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The tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) is an effective treatment for chronic myeloid leukemia (CML). We examined bone marrow samples from 53 patients with CML who were receiving STI571 in 3 multicenter phase 2 trials to assess morphologic changes and cytogenetic response to this drug. In most patients with initially increased blasts, the bone marrow blast count rapidly decreased during STI571 therapy. Reductions in cellularity, the myeloid/erythroid ratio (commonly with relative erythroid hyperplasia), and reticulin fibrosis (if present pretreatment) also were seen in most patients, resulting in an appearance resembling normal marrow in many cases. Eighteen patients (34%) had some degree of cytogenetic response. Surprisingly, these striking morphologic changes occurred irrespective of any cytogenetic response to STI571. Thus, STI571 seems to affect the differentiation of CML cells in vivo, causing even extensively Philadelphia chromosome–positive hematopoiesis to exhibit features resembling normal hematopoiesis.

Kikuchi's disease (KD) is a benign self-limiting febrile illness usually affecting young women, which is manifested clinically by fever and cervical lymphadenopathy. Skin involvement in KD is very rare and is evident clinically in the form of skin rashes and nodules. We describe one such case of KD in a 33-year-old Bulgarian woman who presented with cervical and axillary lymphadenopathy and who developed a transient facial rash. Biopsy of axillary lymph nodes showed the characteristic features of KD with infiltration of the lymph node paracortex by apoptotic plasmacytoid monocytes. Biopsies of the facial skin showed two features: (1) dermal infiltration by apoptotic plasmacytoid monocytes; (2) on immunofluorescence studies of frozen sections prepared from involved and uninvolved facial skin, deposition of immunoglobulins and complement at the dermoepidermal junction and in the walls of dermal blood vessels. Such immunofluorescence findings in the skin of patients with KD have never been described. These findings suggest the presence of an autoimmune reaction as a component of KD.

132 gastric carcinomas were examined immunohistochemically with McAb to p53 protein in order to investigate the relationship between the expression of p53 protein and histological differentiation of gastric carcinoma, and to approach the mechanism of infiltration and metastasis of gastric carcinoma. The results showed thai nuclear expression of p53 protein was significantly related to tumor size, depth of invasion, lymph node and liver metastases; but not related to histological differentiation, it is suggested that the accumulation of p53 protein was increased with the progression of gastric carcinoma, and therefore the cancer clone with p53 gene mutation may play an important role in the development of tumor invasion and metastasis.

Following the recognition of AIDS and the identification of HIV — the retrovirus responsible for its causation, it became apparent that abnormalities of bone marrow (BM) are commonly associated with abnormal peripheral blood findings in HIV infected patients. Anaemia, granulocytopaenia and thrombocytopaenia are frequently present and are reflected by the dyshaematopoiesis found in BM. Both bone marrow aspiration (BMA) and bone marrow trephine biopsies (BMTB) reveal alterations in cellularity (most often hypercellularity), dysplasia of 1, 2 or 3 cell lines; inflammatory and stromal reactions, opportunistic infections (OI) and involvement by high grade lymphomas. The mechanisms responsible for the haematological abnormalities in HIV positive individuals are numerous and are not mutually exclusive; they include the CDC class of the disease, the effects of treatment, the presence of infection and lymphoma (and other malignant diseases), immunological mechanisms and damage to BM cells (stromal cells, stem cells, differentiated macrophages and megakaryocytes) as a result of their direct infection by HIV. Although more pronounced abnormalities are seen in patients with advanced HIV disease who are likely to be taking marrow-toxic drugs and in whom OI and malignancies are common, it is emphasized that important BM changes are present in HIV positive patients who at the time of biopsy do not have evidence of infection or neoplastic disease and who have not received treatment for their positive HIV status. The cell line which most frequently shows changes in haematopoesis is the megakaryocytic lineage; of these changes, the presence of increased numbers of naked megakaryocytic nuclei (NMN) are a consistent and specific feature. The finding of BM changes in patients at an early stage of HIV disease points to either the direct effect of HIV infection of BM cells or to abnormal cytokine production or both.

