Eribulin in cutaneous breast cancer metastasis treatment: clinical activity and symptom control.

AIM: This observational study evaluated the behavior and outcome of cutaneous breast cancer metastasis treated with eribulin. PATIENTS & METHODS: From November 2012 to January 2013, oncologists completed a database with patient, tumor and treatment characteristics from 14 Italian cancer centers. Skin lesions were assessed by Response Evaluation Criteria In Solid Tumors and cutaneous symptoms by present/absent criteria. RESULTS: A total of 23 metastatic breast cancer patients with skin metastasis who were treated with eribulin were analyzed. After treatment, 43% of patients exhibited a partial response, 35% stable disease and 22% progressive disease. Regarding only the skin response, 26% obtained a complete response, 22% a partial response, 39% stable disease and 13% progressive disease. We found an improvement in symptoms, infiltration and ulceration. With a median follow-up of 6 months, median progression-free survival was 4.3 months and median overall survival was 9.1 months. CONCLUSION: The response rate of skin metastasis to eribulin treatment was coherent with systemic responses. The good clinical response in most patients reflected symptom improvement.

Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features.

Mutations of three different genes, encoding ß-amyloid precursor protein (APP), presenilin 1 and presenilin 2 are associated with familial Alzheimer's disease (AD). Recently, the APP mutation A673V has been identified that stands out from all the genetic defects previously reported in these three genes, since it causes the disease only in the homozygous state (Di Fede et al. in Science 323:1473-1477, 2009). We here provide the detailed neuropathological picture of the proband of this family, who was homozygous for the APP A673V mutation and recently came to death. The brain has been studied by histological and immunohistochemical techniques, at the optical and ultrastructural levels. Cerebral Aß accumulation and tau pathology were severe and extensive. Peculiar features were the configuration of the Aß deposits that were of large size, mostly perivascular and exhibited a close correspondence between the pattern elicited by amyloid stainings and the labeling obtained with immunoreagents specific for Aß40 or Aß42. Moreover, Aß deposition spared the neostriatum while deeply affecting the cerebellum, and therefore was not in compliance with the hierarchical topographical sequence of involvement documented in sporadic AD. Therefore, the neuropathological picture of familial AD caused by the APP recessive mutation A673V presents distinctive characteristics compared to sporadic AD or familial AD inherited as a dominant trait. Main peculiar features are the morphology, structural properties and composition of the Aß deposits as well as their topographic distribution in the brain.

[Mortality in the cohort of the asbestos cement workers in the Eternit plant in Casale Monferrato (Italy)]. / Mortalità nella coorte dei lavoratori del cemento amianto della Eternit di Casale Monferrato.

OBJECTIVE: The present report updates the mortality cohort study of "Eternit" workers in Casale Monferrato, one of the major plant for the production of corrugated and plain sheets, tubes and high-pressure pipes in asbestos-cement in Italy active between 1907-1986. DESIGN: Retrospective cohort study. SETTING: The cohort included 3,443 blue-collar workers (2,663 men and 780 women) active between 1950 and 1986. Nine subjects had been excluded because of incomplete data. The follow-up ended in 2003. Mortality in the cohort was compared to the cause-specific rates for age and period of the Piedmont population and the SMR values were calculated for the period 1965-2003. MAIN OUTCOME: Analysis of cause-specific mortality. RESULTS: Follow-up was completed for 99.0% of the subjects. At the end of follow-up, 42% of the subjects were alive, 57% deceased and 1% lost to follow-up or moved abroad. In both sexes, a statistically significant increase of morality for all causes (men: SMR 135.1; 1,438 obs vs 1,064.1 exp; p < 0.01; women: RSM 149.5; 371 obs vs 248.2 exp; p < 0.01) was observed. The SMRs for lung, pleural and peritoneal cancer and for asbestosis increased according to duration of exposure and latency. For pleural cancer, increasing risks at shorter latencies were observed as exposure length increased. In men, the increase in the SMRs for lung and pleural cancer was reduced in the category of longest latency; still increased but declining SMRs were also observed at longer time since first exposure. Mortality from peritoneal cancer and asbestosis on the contrary increased with latency and with time since last exposure. Among women, a significant increase of mortality for uterine cancer (SMR 2569; 15 obs vs 5.8 exp; p < 0.01), ovarian cancer (SMR 227.3; 9 obs vs 4.0 exp; p < 0.05) and rectum cancer (SMR 318.6; 9 obs vs 2.8 exp; p < 0.01) was observed. CONCLUSION: a significant increase in mortality from the main asbestos-related diseases was confirmed by duration of exposure. In relation to latency The SMRs for lung and pleural cancer present a curvilinear trend with a decrease for longest latency periods (after 30 years from the cessation of exposure). The SMRs for peritoneal cancer and asbestosis showed a monotonic increase.

