Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer: cross-over analysis from the SHIVA trial.

Background: Several studies used the ratio of progression-free survival (PFS) on genotype-matched treatment to PFS on genotype-unmatched treatment to assess the efficacy of therapy guided by patients' tumor molecular profiling. We evaluated the PFS ratio from patients who cross-over in the SHIVA trial. Patients and methods: The primary end point of the SHIVA trial was to compare PFS on molecularly targeted agents (MTAs) based on tumor molecular profiling and treatment at physician's choice (TPC) in patients with any kind of cancer who had failed standard-of-care therapy. The experimental treatment included only marketed MTAs given outside their indications according to a pre-specified treatment algorithm. Patients were allowed to cross-over at disease progression in both arms. Response was evaluated according to RECIST 1.1 at randomization and at cross-over. We evaluated the ratio of PFS on MTA (PFSMTA) to PFS on TPC (PFSTPC) in patients who crossed-over. Results: Among 741 patients enrolled in the SHIVA trial, 197 were randomized, and 95 crossed-over, including 70 patients from the TPC to the MTA arm and 25 patients from the MTA to the TPC arm. Two patients crossed-over in the TPC arm without disease progression. The PFSMTA/PFSTPC ratio exceeded 1.3 in 37% of patients who crossed-over from the TPC to the MTA arm. The PFSMTA/PFSTPC ratio exceeded 1.3 in 61% of patients who crossed-over from the MTA arm to the TPC arm. Conclusions: The cross-over analysis of the SHIVA trial identified 37% of patients who crossed-over from TPC to MTA with a PFSMTA/PFSTPC ratio exceeding 1.3.

Prediction of long-term cumulative incidences based on short-term parametric model for competing risks: application in early breast cancer.

Use of parametric statistical models can be a solution to reduce the follow-up period time required to estimate long-term survival. Mould and Boag were the first to use the lognormal model. Competing risks methodology seems more suitable when a particular event type is of interest than classical survival analysis. The objective was to evaluate the ability of the Jeong and Fine model to predict long-term cumulative incidence. Survival data recorded by Institut Curie (Paris) from 4761 breast cancer patients treated and followed between 1981 and 2013 were used. Long-term cumulative incidence rates predicted by the model using short-term follow-up data were compared to non-parametric estimation using complete follow-up data. 20- or 25-year cumulative incidence rates for loco-regional recurrence and distant metastasis predicted by the model using a maximum of 10 years of follow-up data had a maximum difference of around 6 % compared to non-parametric estimation. Prediction rates were underestimated for the third and composite event (contralateral or second cancer or death). Predictive ability of Jeong and Fine model on breast cancer data was generally good considering the short follow-up period time used for the estimation especially when a proportion of patient did not experience loco-regional recurrence or distant metastasis.

Time-varying effect and long-term survival analysis in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Recent studies have indicated the prognostic value of tumour subtype and pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). However these results were reported after a short follow-up and using a standard Cox model which could be unsatisfactory for time-dependent factors. In the present study, we identified the prognostic factors for long-term outcome after NAC, considering that they could have an inconstant impact over time. METHODS: Prognostic factors from 956 consecutive breast cancer patients treated with NAC were identified and associated with long-term outcomes. We estimated survival by a time function multivariate Cox model regression and stratified by follow-up length. RESULTS: The prognostic value of tumour histological grade and hormone receptors status varied as distant recurrence-free interval (DRFI) increased. The multivariate analysis identified the following significant prognostic factors: tumour size, N stage, clinical and pathological response to NAC, hormone receptors (HR) status and histological tumour grade. The 'prognostic benefit' of low-grade and positive-HR status decreased over the years. Thus, in the early years after cancer diagnosis, the hazard ratio of distant recurrences in patients with positive-HR status increased from 0.26 (95% CI 0.1-0.4) at 6 months to 2.2 (95% CI 1.3-3.7) at 120 months. The histological tumour grade followed a similar trend. The hazard ratio of grade III patients compared with grade I was 1.83 (95% CI 1.1-2.8) at 36 months and diminished over time to 0.70 (95% CI 0.4-1.3) at 120 months. This indicates that the risk of recurrence for positive-HR patients was 74% lower at 6 months compared with the negative-hormone receptor group, but 30% higher at 5 years and more than double at 10 years. High-grade tumours presented a risk of 83% in the earlier years decreasing to 30% at 10 years versus the low-grade group. CONCLUSION: From the present study, we conclude the importance of identifying time-dependent prognostic factors. Distant recurrence-free interval within women who receive NAC are influenced by achieving pCR and breast cancer subtype. Tumours with more aggressive biology have poorer survival during the first 5 years, but if they exceed this point their prognostic impact is no longer significant. Conversely, positive-HR patients remain at risk for distant recurrence for many years.

