Search

Perfluorooctanoic acid (PFOA), a global environmental pollutant detected in both wildlife and human populations, has several pathophysiological effects in experimental animals, including hepatotoxicity, immunotoxicity, and developmental toxicity. However, details concerning the tissue distribution of PFOA, in particular at levels relevant to humans, are lacking, which limits our understanding of how humans, and other mammals, may be affected by this compound. Therefore, we characterized the tissue distribution of

International audience; Objective: The aim was to create and validate a community-acquired pneumonia (CAP) diagnostic algorithm to facilitate diagnosis and guide chest computed tomography (CT) scan indication in patients with CAP suspicion in Emergency Departments (ED).Methods: We performed an analysis of CAP suspected patients enrolled in the ESCAPED study who had undergone chest CT scan and detection of respiratory pathogens through nasopharyngeal PCRs. An adjudication committee assigned the final CAP probability (reference standard). Variables associated with confirmed CAP were used to create weighted CAP diagnostic scores. We estimated the score values for which CT scans helped correctly identify CAP, therefore creating a CAP diagnosis algorithm. Algorithms were externally validated in an independent cohort of 200 patients consecutively admitted in a Swiss hospital for CAP suspicion.Results: Among the 319 patients included, 51% (163/319) were classified as confirmed CAP and 49% (156/319) as excluded CAP. Cough (weight = 1), chest pain (1), fever (1), positive PCR (except for rhinovirus) (1), C-reactive protein ≥50 mg/L (2) and chest X-ray parenchymal infiltrate (2) were associated with CAP. Patients with a score below 3 had a low probability of CAP (17%, 14/84), whereas those above 5 had a high probability (88%, 51/58). The algorithm (score calculation + CT scan in patients with score between 3 and 5) showed sensitivity 73% (95% CI 66-80), specificity 89% (95% CI 83-94), positive predictive value (PPV) 88% (95% CI 81-93), negative predictive value (NPV) 76% (95% CI 69-82) and area under the curve (AUC) 0.81 (95% CI 0.77-0.85). The algorithm displayed similar performance in the validation cohort (sensitivity 88% (95% CI 81-92), specificity 72% (95% CI 60-81), PPV 86% (95% CI 79-91), NPV 75% (95% CI 63-84) and AUC 0.80 (95% CI 0.73-0.87).Conclusion: Our CAP diagnostic algorithm may help reduce CAP misdiagnosis and optimize the use of chest CT scan.

High-dose exposure of mice to perfluorooctanoate (PFOA) induces both hepatotoxicity and immunotoxicity. Here, we characterized the effects of 10-day dietary treatment with PFOA (0.002-0.02%, w/w) on the liver and complement system of male C57BL/6 mice. At all four doses, this compound caused hepatomegaly and reduced the serum level of triglycerides (an indicator for activation of the peroxisome proliferator-activated receptor-alpha (PPARα)). At the highest dose (0.02%, w/w), this hepatomegaly was associated with the hepatic injury, as reflected in increased activity of alanine aminotranferase (ALAT) in the serum, severe hepatocyte hypertrophy and hepatocellular necrosis. PFOA-induced hepatic injury was associated with in vivo activation of the complement system as indicated by (i) significant attenuation of the serum activities of both the classical and alternative pathways; (ii) a marked reduction in the serum level of the complement factor C3; and (iii) deposition of the complement factor C3 fragment (C3a) in the hepatic parenchyma. PFOA did not activate the alternative pathway of complement in vitro. At doses lower than 0.02%, PFOA induced hepatocyte hypertrophy without causing liver injury or activating complement. These results reveal substantial involvement of activation of complement in the pathogenesis of PFOA-induced hepatotoxicity.

The present study aimed to assess parental perceptions of weight-based victimization (WBV) and its consequences for children's health as well as how perceptions of WBV vary by parental and child weight status.A national sample of American parents with children ages 2-18 years (N=918) completed an online questionnaire to assess their perceptions of how common WBV is, compared to other forms of victimization among youth, their level of concern with this issue both generally and for their own child, and their perceptions of behavioral and psychological consequences of WBV. Descriptive statistics and censored regression models with standardized coefficients were used to analyze the data.Fifty-three percent of parents perceived "being overweight" to be the most common reason that youth are bullied, regardless of parental or child weight status. Parents, both with and without overweight children, endorsed similar levels of general concern about WBV and its psychological and behavioral consequences for youth. However, parents with overweight children were substantially more concerned about WBV affecting their child(ren) and perceived it to be more common, serious, and posed risks to their child(ren)'s health, compared to parents without overweight children.The present study, to the best of the authors' knowledge, is the first to indicate that parents have substantial concerns about WBV and its health consequences for youth. These findings highlight the need for educators and pediatric healthcare providers to be aware that WBV is a common concern among families, and suggest that increased efforts are needed to address WBV.

The news media has substantial influence on public perceptions of social and health issues. This study conducted a video content analysis to examine portrayals of obese persons in online news reports about obesity. The authors downloaded online news videos about obesity (N = 371) from 5 major news websites and systematically coded visual portrayals of obese and nonobese adults and youth in these videos. The authors found that 65% of overweight/obese adults and 77% of overweight/obese youth were portrayed in a negative, stigmatizing manner across multiple obesity-related topics covered in online news videos. In particular, overweight/obese individuals were significantly more likely than were nonoverweight individuals to be portrayed as headless, with an unflattering emphasis on isolated body parts, from an unflattering rear view of their excess weight, eating unhealthy foods, engaging in sedentary behavior, and dressed in inappropriately fitting clothing. Nonoverweight individuals were significantly more likely to be portrayed positively. In conclusion, obese children and adults are frequently stigmatized in online news videos about obesity. These findings have important implications for public perceptions of obesity and obese persons and may reinforce negative societal weight bias.

Exposure of mice to perfluorooctanoate (PFOA) evokes pronounced hepatomegaly along with significant alterations in both the histological structure and immune status of the liver. The present study was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. In this connection, the influence of both sub-acute (10 days), moderate-dose (0.002% w/w = 3 ± 0.7 mg/kg body weight/day) and short-term (28 days), low-dose (0.00005% w/w = 70 ± 2 μg/kg body weight/day) dietary pretreatment with PFOA on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With sub-acute, moderate, but not short-term, low-dose exposure, PFOA aggravated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This aggravation was associated with significantly enhanced hepatic level of interleukin-6 (IL-6), but unaltered hepatic levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-4 (IL-4). Moreover, hepatic DNA fragmentation was not changed by sub-acute exposure to the moderate-dose. Our findings imply that exposure to PFOA may sensitize hepatic parenchymal cells to other toxicants that activate the hepatic immune system and thereby aggravate liver injury during acute inflammation.

It is well established that exposure of mice to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) exerts adverse effects on the thymus and spleen. Here, we characterize the effects of a 10-day dietary treatment with these compounds (0.001–0.02%, w/w) on the bone marrow (BM) of mice. At a dose of 0.02%, both compounds reduced food consumption and caused atrophy of the thymus and spleen. At this same dose, histopathological and flow cytometric analysis revealed that (i) the total numbers of BM as well as the numbers of myeloid, pro/pre B, immature B and early mature B cells were all reduced significantly; and (ii) these adverse effects were reversed either partially or completely 10 days after withdrawal of these compounds. At the lower dose of 0.002%, only PFOA reduced the B-lymphoid cell population. Finally, mice fed an amount of diet equivalent to that consumed by the animals exposed to 0.02% PFOA also exhibited atrophy of the thymus and spleen, and a reduction in the number of B-lymphoid population, without affecting myeloid cells. Thus, in mice, immunotoxic doses of PFOA or PFOS induce adverse effects on the myeloid and B-lymphoid cells in the BM, in part as a consequence of reduced food consumption.

