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An HIV positive black African woman presented with widespread lymphadenopathy and pancytopenia that had been ascribed to tuberculosis. Lymph node biopsy showed both Kaposi's sarcoma and multicentric Castleman's disease. Despite antiretroviral therapy and chemotherapy the patient deteriorated, developing confusion and dysphasia. A cranial magnetic resonance scan showed central pontine myelinolysis. Despite supportive therapy the patient died.

The robotic mouse is an autosomal dominant mutant that arose from a large-scale chemical mutagenesis program. It has a jerky, ataxic gait and develops adult-onset Purkinje cell loss in the cerebellum in a striking region-specific pattern, as well as cataracts. Genetic and physical mapping of the disease locus led to the identification of a missense mutation in a highly conserved region ofAf4, a putative transcription factor that has been previously implicated in leukemogenesis. We demonstrate thatAf4is specifically expressed in Purkinje cells, and we hypothesize that the expression of mutantAf4leads to neurodegeneration. This function was not identified through knock-out studies, highlighting the power of phenotype-driven mutagenesis in the mouse to identify new pathways involved in neurological disease.

Background The aim of this study was to determine in a randomised trial whether there is any significant difference in toxicity between modified CHOP and MCOP chemotherapy in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL) and to determine whether this reduced dose chemotherapy can be administered with full dose intensity, low toxicity and produce acceptable survival. Patients and methods Between 1993 and 2000, 155 eligible patients were randomised into this trial mainly from three centres (Nottingham, Birmingham and Leeds, UK). The patients were newly diagnosed with aggressive NHL and had a median age of 74 years (range 65–91 years). Ninety-six patients (62%) had bulky stage I or II disease; 59 patients (38%) had either stage III or IV disease; 77% had one or more extranodal sites involved at presentation; and 31% showed B symptoms. Seventy-seven patients were randomised to receive six cycles of modified CHOP (cyclophosphamide 600 mg/m2 i.v., doxorubicin 30 mg/m2 i.v., vincristine 1 mg i.v. all on day 1 with prednisolone 20 mg bd for days 1–5) every 21 days and 78 patients to MCOP (mitozantrone 10 mg/m2 i.v. substituted for doxorubicin). Growth factors were not used routinely. After completion of chemotherapy, 39 patients received involved field radiotherapy (35–40 Gy) in 20 fractions. Results One hundred and one patients (65%) completed all six cycles of chemotherapy. The median course dose intensity was 97%. The median follow-up for 53 surviving patients was 51 months. The median survival was 19 months (95% confidence interval 10–36 months) with an actuarial survival of 47% at 2 years and42% at 3 years (CHOP versus MCOP, P = 0.79). There was no significant difference in any of the toxicities experienced with either CHOP or MCOP, except for white cell count (46 patients on MCOP and 27 patients on CHOP had grade 3 or 4 toxicity, P = 0.002) and red cell transfusion (37 patients, MCOP; 17 patients, CHOP; P = 0.001). Grade 3 or 4 neutropenia was documented in 75 patients (50%). One patient died from toxicity whilst in remission and seven patients died with septicaemia and persistent NHL. Conclusion This multicentre randomised trial provides further information on the dose intensity achievable with CHOP or MCOP regimens in elderly patients (median age 74 years) with aggressive NHL. These dose-reduced regimens can be given with nearly 100% dose intensity with 65% of patients completing all the treatment. Survival is comparable to that observed with the more intensive regimens given in this age group.

Objectives: Understanding barriers to early diagnosis of symptomatic breast cancer among Black African, Black Caribbean and White British women in the UK. Design: In-depth qualitative interviews using grounded theory methods to identify themes. Findings validated through focus groups. Participants: 94 women aged 33-91 years; 20 Black African, 20 Black Caribbean and 20 White British women diagnosed with symptomatic breast cancer were interviewed. Fourteen Black African and 20 Black Caribbean women with (n=19) and without (n=15) breast cancer participated in six focus groups. Setting: Eight cancer centres/hospital trusts in London (n=5), Somerset (n=1), West Midlands (n=1) and Greater Manchester (n=1) during 2012-2013. Results: There are important differences and similarities in barriers to early diagnosis of breast cancer between Black African, Black Caribbean and White British women in the UK. Differences were influenced by country of birth, time spent in UK and age. First generation Black African women experienced most barriers and longest delays. Second generation Black Caribbean and White British women were similar and experienced fewest barriers. Absence of pain was a barrier for Black African and Black Caribbean women. Older White British women (≥70 years) and first generation Black African and Black Caribbean women shared conservative attitudes and taboos about breast awareness. All women viewed themselves at low risk of the disease, and voiced uncertainty over breast awareness and appraising non-lump symptoms. Focus group findings validated and expanded themes identified in interviews. Conclusions: Findings challenged reporting of Black women homogenously in breast cancer research. This can mask distinctions within and between ethnic groups. Current media and health promotion messages need reframing to promote early presentation with breast symptoms. Working with communities and developing culturally appropriate materials may lessen taboos and stigma, raise awareness, increase discussion of breast cancer and promote prompt help-seeking for breast symptoms among women with low cancer awareness.