Immunohistochemistry by anti-cleaved-Lamin A: an improved approach to tackle the misuse of glucocorticoids in cattle.

The illegal use of glucocorticoids (GCs) as growth-promoters (GPs) is prohibited in farm animals in the European Union because the strong pharmacological activity of most synthetic GCs produces residues that are dangerous for human consumption. Among the alternative methods proposed to increase the efficacy of official controls, histology was the technique of choice in Italy on account of its high performance level. The aim of this study was to evaluate the reliability of immunohistochemistry (IHC) using anti-cleaved-Lamin A antibody to enhance the performance of the histological test applied to GC-related microscopic changes in the thymus. Veal calves (VC) and beef cattle (BC) were raised and both underwent different growth-promoting protocols or were left untreated. The morphology of the thymus parenchyma was evaluated for cortical atrophy with concurrent adipose tissue infiltration, and a score of 1 to 3 was attributed. A semi-quantitative IHC analysis was also performed by counting the number of positive thymocytes in 5 randomly selected high-power fields (HPFs). The distribution of the thymus atrophy scores was significantly different among the subgroups in both BC and VC. The IHC values were higher in untreated than in treated animals, for both BC and VC. The association between thymus atrophy score and IHC positivity showed higher median values in control than in treated animals (independently of the treatment protocol), for both BC and VC. Our data shows that IHC against anti-cleaved-Lamin A antibody is a reliable marker to detect illegal GC treatments, administered either alone or in association with other growth promoters, in both BC and VC. Combining IHC with the thymus atrophy score improves the accuracy of the histological method in correctly identifying treated animals and could represent a valuable, reproducible method to be applied to large-scale screening programmes.

Thymus atrophy is an efficient marker of illicit treatment with dexamethasone in veal calves: Results from a triennial experimental study.

Glucocorticoids, used in a wide range of pathologies thank to their therapeutical properties, are also illegally used as growth-promoters in animal breeding even if the European Union regulates their use to protect consumers' health from the adverse effects of residues in food. The first aim of the study was to establish the applicability of two histological parameters - atrophy and cortex-medulla ratio - to detect glucocorticoids misuse in calves. The second aim was to concurrently test the potentiality of both parameters to discriminate between treated and untreated animals. One hundred and seventy-two male Friesian veal calves were raised for six months and divided into two groups: Group A (106 calves) was given dexamethasone per os for twenty days (0.4mg/day), Group B (66 calves) used as control. Thymic samples were microscopically examined. Fat infiltration was evaluated and a degree of atrophy, ranging from 1 to 3 (mild, moderate, severe) was attributed; thymic cortex-medulla ratio was calculated too. Fisher's exact test and a Wilcoxon-Mann-Whitney test were performed to investigate the differences in thymic atrophy and cortex-medulla ratio between the groups. Results demonstrate that the thymic atrophy grading was significantly increased in group A (p=0,006), whereas the cortex-medulla ratio was decreased (p<0,004) when compared to group B; moreover, the parallel testing with fixed degree of atrophy and cortex-medulla ratio cut-off thresholds optimize the sensitivity (90%) in the detection of glucocorticoids anabolic treatments. These data suggest that microscopic thymus analysis represent a valid tool for the screening and monitoring of glucocorticoid illicit treatments.

Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma. A randomized phase III trial.

