Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study.

BACKGROUND: To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. PATIENTS AND METHODS: A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. RESULTS: Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P<0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole+zoledronic acid versus letrozole comparison (P<0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P=0.004 and 0.47, respectively). CONCLUSIONS: In the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.

Electrochemotherapy as palliative treatment in patients with recurrent and/or metastatic head and neck tumours: features analysis for an early determination of the partial responsive patients.

OBJECTIVE: The aim of this study was to identify features mainly involved in determining the partial response (PR) to the Electrochemotherapy (ECT) in patients with recurrent and/or metastatic head and neck (H&N) tumor; the identified features were also used in a decision chart in order to provide the clinician with a support tool in deciding further therapies. PATIENTS AND METHODS: 131 patients (186 treatment sessions) with recurrent and/or metastatic H&N neoplasm were subjected to ECT. Treatment response was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 two months after the ECT. The grade of bleeding and pain before, at the end and one week after ECT treatment were evaluated. Univariate and multivariate analysis were performed to identify features involved in determining the patient PR. RESULTS: In the context of the univariate analysis, tumor size significantly influenced the response to ECT, with higher PR rate of 58.3%: 28 among 48 patients with lesion size ≤ 3 centimeters (p-value < 0.001 at Chi-square test). Pain and bleeding pre-treatment were positively correlated to PR (p-value < 0.001 at Chi-square test). A difference in the current flowing in the tissue during treatment was also observed in partially responsive patients, where the median current value (6.6 A) was higher than that achieved in patients that did not show PR (3.3 A). In the context of the multivariate analysis, the best performances are achieved with the BART method (accuracy of 84%). The main clinical factors to predict the partial response, among investigated features, that have shown to be considered were the pain value felt before performing the treatment and the median current delivered during the ECT treatment. A decision-making support tool to predict the patient prognosis in terms of response rate could be represented by the decision tree obtained with CART algorithm, where a pain pre-treatment more than 5 and a median delivered current not less than 2.8 A led to the prediction a partial responsive patient with an accuracy of 75%. CONCLUSIONS: The study confirmed that ECT is an interesting antitumoral therapy in advanced chemo- and radio-refractory H&N neoplasms, able to reduce frequent symptoms and to improve the quality of life. Pain pre-treatment and delivered current are the most important variables when predicting the partial response of patients.

Antineoplastic drug occupational exposure: a new integrated approach to evaluate exposure and early genotoxic and cytotoxic effects by no-invasive Buccal Micronucleus Cytome Assay biomarker.

Health-care personnel handling antineoplastic drugs could be at risk for adverse health effects. We aimed to evaluate genotoxic and cytotoxic effects of antineoplastic drug exposure of personnel preparing and administering such drugs in three Oncology Hospitals in Italy enrolling 42 exposed subjects and 53 controls. Furthermore, we aimed to study the possible influence of XRCC1 and hOGG1 DNA repair genes polymorphisms on genotoxicity induced on buccal cells. We performed workplace and personal monitoring of some drugs and used exposure diary informations to characterize the exposure. Urinary 5-FU metabolite (α-fluoro-ß-alanine) was measured. Buccal Micronucleus Cytome (BMCyt) assay was used to evaluate DNA damage and other cellular anomalies. GEM and 5-FU contamination was found in 68% and 42% of wipe/swab samples respectively. GEM deposition was found on workers' pads while no α-fluoro-ß-alanine was found. BMCyt-assay showed higher genotoxicity and cytotoxicity on nurses administering antineoplastics than on preparators and controls. Among micronucleus (MN) positive (with MN frequency higher than 1.5‰) exposed subjects, the percentage of those carrying XRCC1 mut/het genotype was higher than in MN positive-controls. Using the sensitive BMCyt assay, we demonstrated that handling antineoplastics still represents a potential occupational health risk for workers that should be better trained/informed regarding such risks.

An anthropomorphic soft skeleton hand exploiting conditional models for piano playing.