Background and aims: Smoking tobacco has opposite effects on the different forms of inflammatory bowel disease (IBD). It predisposes to the development of Crohn's disease (CD) yet is associated with a reduced incidence of ulcerative colitis (UC). We have studied sib pairs discordant for both smoking and IBD phenotype (UC or CD) to investigate whether smoking determines the type of IBD that develops in individuals with very similar genetic susceptibility. Patients: Smoking habits and disease characteristics were analysed in 242 IBD pedigrees (658 patients). Within this group there were 339 affected sibling pairs of whom 89 were discordant for smoking when diagnosed. Results: Smoking at diagnosis was associated with development of CD (odds ratio (OR) 3.55; 95% confidence limits 2.50–5.02; p

A 30 year old man presented with late stage HIV disease and intrathoracic lymphadenopathy. Histology of a mediastinal biopsy suggested infective follicular hyperplasia or a peripheral T cell lymphoma. Subsequently, Epstein-Barr virus (EBV) infection was demonstrated in lymphocytes in the biopsy. Later, hepatosplenomegaly and peripheral lymphadenopathy developed. Histology of a cervical lymph node biopsy showed EBV associated diffuse large B cell (non-Hodgkin's) lymphoma.

BACKGROUNDGenetic anticipation has been proposed to explain observed age differences at diagnosis of Crohn’s disease in affected parents and offspring.AIMSTo compare affected parent-child pairs with Crohn’s disease and ulcerative colitis with a control group of non-familial patients with inflammatory bowel disease (IBD) in order to quantify whether ascertainment bias could account for this effect.METHODS137 affected parent-child pairs from 96 families and 214 patients with sporadic IBD were studied. Age at onset of symptoms and diagnosis were ascertained by interview and disease confirmed from clinical records.RESULTSOf the 137 affected parent-child pairs, 50 had Crohn’s disease only, 51 had ulcerative colitis only, and in 36, one had Crohn’s disease and the other ulcerative colitis. The median age of parents at diagnosis was 17.5 years older, 16 years older, and 18 years older in the Crohn’s disease, ulcerative colitis, and mixed disease families respectively (pCONCLUSIONSThere was no evidence of genetic anticipation or genomic imprinting of age at diagnosis in this sample of IBD families. Ascertainment bias is responsible for the age differences at diagnosis between affected parents and children.

We have analysed 174 gastric carcinomas from the United Kingdom and from Japan for the presence of Epstein-Barr virus (EBV) using in situ hybridisation for the small EBV-encoded nuclear RNAs (EBERs). EBV was detected in the tumour cells in all of six undifferentiated gastric carcinomas with prominent lymphoid stroma (undifferentiated carcinomas of nasopharyngeal type, UCNT) but only in three of the remaining 168 typical gastric adenocarcinomas (1.8%). No differences were observed between the British and the Japanese cases. One case with an EBV-positive UCNT showed adjacent areas of EBV-negative typical adenocarcinoma. It is uncertain whether these patterns represent two independent carcinomas or whether they are the result of heterogeneous EBV infection in a single tumour. In the remaining EBV-positive carcinomas, viral transcripts were detected in virtually all tumour cells, indicating that EBV infection must have taken place early in the neoplastic process and suggesting that the virus is likely to be of pathogenetic significance for the virus-associated tumours. Immunohistology demonstrated absence of detectable levels of the EBV-encoded latent membrane protein, LMP1, and nuclear antigen, EBNA2. The BZLF1 protein which induces the switch from latent to lytic infection was demonstrated in a small proportion of the tumour cells in three cases. The close association of EBV with undifferentiated gastric carcinomas compared to the variable association with gastric adenocarcinomas suggests fundamentally different roles for the virus in the aetiology of these two malignancies. Images Figure 1 Figure 2 Figure 3

