Histological Reassessment of Three Kidneys Originally Described by Richard Bright in 1827-36

Portions of kidney from three patients with renal disease that were originally described by Richard Bright between 1827 and 1836 have been preserved in the Gordon Museum at Guy''s Hospital. Histological study has shown that two cases fall into the current diagnostic category of mesangiocapillary (membranoproliferative) glomerulonephritis. One of these patients had a five-year clinical history and died with chronic renal failure and uraemia. The other patient died after three to four months with a severe nephrotic syndrome. The third patient was a young woman with chronic “phthisis pulmonalis” and renal amyloidosis.     

Third Case of Chronic Lymphocytic Leukaemia in a Carrier of the Inherited Ch1 Chromosome

Chronic lymphocytic leukaemia has developed in three siblings who are all carriers of the abnormal Ch¹ chromosome. ³H-thymidine autoradiography showed Ch¹ to be a G₂ autosome, from which the short arm is absent, and not G₁, which is trisomic in Down''s syndrome and which is believed to form the abnormal Ph¹ chromosome. Ch¹ is not of general significance in the aetiology of chronic lymphocytic leukaemia, but it must be considered as a possible predisposing factor to leukaemia in the present family.     

Towards a more rapid diagnosis of rapidly progressive glomerulonephritis.

An attempt was made to provide simple practical guidelines to alert general practitioners to the diagnosis of rapidly progressive glomerulonephritis and lead to early referral to hospital. The duration of illness before referral to this hospital and its effect on outcome in patients with crescentic nephritis were assessed retrospectively from the case notes of 24 patients referred over two years. Four patients had Goodpasture''s syndrome, 11 Wegener''s granulomatosis, seven microscopic polyarteritis, and two idiopathic progressive glomerulonephritis. The duration of symptoms before referral to the local hospital was similar in the four groups of patients and varied from one week to 28 months (mean 10 months). The duration of stay in the local hospital was two, nine, 11, and 180 days in the patients with Goodpasture''s syndrome and a mean of four days (range one to eight) in those with Wegener''s granulomatosis and 10 days (one to 18 days) in those with microscopic polyarteritis. In the local hospital the diagnosis was based on the results of renal biopsy and detection of antibodies to glomerular basement membrane in two patients with Goodpasture''s syndrome and on the results of renal biopsy in seven of the other patients aided by the detection of antibodies to the cytoplasm of neutrophils (ANCA) in 10. Three of the 24 patients died and four required maintenance haemodialysis. Patients who present to their general practitioners with persistent non-specific symptoms should have a urine dipstick test and then blood tests and emergency referral to hospital if necessary. Hospital physicians should be aware of the speed and accuracy with which current assays can confirm a diagnosis of rapidly progressive glomerulonephritis.     

Selective effect of low protein diets in chronic renal diseases.

It has recently been established that the rate of progression of chronic renal failure in man can be slowed by restricting dietary protein. Consequently, the short term and long term effects of a low protein diet on the course of different chronic nephropathies were studied in an attempt to delineate the factors that determine the response to such a diet. When a low protein diet was given for six months renal function improved significantly in nine patients with chronic tubulointerstitial nephritis (p less than 0.025); the diet had a marginally beneficial effect in 12 patients with chronic glomerulonephritis (p less than 0.05) and no effect in nine with hypertensive nephrosclerosis. The heterogeneous functional response in the patients with chronic glomerulonephritis correlated closely with the effect of the diet on these patients'' proteinuria (r = 0.76, p less than 0.01). In a short term study (four weeks) of 12 patients with chronic renal failure changes in renal plasma flow were proportional to dietary protein intake. Renal vascular resistance fell during a high protein diet and increased when dietary protein was restricted. The changes in renal plasma flow during the low protein diet correlated well with the patients'' long term functional response to the diet (r = 0.76, p less than 0.01). It is concluded that the response to a low protein diet in chronic renal failure is determined, firstly, by the nature of the underlying nephropathy, with maximal benefit being observed in non-glomerular disorders; secondly, by the effect of the diet on the proteinuria in chronic glomerulonephritis; and, thirdly, by the haemodynamic response to the diet, with patients with a reactive renal vascular bed improving with a low protein diet.     

