CHOP-based chemotherapy is as effective as alternating PEEC/CHOP chemotherapy in a randomised trial in high-grade non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma Group.

The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.

Prevalence and pathogenesis of pneumoconiosis in coal workers.

Dust dose and composition do not appear to account wholly for changes in the prevalence of coal workers' pneumoconiosis in Europe. In certain coal pits high progression evidently occurred with relatively low dust exposure or vice versa, whereas progression in relation to dust levels might be variable. Exceptionally high quartz concentrations occur in coal mine dust when pneumoconiosis may progress with unusual rapidity. Under such circumstances lesions resembling silicotic nodules may be found, but with the customarily lower levels of quartz the pathological features assume the form characteristic of coal workers. Morphological changes in relation to dust content of human and animal lungs, as well as cellular behavior, have not accounted completely for the epidemiological findings. Considering all the pathological evidence helps explain the pathogenesis of pneumoconiosis and vagaries of progression. The origin of progressive massive fibrosis cannot be explained simply in terms of dust burden or immunological features, and the role of an infective factor cannot be dismissed. Moreover, lipid secretion by alveolar epithelium introduces a new element that could affect the development of simple and complicated pneumoconiosis. In vitro, cytotoxicity appeared to be too variable for predictive purposes, though direct assay of fibrogenicity using the macrophage fibrogenic factor suggested that dust dose was more important than dust composition. Assessing individual susceptibility presents serious obstacles.

Minerals, fibrosis, and the lung.

Determinants of pulmonary fibrosis induced by inhaled mineral dusts include quantity retained, particle size, and surface area, together with their physical form and the reactive surface groups presented to alveolar cells. The outstanding problem is to ascertain how these factors exert their deleterious effects. Both compact and fibrous minerals inflict membrane damage, for which chemical mechanisms still leave uncertainty. A major weakness of cytotoxicity studies, even when lipid peroxidation and reactive oxygen species are considered, lies in tacitly assuming that membrane damage suffices to account for fibrogenesis, whereas the parallel occurrence of such manifestations does not necessarily imply causation. The two-phase procedure established that particles, both compact and fibrous, induce release of a macrophage factor that provokes fibroblasts into collagen synthesis. The amino acid composition of the macrophage fibrogenic factor was characterized and its intracellular action explained. Fibrous particles introduce complexities respecting type, durability, and dimensions. Asbestotic fibrosis is believed to depend on long fibers, but scrutiny of the evidence from experimental and human sources reveals that a role for short fibers needs to be entertained. Using the two-phase system, short fibers proved fibrogenic. Other mechanisms, agonistic and antagonistic, may participate. Growth factors may affect the fibroblast population and collagen production, with cytokines such as interleukin-1 and tumor necrosis factor exerting control. Immune involvement is best regarded as an epiphenomenon. Downregulation of fibrogenesis may follow collagenase release from macrophages and fibroblasts, while augmented type II cell secretion of lipid can interfere with the macrophage-particle reaction.

Pulmonary toxicology of silica, coal and asbestos.

Mineral particles are customarily inhaled as mixtures, though one component may predominate and determine the response. Although the lesions often possess a characteristic structure, according to the main type of particle deposited, morphology affords little indication of pathogenesis. Being a major element in the evolution of dust lesions, macrophage behavior has been examined extensively in vitro after treatment with mineral particles, attention being directed to membrane and biochemical changes; however, no clear lead to the origin of the lesions has emerged. Pulmonary fibrosis, as one of the ultimate consequences of dust accumulation, required a direct in vitro approach in which the products of the macrophage-particle interaction were utilized to provoke collagen formation by fibroblasts in a two-phase system. By this means, silica and asbestos stimulated connective tissue formation and application of the technique to coal dusts appears promising. Coal workers may develop a peculiar type of emphysema in relation to lesions whose fibrous content is comparatively small. Type II alveolar epithelium is also stimulated by inhaled particles and lipid accumulation follows. Alveolar lipidosis interferes with the fibrotic response by preventing contact between macrophage and particles. This phenomenon may account in part for anomalies, apparent in coal workers, between epidemiological findings and dust composition. Carcinogenesis is a well-recognized feature of asbestos exposure, but, as with fibrosis, risk prediction on the basis of in vitro tests of cytotoxicity is premature and may not be valid.

Correlation between the tissue response and asbestos fiber content.

Asbestos fiber concentration increases in proportion to the degree of pulmonary fibrosis as far as the moderate grade. No such correlation occurs with severe asbestosis, nor with the morphological form which the fibrosis assumes, and here secondary factors may be concerned. Electron microscopy suggests that optically visible fibers constitute a reasonably constant proportion of the total irrespective of the pathological reaction. Light microscopy may thus afford a guide to the total asbestos concentration. Finally, the development of mesothelioma, whether of the pleura or the peritoneum, appears to be unrelated to the concentration of coated or uncoated asbestos fibers residing in the lung.

t(3;5)(q21;q31) in a myelodysplastic syndrome.

