Different toxic, fibrogenic and mutagenic effects of four commercial quartz flours in the rat lung.

There is still intensive debate on the variability in the biological activities of different quartz species. Therefore we examined in a rat lung model the inflammatory, fibrogenic and genotoxic characteristics of four commercial quartz flours. The samples, two with probably low activity and two with probably high activity were selected from a panel of 16 samples on the basis of in vitro investigations. Rats were exposed by a single intratracheal injection of 0.6, 1.2 and 2.4 mg quartz samples per lung or with 1.2 mg standard quartz DQ12. After 90 days the inflammatory response was measured in the bronchoalveolar lavage fluid, as well as the content of 8-oxoguanine in the DNA of the lung cells. Additionally mutated p53 protein was determined. The four quartz samples revealed specific differences in all parameters investigated. In good agreement with the in vitro results the two samples expected as lowly active showed only weak inflammatory and no genotoxic reactions in the rat lungs. In contrast the two samples suspected as highly reactive induced a pronounced inflammatory response and for one of the samples genotoxic effects could be proven. The results raised here show a broad spectrum of biological activities dependent on the type of quartz from almost inert to genotoxic and highly inflammatory.

Investigations on the inflammatory and genotoxic lung effects of two types of titanium dioxide: untreated and surface treated.

TiO(2) is considered to be toxicologically inert, at least under nonoverload conditions. To study if there are differences in lung effects of surface treated or untreated TiO(2) we investigated the inflammatory and genotoxic lung effects of two types of commercially available TiO(2) at low doses relevant to the working environment. Rats were exposed by instillation to a single dose of 0.15, 0.3, 0.6, and 1.2 mg of TiO(2) P25 (untreated, hydrophilic surface) or TiO(2) T805 (silanized, hydrophobic surface) particles, suspended in 0.2 ml of physiological saline supplemented with 0.25% lecithin. As control, animals were instilled with the vehicle medium only or with a single dose of 0.6 mg quartz DQ12. At days 3, 21, and 90 after instillation bronchoalveolar lavage was performed and inflammatory signs such as cells, protein, tumor necrosis factor-alpha, fibronectin, and surfactant phospholipids were determined. Additionally, 8 microm frozen sections of the left lobe of the lung were cut and stored at -80 degrees C. The sections were used for immunohistochemical detection of 8-oxoguanine (8-oxoGua) by a polyclonal antibody in the DNA of individual lung cells. In the quartz-exposed animals a strong progression in the lung inflammatory response was observed. Ninety days after exposure a significant increase in the amount of 8-oxoGua in DNA of lung cells was detected. In contrast, animals exposed to TiO(2) P25 or TiO(2) T805 showed no signs of inflammation. The amount of 8-oxoGua as a marker of DNA damage was at the level of control. The results indicate that both types of TiO(2) are inert at applicated doses.

Quartz exposure of the rat lung leads to a linear dose response in inflammation but not in oxidative DNA damage and mutagenicity.

Exposure to quartz and high concentrations of other poorly soluble particles can lead to the development of lung tumors in the rat. The mechanisms involved in particle-induced carcinogenesis seem to include inflammation-associated production of reactive oxygen species (ROS) and DNA damage. ROS induce 8-oxoguanine (8-oxoGua) and a panel of other oxidation products in DNA. In proliferating cells such DNA lesions can lead to various types of mutations, which might be critical for cancer-related genes with respect to tumor formation. Quartz is known to mediate the induction of 8-oxoGua in the nuclear DNA of lung cells when applied to the lung of rats. We have investigated the time- and dose-dependent biologic effects of quartz and, as a control, corundum, on cell proliferation and various pulmonary inflammation and toxicity markers in rat bronchoalveolar lavage fluid (BALF); on the induction of 8-oxoGua in the DNA of rat lung cells; and on the cellular levels of p53 wild-type and p53 mutant (mut) protein. Rats were exposed by intratracheal instillation to various amounts of quartz (0.3, 1.5, or 7.5 mg/rat) or corundum (0.3, 1.5, or 7.5 mg/rat) and measured at Days 7, 21, and 90 after exposure. Corundum had no adverse effects except a slight elevation of 8-oxoGua at a dose of 7.5 mg/rat. However, significant changes in the BALF were detected at all quartz doses. 8-oxoGua was significantly increased only at 1.5 and 7.5 mg quartz/rat. The amount of cells with detectable p53 wild-type protein levels was increased at 1.5 and 7.5 mg quartz/rat at 7 and 21 d. Elevated amounts of cells with enhanced p53 mut protein levels were measured at all time points after instillation of 7.5 mg quartz/rat.