OBJECTIVE: Combination therapies of fluorouracil (FU) with irinotecan (CPT-11) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer. In this paper, we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C (MMC) monochemotherapy in an adjuvant setting. METHODS: 169 patients with radically resected gastric cancer were randomized to receive CPT-11 (180 mg/m2 day 1), leucovorin (100 mg/m2 days 1-2), FU (400-600 mg/m2 days 1-2, q 14; for four cycles; FOLFIRI regimen), followed by docetaxel (85 mg/m2 day 1), cisplatin (75 mg/m2 day 1, q 21; for three cycles; arm A), or MMC (8 mg/m2 days 1-2 as 2-hour infusion, q 42; for four cycles; arm B). All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4. A total of 166 patients (85 in arm A and 81 in arm B) were treated. Adjuvant treatment was completed in 76% of the patients in arm A and in 70% of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35%, with only 1 febrile patient, and diarrhea in 11% in arm A, and thrombocytopenia in 10% and neutropenia in 7% in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting. This sequence treatment currently represents the experimental arm of an ongoing multicenter trial.

Confirmation of the progesterone receptor as an efficient marker of treatment with 17ß-estradiol in veal calves.

Under current European Union legislation the use of anabolic steroids in food-producing livestock is banned because of their long-term adverse effects on human health. We examined the expression profile of the immunohistochemical marker progesterone receptor in veal calves' sex accessory glands following experimental administration of anabolic compounds. The aim was to confirm the accuracy of the immunohistochemical approach in the detection of the over-expression of the progesterone receptor induced by the administration of sexual steroids at low levels (17ß-estradiol and nandrolone alone or in combination). A total of 217 male veal calves were randomly divided into four groups: group A (104 calves) treated with 17ß-estradiol (5 mg/head; 4 weekly injections); group B (20 calves) treated with nandrolone (50 mg/head; 4 weekly injections); group C (20 calves) treated with the association of the two steroids (5 mg estradiol + 50 mg nandrolone; 4 weekly injections); and group K (73 calves) kept as a control. All the sexual accessory glands were collected at the slaughterhouse (15 days after the last administration) and subjected to immunohistochemical staining with anti-progesterone receptor antibody. All the calves treated with 17ß-estradiol alone or in association with nandrolone (groups A and C) showed strong positivity, while nandrolone-treated calves and controls (groups B and K) gave negative results to the immunohistochemical investigation. The statistical analysis showed that the progesterone receptor is a significant predictor of 17ß-estradiol treatment alone or in association with nandrolone (p < 0.001): the immunohistochemical study resulted in 100% sensitivity (CI = 95%: 97.1-100%) and specificity (CI = 95%: 95.1-100%) for prostate and 99% sensitivity (CI = 95%: 95.6-100%) and 100% specificity (CI = 95%: 95.1-100%) for bulbo-urethral glands. The data confirm that this innovative biological approach offers a reliable tool to enhance the efficacy of the histological test to detect illegal treatments with estrogens alone or in association with androgens.

Sarcocystis Spp. Prevalence in Bovine Minced Meat: A Histological and Molecular Study.

Sarcosporidiosis is caused by ingestion of contaminated raw or undercooked bovine meat and, although considered a minor zoonosis, it can represent a threath for immunocompromised people. Aim of this study was to determine the prevalence of Sarcocystis spp. in bovine minced meat intended for raw consumption collected from butcher shops and retail stores in Turin's province (Piedmont region, Northwest Italy). Twenty-five samples were examined in parallel by histology and polymerase chain reaction (PCR). The prevalence of infestation of Sarcocystis spp. resulted to be 64% [confidence interval (CI) 95% 42-82] and 88% (CI 95% 69-97) respectively by histology and PCR. In detail, the prevalence resulted 80% for S. cruzi (CI 95% 59-93), 68% for S. hominis (CI 95% 46-85) and 4% for S. hirsuta (CI 95% 0.10-20). The high prevalence of S. hominis highlights that sarcosporidiosis may constitute a public health problem in Italy, particularly in regions like Piedmont, that has traditional dishes prepared from raw or undercooked bovine meat.