A 65-year-old man presented in 1997 with a nodule on his back; histology showed apparent high grade T-cell lymphoma, treated after excision with radiotherapy. He relapsed with lesions on the thigh and buttock in 1998 and was treated with CHOP chemotherapy with a complete response. Further relapse occurred in 1999 with a nodule on his thigh again; he received CNOP (doxorubicin substituted with mitozantrone). At no stage was there clinical, bone marrow or radiological evidence of extra cutaneous disease. In November 2000 he presented with widespread indurated plaques and violaceous nodules. Biopsies repeated with extensive immunohistological staining diagnosed aleukaemic leukaemia cutis. Our patient was diagnosed with cutaneous T-cell lymphoma (CTCL) on the basis of clinical and haemotoxylin & eosin appearances. The correct diagnosis was made after extensive immunohistological studies (including myeloid markers) of repeat biopsies. This case illustrates the importance of diagnostic review in atypical CTCL. There is a high incidence of progression to acute myeloid leukaemia.

We have analysed 22 nasopharyngeal carcinomas (NPCs) for expression of the small nuclear Epstein-Barr virus (EBV)-encoded RNAs (EBERs) and for immunohistologically detectable overexpression of p53. In situ hybridization demonstrated expression of the EBERs in 13 undifferentiated NPCs while nine squamous cell NPCs were EBER-negative. These results therefore confirm our previous DNA-DNA in situ hybridization studies and demonstrate that in the nasopharynx EBV is exclusively associated with undifferentiated but not with squamous cell carcinomas. p53 overexpression was demonstrated by immunohistology in 5 of 9 squamous cell NPCs and in 9 of 13 undifferentiated NPCs. Thus, there appears to be no correlation of p53 overexpression with EBV infection. These results are unexpected in the light of previous studies demonstrating that the p53 gene in primary undifferentiated NPC is consistently in the wild-type configuration. By contrast, analyses of squamous cell carcinomas of the head and neck have demonstrated that p53 overexpression in these cases is the result of p53 gene mutation. Whilst more detailed genetic analysis is required, our results suggest that mechanisms other than mutation of the p53 gene may be responsible for the stabilization of the protein in cases of undifferentiated NPC. It is tempting to speculate that an EBV-encoded protein may be involved.

Salivary tissue intraductal papillomas are rare, benign tumours that predominantly affect minor salivary glands. We report a case of an intraductal papilloma arising in the unusual site of the submandibular gland. The tumour was completely excised and recurrence is not expected. A brief review of this histologically distinct lesion is presented.

Sixteen lymph nodes from 14 patients with rheumatoid arthritis were examined immunohistochemically and morphometrically and compared with 10 control nodes showing follicular hyperplasia from patients without rheumatoid disease. Frozen material was available from nine patients and all controls. The nodes from patients with rheumatoid arthritis seemed to share characteristic features. The most striking of these was follicular hyperplasia in which the germinal centres, in spite of being quite large, showed relatively sparse proliferative activity. The nodes often showed infiltration of germinal centres by CD8 positive T lymphocytes and contained fewer IL2R positive cells in the paracortex than controls. These and other features may have some correlation with disease activity. Lymphadenopathy in rheumatoid arthritis may not just be a manifestation of joint inflammation but an active component of this multisystem disease and may reflect a widespread immunological abnormality.

A phase I/II study of Doxil combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects.Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil at a dose of 40 mg m-2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle.Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60 min after either average vaginal and rectal temperatures of 40 degrees C had been achieved or after 30 min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2-8) and six patients had been previously treated with Doxil. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3-4 PPE toxicity. Doxil systemic exposure was higher in those with grade 3-4 PPE compared to those with no PPE. None of the patients had grade 3-4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy.Therapy with intravenous Doxil and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.

Immunoblastic transformation of Waldenström's macroglobulinaemia is normally a preterminal event. We report a case in which the immunoblastic transformation appeared to be limited to the spleen. Splenectomy was more effective than cytotoxic chemotherapy in controlling the disease, and the patient remains free of disease 45 months later.

A case of nasal T-cell lymphoma in a Caucasian male is reported, in which the presence of Epstein-Barr virus within tumour cells was demonstrated by in situ hybridization to the Epstein-Barr virus encoded RNAs EBER-1 and EBER-2.