Significant differences in the cellular and molecular reactions of rat and hamster lung after quartz exposure.

Exposure of rats to high doses of quartz and other insoluble isometric particles can produce lung tumors. In contrast, after exposure of such particles in hamsters no tumor outcome has been observed. Recent studies have demonstrated that the tumorigenic effect of particles is closely linked to the induction of inflammatory processes and the subsequent formation and persistence of mutagenic oxidative DNA-modifications. Species-specific differences in sensitivity to particles should therefore be reflected in the molecular reaction of the lung cells. We exposed rats and hamsters to two different doses of quartz (0.3 mg, 1.2 mg/100 g body weight) by intratracheal instillation and characterized the dose-related pattern of pulmonary inflammation (neutrophil recruitment, TNF), toxicity (protein content, surfactant phospholipids), antioxidant defence (glutathione content), mutagenicity (8-oxoguanine, p53) and proliferation. Our results clearly demonstrate a significantly higher response of the rat to quartz exposure for all determined molecular and cellular parameters. Therefore the examination of these parameters in humans would contribute to the evaluation of the relevance of rats or hamsters as models to predict particle-induced human lung cancer risk.

Evidence of a no-effect level in silica-induced rat lung mutagenicity but not in fibrogenicity.

Exposure to silica can lead to fibrosis and the development of lung tumors in the rat. Based on these animal studies and on epidemiological data, silica has been classified as a human carcinogen. The initial mechanisms have not been finally clarified, but particle-induced tumor formation is at least closely associated with inflammation, the production of reactive oxygen species (ROS) and DNA damage. We investigated the dose-dependent effects of silica on the formation of the major DNA oxidation product 8-oxoguanine (8-oxo-Gua) in rat lung cells, on p53 (p53) and p53 mutant protein (p53 mut) synthesis, as well as on the amount of the surfactant phospholipids phosphatidylinositol (PI) and phosphatidylglycerol (PG) in the bronchoalveolar lavage fluids (BALF) as indicators of fibrotic processes in the lung. Rats were exposed by intratracheal instillation to various amounts of DQ12 quartz (0.15, 0.3, 0.6, 1.2, 2.4 mg/animal) and lungs were investigated after 21 and 90 days. PG decreased and PI increased quartz dose dependently. 8-oxoGua was significantly increased only after 1.2 and 2.4 mg quartz/animal. Cells expressing p53 protein were increased at 1.2 and 2.4 mg, p53 mutant protein only at 2.4 mg/animal. This indicates a no-effect level for mutagenicity at a low, but still fibrogenic quartz exposure.

CT in malignancy grading and prognostic prediction of non-Hodgkin's lymphoma.