The Fifth-Generation Target Study (5GTS) was a conceptual design task for a large target drone aircraft capable of representing key 5 th -generation fighter signature and performance attributes. The target drone’s intended uses are to test air-to-air and surfaceto-air missiles, and to ensure that modern tracking systems are capable of identifying and targeting 5th generation fighters. A delta-winged 5GTS design exhibited a non-linear pitching moment curve when tested with long inlet/strake structures sticking out ahead of the wings. Tests in the United States Air Force Academy’s (USAFA) subsonic wind tunnel revealed that this undesirable behavior disappeared when vertical tails were relocated or canted inward and also when inlet length was reduced. Flow visualization in the USAFA water tunnel showed that leading edge vortices shed from the nose chines, inlet lips, and wing leading edges remained separate from each other and interacted negatively with the vertical tail when the inlet/strakes were relatively large. However, when inlet/strake length was reduced to a critical value, the three separate vortices interacted positively by merging into a single vortex centered well away from the vertical tails.

Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a subacute inflammatory disorder most often seen in young women with clinicopathologic features suggestive of an infectious etiology. The most commonly suspected infectious agents in KFD are the human herpesviruses EBV, HHV6, HHV7 and HHV8. In order to identify herpesviruses in KFD, we have compared the frequency of detection of herpesvirus DNA with a recently developed real time PCR method, EBER in situ hybridization, and EBV latent membrane protein (LMP) immunostaining in 30 cases of KFD and 12 cases of reactive lymphoid hyperplasia (RLH). EBV DNA was commonly detected, while HSV2, CMV, HHV6, and HHV7 DNA were seldomly detected, and HSV1, VZV, and HHV8 DNA were not detected in KFD. EBV was also commonly detected in RLH. EBER-positive cells with apoptotic features were identified in necrotizing regions of many KFD cases, and LMP-positive cell debris was detected in one case. Viable EBER-positive cells were identified in four of twelve RLH cases, and rare LMP positivity detected in three cases. These data lend support to the notion that the necrotizing lesions in KFD may in some cases be due to a vigorous immune response to EBV-infected lymphoid cells.

Thymomas are thymic epithelial tumors. Because most of them are rich in nonneoplastic T-cells, recurrent genetic aberrations have been reported only in the rare, lymphocyte-poor WHO types A, B3, and C. We have now investigated virtually the whole spectrum of thymomas, including the commoner types AB and B2, microdissecting or culturing neoplastic cells from these lymphocyte-rich thymomas and applying 41 microsatellite markers covering 17 loci on 10 chromosomes. In 28 cases, comparative genomic hybridization data were available. Apart from type A, there was striking heterogeneity between thymomas. Allelic imbalances were seen in 87.3% of the 55 cases, and MSI in 9.9%. Losses of heterozygosity (LOHs) were much the commonest aberration. Overall, they were most prevalent at four regions on chromosome 6. Aberrations elsewhere, affecting mainly 8p11.21 and 7p15.3, suggested a cortical footprint because they recurred only in the thymopoietically active type AB and B thymomas. LOHs were also seen at the adenomatous polyposis coli (APC) locus (5q21-22) in subsets of these thymomas, whereas combined LOHs at the APC, retinoblastoma (13q14.3), and p53 (17p13.1) loci were confined to a subset of B3 thymomas that had possibly evolved from APC-hemizygous B2 thymomas by tumor progression; indeed, thymomas combing B2 plus B3 features are common. Notably, some AB and B thymomas shared LOHs despite their nonoverlapping morphology and different clinical behavior. Finally, allelic imbalances at 8p11.21 and 16q22.1 (CDH1) were significantly more frequent in stage IV metastatic thymomas. We conclude that the WHO-defined histological thymoma types generally segregate with characteristic genetic features, type A thymomas being the most homogeneous. Many findings support the view that B2 and B3 thymomas form a continuum, with evidence of tumor progression. However, other findings imply that types A and AB are biologically distinct from the others, any potential invasiveness being severely restricted by a medullary commitment in the precursor cell undergoing neoplastic transformation.

The tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) is an effective treatment for chronic myeloid leukemia (CML). We examined bone marrow samples from 53 patients with CML who were receiving STI571 in 3 multicenter phase 2 trials to assess morphologic changes and cytogenetic response to this drug. In most patients with initially increased blasts, the bone marrow blast count rapidly decreased during STI571 therapy. Reductions in cellularity, the myeloid/erythroid ratio (commonly with relative erythroid hyperplasia), and reticulin fibrosis (if present pretreatment) also were seen in most patients, resulting in an appearance resembling normal marrow in many cases. Eighteen patients (34%) had some degree of cytogenetic response. Surprisingly, these striking morphologic changes occurred irrespective of any cytogenetic response to STI571. Thus, STI571 seems to affect the differentiation of CML cells in vivo, causing even extensively Philadelphia chromosome-positive hematopoiesis to exhibitfeatures resembling normal hematopoiesis.

BACKGROUND This report is a study of prognostic factors, including adjuvant chemotherapy, that influence survival of patients with malignant melanoma who have clinical and pathologic involvement of regional lymph nodes. METHODS A total of 169 evaluable patients with malignant melanoma metastatic to regional lymph nodes were registered consecutively and prospectively between June 1977 and December 1986 in the computerized data base of the melanoma registry at Westminster Hospital. Eighty-seven of these patients received adjuvant chemotherapy with vindesine after resection of palpable metastatic lymph nodes, and 82 had no systemic treatment after surgery. All were followed up for at least 2 years (median, 8 years) after involvement of regional lymph nodes was noted or until death. Statistical analyses included simple life-table comparisons, unadjusted for covariates. In addition, Breslow's thickness, ulceration of the primary lesion, its anatomical location, number of regional lymph nodes histologically involved, dissection site, patient age and sex, and adjuvant vindesine therapy were included as covariates in Cox regression models. RESULTS The disease-free interval (P = 0.0001), time to dissemination from lymph node metastases (P < 0.0001), survival time after lymph node dissection (P = 0.0227) and overall survival time after initial diagnosis of malignant melanoma (P = 0.0095, log-rank chi-square test) were superior for the 87 patients who received adjuvant chemotherapy with vindesine. Cox regression analysis confirmed adjuvant vindesine as a highly significant variable influencing all of these outcomes, including overall survival time after first diagnosis (P = 0.003). CONCLUSIONS The apparent effect of adjuvant vindesine on overall survival in this study is large (hazard ratio, 0.52) and highly statistically significant. Adjuvant vindesine therapy merits consideration for malignant melanoma metastatic to regional lymph nodes. However, these results observed in concurrent, but nonrandomized, patients clearly require confirmation.

The purpose of this communication is to discuss and illustrate the different microscopical features of members of this important group of large cell lymphomas and to give some indication of prognosis in relation to histopathology. The diffuse large cell lymphoma is a heterogeneous category of tumour previously designated reticulum cell sarcoma in traditional classifications, and ‘histiocytic' by Rappaport. The majority are, however, large lymphoid cell tumours which on the basis of their light microscopic anatomy may be subdivided into those of follicle centre (B-lymphocytic) origin, immunoblastic type of either B- or T-lymphocytic origin, and ‘undifferentiated' — meaning that although acceptable as lymphoid in nature at light microscopical level there are no further distinguishing features. Plasma cell (extramedullary) lymphomas are separately categorised. A smaller but significant minority group are of histiocytic (mononuclear phagocytic) derivation. Rarely tumours are encountered involving peripheral lymphoreticular tissue but which are derived from other cell types indigenous to the lymphoreticular and mononuclear and phagocytic system.