An unusual case of a desmoplastic fibroma of the temporal bone is presented. Although classified benign, this intraosseous lesion exhibits local aggressiveness and has a high potential for recurrence. This rare condition occurs predominantly in the mandible and in the long bones and is seldom seen in the calvarium. Here we add another case to the previously described eight in the skull and this is the fourth such case reported in the temporal bone. The clinical features, radiology, histopathology and the therapeutic considerations of this lesion in a 72-year-old female are discussed. In addition, a literature review of all the cases affecting the skull bones is presented.

A true lipoma is a rare lesion in the oral cavity. A histologically distinct variant is the spindle-cell variety, which is an innocuous lesion that can simulate a myxoid liposarcoma.We report a case of intra-oral spindle-cell lipoma in a 42-year-old female and have reviewed the literature pertaining to this unusual histopathological entity. A wareness of the condition is essential for both clinicians and pathologists to avoid any misinterpretation of the benign nature of this condition.

Recent work has shown that p53 gene mutations are frequently found in Epstein-Barr virus (EBV)-positive and EBV-negative cases of Burkitt's lymphoma but not in EBV-associated undifferentiated nasopharyngeal carcinomas (NPCs). Similar viral gene expression patterns are observed in undifferentiated NPCs and in EBV-positive cases of Hodgkin's disease (HD), suggesting that the contribution of the virus to the pathogenesis of these malignancies may also be similar. We have analysed 116 cases of HD for EBV association and for immunohistologically detectable overexpression of p53. p53 overexpression was detected in the tumour cell population of 37 (32 per cent) of the cases. Fifteen cases showed p53-specific labelling of more than 40 per cent of tumour cells; in six of these, virtually all tumour cells were stained. In eight cases, between 5 and 40 per cent of tumour cells were labelled, and in another 14 cases, less than 5 per cent of tumour cells expressed detectable amounts of p53. EBV-positive HD cases were found in all groups with different levels of p53 overexpression as well as amongst p53-negative cases. While a more detailed analysis of the p53 gene in HD is required, these data show that overexpression of p53 in HD is heterogeneous and that there is no simple correlation between EBV infection and p53 overexpression.

The biological rationale of interstitial thermoradiotherapy is based on the complementary actions of hyperthermia and radiation when combined for cancer therapy. As will be reviewed in following chapters, there is significant in vitro and in vivo evidence to suggest interstitial heat and radiation have synergistic interactions. Optimal clinical application of interstitial thermoradiotherapy depends on the essential biological interactions, the physics, and the practical implementation of interstitial thermoradiotherapy. To date, clinical studies using hyperthermia and radiation have yielded mixed results. This is related to variation between studies with regard to doses, timing of treatments, and technical differences. Defining consistent thermal dosimetry and uniform clinical end-points has also complicated results.

A 27 year old woman presented during the third trimester of her second pregnancy complaining of chest pain. A chest radiograph showed a large aneurysm arising from the distal part of the aortic arch. She was transferred to the regional cardiothoracic centre but died suddenly on arrival. Necropsy confirmed a ruptured saccular aortic aneurysm arising just distal to the left subclavian artery. A history of a road traffic accident at the age of 12 was obtained from relatives after the patient's death. Vascular and haemodynamic changes in pregnancy may have caused the rupture of this previously silent post-traumatic aortic aneurysm.

Haemangioma of bone is a rare benign tumour of blood vessels. We report a case arising in a middle phalanx and the problems encountered in its management.

The shape of alpha-naphthyl acetate esterase (ANAE)-positive cells (other than T lymphocytes) has been measured in 40 lymph nodes. The specimens comprised 15 high-grade lymphomas, 15 low-grade lymphomas and 10 reactive lymph nodes. The parameter used for the measurement of shape was form factor (FF), which is readily calculated by the Reichert-Jung (Kontron) MOP-AMO3 user-controlled image analyzer. Perfectly round cells have an FF value of 1.0, whereas the FF of irregularly-shaped cells diverges from unity. It has been demonstrated that the ANAE-positive cells in high-grade lymphomas have mean values for FF of 0.8-0.9, whereas in low-grade lymphomas and reactive nodes the mean value is 0.4-0.5. Thus, high-grade lymphomas contain many more rounded ANAE-positive macrophage type cells than do low-grade lymphomas and reactive nodes. In the latter two types of specimen there is an excess of branching and spindle-shaped ANAE-positive cells.

