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.

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.

Histopathological, histochemical and immunohistochemical findings of the small intestine in goats naturally infected by Trichostrongylus colubriformis.

Gastrointestinal (GI) strongyle infection remains one of the main constraints to goat production worldwide. Samples of small intestine from 15 Syrian goats naturally infected with Trichostrongylus colubriformis were examined by routine histology, histochemistry and immunohistochemistry to describe the histological changes and the phenotypes of inflammatory cellular components of the mucosa. Results indicated that the immune response to infection by T. colubriformis was characterized by an increased rate of the severity of the histologic lesions, an increase rate of T cell lymphocytes recruitment to the intestinal mucosa and quantitative and qualitative changes in the histochemical composition of mucin in goblet cells.

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.

A review of bovine urothelial tumours and tumour-like lesions of the urinary bladder.

Four hundred bovine urothelial tumours and tumour-like lesions were classified in accordance with the 2004 World Health Organization (WHO) morphological classification for human urothelial tumours. The spectrum of neoplastic lesions of the urinary bladder of cattle is becoming wider and bovine urothelial tumours share striking morphological features with their human counterparts. A classification system based on the WHO scheme would also be appropriate for the classification of bovine bladder tumours. Bovine urothelial tumours are most often multiple. Four distinct growth patterns of bovine urothelial tumours and tumour-like lesions are recognized: flat, exophytic or papillary, endophytic and invasive. Carcinoma in situ (CIS) is the most common flat urothelial lesion, accounting for approximately 4% of urothelial tumours. CIS is detected adjacent to papillary and invasive tumours in 80-90% of cases. Approximately 3% of papillary lesions are papillomas and approximately 5% are 'papillary urothelial neoplasms of low malignant potential' (PUNLMP). Low-grade carcinoma is the most common urothelial tumour of cattle. High-grade carcinomas, and low and high-grade invasive tumours, are less commonly seen. Bovine papillomavirus (BPV) infection and ingestion of bracken fern both play a central role in carcinogenesis of these lesions.

Sigma-2 receptor expression in bovine papillomavirus-associated urinary bladder tumours.

The expression of sigma-2 receptors was investigated in nine urothelial tumours of the urinary bladder of cattle. Each tumour was associated with the presence of DNA of bovine papillomavirus type-2 (BPV-2) and expression of the E5 viral oncoprotein. Five tumours were classified as low-grade carcinoma on the basis of morphological criteria and calculation of mean nuclear area (MNA) and mean nuclear perimeter (MNP). Four tumours were classified as high-grade carcinoma. Sigma-2 receptors were overexpressed in both types of carcinoma. In control normal bovine bladder tissue the density of receptors (expressed as the B(max)) was 0.37 pmol/mg of protein. Low-grade carcinomas had a mean B(max) of 1.37+/-0.32 pmol/mg of protein (range 1.03-1.86) and in high-grade carcinomas the mean B(max) was 10.9+/-2.8 pmol/mg of protein (range 8.2-14). The difference in B(max) between low- and high-grade carcinomas was statistically significant (P=0.0001).

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.

Correlation of nuclear morphometric features with animal and human World Health Organization International Histological Classifications of canine spontaneous seminomas.

The aim of this study was to correlate nuclear morphometric features with animal and human World Health Organization International Histological Classifications in canine seminomas. Twenty-three canine seminomas were classified, according to Animal World Health Organization International Histological Classification as intratubular, intratubular with signs of invasion, or diffuse and according to Human World Health Organization International Histological Classification criteria as spermatocytic and typical. The morphonuclear characteristics of tumors were quantitatively evaluated by means of digital cell image analyses of hematoxylin and eosin-stained nuclei. In particular, the mean nuclear area, mean nuclear perimeter, mean nuclear form factor, and their respective standard deviations were calculated. The relationship between the different variables and the tumor histologic types was assessed. On the basis of animal and human classification systems, statistically significant differences were observed only between intratubular seminomas with signs of invasion and the other two types and between spermatocytic and typical seminomas, respectively. In humans, it is well known that typical seminomas are more common and aggressive than spermatocytic ones. In our study, the canine seminomas classified as typical showed significantly larger and more variable nuclear area and perimeter than spermatocytic seminomas. These results support the opinion that most canine seminomas correspond to human spermatocytic seminomas and could explain the benign behavior of canine seminomas, which derive from a more differentiated type of germ cell.

Expression of vascular endothelial growth factor receptor Flk-1 in canine mammary tumours.

Vascular endothelial growth factor (VEGF) induces endothelial cell proliferation, and the beginning of angiogenesis, by interacting with specific endothelial receptors termed VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1). In this study, Flk-1 expression was evaluated immunohistochemically in 10 benign and 40 malignant canine mammary tumours. There was immunolabelling of endothelial cells located within the neoplastic proliferation and at the infiltrating periphery, and also of neoplastic cells. The number of positive endothelial and neoplastic cells, was higher in malignant than in benign tumours. Moreover, in the malignant tumours, expression of Flk-1 increased from well to less differentiated phenotypes (grade 1-3). The presence of VEGF receptor on neoplastic cells suggests that VEGF has an autocrine function in which neoplastic cells act as both VEGF producers and target cells. Thus, in malignant tumours, VEGF may contribute to neoplastic growth by inducing angiogenesis and by stimulating the proliferation of neoplastic cells.

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.

Mitochondrial myopathy in a german shepherd dog.

A 9-month-old male German Shepherd dog was referred for evaluation of progressive exercise intolerance. Clinical examination revealed a stiff, stilted gait and marked atrophy and hypotonia of skeletal muscle. The dog had raised creatine kinase (181 U/liter), lactate dehydrogenase (510 U/liter), and aspartate aminotransferase (123.6 U/liter) levels, suggesting a muscle disease. Histochemical evaluation of muscle biopsies revealed the presence of subsarcolemmal oxidative activity, reduced nicotinamide adenine dinucleotide, and succinate dehydrogenase, and the absence of cytochrome oxidase activity. Ragged red fibers were demonstrated with Gomori trichrome stain. Ultrastructural examination of the muscle confirmed the presence of subsarcolemmal accumulations of mitochondria and morphologically atypical mitochondria.

Evaluation of angiogenesis in canine seminomas by quantitative immunohistochemistry.

Angiogenesis, which assists in supplying the nutritional and respiratory needs of proliferating cells, is essential for tumour growth. Angiogenic control is complex, involving a network of cytokines, in particular vascular endothelial growth factor (VEGF), a potent endothelial cell mitogen which also stimulates neoplastic cell proliferation. The purpose of this study was to evaluate VEGF expression and microvessel density (number of microvessels per mm(2)), in canine seminomas. VEGF expression and microvessel density were higher in seminomas than in normal testicular tissue; both parameters were higher in diffuse tumours than in intratubular tumours. These data demonstrate an increase in angiogenesis in the more malignant histological types of seminoma and suggest that both VEGF and microvessel density are useful criteria for evaluating the intrinsic malignancy and growth potential of canine testicular tumours.