The histology of 125 cases of primary gastrointestinal lymphomas arising in the stomach and small and large intestine has been reviewed. The material was gathered from the Bland-Sutton Institute of Pathology at the Middlesex Hospital and from the Westminster Hospital. Of the initial total of 143 cases diagnosed, 18 were rejected. Of the acceptable 125 cases, 51 lymphomas were arising in stomach, 53 in the small intestine and 21 in the large intestine including rectum. Excluding the four children in the series, ages ranged from 18 to 82 and were fairly evenly distributed across the decades. There was no significant sex difference in the Middlesex Hospital cases but in the Westminster Hospital series the male to female ratio was approximately 2.6 to 1. One significant finding to emerge from this histological survey, and which forms the basis of this communication, is the proportion of lymphomas considered to be predominantly of plasma cell type. These plasma cell tumours, or extramedullary plasmacytomas, accounted for 49 out of the 125 cases (39%) of gastrointestinal lymphomas. They were less common in stomach and most common in the intestine, the majority occurring in the ileocaecal region. Conversely, Hodgkin's disease, in contrast to some series, was not encountered. Of the non-Hodgkin's lymphomas, grade I tumours were uncommon and true histiocytic lymphomas were distinctly rare. The high incidence of plasma cell tumours were uncommon and true histiocytic lymphomas were distinctly rare. The high incidence of plasma cell tumours in our series is in keeping with the morphological findings of a previous study carried out in patients with alpha-chain disease and in a small series of primary gastrointestinal lymphomas.

Nuclear bodies have been consistently observed in the epithelial cell component of normal thymuses from children with congenital heart disease and in the pathological thymuses derived from patients with myasthenia gravis, with or without thymoma. They have also been identified in a few normal adult thymuses. On the basis of their ultrastructural appearances they have been termed either simple or complex nuclear bodies. In normal tissue their incidence was higher in children than in adults, and they were numerous in thymuses showing evidence of thymitis and in thymomas. In children and adults the nuclear bodies were of simple type, whereas in the myasthenic groups there was a greater incidence of the complex type. Although most commonly seen in the epithelial cell nuclei, nuclear bodies were also found in lymphocytes, plasma cells, and mesenchymal reticular cells, in fibroblasts and endothelial cells, and in the thymic striated muscle (myoid) cells. It is concluded that nuclear bodies are a constant nuclear organelle not only of thymic epithelial cells, but also of most other cells. Their function is unknown, but their incidence in the different cell types present in the available material suggests that they are in some way associated with states of nuclear hyperactivity.

A case report is presented of a thymoma with unusual histological features including the presence of striated muscle (myoid) cells as an intrinsic part of the tumour. Both light and electron microscopy of the thymoma are described, the subject of striated muscle (myoid) cells in thymus is briefly reviewed, and the designation of the tumour as a thymic blastoma is suggested.

The findings of 27 lymph node biopsies performed on 24 homosexual patients with lymphadenopathy are presented. Six had acquired immune deficiency syndrome (AIDS) and 18 lymphadenopathy only, of whom one subsequently developed AIDS. All these patients had antibodies to the human T-cell lymphotropic virus type III (HTLV-III) suggesting that HTLV-III is currently the commonest cause of lymphadenopathy in homosexual men. The histopathological findings of six of seven nodes from AIDS patients showed either follicular depletion alone or follicular and paracortical lymphocyte depletion. Nodes from four patients showed Kaposi's sarcoma, three of which also showed follicular hyperplasia. In two of these patients there were no cutaneous manifestations of this condition. One lymph node from a patient with persistent generalized lymphadenopathy (PGL) showed Mycobacterium tuberculosis. Six nodes from six other patients have had features oftoxoplasmosis although there was no serological or clinical evidence of recent toxoplasma infection. The remaining 11 lymph nodes from patients with PGL and one node from a patient with transient lymphadenopathy, showed reactive follicular hyperplasia only. We conclude that homosexuals with lymphadenopathy who are HTLV-III antibody positive do not need a routine node biopsy unless an alternative diagnosis is strongly suspected.

During an ultrastructural study of small-intestinal mucosa from a patient suffering from alpha-chain disease organisms were identified within the epithelial cytoplasm which showed the fine structural features of the coccidian group. Though coccidiosis is well recognized as causing a diarrhoeal and often lethal illness in animals it has been neglected as a cause of disease in man. Thus this finding may be significant and warrants further investigation into its possible role in the pathogenesis of alpha-chain disease.