The development of robotic manipulators and hands that show dexterity, adaptability, and subtle behavior comparable to human hands is an unsolved research challenge. In this article, we considered the passive dynamics of mechanically complex systems, such as a skeleton hand, as an approach to improving adaptability, dexterity, and richness of behavioral diversity of such robotic manipulators. With the use of state-of-the-art multimaterial three-dimensional printing technologies, it is possible to design and construct complex passive structures, namely, a complex anthropomorphic skeleton hand that shows anisotropic mechanical stiffness. We introduce a concept, termed the "conditional model," that exploits the anisotropic stiffness of complex soft-rigid hybrid systems. In this approach, the physical configuration, environment conditions, and conditional actuation (applied actuation) resulted in an observable conditional model, allowing joint actuation through passivity-based dynamic interactions. The conditional model approach allowed the physical configuration and actuation to be altered, enabling a single skeleton hand to perform three different phrases of piano music with varying styles and forms and facilitating improved dynamic behaviors and interactions with the piano over those achievable with a rigid end effector.

The clinical response on bone metastasis from breast and lung cancer during treatment with zoledronic acid is inversely correlated to skeletal related events (SRE).

Current management of bone metastases involves a multimodal approach. Aminobisphosphonates (BPs) are a valid weapon in the treatment of skeletal localization of tumour disease. Patients with bone metastases from breast and lung cancer were enrolled in order to evaluate the impact of the addition of bisphosphonates therapy to standard treatments in terms of (i) pain control, (ii) quality of life (QoL) and (iii) toxicity and to evaluate (iv) any relations between clinical activity and the occurrence of SREs. A total of 60 patients were included in the study. Median age was 76 years (range 40-83). The majority of patients were treated with chemotherapy or hormonal therapy. All patients received zoledronic acid (ZOL) (4 mg) every 3-4 weeks for at least 3 cycles. No significant improvement in Performance Status of patients after 12 cycles of ZOL (p = 0.1672) was recorded. A statistically significant early and long-lasting amelioration of both pain, narcotic scores and QoL was found. Twenty-one patients (48%) experienced at least one SRE during the study. The most common SRE was radiation to bone (30% of patients). An inverse correlation between bone tumour response and SREs was also found (p = 0.019). ZOL addition induces a clinical benefit and improves QoL of patients with bone metastases. Moreover, the occurrence of bone clinical response is related to a reduced risk of SREs.

Nuclear morphometry in relation to lymph node status in canine mammary carcinomas.

The assessment of nuclear area and nuclear shape by morphometric analysis, has been investigated in 40 canine mammary carcinomas in relation to their metastatic behaviour to regional lymph-nodes. The tumours were reviewed by two experienced pathologists blinded regarding their lymph-node status, and were classified according to the histogenetically based criteria suggested by Benjamin et al. (1999). Twenty of these tumours showed lymph-node metastases (node-positive), and the other twenty were node-negative. Node-positive tumours included 6 simple adenocarcinomas, 10 ductular carcinomas, 2 anaplastic carcinomas and 2 carcinomas in mixed tumours; node-negative tumours included 18 adenocarcinomas %96, 10 simple adenocarcinomas, 8 complex adenocarcinomas %96, and 2 carcinomas in mixed tumours. Node-positive tumours showed MNA and mean SDA values significantly higher (p<0.001) than node-negative carcinomas. Data of this study, seems to confirm the importance of an histogenetically based classification in canine mammary tumours, also suggesting that morphometry may increase our prognostic performances allowing a reproducible method for detecting individual tumours with higher metastatic potential.

Nuclear morphometry in canine acanthomatous ameloblastomas and squamous cell carcinomas.