We have previously shown that short-term, high-dose exposure of mice to the environmentally persistent perfluorooctanoate (PFOA) results in thymic and splenic atrophy and the attenuation of specific humoral immune responses. Here we characterize the effects of a 10-day treatment with different dietary doses (1-0.001%, w/w) of perfluorooctanesulfonate (PFOS), a similar fluorochemical, on the immune system of male C57BL/6 mice. At doses greater than 0.02%, PFOS induced clinical signs of toxicity in the animals, whereas at the concentration of 0.02%, this compound caused weight loss, hepatomegaly and atrophy of the thymus, spleen and adipose tissue without toxicity. With this latter dose, histopathological and flow-cytometric analysis revealed that (i) the thymic cortex was virtually depleted of cells; (ii) the total numbers of thymocytes and splenocytes were reduced by 84 and 43%, respectively; (iii) although all populations of thymocytes and splenocytes were smaller, the thymic CD4(+)CD8(+) cells and the splenic B-lymphocytes were most decreased. These alterations resembled those evoked by analogous exposure to PFOA, but were less pronounced. At lower doses (less than 0.02%), PFOS induced hepatomegaly without affecting the thymus or spleen. Finally, comparison of male wild-type 129/Sv mice and the corresponding knock-outs lacking peroxisome proliferator-activated receptor-alpha (PPARalpha) indicated that these effects of PFOS are not strain-dependent. More importantly, hepatomegaly is independent of PPARalpha, the thymic changes are partially dependent on this receptor, and splenic responses are largely eliminated in its absence. Thus, immunomodulation caused by PFOS is a high-dose phenomenon partially dependent on PPARalpha.

SummaryIntrahepatic immune cells (IHIC) are known to play central roles in immunological responses mediated by the liver, and isolation and phenotypic characterization of these cells is therefore of considerable importance. In the present investigation, we developed a simple procedure for the mechanical disruption of mouse liver that allows efficient isolation and phenotypic characterization of IHIC. These cells are compared with the corresponding cells purified from the liver after enzymatic digestion with different concentrations of collagenase and DNase. The mechanical disruption yielded viable IHIC in considerably greater numbers than those obtained following enzymatic digestion. The IHIC isolated employing the mechanical disruption were heterogeneous in composition, consisting of both innate and adaptive immune cells, of which B, T, natural killer (NK), NK T cells, granulocytes and macrophages were the major populations (constituting 37·5%, 16·5%, 12·1%, 7·9%, 7·9% and 7·5% of the total number of cells recovered respectively). The IHIC obtained following enzymatic digestion contained markedly lower numbers of NK T cells (1·8%). The B, T and NK T cells among IHIC isolated employing mechanical disruption were found to be immunocompetent, i.e. they proliferated in vitro in response to their specific stimuli (lipopolysaccharide, concanavalin A and α-galactosylceramide respectively) and produced immunoglobulin M and interferon-γ. Thus, the simple procedure for the mechanical disruption of mouse liver described here results in more efficient isolation of functionally competent IHIC for various types of investigation.

Introduction We designed this phase II trial to evaluate the efficacy and safety of weekly paclitaxel in combination with monthly carboplatin as first-line treatment in elderly patients with advanced non-small cell lung cancer (NSCLC). Methods Main eligibility criteria were histologically or cytologically proven stage IIIB or IV NSCLC, age ≥70 years, Eastern Cooperative Oncology Group performance status 0-2, and measurable disease. The 4-week–based chemotherapy regimen consisted of carboplatin infusion (area under the concentration-time curve 6 mg/ml -1 /min) on day 1 and paclitaxel 90 mg/m 2 as a 1-hour infusion on days 1, 8, and 15. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors criteria, and symptoms were evaluated using the Lung Cancer Symptoms Scale. Analyses were performed on an intention-to-treat basis. Results From February 2002 to August 2003, 51 patients (median age, 74 years) participated in the study. One complete and 21 partial responses were reported by the independent review committee, leading to an intention-to-treat objective response rate of 43% (95% confidence interval, 30–57%). The median progression-free and overall survivals were 7.5 (95% confidence interval, 6.2–9.4) and 13.6 (95% confidence interval, 7.5–17) months, respectively. Longitudinal evaluation of the Lung Cancer Symptoms Scale demonstrated lack of quality of life modification during the treatment period. Neurotoxicity was mild to moderate, with 6% of patients suffering from a grade 3 or 4 neuropathy. Myelosuppression was the main toxicity; 39% of patients experienced grade 3 or 4 neutropenia, 18% experienced grade 3 anemia, and 8% experienced grade 3 or 4 thrombocytopenia. There was no treatment-related death. Conclusions The combination of weekly paclitaxel 90 mg/m 2 administered on days 1, 8, and 15 plus monthly carboplatin area under the curve 6 on day 1 of a 4-week cycle was feasible and active as a first-line treatment for elderly patients with NSCLC with a good safety profile. These results deserve further analysis to compare the standard care for these patients (monotherapies) with this doublet.

Background This multicenter, randomized, phase III study compared the efficacy, including progression-free survival (PFS), and safety of gemcitabine–docetaxel (GD) combination versus cisplatin–vinorelbine (CV) in the treatment of advanced non-small-cell lung cancer (NSCLC). Patients and methods Chemonaive patients with stage IIIB or IV NSCLC were treated with GD (gemcitabine 1000 mg/m2 days 1 and 8 plus docetaxel 85 mg/m2 day 8, every 3 weeks for eight cycles) or CV (cisplatin 100 mg/m2 day 1 plus vinorelbine 30 mg/m2, days 1, 8, 15 and 22, every 4 weeks for six cycles). Results A total of 311 patients were enrolled (155 GD and 156 CV). Neither PFS nor overall survival differed significantly between the two arms (median PFS 4.2 and 4 months; median survival 11.1 and 9.6 months; 1-year survival 46% and 42%, for GD and CV, respectively). For the GD arm compared with the CV arm, the hazard ratio for PFS was 1.04 [95% confidence interval (CI) 0.83–1.32], and for overall survival, it was 0.90 (95% CI 0.70–1.16). Objective response rates did not differ significantly (31% for GD, 35.9% for CV). Myelosupression, emesis and frequency of febrile neutropenia were less pronounced on the GD arm, whereas fluid retention and pulmonary events were more pronounced. The CV arm experienced a higher number of serious adverse events and a lower compliance with the protocol. There was no quality of life (QoL) difference between arms. Median time to definite impairment of health-related QoL was 153 and 168 days in GD and CV arms, respectively. Conclusions There was no advantage in PFS with GD compared with CV; however, the CV regimen had higher rate of toxic events, mainly myelosuppression. The herein, non-platinum-containing regimen could be considered as a rational alternative to the cisplatin-based doublet.

Brain metastases are a frequent feature of the course of non-small cell lung carcinoma (NSCLC). The potential usefulness of prophylactic cranial irradiation (PCI) has led to the search for target groups likely to derive benefit. This multivariate analysis looked for factors predictive of brain metastases in a group of stages I-III NSCLC patients under care of the thoracic oncology unit of Besancon University Hospital from 1977 to 2001. All the patients had the same follow-up. They were divided into two groups: BM+ when they had a brain metastasis as the first site of progression, whether solitary or not, and BM(-) otherwise. Variables analysed were age, gender, performance status (0-1 versus 2-3), weight-loss stage T-status, N-status, pathological type, type of treatment, administration of chemotherapy, use of cisplatin and response to treatment. Three hundred and five patients were eligible and there were 77 patients (25.25%) in the BM+ group. Median time to onset of brain metastases was 12 months (1-163 months) and median survival from the diagnosis of brain metastases was 6 months (1-65 months). Factors predictive of brain progression were age < or =62 years (RR: 2.5, 95% CI: 1.33-4.76 and P = 0.004), T4 tumour status (RR: 3.75, 95% CI: 1.72-8.21 and P = 0.0009), N2-3 (RR: 2.61, 95% CI: 1.32-5.15 and P = 0.0057), and adenocarcinoma (RR: 3.39, 95% CI: 1.78-6.46 and P = 0.0002). No aspect of treatment plays a role in the frequency of this type of metastasis. These factors predictive of brain progression could serve as a basis for the selection of patients with the aim of sitting of studies on prophylactic cranial irradiation in NSCLC.

