Quality-of-life analysis of the MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG study comparing platinum-based versus non-platinum-based chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer.

Background: MITO-8 showed that prolonging platinum-free interval by introducing non-platinum-based chemotherapy (NPBC) does not improve prognosis of patients with partially platinum-sensitive recurrent ovarian cancer. Quality of life (QoL) was a secondary outcome. Patients and methods: Ovarian cancer patients recurring or progressing 6-12 months after previous platinum-based chemotherapy (PBC) were randomized to receive PBC or NPBC as first treatment. QoL was assessed at baseline, third and sixth cycles, with the EORTC C-30 and OV-28 questionnaires. Mean changes and best response were analysed. Progression-free survival, response rate, and toxicity are also reported for proper interpretation of data. All analyses were based on intention-to-treat. Results: Out of the 215 patients, 151 (70.2%) completed baseline questionnaire, balanced between the arms; thereafter, missing rate was higher in the NPBC arm. At mean change analysis, C30 scores were prevalently worse in the NPBC than PBC arm, statistical significance being attained for emotional functioning, global health status/QoL, fatigue, and dyspnoea (effect sizes ranging from 0.30 to 0.51). Conversely, as for OV28 scale, the other chemotherapy side-effects item was significantly worse with PBC at three and six cycles, with a larger effect size (0.70 and 0.54, respectively). At best response analysis, improvement of emotional functioning and pain and worsening of peripheral neuropathy and other chemotherapy side-effects were significantly more frequent in the PBC arm. Progression-free survival (median 9 versus 5 months, P = 0.001) and objective response rate (51.6% versus 19.4%, P = 0.0001) were significantly better with PBC. Allergy, blood cell count, alopecia, nausea, musculoskeletal, and neurological side-effects were more frequent and severe with PBC; hand-foot skin reaction, rash/desquamation, mucositis, and vascular events were more frequent with NPBC. Conclusion: MITO-8 QoL analysis shows that deterioration of some functioning and symptom scales is lower with PBC, with improvement of emotional functioning and pain, despite worsening of toxicity-related items. ClinicalTrials.gov: NCT00657878.

Correlation between benzene and testosterone in workers exposed to urban pollution.

AIM: Many studies have examined the effects of benzene on testosterone. The purpose of this study was to evaluate the possible correlation between the blood levels of benzene and the levels of testosterone. MATERIALS AND METHODS: The study involved a group of 148 subjects. For every worker have been made out a blood sample for the evaluation of benzene and testosterone levels and an urine analysis for the evaluation of the levels of trans, trans-muconic acid and S-phenylmercapturic acid. We estimated the Pearson correlation coefficient between the variables in the sample and the urinary metabolites, age, length of service, gender, BMI. For the analysis of the major confounding factors it was performed a multiple linear regression. RESULTS: The Pearson correlation coefficiet showed: 1. a significant inverse correlation between the S-phenyl mercapturic acid and free testosterone; 2. a significant direct correlation between trans-trans muconic acid and BMI. After dividing the sample according to the median of blood benzene (161.0 ng / L), Pearson correlation coefficient showed a significant inverse correlation between the S-phenyl mercapturic acid and free testosterone in the group with values below this median. CONCLUSIONS: Our results, to be considered preliminary, suggest that occupational exposure to low levels of benzene, present in urban pollution, affect the blood levels of testosterone. These results need to be confirmed in future studies, with the eventual possibility of including more specific fertility tests.

Psychopathology and neoplastic disease: medico-social and medico-legal considerations.

The cognitive disability associated with stress in patients presenting cancer disease may exert a significant impact on the psychological health of the individual and even deteriorate the clinical diagnosis. The present study consists of a review of the available literature and an analysis of the association between psychopathologic disease and cancer by selecting useful contributions to the medicosocial discussion of the topic. Interesting considerations have emerged on the epidemiology and pathogenesis of the association between psychopathology and cancer that initiated possibilities towards a greater accuracy in the assessment of the patient that is not only limited to oncologic problems and outcomes.

[Evaluation of liver function between indoor and outdoor workers: preliminary results].