The aim of this study was to evaluate whether morphometrical analysis can be of diagnostic value for canine acanthomatous ameloblastoma. We calculated, by means of an automated image analyser, some morphometric nuclear parameters, in particular: mean nuclear area (MNA), mean nuclear perimeter (MNP), maximum and minimum diameters (MDx and MDm) coefficient of variation of the nuclear area (NACV), largest to smallest dimension ratio (LS ratio), and form factor (FF), in 8 canine acanthomatous ameloblastomas, and we compared these morphometric data to those of 13 squamous cell carcinomas of canine gingiva. The results indicated a progressive increase of the MNA, NACV, MNP and MDm proceeding from acanthomatous ameloblastomas (MNA: 42.11+/-8.74; NACV: 28,36+/-7,23; MNP: 24.18+/- 2.68; MDm: 5.69+/-0.49) to squamous cell carcinomas (MNA:49,69+/-9,10; NACV: 30,89+/-7,75; MNP: 25.63+/-2.54; MDm: 6.64+/-0.73). On the contrary, the LS ratio and the FF resulted greater in acanthomatous ameloblastomas (LS ratio: 1,63+/-0,12; FF: 1,13+/-0,002) than in SCCs (LS ratio: 1,40+/-0,12; FF:0.91+/-0.38). Moreover, the MNA, MNP,MDx and MDm resulted similar (MNA: p=0.89; MNP: p=0,65; MDm: p=0,16; MDx: p=0,13) in a subset of four acanthomatous ameloblastomas with cellular atypia (MNA:49,01+/-6,88; MNP: 26,28+/-1,99; MDm: 6.08+/-0.41; MDx: 10.18+/-0.88) and in squamous cell carcinomas (MNA:49.69+/-9,10; MNP: 25.63+/-2.54; MDm: 6.64+/-0.73; MDx: 9.26+/-1.05). While the NACV values resulted higher in typical acanthomatous ameloblastoma (29,99+/-6,06) than in atypical acanthomatous ameloblastoma (26,74+/-8,84) and similar to those of the SCCs (30,89+/-7,75). These results seem to confirm that acanthomatous ameloblastoma is a malignant or potentially malignant lesion and emphasizes that nuclear morphometry analysis can be an useful diagnostic and prognostic method in canine oral pathology.

Nucleomorphometric analysis of canine cutaneous mast cell tumours.

Thirty-five canine cutaneous mast cell tumours (CCMCTs) were analysed by computerized nuclear morphometry. In each case, the nuclei of at least 100 neoplastic cells were measured, and the mean nuclear area (MNA), mean nuclear perimeter (MNP) and mean nuclear form factor (FF) were calculated. Significant differences in respect of MNA and MNP occurred between tumours of grades I and III and between those of grades II and III (P<0.01) but not between tumours of grades I and II (P>0.01). No significant differences in respect of FF were observed between tumours of different grades. The results obtained indicate that nuclear morphometric analysis may assist in the grading of CMCTs.

Expression of endothelin-1 and endothelin-1 receptor A in canine mammary tumours.

Endothelins and their receptors have been implicated in numerous diseases and have recently emerged as relevant players in a variety of malignancies. Tumours overexpress the Endothelin-1 (ET-1) and the Endothelin-A receptors (ETAR) and their interaction enhances tumour growth and metastasis by promoting tumour cell survival, proliferation and angiogenesis. In this study we have evaluated the expression of ET-1 and ETAR in 50 canine mammary tumours, compared to normal controls. Results demonstrated a progressive increase in ET-1 and ETAR expression from benign tumour to grade 1 and to grade 2 malignant mammary tumours with a decrease of expression in grade 3 carcinomas. Co-localization of ET-1 and ETAR was observed in benign mammary tumours and in G1 and G2 carcinomas, while absent in G3 carcinomas. Concluding, ET-1/ETAR can be considered reliable markers for evaluating malignancy of canine mammary tumours and could have importance for the development of specific anticancer therapies.

Pharmacodynamic variability of flecainide assessed by QRS changes.

The effect of flecainide on the QRS interval was studied in 10 patients who were receiving long-term oral treatment (50 to 150 mg twice daily) for arrhythmias that were refractory to other drugs. Total and free drug plasma levels and QRS durations were measured at intervals after the morning administration. Free drug plasma levels were linearly correlated with QRS duration in each patient and the slope of the line was widely variable in the population studied. Even after the data from one patient with an unusually high slope (0.454) was excluded from the analysis, the slope range was 0.0284 to 0.144. Pharmacodynamic variability could not be explained by heart rate changes, active metabolites, electrolyte disturbances, or free drug concentration. None of the pharmacokinetic parameters measured (average steady-state concentration, fluctuation of maximum and minimum concentrations, time to peak concentration, final half-life, and protein binding) showed an intersubject variability greater than 4.4 times. Our findings suggest that the determination of flecainide free plasma concentration may not be sufficient to forecast electrophysiologic effects in individual patients.