Concurrent administration of trastuzumab with locoregional breast radiotherapy: long-term results of a prospective study.

This single-center prospective study aims to assess the outcomes and the toxicities related to the concurrent administration of trastuzumab (T) with adjuvant locoregional radiotherapy (RT) in localized breast cancer. Data of 308 patients were analyzed. T was delivered every 3 weeks (loading dose of 8 mg/kg, then 6 mg/kg) for 1 year. Left ventricular ejection fraction (LVEF), measured by echocardiography or myocardial scintigraphy, was considered as impaired when below 55%. Toxicities were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Univariate and multivariate analyses were carried out using the Cox model. Median follow-up was 50.2 months (13.0-126.0). Median age at diagnosis was 52 years (25-83). Internal mammary node (IMN) RT was performed in 227 patients (73.7%). After completion of RT, 26 patients (8.4%) presented an impaired LVEF: 17 (5.5%) of grade 1, 7 (2.3%) of grade 2, and 2 (0.6%) of grade 3. At 48 months, locoregional control rate was 95% [95% CI 92; 98], and overall survival rate was 98% [95% CI 96; 100]. In univariate analysis, neither the treated breast side (p = 0.655) nor IMN RT (p = 0.213) exposed patients to LVEF alteration. In multivariate analysis, clinical lymph node involvement was associated with an increased risk of locoregional and distant recurrence (p = 0.016 and p = 0.007, respectively). In this prospective study, the toxicities of concurrent T with locoregional breast RT were acceptable and the outcomes favorable. Longer follow-up is warranted to confirm these results.

Clinical features and outcomes of patients with pancreatic cancer requiring unplanned medical ICU admission: A retrospective multicenter study.

BACKGROUND: We sought to describe the reasons for intensive care unit (ICU) admission and outcomes of patients with pancreatic cancer requiring unplanned medical ICU admission. PATIENTS AND METHODS: Retrospective cohort study in five ICUs from 2009 to 2020. All patients with pancreatic cancer admitted to the ICU were included. Patients having undergone recent surgery were excluded (< 4 weeks). RESULTS: 269 patients were included. Tumors were mainly adenocarcinoma (90%). Main reason for admission was sepsis/septic shock (32%) with a biliary tract infection in 44 (51%) patients. Second reason for admission was gastrointestinal bleeding (28%). ICU and 3-month mortality rates were 26% and 59% respectively. Performance status 3-4 (odds ratio OR 3.58), disease status (responsive/stable -ref-, newly diagnosed OR 3.25, progressive OR 5.99), mechanical ventilation (OR 8.03), vasopressors (OR 4.19), SAPS 2 (OR 1.69) and pH (OR 0.02) were independently associated with ICU mortality. Performance status 3-4 (Hazard ratio HR 1.96) and disease status (responsive/stable -ref-, newly diagnosed HR 2.67, progressive HR 4.14) were associated with 3-month mortality. CONCLUSION: Reasons for ICU admissions of pancreatic cancer patients differ from those observed in other solid cancer. Short- and medium-term mortality are strongly influenced by performance status and disease status at ICU admission.

Prognosis of glioblastoma patients improves significantly over time interrogating historical controls.

BACKGROUND: Glioblastoma (GBM) is the most common devastating primary brain cancer in adults. In our clinical practice, median overall survival (mOS) of GBM patients seems increasing over time. METHODS: To address this observation, we have retrospectively analyzed the prognosis of 722 newly diagnosed GBM patients, aged below 70, in good clinical conditions (i.e. Karnofsky Performance Status -KPS- above 70%) and treated in our department according to the standard of care (SOC) between 2005 and 2018. Patients were divided into two groups according to the year of diagnosis (group 1: from 2005 to 2012; group 2: from 2013 to 2018). RESULTS: Characteristics of patients and tumors of both groups were very similar regarding confounding factors (age, KPS, MGMT promoter methylation status and treatments). Follow-up time was fixed at 24 months to ensure comparable survival times between both groups. Group 1 patients had a mOS of 19 months ([17.3-21.3]) while mOS of group 2 patients was not reached. The recent period of diagnosis was significantly associated with a longer mOS in univariate analysis (HR=0.64, 95% CI [0.51 - 0.81]), p < 0.001). Multivariate Cox analysis showed that the period of diagnosis remained significantly prognostic after adjustment on confounding factors (adjusted Hazard Ratio (aHR) 0.49, 95% CI [0.36-0.67], p < 0.001). CONCLUSION: This increase of mOS over time in newly diagnosed GBM patients could be explained by better management of potentially associated non-neurological diseases, optimization of validated SOC, better management of treatments side effects, supportive care and participation in clinical trials.

