Traces of heavy metals in children toenails as a bio-indicator of environmental exposure in Forlì (Northern Italy): an observational study.

OBJECTIVES: to assess the concentration of heavy metals in the nails of children aged 6-9 years residing in Forlì (Emilia-Romagna Region, Northern Italy). DESIGN: biomonitoring survey. SETTING AND PARTICIPANTS: in March 2017, a total of 236 toenail samples were collected, 221 of them were eligible; the concentration of 23 metals were measured in these eligible samples. MAIN OUTCOME MEASURES: a spatial analysis was conducted, considering home addresses as grouped in the four macroareas in which the local territory is administratively divided. RESULTS: In the two North-Center and East areas - which include various industrial operations, two waste incinerators and a motorway - the total concentration of all metals resulted 60% higher than in the West and South areas. Given the lack of Italian reference values, comparison tests between areas were performed for aluminum (Al), cadmium (Cd), iron (Fe), manganese (Mn), copper (Cu), and zinc (Zn), which concentrations were detectable in over 50% of the subjects. Higher concentrations were observed in the East area compared with the other areas, with statistical significance for Al (vs North-Center), Cu and Zn (vs West), and Al and Mn (vs South). Further comparisons showed significantly higher concentration of Cu in Nord-Center vs West, which in turn had higher concentrations of Zn compared to the Southern area. By applying a Tobit regression to evaluate possible confounding factors, a marginally significant correlation resulted for the nail concentration of Mn among children practicing outdoor sports and eating locally grown vegetables. The consumption of local vegetables was at the limits of significance also for Cd. CONCLUSIONS: the data obtained came from a voluntary and crowdfunded study and suggest a possible relationship between the exposure to air pollutants and subsequent accumulation of metals in the nails. Further and more detailed epidemiological studies are warranted to identify the exposure sources and to yield preventive intervention.

[SENTIERI studies: scientific evidence and lack of use for prevention]. / Gli studi SENTIERI: evidenza scientifica e mancato utilizzo delle informazioni per la prevenzione.

Studies from SENTIERI project have been crucial to show high-risk levels (mortality and morbidity) in communities living close to polluted sites. Despite the presence of some methodological limits, these studies represent a strong invitation towards primary prevention, also considering a possible underestimation of the health risk. The same pollutants responsible for the results showed in the SENTIERI studies are able to induce diseases (i.e., endocrine-metabolic diseases, spontaneous abortion, foetal malformations, autism, neurologic diseases) still unevaluated or not evaluable considering the actually available tools. SENTIERI illustrated only part of the health risk involving about 6 millions of Italians exposed since decades to environmental toxics, generated by legally approved plants. The well-documented health effects (avoidable since years) should be wider if a more extensive concept of «polluted site¼ was considered, according to the European Environment Agency (EEA) indications. It is ethically unacceptable to drive a model of public health based on damage recording in large communities living since decades in risky areas, absolutely neglecting preventive risk analysis. The clear results from SENTIERI did not induce great attention in politicians, who should be the main drivers of primary prevention measures. Our Country is not structured to act primary prevention actions, an unfeasible target in the short-medium term. Remediation measures were not effectively started or concluded in any of the examined sites; in some of these, additional polluting plants were realised, delaying the risk reduction. Health and environmental policies have not travelled on capable ways, until now. It is crucial to open collaborative and participative path to epidemiologists and experts skilled in environmental medicine to draw plans for prevention, which could be rapidly and effectively useful.

Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response.

BACKGROUND: Tumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines. METHODS/DESIGN: The primary endpoint of this proof-of-principle phase II study is immune response. Secondary endpoints are the identification of biomarkers potentially predictive of response, toxicity, response rate and overall survival. Three daily doses of booster radiotherapy (XRT) at 6-12 Gy will be administered to at least one metastatic field on days -3 to -1 before the first and third cycle. Treatment with IL-2 (dose 18 MIU/m2/day by continuous IV infusion for 72 hours) will start on day +1 and will be repeated every 3 weeks for up to 4 cycles and then every 4 weeks for a further 2 cycles. Immune response against tumor antigens expressed by melanoma and/or RCC will be evaluated during treatment. Circulating immune effectors and regulators, e.g. cytotoxic T lymphocytes and regulatory T cells, as well as serum levels of proangiogenic/proinflammatory cytokines will also be quantified. DISCUSSION: This study aims to evaluate the potential immunological synergism between HD-IL-2 and XRT, and to identify biomarkers that are predictive of response to IL-2 in order to spare potentially non responding patients from toxicity. TRIAL REGISTRATION: EudraCT no. 2012-001786-32.

Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised "proof-of-principle" phase II study.

BACKGROUND: Vaccination with dendritic cells (DC) loaded with tumor antigens elicits tumor-specific immune responses capable of killing cancer cells without inducing meaningful side-effects. Patients with advanced melanoma enrolled onto our phase II clinical studies have been treated with autologous DC loaded with autologous tumor lysate/homogenate matured with a cytokine cocktail, showing a clinical benefit (PR + SD) in 55.5% of evaluable cases to date. The beneficial effects of the vaccine were mainly restricted to patients who developed vaccine-specific immune response after treatment. However, immunological responses were only induced in about two-thirds of patients, and treatments aimed at improving immunological responsiveness to the vaccine are needed. METHODS/DESIGN: This is a phase II, "proof-of-principle", randomized, open-label trial of vaccination with autologous DC loaded with tumor lysate or homogenate in metastatic melanoma patients combined with immunomodulating RT and/or preleukapheresis IFN-α. All patients will receive four bi-weekly doses of the vaccine during the induction phase and monthly doses thereafter for up to a maximum of 14 vaccinations or until confirmed progression. Patients will be randomized to receive:(1.) three daily doses of 8 Gy up to 12 Gy radiotherapy delivered to one non-index metastatic field between vaccine doses 1 and 2 and, optionally, between doses 7 and 8, using IMRT-IMAT techniques;(2.) daily 3 MU subcutaneous IFN-α for 7 days before leukapheresis;(3.) both 1 and 2;(4.) neither 1 nor 2.At least six patients eligible for treatment will be enrolled per arm. Daily 3 MU IL-2 will be administered subcutaneously for 5 days starting from the second day after each vaccine dose. Serial DTH testing and blood sampling to evaluate treatment-induced immune response will be performed. Objective response will be evaluated according to immune-related response criteria (irRC). DISCUSSION: Based upon the emerging role of radiotherapy as an immunologic modifier, we designed a randomized phase II trial adding radiotherapy and/or preleukapheresis IFN-α to our DC vaccine in metastatic melanoma patients. Our aim was to find the best combination of complementary interventions to enhance anti-tumor response induced by DC vaccination, which could ultimately lead to better survival and milder toxicity.

Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort.

BACKGROUND: Ipilimumab improves survival in patients with advanced melanoma. The activity and safety of ipilimumab outside of a clinical trial was assessed in an expanded access programme (EAP). METHODS: Ipilimumab was available upon physician request for patients aged 16 or over with pretreated stage III (unresectable)/IV melanoma, for whom no other therapeutic option was available. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12. Patients were monitored for adverse events (AEs) within 3 to 4 days of each scheduled visit. RESULTS: Of 855 patients participating in the EAP in Italy, 833 were evaluable for response. Of these, 13% had an objective immune response, and the immune-related disease control rate was 34%. Median progression-free survival and overall survival were 3.7 and 7.2 months, respectively. Efficacy was independent of BRAF and NRAS mutational status. Overall, 33% of patients reported an immune-related AE (irAE). The frequency of irAEs was not associated with response to ipilimumab. CONCLUSIONS: Outside of a clinical trial setting, ipilimumab is a feasible treatment option in patients with pretreated metastatic melanoma, regardless of BRAF and NRAS mutational status. Data from this large cohort of patients support clinical trial evidence that ipilimumab can induce durable disease control and long-term survival in patients who have failed to respond to prior treatment.

Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program.

Of 93 patients with pretreated, BRAF(V600) mutation-positive advanced melanoma who received vemurafenib or dabrafenib before (n = 45) or after (n = 48) treatment with ipilimumab 3 mg/kg, median overall survival (mOS) from first treatment was 9.9 and 14.5 months, respectively. Among patients treated with a BRAF inhibitor first, mOS from the end of BRAF inhibition was 1.2 months for those who did not complete ipilimumab treatment as per protocol, compared with 12.7 months for those who did (p < .001). Prospective, randomized studies are required to determine the optimal sequencing of ipilimumab and BRAF inhibitors in patients with BRAF-mutated metastatic melanoma.

Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients.

BACKGROUND: In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4+CD25++Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion. METHODS: Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2. RESULTS: Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells. CONCLUSIONS: Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome.

Surgical treatment of melanoma: a survey of Italian hospitals.

Surgery is the first option for treating melanoma regardless of stage at presentation. We surveyed a representative sample of hospitals to evaluate management and quality of surgical indications for melanoma in Italy. At analysis, hospitals were grouped into high- or low-volume centers, with the population median of 25 diagnoses serving as the cut-off. Surgery for primary melanoma was similar between hospital groups. More high-volume centers were organized to perform sentinel node biopsy (91 vs. 56%). There were no major differences between high- and low-volume centers concerning the surgical approach to stage III and IV disease.

Follow-up of melanoma: a survey of Italian hospitals.

Follow-up is managed internally in 94% of centers and is programmed according to international guidelines in 52% of high-volume hospitals (>25 melanoma diagnoses per year); the remainder use internal guidelines; fewer low-volume centers (≤ 25 diagnoses per year) have internal guidelines (25%, p = 0.001). Instrumental examinations for stage III and IV disease are similar, while the examination interval changes from 3/4 months for stage III to 2/3 months for stage IV, and use of PET/CT increases from 44 to 54%. Overall, thoracic and abdominal CT is used most for follow-up in stage III (83%), while bone scintigraphy is used more commonly in low-volume centers (41 vs. 19%, p = 0.003), despite similar use of PET/CT (48 vs. 41%). Brain CT or MRI is more common in high-volume centers (63 vs. 39%, p > 0.0001), as is echography of draining lymph nodes (71 vs. 52%, p = 0.01). Hepatic/abdominal echography and thoracic radiography are used in about 50% of centers, regardless of type. In stage IV, use of bone scintigraphy is similar among groups (ca. 40%); brain CT/NMR use increases from 51 to 64% and is more common in high-volume centers (p = 0.03). Lymph node echography is more common in high-volume centers (56 vs. 39%, p = 0.03).

Diagnostic and therapeutic approaches in Italian hospitals: adjuvant and metastatic therapy in melanoma.

Melanoma incidence and mortality rates are rising in Italy, indicating that more effective treatments are required both in the adjuvant and metastatic settings. We analyzed clinical practices in the adjuvant and metastatic settings by conducting a nationwide survey of clinicians responsible for managing melanoma treatment and follow-up in a representative sample of Italian hospitals. 95% of participating hospitals completed the panel of questions on adjuvant and metastatic treatment, making it likely that these results give a realistic picture of treatment and follow-up of melanoma patients in Italy. In low-volume hospitals (<25 new melanoma diagnoses yearly) adjuvant therapy was significantly more used than in large-volume hospitals for patients in stage III and IV (82 versus 66% and 56 versus 30%, respectively), and only 11% of patients were enrolled in clinical trials. In the metastatic setting dacarbazine was the preferred first-line treatment (32%) followed by polychemotherapy (23%); 12% of patients were enrolled in clinical trials and less than 10% received interleukin-2, usually subcutaneously. The information provided by this study was used by the Italian Melanoma Intergroup to improve the quality of care and to redirect financial resources.

Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial.

BACKGROUND: Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. METHODS: In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m(2) intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. FINDINGS: 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7-57·6), as did ten with brain metastases (50·0%, 27·2-72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. INTERPRETATION: The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. FUNDING: Bristol-Myers Squibb.

Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy.