Cytogenetic analysis from the bone marrow of a patient with a myelodysplastic syndrome revealed the balanced translocation t(3;5)(q21;q31). Although this translocation has recently been described in six cases of AML, this is the first such observation in a preleukaemic syndrome. Subsequent evolution into RAEB and AML(M2) was noted without the acquisition of additional cytogenetic changes and complete remission achieved with conventional cytotoxic chemotherapy. The relationships with other acquired abnormalities of chromosomes 3 and 5 in MDS/AML are discussed.

The optical and electron microscopic determination of pulmonary asbestos fibre concentration and its relation to the human pathological reaction.

The quantitative extraction of asbestos fibres from asbestotic lung by alkali digestion has been refined by maceration of the tissue without prior drying, the minimum use of centrifugation, and the adoption of phase contrast microscopy. Preliminary experiments suggested that, using this technique, asbestos fibre counts were accurate to within at least +/- 20% and in most instances to within +/- 10%. The method was used to assess asbestos concentrations in lung tissue showing various degrees and forms of fibrosis. The results, as determined by light microscopy, indicated that uncoated fibres generally outnumbered coated fibres. In mild and moderate asbestosis there was a progressive increase in concentration of asbestos fibres, both coated and uncoated, with increasing severity of fibrosis, whereas in severe asbestosis no correlation existed between the fibre concentration and the form or the extent of the pathological reaction. It is suggested that the severe fibrosis results from the supervention of non-specific inflammatory processes. Asbestos fibre diameter distributions, gauged by electron microscopy, were fairly constant irrespective of the degree of fibrosis. Optically visible fibres constituted between 12 and 30% of the total, so that an optical count may be said to give an approximate indication of the total asbestos concentration and, so far as asbestosis is concerned, may well serve for comparative purposes. The relation between asbestos and neoplasia will, however, require identification and quantitation of particular types of the mineral by microanalytical techniques.

Routine bone marrow examination in the management of acute lymphoblastic leukaemia of childhood.

Eighty-four children with acute lymphoblastic leukaemia (ALL) who had relapsed in bone marrow were studied to assess whether treatment would be more successful if relapse was detected before the disease became clinically evident. Patients whose relapse was detected by routine bone marrow examination before the disease became apparent were compared with those whose relapse was suspected from clinical examination or peripheral blood findings. In the former there was a lower percentage of blast cells in the marrow (p less than 0.02) and the patients suffered less from complications of the disease, but there was no difference in the incidence or duration of second remissions between the two groups.

Primary T cell lymphoma of salivary gland: a report of a case and review of the literature.

Lymphoma of the salivary gland accounts for 5% of cases of extranodal lymphoma and 10% of malignant salivary gland tumours. Most primary salivary gland lymphomas are B marginal zone lymphomas arising on a background of sialadenitis associated with autoimmune disorders such as Sjorgen's syndrome. Primary T cell lymphoma of the salivary gland is rare. This report describes a case of primary T cell lymphoma arising in the parotid gland of an elderly white man, which was notable for its striking resemblance to a B cell extranodal marginal zone lymphoma. Immunohistochemistry and gene rearrangement studies confirmed the clonal T cell nature of the tumour. There was no molecular evidence of Epstein-Barr virus (EBV) infection of neoplastic or surroundings cells. Only 14 cases of primary T cell lymphoma of the salivary glands have been recorded in the literature, most being from the Orient and having extremely variable prognosis. Those with a T/natural killer cell phenotype are associated with EBV infection. This case highlights the fact that T cell lymphoma in the salivary gland can mimic closely the morphological features of B cell extranodal marginal zone lymphoma.

Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, UK.

As more centres consider autologous bone marrow and peripheral blood stem cell transplantation for patients with high risk Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) in first complete remission (CR1) the long term sequelae of such treatments have to be considered. One of the most important side effects of such intensive treatment is loss of fertility. Sperm banking before treatment commences is available for males but unfortunately cryopreservation of ova/ovarian tissue is not yet possible for females. We have transplanted 30 women, 23 were under 40 years and report ten females who have had successful pregnancies (including two twin pregnancies and one triplet pregnancy), leading to live births following autologous bone marrow transplantation (ABMT) for poor prognosis HD and NHL in first or second complete remission. None of these children have shown evidence of birth defects (median follow up of two years). Of the twenty one pregnancies reported to the European Bone Marrow Transplantation Registry (EBMTR) following ABMT for lymphoma, eight of the seventeen unassisted cases came from our centres. The Newcastle/SNLG autotransplant differs from the approach in many EBMTR centres in that it uses melphalan or melphalan/etoposide alone instead of the more common four drug containing regimens and yet sustained complete remission rates indicate that the non-ablative approach is equally effective as more aggressive regimens on the disease with the huge advantage of preserved fertility in females. This approach to conditioning for ABMT should be considered when treating women in the reproductive age group.

A case of heavy chain disease: diagnosis and monitoring using assays of immunoglobulin heavy and light chains.