TIRADS score is of limited clinical value for risk stratification of indeterminate cytological results.

CONTEXT: Thyroid nodules with cytological indeterminate results represent a daily and recurrent issue for patient management. OBJECTIVE: The primary aim of our study was to determine if TIRADS (Thyroid Imaging Reporting and Data System) could be used to stratify the malignancy risk of these nodules and to help in their clinical management. Secondary objective was to estimate if this risk stratification would change after reclassification of encapsulated non-invasive follicular variant of papillary carcinomas (FVPTC) as non-invasive follicular thyroid neoplasm (NIFTP). PATIENTS AND METHODS: Single-center retrospective study of a cohort of 602 patients who were referred for ultrasound-guided fine-needle aspiration from January 2010 to December 2016 with an indeterminate cytological result and in whom histological results after surgery were available. TIRADS score was prospectively determined for all patients included. Nodules that had been classified as FVPTC were submitted to a rereading of histological report and reclassified as NIFTP when judged relevant. A table of malignancy risk crossing Bethesda and TIRADS results was built before and after this reclassification. RESULTS: The study included 602 cytologically indeterminate nodules. TIRADS score was positively correlated with the malignancy rate (P < 0.0001). Risk stratification with TIRADS was significant only in Bethesda V nodules (P = 0.0004). However, the risk of malignancy in this Bethesda V category was always above 45%, whatever the TIRADS score. CONCLUSION: For a clinician facing an indeterminate cytological result for a thyroid nodule, return to TIRADS score is of limited value in most conditions to rule in or rule out malignancy and to guide subsequent management of patients.

Evaluation at 3 years of concurrent bevacizumab and radiotherapy for breast cancer: Results of a prospective study.

PURPOSE: To determine the 3 years late toxicity among patients with non-metastatic breast cancer who received concurrent bevacizumab and locoregional radiotherapy. MATERIAL AND METHODS: This is a single-arm, multicentre, prospective study, of the toxicity of adjuvant concomitant association of bevacizumab and radiotherapy in patients with breast cancer. Toxicity was assessed by the Common Terminology Criteria for Adverse Events version 3.0 during the radiotherapy and follow-up clinics at 12 and 36 months after its completion. The study was designed to evaluate the toxicity at one year, 3 years and 5 years. RESULTS: Sixty-four patients were included from October 2007 to August 2010. All of them received concurrent adjuvant radiotherapy and bevacizumab (in 24 cases after primary systemic treatment). All patients received non-fractionated radiotherapy to breast or chest wall with or without irradiation of regional lymph nodes. Early toxicity has been previously reported. Median follow-up was 46.4 months (range: 18-77 months). Median age was 53 years old (range: 23-68 years). The 3-years overall survival was 93% (range: 87-100%). Evaluation of the toxicity at 3 years was available for 67% of the patients. There was a low rate of toxicity: 14% grade 1 pain, 9% grade 1 fibrosis, 2% grade 1 telangiectasia, 2% grade 1 paresis, 7% grade 1 lymphedema and 2% grade 3 lymphedema. No grade 4 toxicity was observed. No patient had a left ventricular ejection fraction below 50% at 3 years. CONCLUSIONS: Concurrent bevacizumab with locoregional radiotherapy is associated with acceptable 3-years toxicity in patients with breast cancer.

Second malignancies after permanent implant prostate cancer brachytherapy: A single-institution study of 675 patients treated between 1999 and 2003.

