[Indoor radon exposure and lung cancer risk. Results of an epidemiological study carried out in France]. / Exposition domestique au radon et risque de cancer du poumon.

INTRODUCTION: Several epidemiological studies have indicated an increased risk of lung cancer associated with indoor radon exposure. As part of a large European project, a hospital based case-control study was carried out in four regions of France: Auvergne, Brittany, Languedoc-Roussillon and Limousin. MATERIAL AND METHODS: Individual data on demographic characteristics, residential history, smoking and occupational exposures were collected during face-to-face interviews. Radon concentrations were measured in each dwelling occupied by the subject during the 30-year period prior to the interview. RESULTS: 486 cases and 984 controls were included in the study. After adjustment for age, sex, region, smoking history and occupational exposure, the risk of lung cancer increased by 4% per 100 Bq/m(3), when considering cumulative exposure in the 30 years prior to diagnosis. CONCLUSION: The study indicates a positive association between lung cancer risk and indoor radon exposure. The risk estimate per unit of exposure is in agreement with other recently published indoor case-control studies.

Preparation, phototoxicity and biodistribution studies of anti-carcinoembryonic antigen monoclonal antibody-phthalocyanine conjugates.

Immunophototherapy of cancer combines the specificity of a monoclonal antibody (MAb) to an overexpressed tumor marker with the phototoxic properties of a conjugated dye. Aluminum tetrasulfophthalocyanine (AlPcS4) was covalently coupled to a 35A7 MAb directed against carcinoembryonic antigen (CEA) via a five-carbon spacer chain (A1) to yield conjugates with a molar ratio ranging from 5 to 16 mol of AlPcS4 per mol of 35A7 MAb. Conjugates were labeled with radioiodine for characterization. The immunoreactivity of the conjugates, determined in a direct binding assay on CEA coupled to sepharose, was not modified by the coupled AlPcS4A1 molecules. In vivo, these conjugates were evaluated in nude mice bearing human colon carcinoma xenografts (T380). 35A7 MAb-(AlPcS4A1)5, 35A7 MAb-(AlPcS4A1)12 and 35A7 MAb-(AlPcS4A1)16 conjugates displayed a tumor uptake of 35 +/- 5.0%, 40 +/- 5.7% and 32 +/- 3.3% of the injected dose per gram of tumor tissue, respectively, corresponding to an uptake of 97%, 104% and 91% as compared to that of the unconjugated 35A7 MAb. In each experimental group, the tumor-to-normal tissue ratios obtained with the conjugates were almost identical to those obtained with unconjugated 35A7 MAb. Average values of 1.8, 7 and about 30 were obtained for blood, liver and muscle, respectively. Phototoxic efficacy of the 35A7 MAb-(AlPcS4A1)12 conjugate was demonstrated in vitro on the LoVo cell line giving a 91% growth inhibition for a 2.50 micrograms/mL AlPcS4A1 concentration. We conclude that these conjugates demonstrate clear in vivo tumor-seeking capacity and in vitro photocytotoxic properties. Such conjugates could thus be promising candidate drugs for clinical photodynamic therapy of cancers expressing CEA.

Phase-I/II radio-immunotherapy study with Iodine-131-labeled anti-CEA monoclonal antibody F6 F(ab')2 in patients with non-resectable liver metastases from colorectal cancer.

Experimental studies in nude mice with human colon-carcinoma grafts demonstrated the therapeutic efficiency of F(ab')2 fragments to carcinoembryonic antigen (CEA) labeled with a high dose of 131Iodine. A phase I/II study was designed to determine the maximum tolerated dose of 131I-labeled F(ab')2 fragments (131I-F(ab')2) from anti-CEA monoclonal antibody F6, its limiting organ toxicity and tumor uptake. Ten patients with non-resectable liver metastases from colorectal cancer (9 detected by CT scan and 1 by laparotomy) were treated with 131I-F(ab')2, doses ranging from 87 mCi to 300 mCi for the first 5 patients, with a constant 300-mCi dose for the last 5 patients. For all the patients, autologous bone marrow was harvested and stored before treatment. Circulating CEA ranged from 2 to 126 ng/ml. No severe adverse events were observed during or immediately following infusion of therapeutic doses. The 9 patients with radiologic evidence of liver metastases showed uptake of 131I-F(ab')2 in the metastases, as observed by single-photon-emission tomography. The only toxicity was hematologic, and no severe aplasia was observed when up to 250 mCi was infused. At the 300-mCi dose, 5 out of 6 patients presented grade-3 or -4 hematologic toxicity, with a nadir for neutrophils and thrombocytes ranging from 25 to 35 days after infusion. In these 5 cases, bone marrow was re-infused. No clinical complications were observed during aplasia. The tumor response could be evaluated in 9 out of 10 patients. One patient showed a partial response of one small liver metastasis (2 cm in diameter) and a stable evolution of the other metastases, 2 patients had stable disease, and 6 showed tumor progression at the time of evaluation (2 or 3 months after injection) by CT scan. This phase-I/II study demonstrated that a dose of 300 mCi of 131I-F(ab')2 from the anti-CEA Mab F6 is well tolerated with bone-marrow rescue, whereas a dose of 200 mCi can be infused without severe bone-marrow toxicity.