Current systemic treatments for metastatic uveal melanoma (UM) have not improved overall survival (OS). The fully human anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, ipilimumab, improved OS of patients with advanced cutaneous melanoma in a phase 3 trial; however, UM patients were excluded. The aim of this subanalysis, performed by the ipilimumab-ocular melanoma expanded access program (I-OMEAP) study group, was to assess the activity and safety of ipilimumab in patients with UM in a setting similar to daily clinical practice. Patients participating in a multicenter expanded access program (EAP) received induction treatment with ipilimumab 10 mg/kg. Maintenance doses were administered in patients who experienced clinical benefit or at physicians' discretion. Tumor assessment was evaluated per modified World Health Organization criteria at baseline, Week 12, Week 24, and Week 36. Adverse events (AEs) and immune-related AEs (irAEs) were collected according to Common Terminology Criteria for Adverse Events version 3.0. Thirteen pretreated patients with metastatic UM were treated at 6 European institutions. All patients received at least one dose of ipilimumab. Overall, no objective responses were observed; however, two patients had stable disease (SD), with a third patient achieving SD after initial progressive disease. Median OS as of July 1, 2011, was 36 weeks (range 2-172+ weeks). No grade 3/4 AEs of non-immune origin were reported. Three patients (23%) experienced grade 3 irAEs (1 thrombocytopenia, 1 diarrhea, and 1 alanine/aspartate aminotransferase elevation) that resolved with steroid therapy. The results indicate UM is a potential indication for ipilimumab treatment that should be further investigated in clinical trials.

Pancreatic resection for metastases from renal cancer: long term outcome after surgery and immunotherapy approach - single center experience.

BACKGROUND/AIMS: Natural history of renal cell carcinoma includes metastases to the pancreas. The literature reports that selected patients may have benefits by pancreatic resection in terms of long term survival. We report patient outcome and considerations on immunotherapy approach. METHODOLOGY: From 2001 to 2010 eight patients underwent pancreatic resection for metastases from renal cancer. We reviewed surgical outcome and following treatment (conventional chemotherapy: 5FU-Vindesine; Immunotherapy: Interleukin 2 - Interferon - Dendritic cells) of these patients. RESULTS: All patients underwent radical pancreatic resection (7 spleno-pancreatectomies; 1 segmental pancreatic resection) and were R0 after surgery. No postoperative mortality was reported. Morbidity was 37% (2 distal leakage; 1 pneumonitis). Two patients did not receive any further treatment; 2 patients received conventional chemotherapy; 2 patients received immunotherapy (interleukin2 + interferon); 2 patients received dendritic cells (DC) interleukin-2 infusion. Three years overall survival rate was 55%. Disease free survival after 3 years was 30%. CONCLUSIONS: Our data confirm that pancreatic resection should be offered to selected patients with no mortality and low morbidity. Long-term survival is achievable, but recurrence rate after surgery is high. Immunotherapy could be effective to control tumour progression especially in selected cases where DC may be used.

Tumor endothelial marker 8 expression levels in dendritic cell-based cancer vaccines are related to clinical outcome.

Previous studies have shown that tumor endothelial markers (TEMs 1-9) are up modulated in immunosuppressive, pro-angiogenic dendritic cells (DCs) found in tumor microenvironments. We recently reported that monocyte-derived DCs used for vaccination trials may accumulate high levels of TEM8 gene transcripts. Here, we investigate whether TEM8 expression in DC preparations represents a specific tumor-associated change of potential clinical relevance. TEM8 expression at the mRNA and protein level was evaluated by quantitative real-time RT-PCR and cytofluorimetric analysis in human clinical grade DCs utilized for the therapeutic vaccination of 17 advanced cancer patients (13 melanoma and 4 renal cell carcinoma). The analyses revealed that DCs from patients markedly differ in their ability to up-modulate TEM8. Indeed, mDCs from eight non-progressing patients [median overall survival (OS) = 32 months, all positive to the delayed-type hypersensitivity test (DTH)], had similar TEM8 mRNA expression levels [mDCs vs. immature iDCs; mean fold increase (mfi) = 1.97] to those found in healthy donors (mfi = 2.7). Conversely, mDCs from nine progressing patients (OS < 5 months, all but one with negative DTH) showed an increase in TEM8 mRNA levels (mfi = 12.88, p = 0.0018). The present observations suggest that TEM8 expression levels in DC-based therapeutic vaccines would allow the selection of a subgroup of patients who are most likely to benefit from therapeutic vaccination.

FRET microscopy autologous tumor lysate processing in mature dendritic cell vaccine therapy.