The relationship between growth of atherosclerotic plaques, variant angina and sudden death.

Clinico-pathological findings are described in two patients with typical variant angina who died suddenly during an ischemic attack. In both cases, detailed pathologic examination of the coronary arteries disclosed severe focal atherosclerosis of the anterior descending coronary artery. The only distinctive histological finding was new intimal proliferation of smooth muscle cells enmeshed within mucoid substance, superimposed on the old fibrous cap of the plaque. These findings agree with experimental and clinical data which suggest that coronary vasospasm may be related to growth of atherosclerotic plaques. This study provides histological evidence that progression of an atherosclerotic plaque may underlie variant angina and sudden death.

Expression of Major Histocompatibility Complex class I and II in a case of Neospora caninum myositis in a dog.

Neosporosis was diagnosed in a 2-month-old dog by indirect immunofluorescence antibody test (IFAT) and confirmed by means of histopathology and immunohistochemistry. The associated myositis was characterized by Major Histocompatibility Complex expression on some muscle fibres. This finding indicates an immunological activation, of the muscle cells that, acquiring Major Histocompatibility Complex expression, may, in some way, contribute to antigen presentation. A possible role of these glycoproteins in the pathogenesis of Neospora-associated myositis is discussed.

Use of Amplatzer septal occluder in a case of residual atrial septal defect causing bidirectional shunting after percutaneous Inoue mitral balloon valvuloplasty.

We describe a 70-year-old woman who underwent successful percutaneous Inoue antegrade-technique mitral valvuloplasty. Three months later, the patient developed right-sided heart failure. Color Doppler echocardiography and cardiac catheterization demonstrated an atrial septal defect with bidirectional shunting and no restenosis of the mitral valve (iatrogenic Lutembacher's syndrome). Percutaneous treatment was successfully accomplished using a 13 mm Amplatzer Septal Occluder (AGA Medical Corporation, Golden Valley, Minnesota). The causes of right-to-left shunting and the effects of body position on gas exchange in such patients are also discussed.

Inhibition of intestinal motility and secretion by flavonoids in mice and rats: structure-activity relationships.

Intraperitoneal administration of some flavonoids (apigenin, flavone, kaempferol, morin, myricetin, naringin and rutin; 12.5-50 mg kg-1) significantly (P < 0.05-0.01) reduced small (28-69%) and large (83-134%) intestinal transit in mice. Other flavonoids (naringenin, silibinin, silymarin and taxifolin, 100-200 mg kg-1) reduced (23-41%; P < 0.05-0.01) intestinal transit at doses of 100-200 mg kg-1 while hesperitin, catechin and phloridzin (up to 200 mg kg-1) had no effect. This effect was antagonized by yohimbine (87-96%) and phentolamine (87-91%) but not by prazosin, propranolol, atropine, hexamethonium, mepyramine, cyproheptadine and naloxone. Yohimbine (92-96%) also antagonized the inhibitory effect of flavonols (12.5-50 mg kg-1) (P < 0.05-0.01) on intraluminal accumulation of fluid and diarrhoea induced by castor oil. By contrast, verapamil potentiated the flavonol effect. It is suggested that these effects, influenced by the structure of the molecules, are mediated by alpha 2-adrenergic receptors and calcium.

Changes in cardiovascular function induced by verapamil in healthy subjects and in patients with ischemic heart disease.