[Positron emission tomography (PET) and (F-18)-fluorodeoxyglucose in (FDG) in cancerology]. / Tomographie par émission de positons (TEP) et [F-18]-fluorodésoxyglucose (FDG) en cancérologie.

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is a scintigraphic imaging technique undergoing a rapid growth in the field of oncology. The constant progress of the detectors, either CDET or PET dedicated cameras, allows to obtain in routine conditions images with a 5 mm spatial resolution. Absolute tracer uptake quantification is also possible, which allows to evaluate objectively therapy efficacy. The mechanisms of FDG tissular accumulation are now better understood. Increase of glycolysis and of transmembrane transport of glucose seems to be at the origin of the high tumorous accumulation of FDG. The main current oncologic application of FDG PET is the diagnosis of malignancy of the isolated pulmonary nodules, with a sensitivity of more than 95%, and in the staging of lung cancer where PET shows higher performances than conventional imaging. The same stands in cutaneous melanoma and for malignancies of the digestive tract, either in colorectal, pancreatic or esophageal localizations. In colorectal cancers, the role of PET has for long being recognized in the differential diagnosis between recurrence and postoperative fibrosis. In the head and neck tumors, FDG also allows to differentiate between recurrence and postradiation necrosis. In lymphoma, the most suitable site for biopsy can be identified on a PET scan and therapy efficacy can also be assessed. In breast cancer, the detection of metastases seems to be possible with FDG. In brain and thyroid cancers, the role of FDG PET remains to be further determined. The low uptake of FDG in prostate cancer metastasis is not in favor of its use in this indication. In conclusion, the indications of FDG PET in oncology are now becoming more precise and it can be expected that clinical PET centers will soon appear in France.

Cytokine targeting in tumors using a bispecific antibody directed against carcinoembryonic antigen and tumor necrosis factor alpha.

The use of tumor necrosis factor alpha (TNFalpha) in cancer therapy is limited by its short circulatory half-life and its severe systemic side effects. To overcome these limitations, we evaluated the capability of a bispecific antibody (BAb) directed against carcinoembryonic antigen (CEA) and human TNFalpha to target this cytokine in tumors. A BAb was constructed by coupling the Fab' fragments from an anti-CEA monoclonal antibody (MAb) to the Fab' fragments from an anti-TNFalpha MAb via a stable thioether linkage. The double specificity of the BAb for CEA and TNFalpha was demonstrated using a BIAcoreTM two-step analysis. The affinity constants of the BAb for CEA immobilized on a sensor chip and for soluble TNFalpha added to the CEA-BAb complex were as high as those of the parental MAbs (1.7 x 10(9) M-1 and 6.6 x 10(8) M-1, respectively). The radiolabeled 125I-labeled BAb retained high immunoreactivity with both CEA and TNFalpha immobilized on a solid phase. In nude mice xenografted with the human colorectal carcinoma T380, the 125I-labeled BAb showed a tumor localization and biodistribution comparable to that of 131I-labeled anti-CEA parental F(ab')2 with 25-30% of the injected dose (ID)/g tumor at 24 h and 20% ID/g tumor at 48 h. To target TNFalpha to the tumor, a two-step i.v. injection protocol was used first, in which a variable dose of 125I-labeled BAb was injected, followed 24 or 48 h later by a constant dose of 131I-labeled TNFalpha (1 microg). Mice pretreated with 3 microg of BAb and sacrificed 2, 4, 6, or 8 h after the injection of TNFalpha showed a 1.5- to 2-fold increased concentration of 131I-labeled TNFalpha in the tumor as compared to control mice, which received TNFalpha alone. With a higher dose of BAb (25 microg), mice showed a better targeting of TNFalpha with a 3.2-fold increased concentration of 131I-labeled TNFalpha in the tumor: 9.3% versus 2.9% ID/g in control mice 6 h after TNFa injection. In a one-step injection protocol using a premixed BAb-TNFalpha preparation, similar results were obtained 6 h postinjection (3.5-fold increased TNFalpha tumor concentration). A longer retention time of TNFalpha was observed leading to an 8.1-fold increased concentration of TNFalpha in the tumor 14 h postinjection (4.4 versus 0.5% ID/g tumor for BAb-treated and control mice, respectively). These results show that our BAb is able, first, to localize in a human colon carcinoma and, there, to immunoabsorb the i.v.-injected TNFalpha, leading to its increased concentration at the tumor site.