A polyclonal commercially available antiserum to alpha 1-antichymotrypsin (alpha 1ACT) was reacted with 194 sarcomas, 38 carcinomas, and 17 malignant melanomas; 61 of 194 sarcomas, 14 of 38 carcinomas, and 10 of 17 malignant melanomas reacted positively. Thirteen categories of sarcomas were examined. All but one group (haemangiopericytomas) showed positively staining tumour cells. Malignant fibrous histiocytomas, angiosarcomas, and Kaposi's sarcomas showed positive staining in over 70% of tumours. All categories of carcinomas examined, with the exception of transitional cell carcinomas, stained positively. The results of this study suggest that the use of alpha 1ACT antiserum is of little value in the differential diagnosis of either sarcomas or carcinomas, nor can it be used as a specific histiocytic marker.

An intracranial tumor classified as a histiocytic lymphoma was studied with light and electron microscopic examination and immunocytochemical methods. The characteristics of the malignant mononuclear phagocyte cells are described. The presence of some cells containing Langerhans' granules suggests differentiation towards a specialized cell of the mononuclear phagocyte system: the Langerhans' cell.

A case of eosinophilic enteritis in a dog is reported and the literature on this subject reviewed. The condition is believed to be similar to eosinophilic enteritis of man and should always be considered in a dog with diarrhoea, vomiting and weight loss and with eosinophilia.

This study examined the staining reactions of a commercially available anti desmin antibody in 192 soft tissue sarcomas, 30 carcinomas and 22 malignant melanomas. Only 63% of rhabdomyosarcomas and 50% of leiomyosarcomas showed a positive reaction. Three non muscle sarcomas also reacted with the antibody. No positivity was seen amongst the carcinomas or the melanomas. These results do not compare favourably with the documented results of non commercial desmin antibodies in the literature. The most likely cause of the discrepancy in the varying results is the differing source of the antibody.

Antiacetylcholine receptor antibody (anti-AChR) was spontaneously synthesized by cultured thymic tissue from 19 of 35 patients with myasthenia gravis. Two other thymus cultures produced antibody after stimulation by pokeweed mitogen. Antibody production correlated with histologic evidence of thymitis, long duration of symptoms, or high serum anti-AChR values. None of seven thymomas synthesized antibody in culture, but evidence suggested that there had been in vivo synthesis or trapping of anti-AChR. Clinical improvement after thymectomy, during the short period of study, did not correlate with synthesis rates of anti-AChR production by the removed thymus. The rates of anti-AChR production in culture were too low to suggest that the thymus is the major source of this antibody. Although we did not find a clear relationship between anti-AChR antibody and clinical state within 3 months of thymectomy, in a study of 25 nonimmunosuppressed, nonthymoma patients followed for 1 to 4 years, we found a significant correlation (p less than 0.05, Spearman Rank correlation) between fall in anti-AChR antibody and clinical improvement after thymectomy (unpublished observations).

Lymphomas by definition are those tumors arising from peripheral lymphoreticular tissue and thus exclude the neoplastic proliferations of bone marrow—the leukemias—and the primary tumors of thymus—the thymomas. In practice most lymphomas arise in lymph nodes in the first instance and are thus derived from the lymphoreticular mononuclear phagocytic system of cells (LRMPS). Therefore, before embarking on a description of our classification of non-Hodgkin’s lymphomas, a brief account will first be given of some of the normal component cells of the lymph node.

Summary A pulmonary blastoma with striated muscle and other mesodermal components is described, and reasons are given for classifying it as such. The presence of striated muscle and the views on the histogenesis of these rare pulmonary tumours are discussed. There is some doubt whether they are true embryonic tumours. However, it is felt that because of their resemblance to fœtal lung and their mesodermal nature the term pulmonary blastoma is fully justified, and we agree that they should be considered as a separate entity from carcinosarcoma of the lung.

A retrospective study of the non-Hodgkin's lymphomas has been set up in order to assess and compare the five new classifications with that of Rappaport and to relate them to clinical data in terms of prognosis. Following analyses of the computer data, agreement has been achieved on an acceptable ‘formulation’ for use in clinical trials for classification of the non-Hodgkin's lymphomas which should prove valuable in allowing cross reference between different centres.