Biological weapons threat leads to inoculations for sailors

The authors describe a 51-year-old man with chronic lymphocytic leukemia who presented with respiratory distress and then died suddenly while in hospital. Autopsy revealed pulmonary leukostasis and a large intracardiac mass containing mostly mature lymphocytes and fibrin. Although leukostasis and lymphocyte thrombi have been described (albeit rarely) in chronic lymphocytic leukemia, an intracardiac "clot" has not. It seems plausible that this intracardiac mass caused the patient''s death.     

Paternal preconceptional radiation exposure in the nuclear industry and leukaemia and non-Hodgkin's lymphoma in young people in Scotland.

OBJECTIVE--To determine if a relation exists between paternal exposure to relatively high levels of radiation in the Scottish nuclear industry and the risk of leukaemia and non-Hodgkin''s lymphoma is subsequently conceived children. DESIGN--Matched case-control study with three controls for each case. SETTING--The whole of Scotland. SUBJECTS--The fathers of 1024 children with leukaemia and 237 children with non-Hodgkin''s lymphoma diagnosed in Scotland below the age of 25 among those born in Scotland since nuclear operations began (in 1958) and the fathers of 3783 randomly chosen controls. The fathers of 80 children with leukaemia and 16 with non-Hodgkin''s lymphoma in north Cumbria were also covered since some workers at one Scottish nuclear site live over the border in that area. Details of all fathers were then matched against records of the nuclear industry. MAIN OUTCOME MEASURES--Paternal preconceptional radiation exposures, particularly relatively high levels, both lifetime and in the six and three months before conception. RESULTS--No significant excess was observed in any subgroup and there was no significant trend: fathers of three controls but no cases were exposed to lifetime preconceptional levels of 100 mSv or greater (Fisher''s exact p value 0.84). In the six months before conception, fathers of two cases and three controls received 10 mSv or more, odds ratio 2.3 (95% confidence interval 0.31 to 17.24). In the three months before conception the fathers of one case and two controls received 5 mSv or more, odds ratio 1.7 (0.10 to 30.76). The results for leukaemia and non-Hodgkin''s lymphoma combined were similar. CONCLUSIONS--No significant excess of leukaemia or of leukaemia and non-Hodgkin''s lymphoma was found at any radiation level in any preconceptional period.     

Renal Involvement in Non-Hodgkin Lymphoma: Proven by Renal Biopsy

Aims

To determine the spectrum of renal lesions in patients with kidney involvement in non-Hodgkin''s lymphoma (NHL) by renal biopsy.

Methods

The clinical features and histological findings at the time of the renal biopsy were assessed for each patient.

Results

We identified 20 patients with NHL and renal involvement, and the diagnosis of NHL was established following the kidney biopsy in 18 (90%) patients. The types of NHL include the following: chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 8), diffuse large B-cell lymphoma (n = 4), T/NK cell lymphoma (n = 3), lymphoplasmacytic lymphoma (n = 2), cutaneous T-cell lymphoma (n = 1), mucosa-associated lymphoid tissue lymphoma (n = 1) and mantle cell lymphoma (n = 1). All presented with proteinuria, and 15 patients had impaired renal function. The pathological findings included (1) membranoproliferative glomerulonephritis-like pattern in seven patients; (2) crescent glomerulonephritis in four; (3) minimal-change disease in three, and glomeruli without specific pathological abnormalities in three; (4) intraglomerular large B-cell lymphoma in one; (5) intracapillary monoclonal IgM deposits in one; (6) primary diffuse large B-cell lymphoma of the kidneys in one; and (7) lymphoma infiltration of the kidney in eight patients.

Conclusion

A wide spectrum of renal lesions can be observed in patients with NHL, and NHL may be first proven by renal biopsies for evaluation of kidney injury or proteinuria. Renal biopsy is necessary to establish the underlying cause of renal involvement in NHL.     

Chromosomes and Transformation of Lymphocytes in Lymphoproliferative Disorders

In chronic lymphocytic leukaemia the majority of circulating lymphocytes which responded to phytohaemagglutinin in vitro were found to have normal karyotypes. A minor population of cells in patients treated with chemotherapy had an increased number of chromosomal rearrangements as compared with cells from normal controls and untreated patients with chronic lymphocytic leukaemia. Probably bonemarrow and lymph-node cells also had a normal karyotype.In the other lymphoproliferative disorders the peripheral blood lymphocytes had either normal karyotypes or chromosomal abnormalities attributable to treatment, even in those cases where the tumour cells of involved lymph nodes were known to have abnormal karyotypes.It was possible that circulating tumour cells were present in one case.     