La detección de IgA para diagnosticar las infecciones retrovíricas en el Caribe / IgA testing for diagnosis of retroviral infections in the Caribbean

En la isla caribeña de Guadalupe, donde hay una alta prevalencia de infección por el virus linfotrópico T humano del tipo 1 (HTLV-1), los métodos de diagnóstico dan lugar a muchos resultados positivos falsos que hay que verificar mediante pruebas adicionales largas y costosas. En el presente artículo se describe una manera simple de solucionar este problema. Consiste, primero, en extraer del suero de un paciente toda la IgG y sus inmunocomplejos circulantes (ICC) mediante un tratamiento con proteína G, para después detectar la presencia de IgA antivírica en el suero tratado usando las pruebas comerciales de ELISA y Western Blot con ligeras modificaciones

La detección de IgA para diagnosticar las infecciones retrovíricas en el Caribe / IgA testing for diagnosis of retroviral infections in the Caribbean

En la isla caribeña de Guadalupe, donde hay una alta prevalencia de infección por el virus linfotrópico T humano del tipo 1 (HTLV-1), los métodos de diagnóstico dan lugar a muchos resultados positivos falsos que hay que verificar mediante pruebas adicionales largas y costosas. En el presente artículo se describe una manera simple de solucionar este problema. Consiste, primero, en extraer del suero de un paciente toda la IgG y sus inmunocomplejos circulantes (ICC) mediante un tratamiento con proteína G, para después detectar la presencia de IgA antivírica en el suero tratado usando las pruebas comerciales de ELISA y Western Blot con ligeras modificaciones

Disponible en inglés en Bull Pan Am. Health Organ 25(3):201-06, 1991

IgA testing for diagnosis of retroviral infections in the Caribbean.

In Guadeloupe, a Caribbean island with a high prevalence of HTLV-I infected subjects, the percentage of false positive results for HIV IgG is high, requiring additional time and expense for confirmatory tests. This article describes a simple way of overcoming this problem. First, all IgG and IgG immune complexes are removed by protein G treatment, and then IgA enzyme-linked immunosorbent assay (ELISA) and the Western blot test are performed with minor modification of commercially available kits.

PIP: Researchers wanted to determine whether they could do a more specific ELISA HIV test directed at IgA rather than IgG antibodies. So they 1st used streptococcal protein G to remove IgG from serum samples of 10 follow up patients from Guadeloupe who previously tested positive via ELISA for HIV-1/2 IgG and HTLV-I IgG. They did this to test sera for IgA. The protein G treatment resulted in a 99.9% reduction in the IgG concentration (12.21.7 mg/ml to .007-.017 mg/ml). After IgG depletion, the researchers noted no ELISA positive samples for HIV-1/2 or HTLV-I IgG. In fact, all the values were well below the cutoff levels. This result indicated that streptococcal protein G treatment followed by IgA ELISA is more specific than testing for IgG. The sera of 8 patients tested negative for HIV-1/2 IgA, but all tested positive for HTLV-1 IgA. This result showed that IgA may be more useful than IgG for also confirming retroviral infections. The sera of 2 patients were 44% and 27% above the cutoff level indicating that these patients had HIV-1/2 IgA antibodies. The researchers observed that protein G treatment suppressed all HIV-1/2 and HTLV-I IgG Western blot reactivity which confirmed the effectiveness of protein G treatment. Further the HIV IgG bands in the 8 false positive sera did not materialize at all suggesting that the IgG reactivity observed was most likely nonspecific. These results indicated that nonspecific HIV-1/2 IgG caused the false positive HIV-1/2 IgG ELISA results. In conclusion, in Caribbean countries where HTLV-1 infection can be as high as 13%, the more specific HIV IgA ELISA test should be used since its use saves time and money. Further it can do generalized testing for HTLV antibodies.