PURPOSE: To analyse the rate of secondary malignancies observed in a series of 675 prostate cancer patients who underwent a permanent implant brachytherapy between 1999 and 2003, and to compare the incidence with the expected rate in a matched general French population. MATERIAL AND METHODS: The cohort included low-risk patients and a selection of "favourable-intermediate" risk patients. All patients were homogeneously treated using an intraoperative dynamic planning prostate brachytherapy technique, with loose 125-iodine seeds and a prescription dose of 145Gy. The mean follow-up was 132 months. RESULTS: The 10-year overall survival for the entire cohort was 92% (95% confidence interval [CI]: 90-94). The 10-year relapse-free survival rate was 82% (95% CI: 79-85). Overall, 61 second cancers were registered. When comparing with a matched general French population, the standard incidence ratio (SIR) for bladder cancer was 1.02 (95% CI: 0.46-1.93). For colorectal cancer, the SIR was 0.45 (95% CI: 0.19-0.89). For lung cancer, the SIR was 0.38 (95% CI: 0.17-0.76). The SIR for all cancers was 0.61 (95% CI: 0.47-0.79). When excluding secondary colorectal and lung cancers (both with low SIRs in this series), the SIR for all cancers was 1.06 (95% CI: 0.77-1.29). CONCLUSION: With a mean follow-up of more than 11 years, this series does not detect any excess risk of second cancers associated with permanent implant prostate brachytherapy. However, due to power limitation, a small increase in the risk of secondary malignancies cannot be totally ruled out.

Salivary gland-sparing helical tomotherapy for head and neck cancer: Preserved salivary function on quantitative salivary gland scintigraphy after tomotherapy.

GOALS: Prospective evaluation of salivary gland preservation, overall survival and local recurrence-free survival after head and neck cancer treated by helical tomotherapy (HT). MATERIAL AND METHODS: From March 2007 to February 2009, 30 patients with head and neck cancer were treated by HT. The salivary excretion fraction (SEF) was assessed by technetium salivary gland scintigraphy before, and 6, 12 and 18 months after HT to define salivary gland preservation rates. Patients were reviewed every 3 months to assess clinical toxicity. RESULTS: The median follow-up was 4.3 years. The mean dose to the ipsilateral parotid gland (IPG) was 25.4Gy. Good preservation of parotid gland function was observed in 84% of the 19 patients evaluated by scintigraphy at 18 months. The 5-year local recurrence-free survival (LRFS) was 100% among the 6 patients who received a dose of more than 26Gy to the parotid gland. The 28-month LRFS was 33% in the group that received a dose of less than 20Gy versus 91% in the group that received a dose of more than 20Gy to the IPG. CONCLUSIONS: Helical tomotherapy reduced the incidence and severity of xerostomia. A mean dose to the parotid between 20 and 26Gy allowed preservation of salivary function without compromising treatment efficacy. However, parotid-sparing HT requiring a mean dose less than 20Gy is associated with an increased risk of recurrence.

Long-term results of permanent implant prostate cancer brachytherapy: A single-institution study of 675 patients treated between 1999 and 2003.

PURPOSE: To analyse long-term overall survival, relapse-free survival and late toxicities in a series of 675 patients treated between 1999 and 2003, with a median follow-up of 132 months. PATIENTS AND METHODS: The cohort included low-risk patients and a selection of "favourable-intermediate" risk patients. All patients were homogeneously treated using an intraoperative dynamic planning prostate brachytherapy technique, with loose 125 iodine seeds. Hormone therapy, consisting most often of an anti-androgen alone, was given in 393 patients (58%). RESULTS: The 10-year overall survival was 92% (95% confidence interval [CI]: 90-94) without a significant difference between the low and the select intermediate-risk groups (P=0.17). The 10-year relapse-free survival rate for the entire cohort was 82% (95% CI: 79-85), and was significantly higher in the low-risk group than in the intermediate one (87 vs 71%; P<0.0001). Twenty-six percent of the relapses observed in this series occurred after more than 10 years of follow-up. The 10-year cumulative incidence of grade 3-4 urinary toxicity (whatever the delay and the recovery) was 5.78%. The cumulative incidence of grades 3-4 rectal toxicity in the present series was 1.65% at 10 years. As for sexual toxicity, 61% of our patients retained an erectile capacity at 10 years (with or without oral medication), with age being a major factor. CONCLUSION: With a median follow-up of more than 11 years, this series appears to confirm the excellent long-term results of low-dose rate prostate brachytherapy, both in terms of survival and in terms of toxicity.

Incidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis.