BACKGROUND: Antigen processing by dendritic cells (DC) exposed to specific stimuli has been well characterized in biological studies. Nonetheless, the question of whether autologous whole tumor lysates (as used in clinical trials) are similarly processed by these cells has not yet been resolved. METHODS: In this study, we examined the transfer of peptides from whole tumor lysates to major histocompatibility complex class II molecules (MHC II) in mature dendritic cells (mDC) from a patient with advanced melanoma. Tumor antigenic peptides-MHC II proximity was revealed by Förster Resonance Energy Transfer (FRET) measurements, which effectively extends the application of fluorescence microscopy to the molecular level (<100A). Tumor lysates were labelled with Alexa-488, as the donor, and mDC MHC II HLA-DR molecules were labelled with Alexa-546-conjugated IgG, as the acceptor. RESULTS: We detected significant energy transfer between donor and acceptor-labelled antibodies against HLA-DR at the membrane surface of mDC. FRET data indicated that fluorescent peptide-loaded MHC II molecules start to accumulate on mDC membranes at 16 hr from the maturation stimulus, steeply increasing at 22 hr with sustained higher FRET detected up to 46 hr. CONCLUSIONS: The results obtained imply that the patient mDC correctly processed the tumor specific antigens and their display on the mDC surface may be effective for several days. These observations support the rationale for immunogenic efficacy of autologous tumor lysates.

Unexpected high response rate to traditional therapy after dendritic cell-based vaccine in advanced melanoma: update of clinical outcome and subgroup analysis.

We reviewed the clinical results of a dendritic cell-based phase II clinical vaccine trial in stage IV melanoma and analyzed a patient subgroup treated with standard therapies after stopping vaccination. From 2003 to 2009, 24 metastatic melanoma patients were treated with mature dendritic cells pulsed with autologous tumor lysate and keyhole limpet hemocyanin and low-dose interleukin-2. Overall response (OR) to vaccination was 37.5% with a clinical benefit of 54.1%. All 14 responders showed delayed type hypersensitivity positivity. Median overall survival (OS) was 15 months (95% CI, 8-33). Eleven patients underwent other treatments (3 surgery, 2 biotherapy, 2 radiotherapy, 2 chemotherapy, and 4 biochemotherapy) after stopping vaccination. Of these, 2 patients had a complete response and 5 a partial response, with an OR of 63.6%. Median OS was 34 months (range 16-61). Our results suggest that therapeutic DC vaccination could favor clinical response in patients after more than one line of therapy.

Biomonitoring of Metals in Children Living in an Urban Area and Close to Waste Incinerators.

The impact of waste incinerators is usually examined by measuring environmental pollutants. Biomonitoring has been limited, until now, to few metals and to adults. We explored accumulation of a comprehensive panel of metals in children free-living in an urban area hosting two waste incinerators. Children were divided by georeferentiation in exposed and control groups, and toenail concentrations of 23 metals were thereafter assessed. The percentage of children having toenail metal concentrations above the limit of detection was higher in exposed children than in controls for Al, Ba, Mn, Cu, and V. Exposed children had higher absolute concentrations of Ba, Mn, Cu, and V, as compared with those living in the reference area. The Tobit regression identified living in the exposed area as a significant predictor of Ba, Ni, Cu, Mn, and V concentrations, after adjusting for covariates. The concentrations of Ba, Mn, Ni, and Cu correlated with each other, suggesting a possible common source of emission. Exposure to emissions derived from waste incinerators in an urban setting can lead to body accumulation of specific metals in children. Toenail metal concentration should be considered a noninvasive and adequate biomonitoring tool and an early warning indicator which should integrate the environmental monitoring of pollutants.

The Italian Network for Tumor Biotherapy (NIBIT): getting together to push the field forward.

As for a consolidated tradition, the 5th annual meeting of the Italian Network for Cancer Biotherapy took place in the Certosa of Pontignano, a Tuscan monastery, on September 20-22, 2007. The congress gathered more than 40 Italian leading groups representing academia, biotechnology and pharmaceutical industry. Aim of the meeting was to share new advances in cancer bio-immunotherapy and to promote their swift translation from pre-clinical research to clinical applications. Several topics were covered including: a) molecular and cellular mechanisms of tumor escape; b) therapeutic antibodies and recombinant constructs; c) clinical trials up-date and new programs; d) National Cooperative Networks and their potential interactions; e) old and new times in cancer immunology, an "amarcord". Here, we report the main issues discussed during the meeting.