[Cardiac myxoma: surgical results and 15-year clinical follow-up]. / Il mixoma cardiaco: risultati chirurgici e follow-up clinico a 15 anni.

BACKGROUND: Among cardiac tumors myxoma is the most common benign neoplasm. The aim of this study was to review our Institution's 15-year experience with intracardiac myxoma. METHODS: From 1985 through 2001, 38 patients (22 males, 16 females, mean age 57.06 +/- 11.1, range 32-74 years) underwent surgical resection of a cardiac myxoma at our Institution. The tumor was located in the left atrium in 29 patients (76.3%), in the right atrium in 8 patients (21%), and in the right ventricle in 1 patient (2.6%). The duration of symptoms prior to surgery ranged from 2 to 30 days. None of the patients had a familial myxoma. The surgical approach comprised complete wide excision in all patients. The incidence of delayed death, thromboembolic complications, valve degeneration, recurrence and reoperation were reviewed and the Kaplan-Meier survival curve was elaborated. RESULTS: There were no perioperative deaths. Three patients (7.9%) developed postoperative neurological sequelae: transient ischemic attacks in 2 patients (5.2%) and a stroke with persistent neurological deficit in 1 patient (2.6%). One patient (2.6%) required pacemaker implantation for complete atrioventricular block. An inferior myocardial infarction occurred in 1 patient (2.6%). During the follow-up, complete in 89.4% of the patients (34 out of 38 patients, mean 96.8 +/- 68.4 months, range 1-218 months), there were 2 (5.8%) non-cardiac related deaths. All the patients underwent clinical examination and echocardiography at regular intervals (1 year): no neurological event was observed during the follow-up and 29 patients (90.6%) are in NYHA functional class I. At 15 years the event-free rate is 85.2%. At 15 years the actuarial survival for the whole group is 92%. CONCLUSIONS: At present, the diagnosis of myxoma is easy to make and two-dimensional echocardiography plays a major role in this field. Surgery is the gold standard treatment and the clinical long-term results are excellent.

Increased frequency of circulating invariant natural killer T cells in malignant pleural mesothelioma patients.

Invariant natural killer T (iNKT) cells are a distinct subset of human T cells, which expresses an invariant T cell receptor Vα24 Jα18 and recognizes glycolipid antigens in the context of CD1d molecules. iNKT cells exert pivotal regulatory roles in many immune responses, including antitumor immune responses. Alterations in iNKT cell frequency, phenotype, and activation state have been reported in cancer patients. No data are available on the iNKT cells in malignant pleural mesothelioma (MPM), a rare, but very aggressive, malignancy of the pleura with a very poor prognosis. Here, we studied the frequency, phenotype, and cytokine profile of circulating iNKT cells in MPM patients, and correlated results with tumor histological types (epithelioid, sarcomatoid, biphasic) and clinical stages (I-III). We found that the iNKT cell frequency was significantly increased in MPM patients with epithelioid and sarcomatoid types in comparison with healthy volunteers (HV); only three biphasic mesotheliomas were available in this study, thus no conclusions can be drawn for this MPM type. The increased frequency significantly correlates with the clinical stage of tumor with the highest value at the stage III in both epithelioid and sarcomatoid subtypes. According to the histological types, we measured changes in the frequencies of CD4⁺ CD8⁺ (DP) and CD4⁻CD8⁻ (DN), but not in the cytokine profiles (IFN-γ/IL-4 expression). These results demonstrate that the frequency of iNKT cells is increased in MPM patients and that this increase correlates with MPM type and stage.

Pooled analysis of NAT2 genotypes as risk factors for asbestos-related malignant mesothelioma.