Background The survival benefit associated with first-line chemotherapy in advanced lung cancer led to the need for second-line chemotherapy. Docetaxel (Taxotere®) has proven efficacy in both settings. This study evaluated the safety and efficacy of two doses of docetaxel in patients with non-small-cell lung cancer who had failed first-line platinum-based chemotherapy. Patients and methods In total, 182 patients from 24 French centres were randomised and treated with either docetaxel 75 mg/m2 (arm A) or 100 mg/m2 (arm B) every 3 weeks. Baseline characteristics were well balanced, except more patients in arm A had metastatic disease (91.4% versus 78.7%) and therefore the median number of sites involved for arm A was three compared with two for arm B. Results Median time to treatment failure was 1.34 months [95% confidence interval (CI) 1.28–1.64] for arm A and 1.64 months (95% CI 1.34–2.62) for arm B. Median overall survival was 4.7 months (95% CI 3.8–5.9) for arm A versus 6.7 months (95% CI 4.8–7.1) for arm B. According to a blinded expert panel, disease control was achieved in 35 (43.8%) patients in arm A and 39 (49.4%) patients in arm B. More patients in arm B experienced grade 3–4 neutropenia (B: 72.7% versus A: 44.0%), asthenia (B: 20.2% versus A: 10.8%) and infection (B: 6.7% versus A: 2.2%). Three treatment-related deaths were reported in each arm. Conclusions The optimal docetaxel dosage in this second-line setting is 75 mg/m2, as it has a more favourable safety profile and on balance a similar efficacy to the 100 mg/m2 dose.

We have previously demonstrated that severe adipose tissue atrophy occurs upon dietary treatment of mice with potent peroxisome proliferators (PPs). This atrophy occurs subsequent to peroxisome proliferation in the liver and may represent a novel addition to the pleiotropic effects exerted by PPs. In the present study we have characterized the recovery of mice from such atrophy following cessation of exposure. Following termination of treatment with perfluorooctanoic acid (PFOA) for 7 days, the adipose tissue atrophy was rapidly reversed, beginning on 2-5 days of recovery and being complete within 10 days. In contrast, hepatic peroxisome proliferation recovered much more slowly, indicating that these processes are not strictly coordinated. Analysis of lipoprotein lipase and hormone-sensitive lipase activities in adipose tissue revealed that the decrease and increase in these activities, respectively, caused by PFOA were both reversed within 10 days of recovery. Overall, these data provide further support for our previous conclusion that the adipose tissue atrophy induced by PFOA is caused, at least in part, by changes in the activities of lipoprotein lipase and hormone-sensitive lipase. The serum level of cholesterol, which increased after termination of PFOA treatment, returned to normal with a time-course similar to the recovery of adipose tissue weight, although hepatic peroxisome proliferation was still present. The possible relationship between the reduction in serum cholesterol and/or in its availability to peripheral tissues and the associated atrophy of adipose tissues caused by PPs is discussed.

Peroxisome proliferators (PPs) are a large class of structurally diverse chemicals, which includes drugs designed to improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin-resistance and atherosclerosis. We have recently demonstrated that exposure of rodents to potent PPs indirectly causes a number of immunomodulating effects, resulting in severe adaptive immunosuppression. Since the peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in mediating the pleiotropic responses exerted by PPs, we have compared here the immunomodulating effects of the PPs perfluorooctanoic acid (PFOA) and Wy-14,643 in wild-type and PPARalpha-null mice. The reductions in spleen weight and in the number of splenocytes caused by PP treatment in wild-type mice was not observed in PPARalpha-null mice. Furthermore, the reductions in thymus weight and in the number of thymocytes were potently attenuated in the latter animals. Similarly, the dramatic decreases in the size of the CD4(+)CD8(+) population of cells in the thymus and in the number of thymocytes in the S and G2/M phases of the cell cycle observed in wild-type mice administered PPs were much less extensive in PPARalpha-null mice. Finally, in contrast to the case of wild-type animals, the response of splenocytes isolated from the spleen of PP-treated PPARalpha-null mice to appropriate T- or B-cell activators in vitro was not reduced. Altogether, these data indicate that PPARalpha plays a major role in the immunomodulation caused by PPs. The possible relevance of these changes to the alterations in plasma lipids also caused by PPs is discussed.

To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC).A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy.Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033).Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease.

International audience; BACKGROUND: Lung cancer in the elderly is considerably increasing in frequency, representing a public health issue. Those patients are underrepresented in clinical trials and probably not optimally treated. METHODS: We performed a survey of the management and the outcome of lung cancer patients aged 70 and more in France between August 2002 and September 2003 according to age categories (70-74, 75-79 and > or =80 years). One thousand six hundred and twenty-seven patients were analysed for descriptive data and 1595 for survival. RESULTS: Median age was 75 (70-96) and male:female ratio was 4.26 with a decrease across the age categories from 5.1 to 3.0. Tobacco-linked comorbidities were frequent. The median value of Charlson's index was 2. About 58% had a performance status (PS) 0 or 1, 30% a PS 2 and 12% a PS>2. The proportion of never-smokers (11.6%) increased significantly with age categories. Regarding imaging procedures, as much as 83.3% of the patients had at least a chest CT-scan and a brain CT-scan (or MRI) and an abdominal ultrasound or CT-scan. Best Supportive Care (BSC) as only treatment was administered to 16.1% of the patients. Among patients specifically treated, 22.9% were operated, 21.8% received mediastinal irradiation and 71.5% chemotherapy. Overall, median survival time was 9.14 months with 23.5% deaths occurring before 3 months. Low category of age, good PS, non-smoking and high body mass index (BMI) were favorable independent prognostic factors of survival. Age, PS and tobacco smoking were prognostic of early death. CONCLUSIONS: A large majority of elderly lung cancer patients in France are managed like younger counterparts regarding diagnostic procedures and treatment. Age remains an independent prognostic factor as well for overall survival as for early death.

A randomized phase II trial of oral vs. intravenous (i.v.) vinorelbine was designed to determine the efficacy and safety of oral vinorelbine with an intrapatient dose escalation in previously untreated patients with advanced non-small-cell lung cancer (NSCLC).Between December 1997 and April 1999, 115 patients with stage IIIB or IV NSCLC were randomized (2 to 1) to receive either oral vinorelbine at a dose of 60 mg/m2/week for the first three administrations and then increased to 80 mg/m2/week in the absence of severe neutropenia, or i.v. vinorelbine at 30 mg/m2/week.One hundred and fourteen patients (76 in the oral arm and 38 in the i.v. arm) were treated. Ninety-eight patients (86%) were eligible and assessable. The two treatment arms were well-balanced for demographic and prognostic features. After external panel review, the response rates in evaluable patients were 14%, in the oral arm and 12% in the i.v. arm. The median progression-free survival with oral and i.v. vinorelbine was 3.2 months and 2.1 months, respectively, and the median survival 9.3 and 7.9 months, respectively. The most common hematological toxicity was neutropenia, which was severe (grade 3-4) in 46% of patients and for 7% of administrations in the oral arm, and in 62% of patients and for 25% of administrations in the i.v. arm. Non-hematological toxicities including nausea, vomiting, anorexia, weight loss, diarrhea .and constipation were generally mild to moderate.The activity of oral and i.v. vinorelbine in advanced NSCLC appears to be comparable. The safety profiles of both formulations look qualitatively similar. Oral vinorelbine can therefore be considered a good alternative to i.v. administration.

