Susceptibility of common marmosets (Callithrix jacchus) to oncogenic and attenuated strains of Herpesvirus saimiri.

Adult common marmosets, inoculated with either of 2 oncogenic Herpesvirus saimiri (HVS) strains, developed fatal lymphoproliferative disease within 23-25 days post inoculation (PI). The disease was identical to HVS-induced lymphoma in cotton-topped and white-lipped marmosets. Common marmosets inoculated with an attenuated HVS strain developed persistent infection; virus has been recovered from cocultivated lymphocytes of these animals for more than 384 days PI.     

The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model

A t(2;5) (p23;q35) chromosomal translocation can be found in a high percentage of anaplastic large-cell lymphomas (ALCL). This genetic abnormality leads to the expression of the NPM-ALK fusion protein, which encodes a constitutively active tyrosine kinase that plays a causative role in lymphomagenesis. Employing a modified infection/transplantation protocol utilizing an MSCV-based vector, we were able to reproducibly induce two phenotypically different lymphoma-like diseases dependent on the retroviral titers used. The first phenotype presented as a polyclonal histiocytic malignancy of myeloid/macrophage origin with a short latency period of 3-4 weeks. Clinically, the diseased mice showed rapidly progressive wasting, lymphadenopathy and pancytopenia. Mice displaying the second phenotype developed monoclonal B-lymphoid tumors with a longer latency of approximately 12-16 weeks, primarily involving the spleen and the bone marrow, with less extensive lymph node but also histologically evident extranodal organ infiltration by large immature plasmoblastic cells. The described retroviral mouse model will be useful to analyse the role of NPM-ALK in lymphomagenesis in vivo and may contribute to the development of new treatment options for NPM-ALK induced malignancies.     

Distribution and metabolism of aflatoxin B1 in the marmoset monkey (Callithrix jacchus)

Whole-body autoradiography of [³H]aflatoxin B₁ (³H-AFB₁) inmarmoset monkeys (Callithrix jacchus) showed a localizationof bound labelling, in addition to the liver, in the nasal olfactoryand respiratory mucosa and the mucosa of the nasopharyngealduct, the pharynx, the larynx, the trachea and the oesophagus.In vitro microautoradiography of these tissues incubated with³H-AFB₁ showed a localization of bound radioactivity in somecells in the epithelial linings of the tissues. This bindingwas abolished when the incubations were performed in the presenceof the cytochrome P-450 inhibitor metyrapone. These resultsindicate a cytochrome P-450-dependent bioactivation of AFB₁in some structures in the epithelia of the nasal olfactory mucosaand the upper respiratory and alimentary pathways, in additionto the liver, in the marmoset monkey. Quantitation of the invitro formation of tissue-bound radioactivity from the ³H-AFB₁showed that the nasal olfactory mucosa had the highest capacityto form bound metabolites among the tissues examined. Liquidchromatography of lipid-soluble metabolites formed by the nasalolfactory mucosa and the liver showed that aflatoxin M₁ (ATM₁)was the major metabolite. AFM₁ was also the major metabolitefound in the liver in vivo. In the pigmented tissues of themarmosets there was an accumulation of nonmetabolized AFB₁.This can be related to a melanin-affinity of AFB₁. The describedtissues with a capacity to accumulate and metabolize AFB₁ maybe potential targets for the carcinogenicity of this substancein the marmoset monkey.     

