lesions, 1 was benign and 2 were malignant. One encysted papillary carcinoma in situ at core-biopsy was classified as invasive papillary carcinoma after surgery. PLB were usually found (52%) in subareolar location and the mean size was 17 mm (range 5-60 mm). The most frequent mammographic appearance of benign PLB was of a well-defined (71%), oval (53%) mass. The microcalcifications had variable features; they were isolated in 3/27 (15%) cases and associated with masses in 4/27 (20%). The mammographic finding of papillary carcinoma was of a well-defined (50%) or ill-defined, oval (50%) or lobulated (50%) mass, but never of a spiculated mass. US finding of the benign PLB most commonly showed a well-defined (84%), oval (84%), complex solid/cystic (52%) mass with frequently (60%) posterior enhancement. US finding of papillary carcinoma was of a well-defined (50%) or ill-defined (50%), oval (50%) or lobulated (50%) mass, most commonly solid-inhomogenous-hypoechoic. Color-Doppler showed high blood flow in 8/10 benign PLB and in 2/3 malignant PLB. Contrast-enhanced MR imaging demonstrated usually well-circumscribed, round masses (71%). The intensity/time curve showed marked focal enhancement (peak signal intensity over 70% at the first minute) in both benign and malignant lesions. DISCUSSION: Often the patients with PBL were symptomatic (for presence of nipple discharge or palpable mass). 31/33 papillary lesions identified at the subsequent imaging-guided large-core biopsy and in the 3/33 remaining lesions percutaneous core-biopsy required a subsequent surgical biopsy for the atypical papillary lesions. US proved to have the highest sensitivity, showing the suggestive feature of a frond-like mass within a dilated duct, and color-Doppler demonstrated high blood flow (which should be considered in differential diagnosis of galactocele). Mammographic finding of papillary lesions was often consistent with benign lesions (fibroadenoma, cyst). MR confirmed the high vascularization of these lesions, showing marked enhancement of the solid component. CONCLUSIONS: US, with Color-Doppler, proved to be the most useful examination for the identification and demonstration of the solid component of these lesions, which, observed further diagnostic investigation. As no definite mammographic, sonographic or RM pattern could be identified to differentiate between benign and malignant PLB, core-biopsy was required. Percutaneous biopsy has shown to be reliable in the diagnosis of benign and malignant PLB (without any false negative): infact, any atypical lesions require surgical examination. The framing of benign and malignant PLB with imaging and core-biopsy was useful because the frequent association of benign PLB with concurrent or subsequent breast carcinoma suggests surgical excision and radiological follow-up.

Mitochondrial localization of APE/Ref-1 in thyroid cells.

Mutations of mitochondrial DNA (mtDNA) are associated with different human diseases, including cancer and aging. Reactive oxygen species produced during oxidative phosphorylation are a major source of mtDNA damage. It is not clear, however, whether DNA repair mechanisms, able to abolish effects due to oxidative damage, are present in mitochondria. APE/Ref-1 is a nuclear protein possessing both redox activity (by which activates, "in vitro", the DNA-binding functions of several transcription factors) and DNA repair activity over apurinic/apyrimidinic sites. Immunohistochemical evidences indicate that in follicular thyroid cells, APE/Ref-1 is located in both nucleus and cytoplasm. Electronmicroscopy immunocytochemistry performed in the rat thyroid FRTL-5 cell line, indicates that part of the cytoplasmatic APE/Ref-1 is located in mitochondria. The presence of APE/Ref-1 inside mitochondria is further demonstrated by western blot analysis after cell fractionation. In the Kimol cell line (which is derived from FRTL-5, transformed by the Ki-ras oncogene) the amount of mitochondrial APE/Ref-1 is reduced by three to fourfold with respect to the normal FRTL-5 cells. These results suggest that: (i) a machinery capable of repairing DNA damaged by oxidative stress is present in mitochondria and (ii) mtDNA repair mechanisms may be impaired during cell transformation.

Evidence for local production of inhibin A and activin A in patients with ovarian endometriosis.

OBJECTIVE: To evaluate the expression of inhibin A and activin A in ovarian endometriosis. DESIGN: Uncontrolled cross-sectional study and controlled prospective in vitro study. SETTING: Academic health centers in Siena, Udine, Sassari, and Milan, Italy. PATIENT(S): A group of women (n = 19) who underwent laparoscopic excision of ovarian endometriotic cysts. INTERVENTION(S): Specimens of serum, peritoneal fluid, and cystic fluid, ovarian tissue for immunohistochemistry, and endometriotic cells for primary culture were collected. Cell cultures were also prepared from proliferative endometrium of women without endometriosis. MAIN OUTCOME MEASURES: Dimeric inhibin A and activin A concentrations in biological fluids; immunostaining of alpha and betaA subunits in ovarian endometrioma; alpha and betaA gene expression in cultured endometriotic cells compared with normal endometrium. RESULT(S): Inhibin A and activin A concentrations in the cystic fluid were slightly higher than in peritoneal fluid and significantly higher than in serum (P<.05). Immunoreactive alpha and betaA subunits were strongly expressed both in the epithelial and stromal components of ovarian endometrioma. The relative abundance of betaA mRNA was significantly decreased in endometriotic cells compared with eutopic stromal cells. CONCLUSION(S): The results of the present study provide evidence for a local production and secretion of inhibin A and activin A in ovarian endometriotic cysts.