A dose escalation study of paclitaxel in combination with vinorelbine was conducted in 21 patients with previously untreated stage IIIb or IV non-small cell lung cancer (NSCLC). All three patients treated with the initial dose of paclitaxel 135 mg/m2 administered as a 1-h intravenous infusion and vinorelbine 25 mg/m2 experienced dose-limiting toxicity (febrile neutropenia). After modification of the dosing schedule, the MTD of paclitaxel was found to be 115 mg/m2 when combined with vinorelbine 20 mg/m2 on day 1, followed by vinorelbine 20 mg/m2 on day 5. Partial responses were achieved in 24% of patients, with a median duration of response of 126 days (range from 84 to 484 days) and a 1-year survival rate of 42%. In conclusion, haematologic toxicity (febrile neutropenia/neutropenia) severely restricts the dosing schedule of combined paclitaxel and vinorelbine, and possibly limits anti-tumour efficacy.

A multi-centre retrospective study involving 4 French university institutions has been conducted in order to identify routine pre-therapeutic prognostic factors of survival in patients with previously untreated non-small cell lung cancer and brain metastases at the time of presentation. A total of 231 patients were recorded regarding their clinical, radiological and biological characteristics at presentation. The accrual period was January 1991 to December 1998. Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The median survival of the whole population was 28 weeks. Univariate analysis (log-rank), showed that patients affected by one of the following characteristics proved to have a shorter survival in comparison with the opposite status of each variable: male gender, age over 63 years, poor performance status, neurological symptoms, serum neuron-specific enolase (NSE) level higher than 12.5 ng ml−1, high serum alkaline phosphatase level, high serum LDH level and serum sodium level below 132 mmol l−1. In the Cox's model, the following variables were independent determinants of a poor outcome: male gender: hazard ratio (95% confidence interval): 2.29 (1.26–4.16), poor performance status: 1.73 (1.15–2.62), age: 1.02 (1.003–1.043), a high serum NSE level: 1.72 (1.11–2.68), neurological symptoms: 1.63 (1.05–2.54), and a low serum sodium level: 2.99 (1.17–7.62). Apart from 4 prognostic factors shared in common with other stage IV NSCLC patients, whatever the metastatic site (namely sex, age, gender, performance status and serum sodium level) this study discloses 2 determinants specifically resulting from brain metastasis: i.e. the presence of neurological symptoms and a high serum NSE level. The latter factor could be in relationship with the extent of normal brain tissue damage caused by the tumour as has been demonstrated after strokes. Additionally, the observation of a high NSE level as a prognostic determinant in NSCLC might reflect tumour heterogeneity and understimated neuroendocrine differentiation. © 2001 Cancer Research Campaignhttp://www.bjcancer.com

An impairment of respiratory function has been demonstrated in dairy farmers. The objective of this study was to evaluate the relationship of allergy to respiratory function in dairy farmers in a longitudinal study conducted in the Doubs (France). A cohort of male dairy farmers constituted in 1990 was re-evalued in 1995. Subjects completed a medical and occupational questionnaire, and a spirometry test in both 1990 and 1995, in 1995 they were also subjected to immunological tests. Relationships between immunological variables and respiratory function were studied by a multiple linear regression model adjusted for age, smoking status, respiratory symptoms, altitude and occupational exposure. Amongst the 394 subjects of the initial cohort, 330 were included in the longitudinal study and 320 had immunological tests. Log immunoglobulin (Ig) E was negatively correlated with the 1995 respiratory function parameters (p

Background . Although a minimal follow-up with periodic clinic visits and chest radiographs is usually recommended after complete operation for non–small cell lung cancer, the ideal follow-up has not been defined yet. Objectives of this prospective study were to determine the feasibility of an intensive surveillance program and to analyze its influence on patient survival. Methods . Follow-up consisted of physical examination and chest roentgenogram every 3 months and fiberoptic bronchoscopy and thoracic computed tomographic scan with sections of the liver and adrenal glands every 6 months. Influence of patient and recurrence characteristics on survival from recurrence was successively analyzed using the log-rank test and a Cox model adjusted for treatment. Results . Among the 192 eligible patients, recurrence developed in 136 patients (71%) and was asymptomatic in 36 patients (26%). In 35 patients, recurrence was asymptomatic and detected by a scheduled procedure: thoracic computed tomographic scan in 10 (28%) patients and fiberoptic bronchoscopy in 10. Fifteen patients (43%) had a thoracic recurrence treated with curative intent. From the date of recurrence, 3-year survival was 13% in all patients and 31% in asymptomatic patients whose recurrence was detected by a scheduled procedure. Asymptomatic recurrences ( p p p = 0.01), and age 61 years or younger ( p = 0.01) were shown to be significantly favorable prognostic factors. Conclusions . This intensive follow-up is feasible and may improve survival by detecting recurrences after surgery for non–small cell lung cancer at an asymptomatic stage.

This study reports the results of 120 patients with inoperable non-small cell lung cancer treated with Navelbine at a dose of 25-30 mg/m2/week in a single-drug chemotherapy regimen. Surgery was contraindicated due to staging or to concomitant morbidity. Twenty patients achieved survival greater than or equal to 18 months, and one patient obtained exceptional survival of more than 120 months. The mean dose intensity of Navelbine in long-term survivors was 21.61 mg/m2/week. Objective response to Navelbine was found by multivariate analysis to be a prognostic factor for survival beyond 18 months. Weight loss of more than 5 kg of corporal weight was an unfavorable prognostic factor in patients with metastatic disease.

Thirty-one previously untreated patients with limited stage small-cell lung cancer (LSCLC) were included in a prospective study, to investigate the feasability and the efficacy of a combined modality treatment using concurrent hyperfractionated chest irradiation and cisplatin (P) plus etoposide (E) chemotherapy. All patients received intravenously P=75 mg/m 2 at day 1, plus E=120 mg/m 2 days 1–3, at 3-week intervals for six cycles. Irradiated patients received 45 Gy in two daily fractions, 5 days a week, from week 4 to week 6. During week 5, prophylactic cranial irradiation was initiated, in one daily fraction of 2.5 Gy for a total dose of 25 Gy. Twenty-nine patients were evaluable for response. Twenty-two (76%) achieved a complete response, five (17%) had a partial response. Five patients are currently alive. The overall response rate was 93% (CI 95% (83.7–100)). The median survival time was 14 months and the 2-year survival rate was 25%. Main toxicities were grade 3–4 esophagitis in half of the patients and myelosuppression. The results are not as optimistic as other studies using a similar regimen.

A novel and rapid procedure for the isolation of catalase from mouse liver, after prior treatment with the peroxisome proliferator perfluorooctanoic acid was developed using immobilized metal ion affinity chromatography involving chelation with zinc ions. The purification developed is simple, rapid (requiring 3 hours from cytosol or peroxisomal matrix to homogeneous proteins), reproducible, and yields virtually complete overall recovery of catalase activity. This procedure makes catalase from a variety of tissues and physiological and environmental conditions more readily available for study.