INTRODUCTION: The aim of our study is to compare liver damage in "outdoor" environment technicians, a category occupationally exposed, and in "indoor" workers. MATERIALS AND METHODS: We studied 142 male technicians of the environment exposed to urban pollution and 142 male "indoor" workers not exposed. We compared mean and standard deviation of the following liver parameters: glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), gamma-glutamyl-traspeptidasi (γGT) and alkaline phosphatase (PHA), total bilirubin (TB) and direct (DB). We made the two groups comparable for age, length of service, BMI, alcohol consumption and smoking habits, and excluded the workers who presented confounding factors. RESULTS: We found statistically significant differences about the levels of γGT, PHA, GPT and albumin between the "outdoor" workers exposed and the "indoor" control group. In the outdoor group we observed statistically significant values, GPT (51.8 ± 30.6 I.U./l vs. 30 ± 22.3 I.U./l; p = 0.000), γ-GT (42.2 ± 29.4 I.U./l vs. 22.4 ± 20.7 I.U./l; p = 0.000) and PHA (75.7 ± 20.6 I.U./l vs. 59.1 ± 19.6 I.U./l; p= 0.000) compared to the unexposed group. No statistically significant difference emerged between the averages for the values of GOT (25.3 ± 20.7 I.U./l vs. 26 ± 17.7 I.U./l; p = 0.736) in two groups. CONCLUSIONS: It clearly emerges that the contaminants may alter the values of liver tests after prolonged exposure.

Plant receptor complexes.

In this issue of Science Signaling, Somssich and co-workers use fluorescence techniques to show the dynamics that occur during the activation of two different receptor complexes in living plant cells.

Correlation between cadmium and blood counts in workers exposed to urban stressor.

The objective of this study was to assess the exposures to cadmium (Cd) in urban workers and the association between Cd exposure and values of blood counts. Urinary Cd, blood Cd, and blood counts were obtained from 355 outdoor workers; a subgroup of 99 subjects were monitored to evaluate personal exposure to airborne Cd. The mean value of personal exposure to Cd was 1.5 ng/m3 for traffic assistants and 1.2 ng/m3 for drivers. Urinary and blood Cd were correlated to the airborne Cd (respectively r=3 and r=4). The multiple linear regression models showed the associations among white blood cell, the percentage of neutrophils (NEU%), the percentage of lymphocytes (LYM%), and the concentrations of blood Cd (respectively R2=27, R2=37, R2=581). The subjects with blood Cd values higher than 1.2 µg/L showed an increase of LYM% mean values and a decrease of NEU% mean values with respect to the group with blood Cd values lower than 1.1 µg/L.

Occupational exposure to urban stressors and effects on atrial natriuretic peptide: preliminary results.

PURPOSE: The aim of this pilot study is to evaluate whether occupational exposure to low doses of pollutants present in the air of the city selected for the study could cause alterations in the concentration of atrial natriuretic peptide (ANP) in workers from the Municipal Police with outdoor tasks, compared to those with indoor tasks. METHODS: A total of 208 non-smoking male and female subjects were enrolled and divided on the basis of whether their tasks were mainly outdoors or indoors. The dosage of plasma ANP was carried out on all workers included in the study. Differences between means and frequencies were compared using student's t-test for unpaired data and chi-square test with Yates' correction, and they were considered significant when the p value was <0.05. RESULTS: Even after the subdivision of the total sample on the basis of sex, mean plasma levels of ANP were higher but not statistically significant in traffic police compared with controls. CONCLUSIONS: The preliminary results suggest that further studies should be conducted before the influence of urban pollution on ANP could be confirmed or rejected.

Urinary hydroxypyrene and estradiol in an occupationally exposed "outdoor" population.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are widely present in the air pollution. The urinary hydroxypyrene (1-HOPu) is considered the main biological biomarker currently available to measure the exposure to PAH. It is supposed responsible of an increase of estradiol levels in males. Aim of this study is to verify whether there is a relation between 1-HOPu and plasmatic estradiol in non-smoker male workers. METHODS: The study was conducted on a sample of 122 non-smoker policemen in a large Italian city; we monitored their levels of 1-HOPu and the values of estradiol. The sample was divided into three groups according to the levels of urinary hydroxypyrene. The indices of correlation (r) and multiple linear regression (ß), between levels of 1-HOPu and estradiol were calculated. It was also calculated the student's t-test among the groups to check the differences. RESULTS: We found statistically significant correlations and multivariate linear regressions between 1-HOPu and estradiol in the total sample and in group III (levels of 1-HOPu above the 75th percentile). The average levels of estradiol in group III was statistically and significantly higher than in the group I (levels of 1-HOPu below the 25th percentile) and group II (levels 1-HOPu between 25th and the 75th percentile). CONCLUSIONS: 1-HOPu in non-smoker male workers is related with an increase of plasmatic estradiol. We believe that PAHs, of which 1-HOPu is the main biomarker, can interact with the hypothalamic-pituitary axis. The preliminary results suggest that the topic needs further research on male and female as well.