Alterations in cardiovascular function induced by the acute intravenous administration of verapamil (5 or 10 mg) in 52 patients (29 with ischemic heart disease and 23 without heart disease) were evaluated with use of invasive techniques (right and left heart catheterization, left ventricular cineangiography, and coronary arteriography). The most significant changes were represented by a decrease in systemic vascular resistance and systemic arterial pressure, and an increase in heart rate and cardiac output. Contractility indexes were not depressed in either group, and altered ventricular wall motion tended to improve to a slightly smaller degree than in patients treated with nitroglycerin. The use of verapamil in patients with ischemic heart disease appears to be safe, and concern about the negative inotropic influences in humans no longer seems justified.

Prognostic value of nuclear morphometry in feline mammary carcinomas.

This study of 30 cats with mammary carcinoma was designed to investigate the relationship between (1) six nuclear morphometric parameters (mean nuclear profile area [MNA], standard deviation of MNA [SDa], coefficient of variation of MNA [CVa], nuclear form factor (p2/4 pi area) [FF], standard deviation of FF [SDf], and coefficient of variation of FF [CVf]) assessed by image analysis, and (2) survival for > 1 year or < 1 year after surgical removal of the tumour. Only the SDf and the CVf appeared to be related to survival. Cats that died within 1 year had an SDf or CVf (or both) higher than the corresponding mean values (SDft and CVft) for all 30 cats; but only four of 16 cases (25%) with a SDf lower than SDft and five of 17 cases (29.4%) with a CVf lower than CVft died within 1 year. The authors conclude that SDf and CVf represent reliable prognostic parameters in feline mammary carcinomas.

Expression of beta 1 integrin in normal, dysplastic and neoplastic canine mammary gland.

The expression of beta 1 integrin was evaluated immunohistochemically in a series of normal, dysplastic and neoplastic canine mammary glands, and in lymph node metastases. The tissues were formalin-fixed and paraffin wax-embedded. In malignant neoplasms, beta 1 integrin was decreased and redistributed along the entire cell membrane. In lymph nodes, strong immunohistochemical staining was seen intercellularly in clusters of metastatic cells within subcapsular sinuses and at the periphery of intranodal metastases. These results suggest that the expression of integrin molecules may be related to malignancy and to the metastatic potential of neoplastic cells.

Silver-stained nucleolar (Ag-NOR) cluster size in feline mammary carcinomas: lack of correlation with histological appearance, mitotic activity, tumour stage, and degree of nuclear atypia.

The relationship between Ag-NOR cluster size, mitotic index, tumour stage, degree of nuclear atypia and histological appearance was evaluated in a series of feline mammary carcinomas. The mean Ag-NOR cluster area per cell in these tumours ranged from 1.86 to 6.25 microns 2 and was not related to any other parameter studied. This suggests that Ag-NOR cluster size measurement is of poor diagnostic and prognostic value for feline mammary carcinomas.

Expression of matrix metalloprotease-2 (MMP-2) and the activator membrane type 1 (MT1-MMP) in canine mammary carcinomas.

An immunohistochemical approach was used to examine the expression of MMP-2 and the activator MT1-MMP in a series of 50 canine mammary carcinomas of different histotype and stage. MMP-2 and MT1-MMP were mainly expressed in the cytoplasm of carcinoma cells and in fibroblasts. Immunolabelling for both MMP-2 and MT1-MMP was also seen on the tumour cell membranes. This labelling pattern showed no significant association with either the histological sub-type or stage of the carcinomas. Therefore, although distinct patterns of expression of MMP-2 and MT-MMP1 were shown by these carcinomas, functional studies by means of zymography would be required to provide useful information on tumour behaviour.

Expression of vascular endothelial growth factor in basal cell tumours and in squamous cell carcinomas of canine skin.

The expression of vascular endothelial growth factor (VEGF) was evaluated immunohistochemically in 20 basal cell tumours (BCTs) and 15 squamous cell carcinomas (SCCs) of canine skin. VEGF was identified in all the SCCs and was particularly striking in those occurring on the toe. On the other hand, VEGF was absent in the great majority of BCTs, occurring only in those of the solid type. The results suggest that presence of VEGF is a useful additional criterion for evaluating malignancy and growth potential in tumours of these types.