A nationwide retrospective study of exogenous lipid pneumonia (ELP) was carried out to update the data on this disease, with emphasis on thoracic computed tomography (CT) scan and bronchoalveolar lavage (BAL) findings. The inclusion criteria were: 1) presence of abnormal imaging features compatible with the diagnosis of ELP; 2) presence of intrapulmonary lipids; and 3) exogenous origin of the lipid pneumonia. Forty four cases were included (20 males and 24 females; mean age 62 +/- 11 yrs), of which four were occupational (chronic inhalation of cutting mist or oily vapour in an industrial environment). Thirty of the 40 nonoccupational cases were related to aspiration of liquid paraffin used for the treatment of constipation. A condition possibly favouring oil aspiration or inhalation was present in 34 patients (77%), most commonly gastro-oesophageal reflux (n = 20) and neurological or psychiatric illness (n = 14). Fever (39%), weight loss (34%), cough (64%), dyspnoea (50%) and crepitations (45%) were the most frequent symptoms. BAL was performed in 39 cases: 23% had a lymphocytic alveolitis; 14% neutrophilic alveolitis; and 31% a mixed alveolitis (lymphocytic and neutrophilic). Alveolar consolidations (57%), ground glass opacities (39%), and alveolar nodules (23%) were the most common radiological abnormalities. The changes were bilateral (79%), predominant in the posterior and lower zones of the lobes concerned (74%), hypodense (71%), and spared the subpleural zones (52%). In 13 cases, hypodensity was retrospectively established on CT scan by the presence of a "positive angiogram". This sign may be of diagnostic value when the density measurement is either not possible or not reliable. In conclusion, this study provides an update of the clinical, biological and radiological profile of exogenous lipid pneumonia and, in particular, confirms the diagnostic benefit of computed tomography scan, which revealed bilateral and hypodense changes in a large majority of cases.

Thirty-one patients with previously untreated advanced non-small cell lung cancer were included in a Phase I study to determine the optimal dose of Carboplatin (CBDCA) which preserves the best Navelbine (NVB) dose-intensity. NVB was administered at a 30-mg/m 2 fixed-dose on days 1–8/q 3 weeks, whereas CBDCA doses were planned to be escalated from 275 to 400 mg/m 2 on day 1/q 3 weeks for six successive groups of patients. The toxicity limiting dose of CBDCA in the combination was 350 mg/m 2 on day 1/q 3 weeks because of repetitive Grade IV neutropenia, and the optimal dose of CBDCA was 325 mg/m 2 on day 1/q 3 weeks, offering a 86.4% NVB and a 92.6% CBDCA relative dose-intensity for the first 9 weeks. Responses were observed at each step. This study demonstrates the feasibility and the efficacy of the NVB-CBDCA combination. It suggests that dose-intensity calculation can be helpful to determine the recommended dose for Phase II studies of new drug combinations.

Perfluorobutanesulfonyl fluoride (PBSF) has been introduced as a replacement for its eight-carbon homolog perfluorooctanesulfonyl fluoride (POSF) in the manufacturing of fluorochemicals. Fluorochemicals derived from PBSF may give rise to perfluorobutanesulfonic acid (PFBS) as a terminal degradation product. Although basic mammalian toxicokinetic data exist for PFBS, information on its tissue distribution has only been reported in one study focused on rat liver. Therefore, here we characterized the tissue distribution of PFBS in mice in the same manner as we earlier examined its eight-carbon homolog perfluorooctanesulfonate (PFOS) to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1, 3 or 5d to 16 mg (35)S-PFBS kg(-1) d(-1), both scintillation counting and whole-body autoradiography (WBA) revealed the presence of PFBS in all of the 20 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. After 5d of treatment the highest levels were detected in liver, gastrointestinal tract, blood, kidney, cartilage, whole bone, lungs and thyroid gland. WBA revealed relatively high levels of PFBS in male genital organs as well, with the exception of the testis. The tissue levels increased from 1 to 3 d of exposure but appeared thereafter to level-off in most cases. The estimated major body compartments were whole bone, liver, blood, skin and muscle. This exposure to PFBS resulted in 5-40-fold lower tissue levels than did similar exposure to PFOS, as well as in a different pattern of tissue distribution, including lower levels in liver and lungs relative to blood.

Research has documented negative stigma by health providers toward overweight and obese patients, but it is unknown whether physicians themselves are vulnerable to weight bias from patients. This study assessed public perceptions of normal weight, overweight or obese physicians to identify how physicians’ body weight affects patients’ selection, trust and willingness to follow the medical advice of providers. An online sample of 358 adults were randomly assigned to one of three survey conditions in which they completed a questionnaire assessing their perceptions of physicians who were described as normal weight, overweight or obese. Participants also completed a measure of explicit weight bias (Fat Phobia Scale) to determine whether antifat attitudes are associated with weight-related perceptions of physicians. Respondents reported more mistrust of physicians who are overweight or obese, were less inclined to follow their medical advice, and were more likely to change providers if the physician was perceived to be overweight or obese, compared to normal-weight physicians who elicited significantly more favorable reactions. These weight biases remained present regardless of participants’ own body weight. Inspection of interaction effects revealed opposing effects of weight bias between the obese/overweight and normal-weight physician conditions. Stronger weight bias led to higher trust, more compassion, more inclination to follow advice, and less inclination to change doctors when the physician was presented as normal weight. In contrast, stronger weight bias led to less trust, less compassion, less inclination to follow advice and higher inclination to change doctors when the physician was presented as obese. This study suggests that providers perceived to be overweight or obese may be vulnerable to biased attitudes from patients, and that providers’ excess weight may negatively affect patients’ perceptions of their credibility, level of trust and inclination to follow medical advice.

Exposure of rodents to perfluorooctane sulfonate (PFOS) induces pronounced hepatomegaly associated with significant alterations in hepatic histophysiology and immune status. The present investigation was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. Accordingly, the influence of both sub-acute (10 days), moderate-dose (0.004%, w/w = 6 ± 1.3 mg/kg body weight/day) or short-term (28 days), low-dose (0.0001%, w/w = 144 ± 4 μg/kg body weight/day) dietary pretreatment with PFOS on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With either regimen of exposure, PFOS exacerbated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This exacerbation was associated with either reduced (moderate dose) or unaltered (low dose) hepatic levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). Moreover, hepatic DNA fragmentation was enhanced, particularly following short-term exposure to a low-dose. Our findings suggest that exposure to PFOS may sensitize hepatic parenchymal cells to other insults that activate the hepatic immune system and thereby exacerbate liver damage during acute inflammation.

International audience; INTRODUCTION:: Our study aimed to evaluate whether pathologic complete response (pCR) in early-stage non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy resulted in improved outcome, and to determine predictive factors for pCR. METHODS:: Eligible patients with stage-IB or -II NSCLC were included in two consecutive Intergroupe Francophone de Cancérologie Thoracique phase-III trials evaluating platinum-based neoadjuvant chemotherapy, with pCR defined by the absence of viable cancer cells in the resected surgical specimen. RESULTS:: Among the 492 patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year overall survival was 80.0% compared with 55.8% in the non-pCR group (p = 0.0007). In multivariate analyses, pCR was a favorable prognostic factor of overall survival (relative risk = 0.34; 95% confidence interval = 0.18-0.64) in addition to squamous-cell carcinoma, weight loss less than or equal to 5%, and stage-IB disease. Five-year disease-free survival was 80.1% in the pCR group compared to 44.8% in the non-pCR group (p < 0.0001). Two patients (4.9%) in the pCR group experienced disease recurrence compared to 193 patients (42.8%) in the non-pCR group. SCC subtype was the only independent predictor of pCR (odds ratio [OR] = 4.30; 95% confidence interval = 1.90-9.72). CONCLUSION:: Our results showed that pCR after preoperative chemotherapy was a favorable prognostic factor in stage-IB-II NSCLC. Our study is the largest published series evaluating pCRs after preoperative chemotherapy. The only factor predictive of pCR was squamous-cell carcinoma. Identifying molecular predictive markers for pCR may help in distinguishing patients likely to benefit from neoadjuvant chemotherapy and in choosing the most adequate preoperative chemotherapy regimen.