The mean nuclear area, maximum nuclear diameter (Dmax) and form factor (FF) have been measured in 30 specimens of non-Hodgkin's lymphoma (NHL) and 10 reactive lymph nodes, using the Reichert-Jung (Kontron) MOP-AMO3 image analyzer. Nuclear area and Dmax were found to be greater in high-grade NHL than in low-grade lymphomas and reactive nodes. In addition, there was close correlation between nuclear area and Dmax, especially for low-grade NHL and reactive specimens. As a means of distinguishing between high- and low-grade lymphomas, however, the FF appears to be of little value.

Two proprietary semi-permanent hair dyes were tested for carcinogenicity in A and DBAf mice by repeated topical applications in aqueous acetone. Mice of both strains developed lymphoid tumours but experimental differences were marked only in DBAf mice. A number of tumours of the ovary and uterus, and some skin papillomas near the penis, occured in dye-treated but not in control DBAf mice. As many hair-dye constituents are known mutagens, adequate carcinogenicity testing of these substances, and epidemiological study of exposed human populations, are needed for evaluating possible health hazard from hair dyeing. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6

A series of cases of high grade non-Hodgkin's lymphomas has been studied by morphology (110 cases), immunocytochemistry (90 cases), using reagents reactive in fixed paraffin-embedded tissue, and flow cytometry (77 cases). B-cell tumours constituted 67.0 per cent of the total, T-cell tumours 22.0 per cent, and unclassified cases 8.8 per cent. Immunocytochemistry revealed two anaplastic carcinomas. Of the 77 cases studied by flow cytometry, 67.5 per cent were diploid and 32.5 per cent DNA aneuploid. T-cell tumours were more likely to be diploid than B-cell tumours, though the difference did not reach statistical significance. T-cell tumours had a significantly lower proliferative index (%S + G2) than B-cell tumours (P = 0.002). The overall remission induction rate was 68 per cent and actuarial 3-year survival 47 per cent. There was a trend for cases with %S + G2 less than 22 per cent to survive longer (P = 0.07). This trend became statistically significant when aneuploid cases were added to the high PI group (P = 0.04). No correlation was seen between morphological or immunophenotypic groups and remission induction rates or survival.

SUMMARY A patient is described with malignancy, hypercalcaemia and radiological evidence of severe parathyroid bone disease but undetectable concentrations of circulating immunoreactive PTH. Autopsy showed the tumour to be a metastatic bronchial carcinoid with no evidence of primary parathyroid disease. Extracts of the tumour had no PTH immunoreactivity but had high concentrations of a substance with identical activity to PTH in a cytochemical bioassay. The biological activity of the extract was not inhibited by PTH antibodies but was inhibited by an antagonist to PTH bioactivity.

Eighty-four patients who had undergone different types of operation for duodenal ulcer have been studied by endoscopy and gastric biopsy. Half suffered from dyspepsia and vomiting but the other half had no symptoms and acted as controls. Endoscopic and histological abnormalities were found in both groups of patients. However, certain findings occurred more commonly in those with symptoms; severe and extensive hyperaemia, bile staining of the gastric mucus, and bile reflux seen on endoscopy were all significantly more common in those with symptoms than in those without. Active gastritis in the proximal stomach was also more common in those with symptoms. Gastritis of the stoma and antrum was found in 89% of all patients; as it was unconnected with symptoms it can be regarded as a "normal" finding. The incidences of contact bleeding, erosions, and oedema were not significantly different in the two groups.

The magnesium contents of mixed herbage and four individual grass and clover species were studied under four treatments—control, magnesium sulphate, magnesian limestone and carboniferous limestone. The magnesium values were lowest in the spring and early summer and then increased to maximum values by the autumn. The seasonal variations, however, differed appreciably from year to year. The effect of magnesian limestone on the magnesium content of mixed herbage was relatively small in the year of application, but increased during the following years and reached a maximum in the fourth year after application. The increase in magnesium uptake from the magnesium sulphate treatment was small after the first year, whilst carboniferous limestone slightly depressed the magnesium content. This depression, however, was very small and probably of no practical significance. The magnesium content of red clover was about 50% higher than that of Italian ryegrass, cocksfoot and white clover. In the second year after application magnesian limestone had a much greater effect on the magnesium content of the clovers than on that of the grasses.