PURPOSE: The presence of tumor inhomogeneities in MR images of non-Hodgkin's lymphoma (NHL) provides information about malignancy grade and prognosis. The aim of this study was to determine whether CT images are also informative in these respects. MATERIAL AND METHODS: Sixty-three CT examinations in patients with NHL (32 high-grade and 31 low-grade tumors) were reviewed retrospectively by two senior radiologists. The tumor patterns were classified subjectively as homogeneous, slightly inhomogeneous or severely inhomogeneous and their relations to malignancy grade, clinical characteristics and prognosis were determined. RESULTS: Sixteen out of 17 patients with a severely inhomogeneous tumor pattern had high-grade NHL tumors while 21 out of 29 patients with a homogeneous tumor appearance had low-grade NHL tumors. Among chemotherapy-treated patients, those with the highest degree of inhomogeneity had a significantly worse prognosis (9 out of 11 patients died). This relationship was not found in patients treated with radiotherapy. CONCLUSION: A severely inhomogeneous tumor pattern on CT images was found to be associated with a high malignancy grade in NHL. This CT pattern was also compatible with a poor prognosis in patients treated with chemotherapy.

Tumour inhomogeneities on magnetic resonance imaging, a new factor with prognostic information in non-Hodgkin's lymphomas.

The prognostic importance of inhomogeneities on magnetic resonance imaging (MRI) in non-Hodgkin lymphomas (NHL) was evaluated. Forty-six consecutive patients with high-grade NHL were examined and, for comparison purposes, 13 patients with low-grade NHL. The degree of inhomogeneity was measured with a quantitative method (IH8) and a subjective evaluation was also performed. Patients with localized disease (stage I), who had all been treated with radiotherapy, had an excellent prognosis, which was independent of the degree of tumour inhomogeneity. In generalized NHL (stages II-IV) treated with chemotherapy, IH8 provided prognostic information in high-grade NHL. Patients with pronounced tumour inhomogeneity, in particular, had a very poor prognosis. The prognostic impact was also seen if the analyses were performed with high-grade and low-grade NHLs grouped together. The inhomogeneities may indicate a mechanism related to treatment failure after chemotherapy, but not after fractionated radiotherapy.

[18F] FDG PET in gastric non-Hodgkin's lymphoma.

The possibility of using [18F] FDG PET for assessment of tumor extension in primary gastric non-Hodgkin's lymphoma (NHL) was studied in 8 patients (6 high-grade and 2 low-grade, one of the MALT type) and in a control group of 7 patients (5 patients with NHL without clinical signs of gastric involvement, 1 patient with NHL and benign gastric ulcer and 1 patient with adenocarcinoma of the stomach). All patients with gastric NHL and the two with benign gastric ulcer and adenocarcinoma, respectively, underwent endoscopy including multiple biopsies for histopathological diagnosis. All patients with high-grade and one of the two with low-grade NHL and the patient with adenocarcinoma displayed high gastric uptake of [18F] FDG corresponding to the pathological findings at endoscopy and/or CT. No pathological tracer uptake was seen in the patient with low-grade gastric NHL of the MALT type. In 6/8 patients with gastric NHL, [18F] FDG PET demonstrated larger tumor extension in the stomach than was found at endoscopy, and there was high tracer uptake in the stomach in two patients who were evaluated as normal on CT. [18F] FDG PET correctly excluded gastric NHL in the patient with a benign gastric ulcer and in the patients with NHL without clinical signs of gastric involvement. Although the experience is as yet limited, [18F] FDG PET affords a novel possibility for evaluation of gastric NHL and would seem valuable as a complement to endoscopy and CT in selected patients, where the technique can yield additional information decisive for the choice of therapy.

Predicting malignancy grade with PET in non-Hodgkin's lymphoma.

UNLABELLED: Our goal was to determine whether PET with 11C-methionine and/or 18FDG could predict malignancy grade in non-Hodgkin's lymphoma (NHL). METHODS: Twenty-three patients with high-grade, low-grade or transformed low-grade NHL were investigated. Standardized uptake values (SUV), transport rate and mass influx values were calculated both for the whole tumor [mean regions of interest, (ROI)] and for the tumor area with the highest levels of activity, comprising four contiguous pixels within each tumor and designated as a hot spot. RESULTS: Both 11C-methionine and 18FDG detected all tumors. In addition, 18FDG discriminated between high- and low-grade NHL, whereas 11C-methionine did not. With 18FDG, three transformed low-grade NHLs behaved in an intermediate manner. All quantitative uptake values correlated well with each other for both tracers, except for the mean ROI SUV and transport rate of 11C-methionine. Quantifications of mean ROI uptake and hot spots were strongly correlated. CONCLUSION: The results of this study together with previous findings from other studies indicate that 18FDG but not 11C-methionine can predict malignancy grade in NHL. Further studies with a larger series of patients are needed.