In a French region where farmer's lung (FL) is common, we determined the prevalence of FL precipitins in dairy farmers and analyzed the relation between the presence of FL precipitins and the clinical probability of the disease. All the exposed dairy farmers of both sexes (n = 2555) from five districts of the Doubs department were asked to respond to a medical and professional questionnaire. A total of 1763 (69%) farmers agreed to participate. Precipitins tests were conducted in 551 (31%) farmers who showed any respiratory symptom and in a random sample of 100 asymptomatic farmers. Serum for each farmer was analyzed by both double diffusion and immunoelectrophoresis against Micropolyspora faeni (MF) and extracts of moldy hay (HE) from Doubs. The 651 farmers were then divided into four groups (G 1–4) with a decreasing probability of FL (G1: typical FL symptoms; G4: asymptomatic farmers). The estimated prevalence of precipitins in the whole population was as follows: 1) by double diffusion, against HE: 83%, against MF: 27%; 2) by immunoelectrophoresis, against HE: 26%, against MF: 19%. There was a close “linear” relation between the prevalence of precipitins detected by immunoelectrophoresis against HE and the symptoms: 51% in G1, 36% in G2, 29% in G3, and 13% in G4. Precipitins detected by immunoelectrophoresis were also related to exposure and geography (more immunization in tableland area than in plain or mountain area). Presence of precipitins detected by double diffusion was not related to symptoms, exposure, or geography. This study shows that the prevalence of precipitins is high in the exposed dairy farmers of Doubs, and suggests that immunoelectrophoresis (with the antigens used) is a more effective method for the diagnosis of FL than double diffusion.

The membrane topology of rat liver microsomal glutathione transferase was investigated by comparing the tryptic cleavage products from intact and permeabilized microsomes. It was shown that lysine-4 of microsomal glutathione transferase is accessible at the luminal surface of the endoplasmic reticulum, whereas lysine-41 faces the cytosol. These positions are separated by a hydrophobic stretch of 25 amino acids (positions 11–35) which comprises the likely membrane-spanning region. Reaction of cysteine-49 of the microsomal glutathione transferase with the charged sulfhydryl reagent DTNB (2,2′-dithiobis(5-nitrobenzoic acid))) in intact microsomes further supports the cytosolic localization of this portion of the polypeptide chain. The role of two other potential membrane-spanning/associated segments in the C-terminal half of the polypeptide chain was examined by investigating the association of the protein to the membrane after trypsin cleavage at lysine-41. Activity measurements and Western blot analysis after washing with high concentrations of salt, as well as after phase separation in Triton X-114, indicate that this portion of the protein also binds to the membrane. It is also shown that cleavage of the purified protein at Lys-41 and subsequent separation of the fragments obtained yields a functional C-terminal polypeptide with the expected length for the product encompassing positions 42–154. The location of the active site of microsomal glutathione transferase was investigated using radiolabelled glutathione together with a second substrate. Since isolated rat liver microsomes do not take up glutathione or release the glutathione conjugate into the lumen, it can be concluded that the active site of rat liver microsomal glutathione transferase faces the cytosolic side of the endoplasmic reticulum.

Summary Purpose The purpose of the study was to assess the possible benefit of the combination vinorelbine (NVB)-cisplatin (DDP) in comparison with NVB alone in advanced non- small cell lung cancer (NSCLC), not treated previously. It also involved confirmation of the efficacy of vinorelbine as monotherapy. Patients and methods In this phase 111 trial, 231 eligible patients were stratified by centre and randomized to receive either NVB alone, 30 mg/m2/week or the combination of NVB 30 mg/m2/week and DDP 80 mg/m2/3 weeks. Patients were to be treated for a minimum of 6 weeks, with the first response assessment performed 9 weeks after the beginning of treatment. Results The two groups differed in terms of objective response rates (16% and 43%, respectively, p = 0.0001) and median time to progression (10 weeks and 20 weeks, p = 0.0001). However, the difference was not significant for median survival time (32 weeks, 33 weeks, p = 0.48). The addition of DDP resulted in an increase in toxicity, in particular renal, hematologic, neurologic and emetic. This toxicity led to treatment discontinuation in 8% and 21% of patients, respectively. Respectively 3% and 13% of patients stopped treatment early during objective response (toxicity or refusal). Conclusions The NVB-DDP combination increased objective response rates and time to progression in comparison with NVB alone, but did not influence the survival of patients. The activity of NVB in the treatment of advanced NSCLC was confirmed.

BACKGROUND--A previous study showed there to be fewer microorganisms (especially thermophilic actinomycetes) on farms with artificial barn drying of fodder than on those using traditional storage methods. A cross sectional study was performed to see whether barn drying provides protection against respiratory problems in dairy farmers. METHODS--The respiratory symptoms and function of a group of 123 farmers with daily exposure to cattle foddering from farms which had had a barn drying system for at least three years were compared with those of a representative sample of 274 farmers working in farms with traditional storage in five districts in the Doubs region of France. RESULTS--Both groups were comparable for mean age, weight, height, smoking habits, alcohol consumption, past history of respiratory disease, history of allergy, geographical location of the farm, and length of exposure. Retrospectively estimated exposure to fodder was greater in the group using a barn drying system than in the group working with traditional storage. Acute symptoms at exposure (rhinitis, eye irritation, dry cough, asthma symptoms) and chronic symptoms all tended to be less frequent in the barn drying group, although not individually significantly so. Mean (SD) respiratory function parameters were higher in the barn drying group than in the traditional group: % vital capacity (VC) 104 (14) v 102 (15); % forced expiratory volume in one second (FEV1) 99 (14) v 94 (18); % FEV1/VC 96 (11) v 92 (16); % forced mid expiratory flow (FEF25-75) 87 (24) v 79 (25). CONCLUSION--The results of this cross sectional study suggest that barn drying of fodder may protect respiratory function in dairy farmers.

It is now well established that the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARα) is expressed in different types of immune cells and plays a pivotal role in the regulation of age-related production of inflammatory cytokines. However, the role(s) of this receptor in the regulation of immune cell homoeostasis in ageing non-lymphoid and lymphoid organs has not yet been resolved. We examine this issue here by evaluating the hepatic and splenic immune status and immunoglobulin (Ig) production in male PPARα-null mice and their wild-type littermates at one and 2 years of age. In comparison with the age-matched control animals, PPARα-null mice exhibited age-related elevations in the numbers of total, as well as of phenotypically distinct subpopulations of intrahepatic immune cells (IHIC) and splenocytes. Moreover, at 2 years of age, these alterations in hepatic immune cells were accompanied by significant increases in hepatic levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interferon-gamma (IFN-γ), in combination with the development of hepatic inflammatory loci containing mixtures of leucocytes. Alterations in splenocytes of old PPARα-null mice were also accompanied by increases in cellularity of both white and red pulps of the spleen. Furthermore, these same animals exhibited pronounced increases in the numbers of splenic plasma cells and enhanced production of Ig of different isotypes, including IgG1, IgG2a and IgE. Thus, our findings indicate that upon ageing, PPARα plays a crucial role in regulating the total numbers, compositions and functions of immune cells in both lymphoid and non-lymphoid immune organs of mice.

The aim of this study was to determine the usefulness of recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) following conventional chemotherapy for small cell lung cancer. 130 previously untreated patients were randomised to receive either r-metHuG-CSF (230 micrograms/m2) or placebo on days 4-17 following CDE (cyclophosphamide, doxorubicin and etoposide) chemotherapy. Over all cycles, 53% of 64 patients on placebo and only 26% of 65 patients on r-metHuG-CSF had at least one experience of neutropenia with fever defined as a neutrophil count less than 1.0 x 10(9)/l and a temperatureor = 38.2 degrees C (P0.002). It resulted in a reduction in the requirement for parenteral antibiotics from 58% in placebo patients compared with 37% in the r-metHuG-CSF group (P0.02), and a significant reduction in the incidence of infection-related hospitalisation. Chemotherapy doses were reduced by 15% or more at least once in 61% of the placebo group compared with 29% in the r-metHuG-CSF group (P0.001). 47% of the patients treated with placebo and 29% of the patients treated with r-metHuG-CSF experienced at least one cycle with a delay of 2 days or more in the administration of chemotherapy (P0.04). r-metHuG-CSF was well tolerated. There were no significant differences between the two groups in terms of response or survival.