The finding of diffuse pulmonary calcification is reported in a 19-month-old female infant who died from an apparent viral pneumonia with systemic involvement due to varicella or herpes simplex infection. The observation is of interest because of the recently described occurrence of lung calcification following chickenpox in adults.

A pulmonary lipoma is described in a 64-year-old male, involving the right middle lobe, associated with a separate area of intrapulmonary ossification and a central intrabronchial hamartoma. It is postulated that the lipoma most probably arose from one of the multiple pulmonary hamartomas.

The sizes of follicle centre cells in 15 specimens of follicular (centroblastic-centrocytic) non-Hodgkin's lymphoma and 15 specimens of reactive follicular hyperplasia have been measured. The findings differ from previous studies, where nuclei of cells from follicle centres and interfollicular areas were measured and revealed no significant difference between follicular lymphoma and reactive follicular hyperplasia. In the current study, by measuring only follicle centre cell nuclei, it has been found that, in reactive follicular hyperplasia, the mean nuclear maximum diameter (Dmax) and area are significantly greater than in centroblastic-centrocytic follicular lymphoma. In addition, the standard deviation of these data is greater for reactive follicular hyperplasia than follicular lymphoma, implying greater "scatter" or heterogeneity of the nuclear sizes in the follicle centre cells of the former than the latter. Thus, the size of these cells appears to be of value as an histological discriminator between these benign and malignant conditions.

A case of pachymeningitis cranialis hypertrophica is described and the CT appearances are presented. The likely cause was syphilis, though sarcoidosis and tuberculosis were not completely excluded.

A series of 20 patients with definite or classical rheumatoid arthritis who subsequently developed a lymphoproliferative malignancy are described. The mean time between the onset of the 2 diseases was 13.2 years. A wide range of types of non-Hodgkin's lymphoma and Hodgkin's disease were found; there were no unusual histological features in the lymphomas. Although many of the patients had had gold, penicillamine, and other second-line drugs, none of them had received cytotoxic drugs, and there was no evidence that therapy was a cause of their malignancies. The likely cause of the association is a predisposition to both diseases.

The mean areas of lymphoid follicles have been determined in 20 specimens of malignant follicular (centrocytic-centroblastic) lymphoma, 15 specimens of reactive follicular hyperplasia and 10 palatine tonsils. In all of the benign specimens and whenever possible for those showing malignancy, the areas of both the whole follicles (including the "mantle" zones) and of the follicle centres were measured; this procedure was facilitated by means of the Reichert-Jung (Kontron) MOP-AMO3 image-analyser. Reactive lymph nodes were found to have larger mean follicle areas than centrocytic-centroblastic lymphomas; the areas of reactive follicles also show greater variation than do those of their malignant counterparts. In addition, the "mantle" zone is usually absent from malignant follicles but may account for up to 65.5% of the mean total follicle size in reactive lymph nodes and tonsils.

The use of immunohistochemistry is discussed with respect to its role in assisting with the classification and diagnosis of lymphomas. Attention is drawn to methods of achieving optimal tissue fixation and preparation, which are necessary prerequisites for the precise cytochemical demonstration of the various lymphocyte and related cell type markers.

The morphological features of 32 cases of malignant lymphomas involving the central nervous system presenting over a 32 year period were reviewed and the lymphomas redefined using current classifications. Twenty-four cases (75%) of non-Hodgkin's lymphomas were reclassified using the Kiel classification. There were 18 low grade non-Hodgkin's lymphomas (comprising 11 lymphoplasmacytoid, five lymphocytic and two centroblastic-centrocytic) and six high grade tumours (comprising two centroblastic, two immunoblastic, one unclassifiable and one lymphoblastic lymphoma). Cytologically the great majority of non-Hodgkin's lymphomas were B-cell lymphomas. The eight cases (25%) of Hodgkin's disease were classified by the Rye subtype and consisted of three mixed cellularity, two lymphocyte depletion, two lymphocyte predominant and one nodular sclerosis. The presence of intracytoplasmic immunoglobulins as well as markers for histiocytic cells were studied by the immunoperoxidase technique using polyclonal antisera. A monoclonal staining pattern, as revealed by light chain restriction, was found in nine cases (38%) of the non-Hodgkin's lymphomas confirming their B-cell origin. With the Marshall's metalophil method and the other histiocytic markers, scattered reactive microglial cells and histiocytic reticulum cells were found throughout the tumours in most cases. No histiocytic lymphomas were present in the series.