Deoxythymidine kinase in the tumour cells and serum of patients with non-Hodgkin lymphomas.

The levels of deoxythymidine kinase in tumour cells (C-TK) and in serum (S-TK) were investigated and the tumour volume calculated in 89 patients with non-Hodgkin lymphoma (NHL), in order to ascertain the importance of C-TK and tumour burden as regards the S-TK levels. Among all patients, a correlation was seen between S-TK and tumour volume but not between S-TK and C-TK. However, within different tumour volume categories (small, medium-sized and large), there was a correlation between S-TK and C-TK. Multiple regression analysis supported this notion. C-TK correlated with the proliferation-associated parameters, S-phase fraction and mitotic index. As already known, S-TK was found to have a strong prognostic value. C-TK and tumour burden were also of prognostic value. In multivariate analyses, C-TK and tumour volume did not provide prognostic information in addition to S-TK, whereas, in the absence of S-TK, C-TK and tumour volume did provide additional information. It is concluded that the serum level of TK depends on both the tumour burden and the tumour cell proliferation rate. Based upon estimations of S-TK in patients assessed shortly after chemotherapy, we also suggest that S-TK reflects the number of proliferating cells that have died during the period immediately before sampling.

Gd-DTPA-enhanced MR imaging in mediastinal Hodgkin's disease.

Gd-DTPA-enhanced MR imaging of 15 patients with primary mediastinal Hodgkin's disease was done before, during and after treatment. A total of 43 MR examinations were performed. After successful treatment, 13 patients had residual masses with reduced signal intensity (SI) ratio in the T2-weighted images. The majority of these also had decreased contrast enhancement as compared with the corresponding primary tumour. There was a significant positive correlation between the contrast enhancement and the SI ratios in the T2-weighted images of the primary tumours and/or the residual masses. Necrosis was seen in 3 of the primary tumours and one patient had a cystic residual mass. These necrotic/cystic lesions were easier to detect with the use of Gd-DTPA. Low SI ratio in the T2-weighted image and low contrast enhancement of the residual mass seem to indicate residual inactivity. Gd-DTPA facilitates the differentiation between cystic/necrotic and solid lesions.

Diagnostics of malignant lymphomas with ultrasound guided 1.2 mm biopsy-gun.

In a retrospective analysis of 129 ultrasound-guided biopsy-gun biopsies (USGB) from patients with known or suspected malignant lymphoma, a histopathological diagnosis was obtained in 101 (78%) instances and no further procedures for histological verification were required. In the 28 cases with initially non-diagnostic results, 14 new USGBs were performed and a diagnosis was obtained in 11. Thus, a total success rate of 87% was achieved. The correct diagnosis was confirmed with either surgery, autopsy, or radiological or clinical follow-up (median 40 months). The diagnoses were categorised as Hodgkin's disease and high-grade or low-grade non-Hodgkin's lymphoma. Further subtyping of the lymphoma was possible in a few cases only. Immunohistochemistry was utilised only in a minor proportion of the cases (25/129), but refined the diagnosis in several instances. The biopsy-gun method was safe and minor adverse effects were seen in two patients only.

Quantification of inhomogeneities in malignancy grading of non-Hodgkin lymphoma with MR imaging.