[Urban individual exposure to cadmium and baroreceptor response to posture]. / Esposizione ad inquinanti urbani e riflessi barocettivi posturali.

OBJECTIVE: Outdoor workers are daily exposed to urban pollutants. The aim of the study is to evaluate the relationship between the values of environmental monitoring collected by personal dosimetries and changes in blood pressure due to posture in outdoor workers. MATERIALS AND METHODS: 32 subjects of both sexes were enrolled in the study, we evaluated the values of environmental monitoring of breathable dust, nickel, arsenic, cadmium, lead, benzene, toluene, xylene and 16 PAHs. Blood pressure in supine and standing positions was measured in all subjects. RESULTS: The multiple linear regression analysis showed a significant reduction of orthostatic response of diastolic blood pressure in non-smoking outdoor workers occupationally exposed to cadmium. CONCLUSIONS: The results of our study let us to believe that exposure to low doses of urban polluted cadmium may affect the response of diastolic blood pressure to orthostatism, as per a paraphysiological condition of sympathetic down-regulation.

Liver damage in automotive and industrial workers of the glass.

OBJECTIVE: High doses of organic solvents can cause hepatic disease. We investigated whether exposure to low doses of solvents in automotive and industrial workers may lead to changes in liver tests. METHODS: We studied the liver parameters (glutamic oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), gamma-glutamyl-traspeptidasi (γ-GT), alkaline phosphatase (PHA), total (TB) and direct bilirubin (DB) of 24 workers exposed to organic solvents and of 30 unexposed controls. RESULTS: A significant increase of GOT, GPT and γ-GT was found in exposed workers compared to unexposed controls workers. The ratio GPT/GOT was significantly higher among the exposed compared to controls. CONCLUSIONS: The results confirmed the hypothesis that exposure to low doses of solvents may determine a liver damage.

Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pazopanib: the role of circulating interleukin-8 to enhance the prognostic accuracy.

BACKGROUND: Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients. METHODS: EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model. RESULTS: Increasing IL8(T1) level associated with lower response probability at covariance analysis (P=0.010). Both IL8(T0) (P=0.019) and IL8(T1) (P=0.004) associated with OS and the prognostic model, including clinical variables and IL8(T1) best-predicted OS after backward selection. The NRI for this model was 39%.When analysed as a time-varying covariate, IL8(T1) level<80 pg ml(-1) portended significantly greater response (∼80%) and 6-month OS (∼60%) probability than level ≥ 80. CONCLUSION: IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.

Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): final results of the ROSORC trial.

BACKGROUND: The ROSORC trial, a randomised, phase II trial comparing sorafenib plus interleukin (IL-2) versus sorafenib alone as first-line treatment of metastatic renal cell carcinoma (mRCC) failed to demonstrate differences in progression-free survival (PFS). Updated overall survival (OS) results are reported. PATIENTS AND METHODS: In this study, 128 patients were randomised to receive sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 million international units (MIU) five times per week for 6 weeks every 8 weeks (arm A) or sorafenib alone (arm B). OS was estimated with the Kaplan-Meier method and compared with the two-sided log-rank test. RESULTS: After a median follow-up of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in arms A and B, respectively (P = 0.667). The 5-year OS was 26.3% [95% confidence interval (CI) 15.9-43.5) and 23.1% (95% CI 13.2-40.5) for the combination- and single-agent arm, respectively. Most of the patients who were refractory to first-line treatment were subsequently treated with different targeted agents; they had a median survival greater than expected. CONCLUSIONS: This outcome suggests a synergistic effect of the subsequent therapies following sorafenib failure. CLINICALTRIALSGOV IDENTIFIER: NCT00609401.

Unplanned presentations of cancer outpatients: a retrospective cohort study.