The incidence of B cell leukaemia in 186 consecutive untreated patients with histologically defined B cell neoplasms is described. The lymphomas were classified by the Kiel convention. B cell leukaemia in the context of this paper refers to the situation where a neoplastic clone of B cells in the blood greatly outnumbers normal blood B cells. It is defined as an absolute blood B cell count greater than 0.75 X 10(9)1(-1) where either greater than 90% B cells express kappa immunoglobulin light chains or greater than 80% express lambda light chains. This was found in several patients where the total blood lymphocyte count was within normal limits. All patients with diffuse lymphocytic lymphoma with the histological appearances of B cell chronic lymphocytic leukaemia (ML-BCLL) were found to have B cell leukaemia. However, more than half these patients had blood B cell counts less than 10 X 10(9)1(-1). B cell leukaemia was also a feature in approximately 33% of patients with follicle centre cell tumours and 33% of those with lymphoplasmacytoid tumours. B cell leukaemia was not detected in 34/35 patients with myelomatosis. The 35th patient had plasma cell leukaemia. Only 3/22 patients with high grade lymphoma had B cell leukaemia. In the three principal tumour types associated with B cell leukaemia mu + delta was the most common immunoglobulin heavy chain phenotype. Spontaneous mouse red cell rosette formation also characterised leukaemic B cells in these three groups but high proportions of mouse rosetting cells were seen only in association with ML-BCLL. None of 4 cases of prolymphocytic leukaemia showed mouse red cell rosetting. HLA-DR alpha chain was found on the leukaemic cells of all patients except one with ML-BCLL. B cell lymphopenia was a frequent finding in all histological groups in those patients who did not have B cell leukaemia.

Ten cases of malignant lymphoma of the colon and rectum complicating chronic inflammatory bowel disease are presented. Seven patients had chronic ulcerative colitis with a history varying from 6 to 20 years. There was extensive colitis in six of these patients and left-sided colitis in one. All seven lymphomas showed the pathological and immunohistological features of primary B-cell tumours of the gastrointestinal tract with a predominance of high-grade tumours. Three patients had Crohn's disease of the large intestine complicated by malignant lymphoma of the sigmoid colon or rectum. The history of Crohn's disease varied from 30 months to 20 years and in each case there was fissuring and fistulae. There was extensive anal involvement in two cases. Histologically the three lymphomas were heterogeneous: one was of 'granulomatous' T-cell type and the other two were markedly polymorphic and of equivocal phenotype. They were also characterized by numerous multinucleate tumour giant cells. Primary colorectal malignant lymphoma should be regarded as a rare, but significant, complication of ulcerative colitis. Immunosuppression may be an additional factor in the genesis of intestinal lymphoma in Crohn's disease. The prognosis appears to be dependent on factors already known to be of prognostic significance in primary gut lymphomas: a predominance of high-grade tumours suggests that the outlook is generally worse than that for idiopathic primary large intestinal lymphoma.

The mean maximum nuclear diameter (D max ) in 21 cases of non-Hodgkin9s lymphoma (NHL) has been determined, using the Reichert-Jung (Kontron) MOP-AMO 3 user-controlled image analyser. Nuclear diameters of high-grade malignancy NHL were found to be considerably greater than those of low-grade malignancy lymphomas, although there was some overlap of their ranges. These findings confirm objectively subjective estimates of nuclear size in NHL. The relative usefulness of the user-controlled (interactive) image analyser for the measurement of nuclei in tissue sections is compared with that of a fully automatic machine.

A total of 110 patients with high-grade non-Hodgkin's lymphoma (NHL) not previously treated by chemotherapy or by radiotherapy at more than one site of disease underwent a regimen comprising an intensive 6-week initial, induction phase using vincristine, adriamycin, methotrexate, and prednisolone (VAMP) followed by the non-cross-resistant combination cyclophosphamide, etoposide, and vindesine (EEE). The median age of patients was 54 years, the majority having stage IV disease. The median follow-up was 34 months and all patients have completed treatment. The overall complete remission (CR) rate for all patients was 68%. The initial phase of treatment produced a CR rate of 49%. The full regimen was completed by 87 patients, and of these, 66 (76%) achieved CR. Of those achieving CR, 72% were relapse-free, on an actuarial basis, at 2 years. Overall 2-year survival was 53%, with a median survival of 31 months. The survival of older patients and those with lymphoblastic histology was comparable to that of other groups. The survival prospects of patients with stage IV disease was not as good as that of other patients, with a significant trend to shorter survival in patients with more advanced disease. Toxicity was predictable and manageable for both phases of the regimen, although it was more severe for the initial phase. Dose-limiting toxicities were neutropenia and mucositis. This regimen is active in the treatment of advanced high-grade NHL with acceptable toxicity. These results have encouraged us to continue the study of weekly chemotherapy, which we will compare with standard cyclical chemotherapy in a prospective, randomized trial.