In a previous study of 50 patients with non-Hodgkin lymphoma (NHL) it was shown that the inhomogeneous appearance of a tumor at MR imaging strongly indicated a high malignancy grade. In this study of 33 patients with NHL, the administration of an i.v. contrast medium, Gadolinium-DTPA, improved the subjective detectability of the inhomogeneities. A method of quantifying the degree of inhomogeneity in the tumors (inhomogeneity index, IH-index) was developed and tested. The mean value of IH-index in the T2-weighted image before contrast medium administration, and of the T1-weighted image after contrast medium administration, as well as the IH-index value in the T2-weighted image before contrast medium administration alone, was able to discriminate well between low- and high-grade NHL. This method of quantifying the degree of inhomogeneity in tumors improved sensitivity in detecting high-grade NHL.

Therapeutic effects of brief hospitalization : the role of a therapeutic alliance.

Correlational data in this study suggest that a strong therapeutic alliance is associated with improvement during brief hospitalization. Two measures of alliance were used: patient-staff agreement on treatment goals and patient expectations of benefit from treatment. Greater patient-staff agreement at admission was associated with symptomatic improvement, independent of medication use; less use of immature defense mechanisms at discharge; and reduced risk of precipitous discharge. For a given level of symptoms, greater agreement was associated with lower doses of antipsychotics but higher doses of minor tranquilizers and antidepressants. Perception of the ward was associated with patients' expectation of benefit.

A comparative study of proliferation-associated parameters in B-cell non-Hodgkin lymphoma.

The prognostic value of three proliferation-associated parameters, the frequency of cells in S-phase, mitotic index (MI) and serum deoxythymidine kinase levels (S-TK), was examined in 106 primary cases of B-cell non-Hodgkin lymphomas (NHL), 76 'low grade' NHL and 30 'high grade' NHL and compared with morphology and clinical variables. All three proliferation factors displayed large differences in the mean values of the two groups 'low grade' and 'high grade' NHL, and all revealed significant prognostic information. In 'low grade' NHL, the information decreased with follow-up time. A correlation (r = 0.7) was noted between S-phase values and MI but not between S-TK and the two others. In the entire patient material and in the two prognostic groups defined by morphology, S-TK gave the best prognostic information. MI gave better prognostic information than S-phase values in the whole material and in 'low grade' NHL, whereas the reverse appeared to be true for 'high grade' NHL. In the multivariate analyses, no other parameter apart from S-TK provided any further prognostic importance in the cases of 'high grade' NHL, whereas in that of 'low grade' NHL, MI, stage, age and histology had independent importance.

Non-Hodgkin lymphoma: predicting prognostic grade with MR imaging.

Fifty patients with non-Hodgkin lymphoma (NHL) were examined with magnetic resonance (MR) imaging in order to analyze whether it is possible to distinguish in vivo between the two major prognostic groups, low-grade NHL and high-grade NHL. Most high-grade NHL nodes (15 of 24 [63%]) had an inhomogeneous appearance at MR imaging, in contrast to low-grade NHL nodes, which were homogeneous in almost all patients (18 of 20 [90%]) (P less than .001). A homogeneous image was also found in six patients who had previously received a diagnosis of low-grade NHL; at the time of examination their lesions had transformed into high-grade NHL. Necrosis, detectable in the histopathologic sections, was usually (five of six cases) associated with an inhomogeneous image. However, the images were also inhomogeneous [corrected] in 12 of 44 cases (27%) in which there were no signs of necrosis in the histopathologic sections. Patients with high-grade NHL and a homogeneous signal intensity pattern tended to have a better survival rate than those with an inhomogeneous pattern.

Prognostic significance of flow cytometry studies in B-cell non-Hodgkin lymphoma.