The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of ³⁵S-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.

It is well established that exposure of mice to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) induces hepatomegaly and, concurrently, immunotoxicity. However, the effects of these perfluorochemicals on the histology and immune status of the liver have not been yet investigated and we have examined these issues here. Dietary treatment of male C57BL/6 mice with 0.002% (w/w) PFOA or 0.005% (w/w) PFOS for 10 days resulted in significant reductions in serum levels of cholesterol and triglycerides, a moderate increase in the serum activity of alkaline phosphatase (ALP) and hepatomegaly, without affecting other immune organs. This hepatomegaly was associated with marked hypertrophy of the centrilobular hepatocytes, with elevated numbers of cytoplasmic acidophilic granules and occasional mitosis. Furthermore, dietary exposure to PFOA or PFOS altered the hepatic immune status: whereas exposure to PFOA enhanced the numbers of total, as well as of phenotypically distinct subpopulations of intrahepatic immune cells (IHIC), and in particular the presumptive erythrocyte progenitor cells, treatment with PFOS enhanced only the numbers of hepatic cells that appear immunophenotypically to be erythrocyte progenitors, without affecting other types of IHIC. In addition, exposure to these compounds attenuated hepatic levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-4 (IL-4). Furthermore, the exposed animals exhibited a significant increase in hepatic levels of erythropoietin, a hormone required for erythropoiesis. Thus, in mice, PFOA- and PFOS-induced hepatomegaly is associated with significant alterations in hepatic histophysiology and immune status, as well as induction of hepatic erythropoiesis.

The effects of dietary treatment with clofibrate (0.5% w/w for 10 days) on the livers of selenium-deficient male rats were examined. The peroxisome proliferation (as determined by electron microscopy) in the livers of selenium-deficient animals was much less pronounced than in the case of selenium-adequate rats and no increase in peroxisomal fatty acid beta-oxidation (assayed both as antimycin-insensitive palmitoyl-CoA oxidation and lauroyl-CoA oxidase activity) was observed in the deficient animals. On the other hand, in selenium-deficient rats clofibrate caused increases in the specific activity of microsomal lauric acid omega- and omega-1-hydroxylation and an apparent change in mitochondrial size, seen as a redistribution of mitochondria from the 600 x g(av) pellet to the 10,000 x g(av) pellet, which were approximately 50% as great as the corresponding effects on control animals. Obviously, then, these three different effects of clofibrate are not strictly coupled and may involve at least partially distinct underlying mechanisms. Initial experiments demonstrated that peroxisome proliferation could be obtained by exposing primary hepatocyte cultures derived from selenium-deficient rats to clofibric acid (an in vivo hydrolysis product of clofibrate which is the proximate peroxisome proliferator), nafenopin or mono(2-ethylhexyl)phthalate. This finding suggests that selenium deficiency does not have a direct influence on the basic process(es) underlying peroxisome proliferation, but rather has indirect effects, influencing, for example, the pharmacokinetics of clofibrate and/or hormonal factors.

Male mice were exposed via their diet to perfluoro fatty acids of various chain-lengths (2-10 carbon atoms) at different doses (0.02 and 0.1% weight) and for different periods of time (2-10 days). Thereafter, we monitored effects on liver and body weights and a number of hepatic parameters, including mitochondrial protein content, microsomal contents of cytochromes P450 and b5, NADPH-cytochrome P450 reductase activity [measured as NADPH-cytochrome c reductase (EC 1.6.2.3)], microsomal and cytosolic epoxide hydrolase (EC 3.3.2.3) activities, cytosolic DT-diaphorase (EC 1.6.99.2), glutathione transferase (EC 2.5.1.18), glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities, and levels of thiobarbituric acid-reactive material (as an indicator of lipid peroxidation) in the mitochondrial subfraction. The most dramatic changes observed were a 5-9-fold increase in mitochondrial protein, a 3-6-fold increase in the microsomal content of cytochrome P450, a 3-10-fold increase in cytosolic DT-diaphorase activity, an approximately 2-fold increase in cytosolic epoxide hydrolase activity and as much as a 60% decrease in the level of thiobarbituric acid-reactive compounds in the mitochondrial fraction. Smaller increases in microsomal epoxide hydrolase activity and decreases in cytosolic glutathione peroxidase activity were also observed. Of the perfluoro fatty acids tested, perfluorooctanoic acid caused the largest changes in the parameters examined here. Dietary exposure of mice to a 0.02% dose of this substance for 10 days results in a maximal or near-maximal effect in most cases.

Male C57Bl/6 mice were treated for 5 days with 0.05% perfluorooctanoic acid (PFOA) in their diet. This treatment resulted in a potent induction of peroxisomal fatty acid beta-oxidation in the liver. In order to investigate recovery from treatment with PFOA, mice were given normal laboratory chow for up to 20 days after termination of PFOA administration. It was established that the activities of peroxisomal lauoryl-CoA oxidase and palmitoyl-CoA oxidation were still elevated 2-3 weeks after termination of treatment. The catalase activity recovered in the cytosolic fraction was also still significantly elevated after 20 days with normal laboratory chow. Furthermore, the protein content of the mitochondrial fraction was increased by PFOA and had not returned to control level at the end of the recovery period. Perfluorooctanoic acid also caused a persistent effect in omega hydroxylation of lauric acid (cytochrome P-452). The activities of cytosolic DT-diaphorase and glutathione transferase were also enhanced by PFOA. However, these two enzymes recovered relatively rapidly from the treatment (2-20 days). This study reveals two different patterns of recovery from PFOA treatment, one involving parameters that recovered completely, or almost completely, from PFOA treatment after 20 days and another involving parameters that were still elevated at the end of the recovery period.

Short-term exposure of mice to high doses of perfluorooctanesulfonate (PFOS), an ubiquitous and highly persistent environmental contaminant, induces various metabolic changes and toxic effects, including immunotoxicity. However, extrapolation of these findings to the long-term, low-dose exposures to which humans are subject is highly problematic. In this connection, recent studies have concluded that sub-chronic (28-day) exposure of mice by oral gavage to doses of PFOS that result in serum levels comparable to those found in general human populations suppress adaptive immunity. Because of the potential impact of these findings on environmental research and monitoring, we have examined here whether sub-chronic dietary exposure (a major route of human exposure) to a similarly low-dose of PFOS also suppress adaptive immune responses. Dietary treatment of male B6C3F1 mice for 28 days with a dose of PFOS that resulted in a serum concentration of 11mug/ml (ppm) significantly reduced body weight gain and increased liver mass. However, this treatment did not alter the cellular compositions of the thymus and spleen; the number of splenic cells secreting IgM antibodies against sheep red blood cell (SRBC); serum levels of IgM and IgG antibodies specifically towards SRBC; or circulating levels of IgM antibodies against the T-cell-independent antigen trinitrophenyl conjugated to lipopolysaccharide (TNP-LPS). These findings indicate that such sub-chronic dietary exposure of mice to PFOS resulting in serum levels approximately 8-85-fold greater than those observed in occupationally exposed individuals does not exert adverse effects on adaptive immunity.