Newborn mice of four inbred strains were injected with a single dose of N-ethyl-N-nitrosourea. The wide range of tumours induced included a small number in the central and peripheral nervous systems. The 4 brain tumours all arose in the cerebellum. Three in one strain were medulloblastomas showing continuity with the internal granular layer. All three tumours showed diffuse infiltration through the molecular layer and continuity with densely-packed islets of cells that marginated immediately beneath the pia and closely resembled remnants of a persistent fetal external granular layer. The medulloblastomas are discussed with special relevance to the histogenesis of the equivalent tumour in man.

Newborn A, C57BL, DBAf and IF mice were injected s.c. with a range of doses of N-ethyl-N-nitrosourea (ENU). A high proportion of treated mice developed tumours, particularly hepatomata, pulmonary adenomata and carcinomata, and malignant lymphomata of thymus and spleen. Liver tumours occurred most frequently in C57BL and DBAf mice, lung tumours in A mice, and lymphomata in A and DBAf mice. A small proportion of C57BL, DBAf and IF mice developed tumours of the nervous system. The results are discussed with reference to the ready induction of nervous system tumours in similarly treated rats, and their relevance for human cancer. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7

Rats fed clioquinol and a maize diet developed much more severe neuropathy in old age than did rats fed only a maize diet. The findings suggest that, in the rat, clioquinol can accentuate other known causes of neuropathy.

Case Report The patient was a previously healthy 39-year-old housewife. She was not taking oral contraceptives. On 29th October, 1964, she awoke with a right hemiparesis and was admitted to hospital some hours later. On examination she showed weakness of the right face, arn and leg, a right Babinski response, and total right hemianaesthesia. (BP 150/80 mm. Hg., pulse rate 90, in sinus rhythm. There were no abnormal signs elsewhere in the body. Rectal and vaginal examinations were negative. Investigations: Hb 78%, WBC 5,600/cu. mm., normal differential count. ESR (Westergren) 10 mm/ hr. Serum Na 132, K 4.1, Cl 92 m.Eq/l. Blood urea 32, cholesterol, 187 mg/100 ml., (DSF: normal pressure with a free rise and fall, 41 lymphocyte/ cu. mm., protein 25 mg/ 100 ml. WR and Kahn negative. Skull and chest X-rays normal. ECG normal. On 9th November, 1964, she developed a total left hemiplegia with aphasia and increased involvement of the right side, no pyrexia or cardiac murmurs. Bilateral carotid angiograms (Fig. I) showed occlusion of the right middle cerebral artery 1 cm. beyond its origin, the left posterior parietal artery, and the angular branches of the left middle cerebral artery. There was an anastomotic supply from the anterior cerebral arteries. No evidence of atherosclerosis. Phenindione therapy was commenced. A glucose tolerance test showed a definite diabetic curve: FBS [10, I hr., 190, 1 hr., 240, 11 hr., 230, 2 hr. 200 mg/'l00 ml. On 26th November, 1964, she developed sudden dvspnoea and right pleuritic pain. The left calf was slightly tender. Chest X-ray showed bilateral diffuse nodular shadowing coalescent in the midzones, probably due to multiple pulmonary infarcts. At this time anticoagulant therapy was thought adequate from estimations of rprothromrbin times. On 3rd December, 11964, gross swelling of the left thigh and leg developed suggesting extension of the deep vein thrombosis. Intravenous heparin therapy (40,000 units/day) was started. E. L. JoNEs, M.B., Ch.B.

A cardiomyopathy is described affecting three of five siblings, characterized by first-degree heart block and ectopic supraventricular rhythms progressing over some years to persistent atrial standstill with complete loss of response to direct atrial stimulation. At least two children of one of the patients appear to be similarly affected. We have found only 11 documented cases of this persistent arrhythmia. A familial incidence has been reported twice, but in both was due to amyloidosis. This appears to be the amyloid description of familial persistent atrial standstill not due to amyloid disease.