Membrane phenotype and response to deoxycoformycin in mature T cell malignancies.

The adenosine deaminase inhibitor deoxycoformycin was used in low doses to treat 19 patients with clinically aggressive T cell malignancy with a mature membrane phenotype. The patients comprised eight with prolymphocytic leukaemia, two with chronic lymphocytic leukaemia, four with adult T cell leukaemia-lymphoma, three with Sézary syndrome, and two with T cell lymphoma. Two thirds of the patients had been resistant or minimally responsive to combination chemotherapy. Complete remission was obtained in five patients (two with prolymphocytic leukaemia and one each with chronic lymphocytic leukaemia, adult T cell leukaemia-lymphoma, and Sézary syndrome) and partial remission in two others. Unmaintained complete remission lasting more than one year was seen in three patients. Responses were obtained only in patients with CD4+,CD8-membrane markers (seven out of 10), and no responses were recorded in any of the nine patients with a different phenotype. In this series remission appeared to correlate with the membrane phenotype of the neoplastic cell and not with the cytopathological diagnosis. Future studies should establish the biochemical basis for the greater sensitivity of CD4+ lymphoid cells to deoxycoformycin.     

Goodpasture's Syndrome: Pulmonary Hemosiderosis with Glomerulonephritis

Three cases of Goodpasture''s syndrome (pulmonary hemosiderosis and glomerulonephritis) are described. Each presented with unexplained hemoptysis and subsequently developed glomerulonephritis which caused uremia. These cases include the youngest and the oldest individuals yet reported with the condition. Steroid therapy was administered to one patient but apparently did not influence the course of the disease. The variations in the clinical course and the pathology of the disease are discussed.     

Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria.

OBJECTIVE--To examine whether the observed excess of childhood leukaemia and lymphoma near the Sellafield nuclear plant is associated with established risk factors or with factors related to the plant. DESIGN--A case-control study. SETTING--West Cumbria health district. SUBJECTS--52 Cases of leukaemia, 22 of non-Hodgkin''s lymphoma, and 23 of Hodgkin''s disease occurring in people born in the area and diagnosed there in 1950-85 under the age of 25 and 1001 controls matched for sex and date of birth taken from the same birth registers as the cases. MAIN OUTCOME MEASURES--Antenatal abdominal x ray examinations, viral infections, habit factors, proximity to and employment characteristics of parents at Sellafield. RESULTS--Expected associations with prenatal exposure to x rays were found, but little information was available on viral illnesses. Relative risks for leukaemia and non-Hodgkin''s lymphoma were higher in children born near Sellafield and in children of fathers employed at the plant, particularly those with high radiation dose recordings before their child''s conception. For example, the relative risks compared with area controls were 0.17 (95% confidence interval 0.05 to 0.53) for being born further than 5 km from Sellafield 2.44 (1.04 to 5.71) for children of fathers employed at Sellafield at their conception, and 6.42 (1.57 to 26.3) for children of fathers receiving a total preconceptual ionising radiation dose of 100 mSv or more. Other factors, including exposure to x rays, maternal age, employment elsewhere, eating seafood, and playing on the beach did not explain these relationships. Focusing on Seascale, where the excess incidence has predominantly been reported, showed for the four out of five cases of leukaemia and one case of non-Hodgkin''s lymphoma whose fathers were employed at Sellafield and for whom dose information was obtained that the fathers of each case had higher radiation doses before their child''s conception than all their matched control fathers; the father of the other Seascale case (non-Hodgkin''s lymphoma) was not employed at the plant. These results seem to explain statistically the geographical association. For Hodgkin''s disease neither geographical nor employment associations with Sellafield were found. CONCLUSIONS--The raised incidence of leukaemia, particularly, and non-Hodgkin''s lymphoma among children near Sellafield was associated with paternal employment and recorded external dose of whole body penetrating radiation during work at the plant before conception. The association can explain statistically the observed geographical excess. This result suggests an effect of ionising radiation on fathers that may be leukaemogenic in their offspring, though other, less likely, explanations are possible. There are important potential implications for radiobiology and for protection of radiation workers and their children.     