Metabolism and tissue distribution of tobacco-specific N-nitrosamines in the marmoset monkey (Callithrix jacchus)

Three male marmoset monkeys (Callithrix jacchus) were injectedi.v. with the tobacco-specific carcinogen [2'-¹⁴C]N'-nitrosonornicotine(NNN) (20.3 µmol/kg body weight) or [carbonyl-¹⁴C]4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) (18.8 or 420 µmol/kg body weight). They were sacrificed4 h later. Tissue distribution was studied in two monkeys bywhole-body autoradiography and by computer-assisted densitometricanalysis of the autoradiograms. The autoradiograms showed ahigh level of radioactivity in the liver, nasal mucosa, kidneys,melanin of the eyes, hair-follicles of the skin and in the ceruminousear glands of the monkeys. Total level of radioactivity was5.7 times higher in the liver of the [carbonyl-¹⁴C]NNK-injectedmonkey than in that of [2'-¹⁴C]NNN-injected monkey. Washingthe sections with trichloroacetic acid and organic solventsselectively removed free metabolites leaving metabolites boundto cellular macromolecules. Level of bound metabolites was 1.5times higher in the nasal mucosa than in the liver of the [2'-¹⁴C]NNNmonkey. Levels of bound metabolites were similar in the liverof NNN-and NNK-treated monkeys. The results indicate that theliver and nasal mucosa of C. jacchus can activate NNN and NNKto alkylating species. Unbound metabolites present in the liver,lung, kidneys, eye, blood and urine were extracted and separatedby h.p.l.c. Hydroxylation of the carbons to the N-nitroso groupof NNN were the major metabolic pathways. Unmetabolized NNNwas the major radioactive component in the liver, lung, eyeand blood. Reduction of the carbonyl of NNK yields 4-(methylnitrosamino)-1-(3-pyridyl)butan-1-ol(NNAI). NNAI was present in all tissues analyzed and was themajor radioactive component in the eye and stomach lumen. Itwas also excreted in the urine. NNK and NNAI were metabolizedby -carbon hydroxylation. These results suggest that in C. jacchus,NNN, NNK and NNAI are activated to alkylating species by -carbonhydroxylation. In the third monkey injected with NNK, DNA methylationwas observed in the liver and nasal mucosa but not in the lungand kidneys. Pulmonary tissues of C. jacchus, unlike those of F344 rats,do not have the enzymic capacities to activate NNK to methylatingspecies.     

Persistent active herpes virus infection associated with atypical polyclonal lymphoproliferation (APL) and malignant lymphoma

This study focuses on lymphoproliferative diseases associated with persistent infection by Epstein-Barr virus (EBV) and human herpes virus 6 (HHV-6). A suggestive premalignant lymphoproliferative state is distinguished from malignant lymphoma and identified as "atypical polyclonal lymphoproliferation" (APL). Sixteen cases of herpes virus (HHV)-associated APL are compared with 21 cases of HHV-associated malignant lymphomas (ML), with 108 cases of EBV or HHV-6 related acute infections mononucleosis, with 14 cases of seronegative non-specific lymphoid hyperplasia and with 304 cases of HHV-unrelated ML. Six cases of APL and two ML occurred in AIDS patients, two cases in Sjogren's syndrome, one in a kidney allograft recipient, and the remaining cases had no identified underlying disease. APL was histologically reminiscient of excessive infectious mononucleosis, while other cases of Castleman's disease or even of malignant lymphoma. Seropositive APL and ML contained significantly more virus genome than is found in latent background infection. There was no histologic difference between HHV-6 or EBV-positive APL or ML, although both viruses infect different lymphocyte populations. From histology alone, seropositive ML cases were not distinguished from seronegative ones, yet persistent active EBV and HHV-6 appear to predominate in follicular center cell- and immunoblastic lymphoma and in HOdgkin's disease. Although no a direct oncogenic activity of these viruses could be observed in our cases, they may contribute to lymphomagenesis by inducing progressive lymphoproliferation.     