PURPOSE: As a result of the growing cancer incidence and the increasing trend towards chemotherapy treatment, a higher number of cancer outpatients ask for unplanned visits. This study aimed to describe the nature and magnitude of this phenomenon and to identify risk factors for repeated unplanned presentations and hospital admission. METHODS: Unplanned consultations (2,811) of 1,431 cancer patients who accessed our acute oncology clinic over a 2-year period were reviewed. Demographics, clinical variables and reason(s) for presentation were all recorded. Recurrent event survival analysis was used to evaluate the relation of potential predictors to the two outcome events repeated presentations and hospitalization. A stratified Cox proportional hazard model was used. RESULTS: Of 1,431 patients, 625 (43 %) received chemotherapy during the 90 days before the unplanned visit. Pain (27.7 %), fatigue (17.6 %), dyspnoea (13.8 %), fever (11.5 %) and gastrointestinal problems (31 %) were reported frequently. The time interval since the last chemotherapy was significantly related to the rate of repeated presentation. Two hundred and nine patients (7 %) were hospitalized after an unplanned presentation. Number of symptoms and selected toxicities, along with distance from the hospital, were all predictors for hospitalization. CONCLUSIONS: The management of unscheduled presentations of cancer outpatients is becoming crucial to avoid inappropriate selection for hospital admission and interferences with the ordinary work plan, improving quality of oncology services.

Safety and activity of sunitinib in elderly patients (≥ 70 years) with metastatic renal cell carcinoma: a multicenter study.

BACKGROUND: Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives). RESULTS: Sixty-eight patients were eligible, and the median age was 74 years. CGA was carried out in 34 patients (41% fit, 41% vulnerable and 18.5% frail). The dose reduction to 37.5 mg was made upfront or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%) and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%: 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response. CONCLUSIONS: Treatment with sunitinib is effective in elderly patients; yet early interruptions were frequent. Starting treatment at reduced dose and escalating in the absence of severe toxicity could be suggested.

[Exposure to cadmium and plasma cortisol in workers exposed to urban stressor]. / Esposizione a cadmio e cortisolo plasmatico in lavoratori esposti a stressor urbani.

OBJECTIVES: The aim of this study is to estimate the exposure to Cd in a group of roadmen compared to a group of drivers by environmental monitoring and biological monitoring of blood and urinary Cd. It aims to evaluate whether exposure to Cd can affect plasma cortisol. MATERIALS AND METHODS: The initial sample was composed by 130 employees of Municipal Police Force (roadmen and drivers). After administration of a clinical-anamnestic questionnaire were excluded 50 subjects who presented confounding factors and 30 subjects who weren't comparable. On a final sample of 25 drivers and 25 roadmen were conducted environmental monitoring of Cd, biological monitoring of urinary and blood Cd and assessment of cortisol. RESULTS: Personal exposure to Cd in air was significantly higher in roadmen compared to drivers (p = 0.015). Urinary and blood Cd were significantly increased in roadmen compared to drivers (p = 0.18 and p = 0.025). There weren't significant differences in plasma cortisol between drivers and roadmen (p> 0.05). The multiple linear regression analysis shows that urinary and blood Cd are dependent on the environment Cd levels and on the job (driver or roadmen) (p = 0.014 and p = 0.012) and plasma cortisol isn't dependent on blood and urinary Cd. CONCLUSIONS: The results show a higher concentration of Cd in roadmen both in air and urine and they don't indicate an influence of exposure to low doses of Cd on plasma cortisol.

Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial.

BACKGROUND: Preclinical investigations support combining sorafenib with IL-2 in the treatment of metastatic renal cell carcinoma (mRCC). METHODS: In this open-label, phase II study, 128 patients with mRCC were randomised to receive oral sorafenib, 400 mg twice daily, plus subcutaneous IL-2, 4.5 million international units (MIU) five times per week for 6 in every 8 weeks, or sorafenib alone. After enrolment of the first 40 patients, IL-2 dose was reduced to improve the tolerability. RESULTS: After a median follow-up of 27 months, median progression-free survival (PFS) was 33 weeks with sorafenib plus IL-2, and 30 weeks with sorafenib alone (P=0.109). For patients receiving the initial higher dose of IL-2, median PFS was 43 weeks vs 31 weeks for those receiving the lower dose. The most common adverse events were asthenia, hand-foot syndrome, hypertension, and diarrhoea. Grade 3-4 adverse events were reported for 38 and 25% of patients receiving combination and single-agent treatment, respectively. CONCLUSION: The combination of sorafenib and IL-2 did not demonstrate improved efficacy vs sorafenib alone. Improvements in PFS appeared greater in patients receiving higher-dose IL-2.

Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis.

The transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is an important regulator of hepatic lipid metabolism. While PPARalpha is known to activate transcription of numerous genes, no comprehensive picture of PPARalpha binding to endogenous genes has yet been reported. To fill this gap, we performed Chromatin immunoprecipitation (ChIP)-chip in combination with transcriptional profiling on HepG2 human hepatoma cells treated with the PPARalpha agonist GW7647. We found that GW7647 increased PPARalpha binding to 4220 binding regions. GW7647-induced binding regions showed a bias around the transcription start site and most contained a predicted PPAR binding motif. Several genes known to be regulated by PPARalpha, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPARalpha binding to their promoter. A GW7647-induced PPARalpha-binding region was also assigned to SREBP-targets HMGCS1, HMGCR, FDFT1, SC4MOL, and LPIN1, expression of which was induced by GW7647, suggesting cross-talk between PPARalpha and SREBP signaling. Our data furthermore demonstrate interaction between PPARalpha and STAT transcription factors in PPARalpha-mediated transcriptional repression, and suggest interaction between PPARalpha and TBP, and PPARalpha and C/EBPalpha in PPARalpha-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPARalpha in human liver and highlight the importance of cross-talk with other transcription factors.

Neo-adjuvant exemestane in elderly patients with breast cancer: a phase II, multicentre, open-label, Italian study.

BACKGROUND: The steroidal aromatase inhibitor exemestane has demonstrated efficacy for the treatment of breast cancer in the metastatic and adjuvant settings. Smaller trials have also reported efficacy in the neo-adjuvant setting. PATIENTS AND METHODS: This phase II, open-label, multicentre study examined the efficacy and safety of neo-adjuvant exemestane in women aged >70 years with operable, receptor-rich breast cancer. Consecutive eligible patients received exemestane 25 mg/day for 6 months before planned surgery. The primary end point was clinical response. RESULTS: Overall, 117 patients were recruited (median age 80 years). The objective response rate in 112 assessable patients (85 with clinical and mammographic evaluation; 27 with clinical evaluation only) was 69.6% (two complete responses; 76 partial responses). In patients who responded, median tumour size reduced from 4.81 to 2.12 cm. Seventy-seven patients (68.7%) continued to surgery. Of the 40 patients eligible for breast-conserving surgery, 34 (85%) deemed unfit for this procedure at baseline. Exemestane-related adverse events were unremarkable except for grade 3 allergic skin reactions in two patients (1.8%). CONCLUSION: Neo-adjuvant exemestane given for 6 months appears to be effective for receptor-rich breast cancer in older patients. There may now be sufficient evidence to support the use of neo-adjuvant in this patient population.

Simplified gemcitabine and platin regimen in patients with advanced or metastatic non-small cell lung cancer (NSCLC) to be proposed as neoadjuvant therapy.

BACKGROUND: Chemotherapy of non-small-cell lung cancer (NSCLC) has been improved by the use of cis-platin (P) and the pyrimidine antimetabolite gemcitabine (G) (2',2'-difluorodeoxycytidine). GP regimens currently used in Italy for NSCLC were and are mainly based on G day 1, 8 and 15; P on day 2, every 28 days (4 Day-Hospital admissions per cycle). However, the third G dose is frequently omitted because of myelo-toxicity, with a consistent dose decrease of both G and P in comparison with the intended dose. The 24-h lag time from 1(st) G and P has not reasonable clinical pharmacology base. AIM OF THE STUDY: To have a simplified GP regimen based on two Day-Hospital admissions per cycle, with G on day 1 and 8, P after G on day 8; every 21 days, with the goal to use it in the neoadjuvant setting. MATERIAL AND METHODS: The study was designed as a controlled, prospective, multicentre investigation, based on G (1500 mg/m(2)) on day 1 and 8, and P (100 mg/m(2)) on day 8 immediately following G, administered on a 3-week cycle. Quality of life (EORTC) was valuated in 46 patients out of 95 valuable patients. Restaging procedures were repeated after the 3rd and the 6th cycle. RESULTS: Enrolled patients were 105 (stage IV: 63: IIIB: 29; IIIA: 13). GP cycles were 488 (1 to 6 per patient) 95 patients had at least 3 cycles and 59 of them had further 3 cycles. Myelotoxicity >or= g3 was mainly neutropenia, easily amenable with symptomatic and GCSF therapies (12.6% neutropenic fever); PNS toxicity occurred in 17.9% of patients. QoL was ameliorated (P < 0.05). Therapy was tolerable and gave a Response Rate (RR) of 52.3% after 3 cycles (Intention-to-treat analysis) and of 57.9% in 95 valuable patients who received at least 3 therapy cycles. CONCLUSION: Present results confirm a good efficacy and/or synergism of G to P, with G on day 1 and 8 and P on day 8. This two day-hospital admissions regimen is at least as good as more complex GP regimens, and may be proposed in the neoadjuvant setting.