Heavy chain diseases (HCD) are uncommon. We report the first use of recently developed analytical techniques for the assay of immunoglobulin heavy and light chains in the diagnosis and monitoring of a patient with gamma-HCD.

Relationship of lipid secretion and particle size to diffuse interstitial change in pneumoconiosis: a pathogenetic perspective.

Simple pneumoconiosis due to compact particles, notably in coal workers, sometimes departs from its customary focal formations and a more diffuse distribution of dust-impregnated fibrosis is superimposed. To account for this change, which may be reflected in the acquisition of radiologically irregular opacities in addition to rounded ones, attention is directed first toward type II alveolar epithelium. These cells come early into contact with inhaled particles and the lipid secretion provoked prevents their characteristic aggregation, so they remain in a more dispersed state and the consequent fibrotic reaction then tends to become diffuse. Second, submicron particles appear to act not from within the alveolus like the more usual larger ones, but after direct passage through type I epithelium into the interstitium, where lacking focal accumulation they are able to produce diffuse changes. Complexities, however, remain, among which are coalescence of focal lesions as their severity increases and interplay of agents producing interstitial fibrosis in the general population.

Silica, pneumoconiosis, and carcinoma of the lung.

The current argument about the carcinogenicity of inhaled silica is not clarified by reliance on morbidity and mortality experience divorced from or incompletely related to data on environmental exposure. Human evidence provides the ultimate basis for assessing such risks, and numerous studies of the effects of inhaling dusts rich or poor in silica content on the prevalence of pulmonary carcinoma have been performed on large series of cases from major mining areas of the world. When due allowance is made for substances inhaled concomitantly with exposure to silica and for personal pollution by cigarette smoking, the weight of evidence is against a carcinogenic role for uncombined silicon dioxide. Moreover, pneumoconiosis due to compact mineral particles does not appear to determine the onset of lung cancer. Cellular behaviour suggests reasons for the different responses to compact and fibrous particles acting alone.

Determinants of pulmonary fibrosis and lipidosis in the silica model.

The conditions which might favour development of the fibrotic or the lipid component of the pulmonary reaction to inhaled quartz were examined in rats. Smaller particle size and freedom from surface contamination by amorphous silica or iron oxide, status of the animals whether specific pathogen-free or conventional, and the resistance of cell membranes to damage appeared to bear on fibrogenesis. Increased membrane stability by treatment with polyvinylpyridine-N-oxide abolished not only the fibrosis but also the response of type II cells and hence lipidosis. The rate and intensity of quartz deposition may also affect the response, a low concentration inhaled over a long period favouring nodulation. No other manipulations, environmental or pharmacological, succeeded in inhibiting lipidosis to the benefit of fibrosis. Guinea pigs, however, behaved differently, their reaction being characterized by massive alveolar accumulation of dust-bearing macrophages and type II cell hyperplasia but not by lipidosis. The species variation is unexplained but macrophage predominance may represent a phase that later transforms to lipidosis. The experimental findings may have implications for forms of pneumoconiosis other than silicosis.

Coal workers' pneumoconiosis: a historical perspective on its pathogenesis.

The earliest observations on coal workers' pneumoconiosis identified fundamental factors and posed particular problems in its genesis. Among the former, intensity of exposure and particle size were recognized, while argument commenced on the roles of stone dust, thus anticipating the quartz question, and of complicating pulmonary states, which introduced the idea of infection. Major studies of the disease were precipitated by its greatly increased prevalence, which became evident among South Wales coal workers from the 1930s. The principal directions of enquiry remained the same as in Scotland a century before, namely the components of coal mine dust responsible for fibrosis and the additional factor required for the development of massive fibrosis. The combined human and experimental evidence now makes possible conclusions in which confidence may be placed.

Fibrogenesis by mineral fibres: an in-vitro study of the roles of the macrophage and fibre length.

Evidence on the mechanism by which inhaled mineral fibres lead to pulmonary fibrosis has not been forthcoming. As with silica, a biphasic cell culture system was required to distinguish phagocytosis from collagen formation. Synthesis of total protein and collagen by rat fibroblasts was estimated by incorporation of labelled proline after treatment with the medium from rat peritoneal macrophages that had been cultured in the presence of different types of mineral fibre. The influence of fibre length was also examined. All the main varieties of asbestos reacted with macrophages to produce or release a fibrogenic factor. However, chrysotile and the longer amosite fibres evoked the response only after prolonging the period of incubation with macrophages, presumably by permitting more complete phagocytosis of curled or longer fibres. Short amosite fibres proved to be more active than longer ones and under certain conditions were as potent as quartz. Fibrous glass also possessed stimulatory properties and again a sample having a short length gave a stronger response than a long one. Collagen formation by asbestos thus appears to be mediated by a macrophage factor, so operating in a manner similar to that previously demonstrated for quartz. The conventional view that short fibres are comparatively insignificant in asbestos fibrogenesis cannot, on the present evidence, be sustained. Furthermore, it should not be assumed than man-made mineral fibres of respirable diameter are innocuous or that short ones can be ignored.