Having found previously that high-dose, short-term dietary exposure of mice to perfluorooctanesulfonate (PFOS) or perfluorooctanoate (PFOA) suppresses adaptive immunity, in the present study we characterize the effects of these fluorochemicals on the innate immune system. Male C57BL/6 mice receiving 0.02% (w/w) PFOS or PFOA in their diet for 10 days exhibited a significant reduction in the numbers of total white blood cells (WBC), involving lymphopenia in both cases, but neutropenia only in response to treatment with PFOA. Moreover, both compounds also markedly reduced the number of macrophages (CD11b(+) cells) in the bone marrow, but not in the spleen or peritoneal cavity. The ex vivo production of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) by peritoneal macrophages isolated from animals treated with PFOA or PFOS was increased modestly. Moreover, both fluorochemicals markedly enhanced the ex vivo production of these same cytokines by peritoneal and bone marrow macrophages stimulated either in vitro or in vivo with lipopolysaccharide (LPS); whereas there was no such effect on splenic macrophages. The serum levels of these inflammatory cytokines observed in response to in vivo stimulation with LPS were elevated substantially by prior exposure to PFOA, but not by PFOS. None of these parameters of innate immunity were altered in animals receiving a dietary dose of these compounds that was 20-fold lower (0.001%, w/w). These findings reveal that in addition to suppressing adaptive immunity, high-dose, short-term exposure of mice to either PFOS or PFOA augments inflammatory responses to LPS, a potent activator of innate immunity.

International audience; BACKGROUND: The interest of first- and second-line treatments in non-small cell lung cancer (NSCLC) has been demonstrated by successive randomized trials. Improvements in lung cancer care have routinely allowed a significant proportion of patients to be considered for third-line treatment. METHODS: A retrospective analysis was performed, including all consecutive patients with advanced NSCLC, who received at least three lines of systemic antineoplastic treatment at our institution. RESULTS: From a population of 613 patients treated with first-line treatment, a total of 173 patients received third-line treatment (cytotoxic chemotherapy in 131 patients; epidermal growth factor (EGFR) tyrosine kinase inhibitors in 42 patients). Only 13 patients (8%) received less than 75% of the theoretical dose intensity; 22 patients (13%) presented with severe toxicities. Symptom relief and performance status (PS) improvement were observed in 121 (92% of the 131 patients with symptoms) and 90 patients (52%), respectively. Using multivariate analysis, survival after third-line treatment was significantly increased in patients younger than 70 years-old (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.53-0.99, p = 0.047), who smoked less than 10 pack-years (HR = 0.82, 95% CI: 0.57-0.93, p = 0.036), with no cancer-related symptoms (HR = 0.75, 95% CI: 0.61-0.92, p = 0.007), a weight loss inferior to 5 kg since the beginning of second-line (HR = 0.63, 95% CI: 0.52-0.75, p = 0.013), a PS 0 to 1 (HR = 0.81, 95% CI: 0.76-0.86, p = 0.008), and no extrathoracic tumor spread at initiation of third-line treatment (HR = 0.67, 95% CI: 0.47-0.94, p = 0.042). Disease control after both first- and second-line treatments was the strongest predictor of prolonged survival after third-line treatment (HR = 0.47, 95% CI: 0.33-0.67, p = 0.001). CONCLUSIONS: Patients with advanced NSCLC may benefit from third-line treatment. The best candidates can be identified using standard prognostic factors, such as PS, and disease control after first- and second-line treatments.

Myelin bodies were isolated from the renal cortex of gentamicin-treated rats (100 mg/kg body weight, twice daily for 3 days, i.p.) employing an initial pelleting by differential centrifugation and subsequent flotation on a discontinuous sucrose gradient. These structures were found to contain almost twice as much protein as phospholipid and SDS-polyacrylamide gel electrophoresis revealed the presence of many different polypeptides. All the major phospholipids are present, although myelin bodies contain a considerably higher proportion of phosphatidylinositol, somewhat more phosphatidylcholine and considerably lower percentages of phosphatidylserine and sphingomyelin than do normal renal phospholipids. The fatty acids of myelin body phospholipids are highly saturated (67.3-87.9%) and a striking feature is the occurrence of relatively large amounts of 22:1, presumably erucic acid, especially in sphingomyelin. Myelin bodies contain small amounts of unesterified cholesterol, unesterified dolichol and coenzymes Q9 and Q10.

Navelbine (vinorelbine, NVB) is the first semisynthetic 5'-nor-vinca-alkaloid selected for clinical trial. NVB has been shown to have a good level of activity against different experimental solid tumors in animals, with low neurotoxicity. In the phase II study, 78 patients with an inoperable non-small-cell lung cancer (NSCLC) were treated with NVB at a weekly dose of 30 mg/m2. No patient had previously received chemotherapy. Twenty-three of the 78 eligible patients showed a partial response (29.4% with a 95% confidence limits: 19.5-39.5). Eight patients were not evaluable and the percentage of partial response were 32.8% in the evaluable patients group. The median response duration was 34 weeks, and the median survival time for the overall population reached 33 weeks. Grade 3-4 leukopenia was seen in 12.5% of cycles. No thrombocytopenia occurred. At the dosage schedule used, NVB seems a very promising agent in the treatment of NSCLC.

Male C57bl/6 mice were administered clofibrate (0.5%, w/w), nafenopin (0.12%, w/w) or WY-14.643 (0.125%, w/w) in their diet for 4 days. Assay of eight mitochondrial marker enzymes, - i.e., malate and glutamate dehydrogenases (matrix markers), cytochrome oxidase and cytochromes c + c1 and a (inner membrane), adenylate kinase (intermembrane space) and monoamine oxidase and microsomal glutathione transferase (outer membrane) - and morphometric analysis of electron micrographs was used to examine hepatic mitochondria after treatment with these peroxisome proliferators. A moderate increase in the number of hepatic mitochondrial profiles, with a simultaneous decrease in the average size of these organelles, was observed. The total mitochondrial volume is apparently unchanged during this process. An important experimental consequence of the apparent decrease in mitochondrial size is the redistribution of a large portion of the total hepatic mitochondria from the ‘nuclear’ to the mitochondrial fraction. A similar effect was seen with rats.

The present study demonstrates that during the first 1.5-3 min after a single intraperitoneal administration of [3H]gentamicin to rats, most of the radioactivity in the kidney cortex is recovered in the cytosolic and microsomal fractions upon subcellular fractionation. Subsequently, the level of radioactivity recovered in the cytosolic fraction decreases markedly, whereas this level remains relatively unchanged in microsomes and increases somewhat in the nuclear and mitochondrial fractions. A steady state is apparently reached 13 hr after the injection. The high initial concentration of gentamicin in the cytosol may indicate that this substance is taken up to a large extent by diffusion. Such uptake is somewhat surprising, because of the polar nature of gentamicin. The small size of this drug may, however, allow it to diffuse through so-called pores and/or interaction with negatively charged phospholipids may be involved in the uptake of gentamicin. The initial total level of radioactivity recovered in microsomes after in vivo administration of [3H]gentamicin was considerably higher than in the nuclear and mitochondrial-lysosomal fractions. Furthermore, when gentamicin was added directly to kidney homogenate prepared from untreated rats, instead of being administered in vivo, this substance was still recovered in highest amounts in the total microsomal fraction. This observation may indicate that enrichment of gentamicin in the endoplasmic reticulum (or fragments thereof) reflects a special affinity of this drug for these membranes and is probably not the result of a particular in vivo process. There was no difference in the levels of radioactivity recovered in smooth and rough microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

International audience; INTRODUCTION: Several studies have suggested that rurality is a risk factor for worse prognosis in cancer. METHODS: The study population included the 2268 lung cancer cases collected between 1981 and 1996 in the Doubs Cancer Registry (France). RESULTS: The numbers of patients were 849 (31.8%) in rural areas and 89 (3.3%) in very rural areas. The relative 5-year survival was 15.2% in rural areas and 13.4% in urban areas (p = 0.5), and 2.7% in very rural areas and 14.4% in extended urban areas (p = 0.02). Multivariate analyses of observed and relative survival showed that patients living in very rural areas (p < 0.0001), 65 years of age and older and having small cell carcinoma had a significantly shorter survival. CONCLUSIONS: This study showed that the multidimensional definition of rurality identified a population with unfavorable prognoses.