IgA testing for diagnosis of retroviral infections in the Caribbean

In Guadeloupe, a Caribbean island with a high prevalence of HTLV-I infected subjects, the percentage of false positive results for HIV IgG is high, requiring additional time and expense for confirmatory tests. This article describes a simple way of overcoming this problem. First, all IgG and IgG immune complexes are removed by protein G treatment, and then IgA enzyme-linked immudosorbent assay (ELISA) and the Western blot test are performed with minor modification of commercially available kits

IgA testing for diagnosis of retroviral infections in the Caribbean

In Guadeloupe, a Caribbean island with a high prevalence of HTLV-I infected subjects, the percentage of false positive results for HIV IgG is high, requiring additional time and expense for confirmatory tests. This article describes a simple way of overcoming this problem. First, all IgG and IgG immune complexes are removed by protein G treatment, and then IgA enzyme-linked immudosorbent assay (ELISA) and the Western blot test are performed with minor modification of commercially available kits

Available in spanish in Bol. Oficina Sanit. Panam 112(1):12-18, 1992

Hepatotoxicity of the daily combination of 5 mg/kg prothionamide + 10 mg/kg rifampin.

Because a 13% incidence of hepatotoxicity was observed in a first study of multibacillary leprosy patients treated daily with dapsone, rifampin, and 10 mg/kg thioamide, the patients were treated in a second study with 5 mg/kg thioamide in daily combination with dapsone and rifampin. In this study, monthly assessments of liver function were performed in order to detect early hepatic disturbances. Despite the reduced dosage of thioamide, a 16.5% incidence of hepatotoxicity was observed among 110 multibacillary patients. However, jaundice was observed in only 2 out of 18 cases of hepatotoxicity (11%); whereas it was observed in 5 out of the 7 cases of hepatotoxicity (71%) in the first study (p less than 0.05). The decrease in the thioamide dosage and the performance of monthly assessments of liver function did not decrease the incidence of hepatotoxicity but did decrease its severity. It is concluded that thioamide should not be used in daily combination with rifampin unless the daily dose is 5 mg/kg and monthly assessments of liver function are routinely performed.

The anatomical value of technetium-thallium subtraction scanning in detection and location of parathyroid adenomas.

99mTechnetium-201Thallium subtraction scanning was performed in 24 patients with primary (N = 5) and secondary (N = 19) hyperparathyroidism. The preoperative scintigraphy (N = 12) detected 21 of 23 enlarged glands surgically removed and was helpful for detecting abnormal location especially in the mediastinum. Postoperative scanning in patients with recurrent hyperparathyroidism confirmed the excessive growth of the remaining half parathyroid after subtotal parathyroidectomy or a missing fifth parathyroid after total parathyroidectomy and autotransplantation. False negative results were due to tumor hyperplasia. The technique is recommended prior to repeated exploration in patients presenting persistent disease to predict the location of adenomas generally unsuccessfully detected by ultrasonography and computed tomography.

[Pulmonary surfactant in neonatal pathology]. / Le surfactant pulmonaire dans la pathologie néonatale

Following some preliminary remarks on the role of the surfactant in pulmonary physiology and physiopathology, a physiochemical study of the lungs of 26 infants who died in the neonatal period is reported. Two techniques for measuring the decrease in surface tension are set out. The results in the first case (tensiometric method) allow an explanation of the physiopathological aspect of respiratory distress; in the second case (manometric method) the diagrams obtained are characteristic of different clinical states (normal subjects; subjects born prematurely without any hyaline membrane etc...). Furthermore, the second method gives rise to certain hypotheses as to the physiochemical structure of the substances responsible for the tensio-active properties of the surfactant.

[Pulmonary surfactants. Generalities]. / Le surfactant pulmonaire. Généralités

The alveolar wall on contact with air can be compared with a biological air-liquide interface. As with all interfaces, there are therefore superficial forces which tend to reduce the surface to a minimum. In the case of a pulmonary alveolus with a spherical surface, these forces are at the origin of an internal pressure excess dependent on the radius of the alveolus and on the superficial tension related to the nature of the interface. Owing to the disparity in the alveolar radii, under these conditions the smaller alveoli would collapse to the benefit of a larger one, the pressure being lower and lower in the latter. In addition, at any time in the respiratory cycles, this surpression must be negligible in order to avoid rupture of the equilibrium of the forces exerted on the alveolar wall. Consequently, it is necessary that this air-alveolar wall interface should have a superficial tension on the one hand variable with the surface, and on the other hand always very low. Owing to the demonstration of large concentrations of phospholipid in this area, it can be thought that a superficial film is substituted at the air-biological liquid interface and owing to this fact effectively has superficial properties necessary for alveolar stability. The "surface-tensio-active" effect of this film lead to the giving of the name of "surfactant" to these constituents as a whole.