BACKGROUND: Long-term parenteral beta-lactam treatment is often complicated by adverse reactions that necessitate drug withdrawal. OBJECTIVE: To evaluate the incidence and mechanism of beta-lactam adverse reactions during an 8-year period in all episodes of suspected infective endocarditis in patients treated at a university-affiliated institution. METHODS: Patients with 215 consecutive episodes of beta-lactam treatment for 10 days or more were prospectively enrolled during 2 periods, January 1984 through December 1988 and January 1993 through December 1995, and compared with 51 episodes of vancomycin hydrochloride treatment for 10 days or more. Incidents of adverse reactions, such as fever, rash, or neutropenia, were registered. Neutrophil counts, eosinophil counts, and penicillin antibodies were studied. Patients with delayed adverse reactions to penicillin G sodium were rechallenged with penicillin v potassium. RESULTS: Incidence of delayed adverse reactions during treatment was 33% with beta-lactams compared with 4% with vancomycin. Rates of adverse event for beta-lactams increased continuously from treatment day 15 to day 30. A 6-fold difference in capacity to induce adverse events was found with different beta-lactams. Penicillin G induced neutropenia in 14% and any adverse event in 51% of treated episodes. Mean daily doses significantly influenced the frequency of adverse events. Occurrence of hemagglutinating penicillin antibodies was significantly related to patients whose penicillin-treated episodes were complicated with adverse events. Patients with delayed adverse reactions to penicillin G were safely rechallenged with penicillin. CONCLUSIONS: Incidence of delayed adverse reactions to beta-lactams increases sharply when parenteral treatment is extended beyond 2 weeks. Penicillin G is the most frequent inducer of adverse reactions among beta-lactams studied. An immunological reaction mediated by antibodies to the penicilloyl determinant may be involved in the pathogenesis, possibly enhanced by a dose-related toxic trigger mechanism. Beta-Lactam-induced neutropenia followed a uniform pattern, occurring after, on average, 21 days of treatment, and might be due to both immunologic and toxic effects of treatment. Patients with a late adverse reaction to penicillin can safely be re-treated with penicillin, although they should remain under close surveillance if treatment extends beyond 2 weeks.

Late toxicities and outcomes of adjuvant radiotherapy combined with concurrent bevacizumab in patients with triple-negative non-metastatic breast cancer.

OBJECTIVE: To evaluate the safety of the concurrent combination of bevacizumab with adjuvant radiotherapy (B-RT) in breast cancer (BC). METHODS: Multicentre, prospective study, of the toxicity of adjuvant radiotherapy (RT) alone or B-RT in patients with non-metastatic BC enrolled in randomized Phase 3 BEATRICE trial. Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events v. 3.0 during and 12 months after the completion of RT. RESULTS: From 2007 to 2012, 39 females received adjuvant B-RT and 45 received adjuvant RT alone. Median follow-up was 21.5 months. All patients had triple-negative non-metastatic BC and received adjuvant chemotherapy followed by RT. 90% of the 39 females treated by concurrent B-RT received whole breast irradiation (WBI) with a boost and 4 (10%) received post-mastectomy RT. Lymph node RT was delivered in 49% of the females with internal mammary chain irradiation. The mean duration of bevacizumab was 11.7 months. 38 (84%) females treated by RT alone received WBI with a boost and 16% of the females received post-mastectomy RT. Lymph node RT was delivered in 47% of the females with internal mammary chain RT in 31%. Grade 3 acute dermatitis was observed in 9% of patients receiving B-RT and 5% of patients receiving RT alone with no significant difference. 1 year after the completion of RT, the most common late grade 1-2 toxicities in the B-RT group were pain (18%), fibrosis (8%) and telangiectasia (5%). CONCLUSION: The concurrent bevacizumab with locoregional RT is associated with acceptable early and late 1-year toxicities in patients with BC. ADVANCES IN KNOWLEDGE: The largest series of this association.

Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group.

As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.

Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties.

A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.

Alterations in bronchoalveolar lavage fluid but not in lung function and bronchial responsiveness in swine confinement workers.

Testing of lung function and bronchial reactivity, bronchoalveolar lavage (BAL), and a skin prick test with a standard panel and six "swine" extracts obtained from swine and swine environment were performed in 20 randomly selected nonsmoking swine confinement workers. In addition, blood samples for detection of antibodies by the diffusion in gel-enzyme-linked immunosorbent assay (DIG-ELISA) technique and precipitating antibodies were drawn. Air samples for measurement of dust and endotoxin levels were collected. All the farmers regarded themselves as healthy. The results were compared with reference groups consisting of urban nonsmoking subjects who had not been exposed to pig farming environment. The pig farmers had normal lung function and the bronchial reactivity was not different from the reference group. In the BAL fluid of the farmers, the concentration of total cells and granulocytes was increased while the concentrations of lymphocytes and macrophages were normal. The BAL fluid concentrations of albumin, fibronectin, and hyaluronan were elevated in the farmers. Skin prick tests with swine extracts were negative in all farmers. Antibodies (assessed by DIG-ELISA) against swine dander, swine dust, and pig feed were increased and precipitating antibodies against swine dander were found in 14, against pig food in five, and against swine confinement dust in three of the 20 pig farmers. The concentration of airborne total dust was 7.4 mg/cu mm and the endotoxin concentration was 37 (22 to 60) ng/cu mm during tending the pigs and increased, during feeding, to 13.8 mg/cu mm and 315 (194 to 716) ng/cu mm, respectively. There was no correlation between exposure and lung function or lavage findings. In conclusion, randomly selected pig farmers had signs of airway inflammatory reaction and activation of the immune system without alteration in lung function and bronchial reactivity.