Blast Cells with Monoclonal Surface Immunoglobulin in Two Cases of Acute Blast Crisis Supervening on Chronic Lymphocytic Leukaemia

Acute blast crisis occurred in two patients with previously well-confirmed chronic lymphocytic leukaemia. The finding by direct immunofluorescence of membrane-bound monoclonal immunoglobulins on the surface of the blast cells showed that they were related to B cells in the same way as the proliferating lymphocytes in most patients with chronic lymphocytic leukaemia. In one patient the surface monoclonal IgM detected on both the lymphocytes and the blast cells had the same rheumatoid antibody activity, supporting the concept that the leukaemic cells found during the acute and chronic phases of the disease originated from the same clone.     

Epipodophyllotoxins,alkylating agents,and radiation and risk of secondary leukaemia after childhood cancer.

OBJECTIVE--To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN--Cohort study and a case-control study. SETTING--Britain and population based National Register of Childhood Tumours. SUBJECTS--Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES--Dose of radiation averaged over patients'' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS--Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin''s lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin''s lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients'' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS--Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer.     

Leukaemia complicating treatment for Hodgkin's disease: the experience of the British National Lymphoma Investigation.

OBJECTIVE--To determine the incidence of and risk factors for the development of secondary acute leukaemia and myelodysplasia in patients treated in British National Lymphoma Investigation''s studies of Hodgkin''s disease since 1970. PATIENTS--2676 Patients entered into Hodgkin''s disease studies between February 1970 and November 1986. Data accrued up to November 1988 were analysed, ensuring a minimum follow up period of two years. DESIGN--Retrospective analysis of multicentre trial data by case-control and life table methods. RESULTS--17 Cases of secondary leukaemia were recorded in this group of 2676 patients, giving an overall risk at 15 years of 1.7%. The risks of leukaemia after chemotherapy alone and chemotherapy with radiotherapy were not significantly different. The risk of leukaemia increased sharply with the amount of treatment given as measured by the number of attempts at treatment. The 15 year risks of leukaemia were 0.2%, 2.3%, and 8.1% for patients receiving one, two, or three or more attempts at treatment. The highest risk, 22.8% at 15 years, was observed in patients treated with lomustine (CCNU), and a case-control study suggested that this was an independent risk factor. The risk of secondary leukaemia was largely related to the overall quantity of treatment, although exposure to lomustine seemed to be an important risk factor. Treatment with both drugs and radiation was not more leukaemogenic than treatment with drugs alone. The greatest risk of secondary leukaemia was seen in multiply treated patients who were unlikely to be cured of Hodgkin''s disease. CONCLUSIONS--Avoidance of secondary leukaemia should be a minor factor in the choice of treatment for Hodgkin''s disease.     

Glomerulonephritis Associated with Antibody to Glomerular Basement Membrane

Glomerulonephritis associated with antibody to glomerular basement membrane, shown by linear staining of the glomerular basement membrane with fluoresceinated anti-IgG antisera, was found in only 10 out of 400 (2·5%) renal biopsy specimens studied by immunofluorescence. Seven of these cases had rapidly progressive glomerulonephritis, five with lung haemorrhage (Goodpasture''s syndrome) and two without, and three had less severe nephritis without lung haemorrhage. Circulating antibody to glomerular basement membrane, measured by a passive haemagglutination technique and by indirect immunofluorescence, was detected in the serum of all patients with rapidly progressive glomerulonephritis by both techniques but only by the passive haemagglutination method in two of the other three patients. Two patients died of their lung haemorrhage, one despite bilateral nephrectomy, and lung haemorrhage and circulating antibody to glomerular basement membrane persisted after bilateral nephrectomy in another patient.     

Bilateral nephrectomy for massive pulmonary hemorrhage in Goodpasture's syndrome

A case of Goodpasture''s syndrome is described in which bilateral nephrectomy was undertaken because of massive pulmonary hemorrhage. Similar cases recorded in the literature are reviewed. Various hypotheses to explain the beneficial effects of renal ablation on lung purpura are considered. It is suggested that the pulmonary hemorrhage in Goodpasture''s syndrome is mediated in part by a non-antibody humoral factor with permeability-increasing properties that is released from the nephritic kidney.     

Mortality and occupational exposure to radiation: first analysis of the National Registry for Radiation Workers.