Malignant mesothelioma (MM) is a rare and aggressive tumor of the pleura. The most important causal factor for the development of MM is occupational exposure to asbestos. Different lines of evidence suggest a role of genetic background in MM development, as for other cancers. Two published studies observed an association between MM and N-acetyl-transferase 2 (NAT2) polymorphisms. First, a Finnish study observed that the NAT2 slow acetylator phenotype was associated with an increased risk of MM. Conversely, MM risk was higher in Italian subjects carrying the NAT2 fast acetylator genotypes. The conflicting results obtained in Finland and Italy could be ascribed to random chance, considering the small panel of patients and controls in the two studies, but also ethnic or other differences may have been important. To ascertain the role of NAT2 genotype, we performed a study on 252 MM patients and 262 controls recruited in two Northern Italy areas that were characterized by high asbestos exposure, due to intense industrial activities (an asbestos cement factory in Casale Monferrato, mainly shipyards and refineries in Liguria). Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). NAT2 fast acetylator genotypes showed an increased OR, although not statistically significant, both in asbestos-exposed subjects (OR=1.47; 95% CI=0.96-2.26) and in the entire population (OR=1.38; 95% CI=0.93-2.04). These results suggest that NAT2 polymorphisms do not exert a strong effect on individual susceptibility to MM.

Cisplatin and gemcitabine in malignant pleural mesothelioma: a phase II study.

Aims of this study were to evaluate the activity and toxicity of gemcitabine and cisplatin combination in malignant pleural mesothelioma (MPM). Patients with histologically proven MPM, < 75 years of age, Eastern Cooperative Oncology Group (ECOG) performance status (PS) < or = 2, and measurable MPM were eligible. Patients received gemcitabine 1250 mg/m intravenously on days 1 and 8 and cisplatin 75 mg/m on day 2, every 21 days, for a maximum of 6 cycles. From May 1999 to May 2001, 35 chemonaive patients (median age, 61 years) were enrolled. A total of 177 cycles were administered (median 5 cycles; range 1 to 6). One patient was not evaluable for response and toxicity. Nine (26%) patients had partial responses, 11 (32%) patients had progressive disease, and 14 (41%) stable disease. Median survival for all patients was 13 months. Median progression-free survival was 8 months. Grade 3 (World Health Organization) nausea and vomiting occurred in 35% of patients. Grade 3/4 anemia, grade 3/4 thrombocythemia, and grade 3/4 neutropenia were assessed in 24%, 52%, and 61% of patients, respectively. All other side effects were mild. In conclusion, gemcitabine-cisplatin combination seems to be moderately active in MPM. Furthermore, at this dose and schedule, the toxicity profile could be acceptable.

Single-agent gemcitabine in previously untreated elderly patients with advanced bladder carcinoma: response to treatment and correlation with the comprehensive geriatric assessment.

OBJECTIVE: The study aimed at evaluating the activity and toxicity of gemcitabine monochemotherapy in a unselected series of elderly patients with advanced bladder cancer. The secondary objectives were to establish whether there is a correlation between treatment and Comprehensive Geriatric Assessment (CGA) and, in addition, to determine overall patient survival. METHODS: Treatment consisted of six courses of chemotherapy with gemcitabine at a dosage of 1,200 mg/m2 on days 1 and 8, every 21 days. CGA, as described by Gruppo Italiano di Oncologia Geriatrica, was assessed for evaluating the functional status of patients before, during, and after treatment. RESULTS: Twenty-five patients were enrolled (M/F 22/3), 22 of these were evaluable for response and 23 for toxicity. Characteristics of patients: median age 76 years (range 71-87); ECOG performance status (PS) 1 in 12 patients and 2 in 13 patients; clinical stage III in 6 patients and IV in 19 patients. At the end of the therapy the parameters of CGA improved in 4 cases (17%), remained unchanged in 17 cases (74%) and worsened only in 2 cases (9%). Two patients were not evaluable. Response evaluation showed 3 (13.5%) complete responses (CRs) and 7 (32%) partial responses (PRs), for an overall response rate of 45.5% [95% confidence interval (CI), 24.3-65.7%]. Three (13.5%) patients had stable disease (SD ) and 9 (41%) disease progression (DP). Median overall survival was 8 months and median time to progression was 5 months. Treatment was generally well tolerated, with 1 patient having grade 3 gastrointestinal toxicity and 3 having grade 4 neutropenia. CONCLUSIONS: We conclude that gemcitabine can be safely administered in monochemotherapy, is effective and does not worsen the functional status of elderly patients with advanced bladder cancer.