Hyaluronic acid (hyaluronan) in BAL fluid distinguishes farmers with allergic alveolitis from farmers with asymptomatic alveolitis.

Pulmonary function measurements, bronchoalveolar lavage (BAL), and analyses of precipitating antibodies in blood were performed in 12 farmers wtih no symptoms from the airways and 12 farmers who were admitted to the hospital due to acute symptoms of alveolitis (all nonsmokers). In addition, a bronchial methacholine provocation test was performed in the asymptomatic farmers. In 11 of the 12 symptomatic farmers but in none of the asymptomatic farmers, precipitating antibodies against one or more of the microorganisms which usually occur in a farmer's environment were found. In the farmers with symptomatic alveolitis, a restrictive impairment of pulmonary function was found, while pulmonary function was normal in all asymptomatic farmers. Findings in the BAL fluid showed increased concentrations of total cells, lymphocytes, and neutrophils and elevated levels of albumin, fibronectin, and angiotensin-converting enzyme in asymptomatic farmers compared with our own reference group. The same analyses in BAL fluid from the symptomatic farmers revealed a further increase in all parameters compared with the asymptomatic farmers. The BAL fluid from asymptomatic farmers had normal levels of hyaluronic acid (hyaluronan) and procollagen 3 N-terminal peptide, while these levels were significantly increased in the symptomatic group. We conclude that inflammation in the alveolar space and signs of activation of alveolar macrophages are present in farmers regardless of respiratory symptoms, although these findings are more pronounced in the presence of symptoms of acute alveolitis; however, the findings of impaired pulmonary function and the occurrence of precipitins and elevated levels of hyaluronic acid and procollagen 3 N-terminal peptide in BAL fluid were exclusively found in the farmers with airways symptoms. We postulate the hyaluronic acid, due to its pronounced ability to immobilize water, may be of importance in the development of the pulmonary function impairment observed in farmer's lung disease.

An in vitro method for predicting sensitizing properties of inhaled chemicals.

A method for monitoring chemical reactivity in aqueous solutions, at neutral pH and 37 degrees C, was developed. The chemical was allowed to react with a lysine-containing peptide, and the reaction was monitored with high-performance liquid chromatography. Simple acids, bases, and solvents did not react with the peptide, whereas isocyanates, anhydrides, and chloramine-T, substances well known for their sensitizing and asthma inducing properties, did. Thus a positive test strongly suggested that the chemical had the potential to act as a hapten and cause sensitization when inhaled. Prepolymers of diphenylmethane diisocyanate were considerably more reactive than prepolymers of toluene diisocyanate or hexamethylene diisocyanate. Isocyanates blocked with caprolactam, butanone oxime, malonic acid diethylester, or isononyl phenol showed no reactivity. This result suggested a significantly reduced risk of respiratory reactions when such blocked isocyanates are handled at room temperature. One blocked isocyanate showed, however, considerable reactivity.

Allergic alveolitis in a school environment.

BACKGROUND: A considerable fraction of newly constructed buildings have indoor air problems associated with health effects, usually of the nonspecific sick building syndrome variety. Specific health effects such as asthma, rhinitis, and allergic alveolitis can also occur. CASE: On 1 September 1988 a school teacher showed symptoms of an acute respiratory illness, which was first interpreted as pulmonary embolism and then later as atypical sarcoidosis. The illness slowly progressed over six years, at which time the diagnosis was revised to chronic allergic alveolitis, related to her school environment. The school had had indoor-air quality problems off and on for several years. CONCLUSIONS: The case illustrates the difficulties of diagnosing cases of chronic allergic alveolitis, especially when it appears in environments where it is not generally encountered. It also raises questions regarding a possible relation between environments associated with the sick building syndrome and the occurrence of building-associated illnesses.