OBJECTIVE--To study cause specific mortality of radiation workers with particular reference to associations between fatal neoplasms and level of exposure to radiation. DESIGN--Cohort study. SETTING--United Kingdom. SUBJECTS--95,217 radiation workers at major sites of the nuclear industry. MAIN OUTCOME MEASURE--Cause of death. RESULTS--Most standardised mortality ratios were below 100: 83 unlagged, 85 with a 10 year lag for all causes; 84 unlagged, 86 lagged for all cancers; and 80 for all known other causes, indicating a "healthy worker effect." The deficit of lung cancer (75 unlagged, 76 lagged) was significant at the 0.1% level. Standardised mortality ratios were significantly raised (214 unlagged, 303 lagged) for thyroid cancer, but there was no evidence for any trend with external recorded radiation dose. Dose of external radiation and mortality from all cancers were weakly correlated (p = 0.10), and multiple myeloma was more strongly correlated (p = 0.06); for leukaemia, excluding chronic lymphatic, the trend was significant (p = 0.03; all tests one tailed). The central estimates of lifetime risk derived from these data were 10.0% per Sv (90% confidence interval less than 0 to 24%) for all cancers and 0.76% per Sv (0.07 to 2.4%) for leukaemia (excluding chronic lymphatic leukaemia). These are, respectively, 2.5 times and 1.9 times the risk estimates recommended by the International Commission on Radiological Protection, but 90% confidence intervals are large and the commission''s risk factors fall well within the range. The positive trend with dose for all cancers, from which the risk estimate was derived, was not significant. The positive association between leukaemia (except chronic lymphatic leukaemia) was significant and robust in subsidiary analyses. This study showed no association between radiation exposure and prostatic cancer. CONCLUSION--There is evidence for an association between radiation exposure and mortality from cancer, in particular leukaemia (excluding chronic lymphatic leukaemia) and multiple myeloma, although mortality from these diseases in the study population overall was below that in the general population. The central estimates of risk from this study lie above the most recent estimates of the International Commission on Radiological Protection for leukaemia (excluding chronic lymphatic leukaemia) and for all malignancies. However, the commission''s risk estimates are well within the 90% confidence intervals from this study. Analysis of combined cohorts of radiation workers in the United States indicated lower risk estimates than the commission recommends, and when the American data are combined with our analysis the overall risks are close to those estimated by the commission. This first analysis of the National Registry for Radiation Workers does not provide sufficient evidence to justify a revision in risk estimates for radiological protection purposes.     

Clinicopathological aspects of Richter's syndrome

Richter's syndrome represents an acute transformation of chronic lymphocytic leukaemia or other type of low-grade malignant non-Hodgkin lymphoma to highly malignant anaplastic large-cell lymphoma. The prognosis of this complication is highly unfavourable. The authors report on eight cases of Richter's syndrome observed in a series of 198 patients with the clinical diagnosis of chronic lymphocytic leukaemia and evaluate some clinicopathological and immunological peculiarities of this disease.     

Karyotypes of 33 patients with clonal aberrations in chronic lymphocytic leukaemia. Review of 216 abnormal karyotypes in chronic lymphocytic leukaemia

We report on 33 unpublished patients with clonal anomalies in chronic lymphocytic leukaemia. The literature was thoroughly reviewed in order 1) to quantify the frequency of anomalies found in chronic lymphocytic leukaemia and to give new status to the rarest, 2) to determine whether a given anomaly was an additional anomaly and/or a primary anomaly, and 3) to find out whether strong associations between different anomalies exist in this disease.     

A p50 surface antigen restricted to human urinary bladder carcinomas and B lymphocytes

Summary We have previously described the derivation of a monoclonal antibody, S2C6, to a novel 50 Kdalton antigen associated with human urinary bladder carcinoma. No reactions were obtained with carcinomas of unrelated origin or with normal urothelial cells. However, the antibody also reacted with a similar antigen on some cell lines of B lymphocyte origin. Using large panels of target cells we have now shown that this reactivity was entirely restricted to cells of the B lineage within the haematopoietic system. As opposed to its apparent restriction to malignant cells of the urothelium, the S2C6 antigen was expressed by normal B lymphocytes as well as by many malignant B cells (chronic lymphocytic leukaemia, hairy cell leukaemia and immunocytoma). Pre-B cells derived from acute lymphocytic leukaemia and plasma cells from multiple myeloma lacked the antigen. Expression was significantly enhanced on cultured B cells from Burkitt lymphomas and on Epstein-Barr virus-transformed lymphoblastoid cell lines including those of the pre-B phenotype derived from fetal bone marrow. As judged from the molecular size and the distribution pattern displayed by the S2C6 antigen it appears to be distinct from other B cell antigens previously described. A possible relation of the S2C6 antigen to a receptor for B cell growth factors is discussed.