The prognostic relevance of flow cytometric DNA measurements of lymph node biopsies in relation to histopathology according to the Kiel classification, stage, age and presence or absence of B-symptoms was investigated in 106 patients with non-Hodgkin lymphomas (NHL) of proven B-cell type. Biopsies were taken at diagnosis before treatment. The mean proportion of cells in S-phase was significantly lower in the 76 patients with a 'low grade' NHL (4.4 per cent) than in the 30 patients with a 'high grade' NHL (13.0 per cent) (p less than 0.0001). High S-phase rates were associated with a poor prognosis within the whole material (p less than 0.01) and within the group of 'high grade' NHL (p less than 0.05). In the subgroup CB-CC lymphomas of 'low grade' NHL, the prognostic value of the S-phase rate was stronger than any other investigated parameter (p less than 0.05). In multivariate analyses, the S-phase rate gave, in several subgroups, independent prognostic information, besides clinico-pathological variables.

Residual mediastinal masses in Hodgkin disease: prediction of size with MR imaging.

Eighteen patients with mediastinal involvement of Hodgkin disease were examined with magnetic resonance (MR) imaging before and during therapy to find out if size of residual masses could be predicted from the MR characteristics of the tumor at diagnosis. After the first treatment, a significant decrease in T2 values and signal intensity ratios of tumor to fat and tumor to muscle was found in all patients. There was no significant change in T1 values. The relative decrease in tumor size correlated well with signal intensity ratios and poorly with T2 values of the original tumor. No correlation with T1 values was found. The authors conclude that size of the residual mass can be predicted from the initial size of the tumor and the signal intensity ratios at diagnosis. Since the degree of low signal intensity in the tumor before treatment probably reflects the amount of fibrotic tissue, these results support the hypothesis that residual masses after treatment are remnants of the fibrotic stroma of the original tumor.

Magnetic resonance imaging, chest radiography, computed tomography and ultrasonography in malignant lymphoma.

Magnetic resonance imaging (MRI) was compared with chest radiography, computed tomography (CT) and ultrasonography (US) for demonstration of spleen and liver engagement and enlarged lymph nodes in patients with malignant lymphoma. The investigation comprised 24 patients with Hodgkin's disease (HD) and 39 with non-Hodgkin lymphoma (NHL). MRI demonstrated enlarged lymph nodes, distinctly separated from vessels, fat, muscle, liver and occasionally also pancreas without any contrast medium. The distinction between lymph nodes and spleen was, however, poor in the images. In the mediastinum, MRI was superior to chest radiography and had an accuracy similar to that of CT. In the abdomen and the pelvis MRI had slight advantages over CT in detection of enlarged lymph nodes. Compared with US the MRI results were similar in the abdomen and somewhat better in the pelvis. MRI and US were better than CT in revealing HD infiltrates in the spleen. Infiltration of NHL in the spleen was slightly better disclosed at US than at CT and MRI; most of the NHL infiltration, confirmed at histopathology, could, however, not be revealed with any of the modalities, except when the size of the spleen was considered. Regions in the spleen, displayed with low image intensity in the T2 weighted image, were most likely due to increased amount of fibrotic tissue in the lymphomatous lesions. Good demonstration of lymph nodes and lymphomatous lesions in the spleen with MRI required two sequences; one with short TR and TE (T1 weighted image) and one with long TR and TE (T2 weighted image).

Magnetic resonance imaging for assessment of treatment effects in mediastinal Hodgkin's disease.

Six patients with mediastinal involvement of Hodgkin's disease were examined with magnetic resonance imaging (MRI) at 0.35 T before and/or at various stages of therapy, with the sequences TR/TE: 500/35, 500/70, 1600/35 and 1,600/70. Before therapy the image intensity of tumour involved lymph nodes deviated considerably from fat and muscle, but no clear difference was discerned between histopathologic subtypes or tumour localizations. After efficient therapy, the tumour image intensities and relaxation rates approached those of muscle and fibrous tissue, but remained at pre-therapy values when the patient was not in full remission. A similar pattern was found in a 'normal-tissue'--'tumour' plot, based on vector analysis of the original sets of 4 images. It is concluded that persistent tumour involvement in the mediastinum may be distinguished from fibrosis and that MRI may thus be of value in the follow-up of patients with Hodgkin's disease.