Management of malignant lymphoma in two siblings with Bloom's syndrome

Treatment of the malignant neoplasms which develop in patients with chromosome fragile syndrome, such as Bloom's syndrome (BS), requires extremely careful planning of the chemotherapy regime because of the excessive chemosensitivity of patients with such syndromes. Two siblings with BS developed B cell-type non-Hodgkin's lymphoma in the third decade of their lives. In both cases a 3-bp homozygous deletion of the BLM gene was detected. Since the lymphoma of the older brother was nasopharyngeal in origin, he was administrated radiation therapy as the primary treatment. However, hepatic metastasis was detected and this was the cause of his death. A 9-bp deletion in exon 7 of the p53 gene was detected in the metastatic lymphoma. His younger sister developed a lymphoma of abdominal lymph node in origin. She received a half dose of the drugs used in the acute lymphoblastic leukemia treatment without radiation, and twenty months after the diagnosis of her lymphoma she continues to be in complete remission and free of treatment complications. The p53 gene mutation was not detected in her lymphoma. These results suggest that radiation therapy and the radiation dose for the treatment for lymphoma in patients with BS should be carefully considered.     

Epstein-Barr virus-related herpesvirus from a rhesus monkey (Macaca mulatta) with malignant lymphoma

A herpesvirus (RhEBV) was isolated from a lymphoblastoid cell line (LCL) that became established from a malignant lymphoma in a rhesus monkey. The predominant cell marker in the LCL was that of B lymphocytes. RhEBV-induced viral capsid (VCA) and nuclear antigens (NA) in the LCL were serologically related to similar antigens known to be induced by human Epstein-Barr virus (EBV). RhEBV was of nonhuman primate origin and was clearly differentiated from EBV in the anti-complement immunofluorescence reaction using human and non-human primate sera with antibodies to the NA induced by the respective viruses. While human sera reacted with NA induced by both EBV and RhEBV, monkey sera failed to recognize the NA induced by EBV. RhEBV-induced NA was present in nearly all the cells of a suspension prepared from the tumor tissue mass, but not in the monolayer fibroblasts derived from the tumor tissue or in the blood and lymph-node lymphocytes of clinically healthy animals. RhEBV induced in vitro transformation and establishment of LCLs from peripheral blood lymphocytes of normal rhesus and cynomolgus monkeys but not from those of 6 other non-human primate species tested. The LCLs, with predominant B-lymphocyte markers, established after treatment with RhEBV, all had evidence of the virus infection since nearly all cells in the culture expressed the virus-induced NA.     

EBV infection induced transformation of benign T lymphoproliferative state in patient with chronic active EBV infection into malignant lymphoma: implication of EBV infection as additive oncogenic factor in tumorigenesis

An 11-year-old girl with chronic EBV (Epstein-Barr virus) infection, who later developed malignant lymphoma in the lung, is reported. She had an increased number of V alpha2, V beta8, CD3, CD4, and HLADR positive activated lymphocytes (20-30% of total lymphocytes) in peripheral blood. One year later, she developed lymphoma in the lung, which was V alpha2, V beta8, CD3, CD4, HLADR and IL2Rbeta positive. At that time, the population in the peripheral blood increased up to 40%, but there was no evidence of lymphoma in the bone marrow. In situ hybridization revealed lymphoma cells were EBER-1 positive but gp350/220 and LMP mRNA negative. The EBV genome was detected in the tumor, but not in the peripheral T cells. Clonal analysis of the lymphoma cells revealed monoclonal rearrangement of the TcRbeta and gamma gene, however, investigation of the terminal repeat of EBV gene did not show the monoclonal pattern. These results indicate that infection of EBV into clonally activated T cells was related with transformation from benign lymphoproliferative disease to malignant lymphoma in this patient.     

Two cases of malignant lymphoma with high fever and C-reactive protein (CRP) elevation after treatment with granulocyte colony-stimulating factor (G-CSF)

We present two cases of malignant lymphoma that developed a high fever that eventually reached an extremely high 38.9 degrees C. The C-reactive protein( CRP) elevation also climbed to a very high 12.2 mg/dl after treatment with granulocyte colony-stimulating factor (G-CSF). In the one case, after stem cells were mobilized with CHASER therapy (cyclophosphamide, cytarabine, etoposide, dexamethasone and rituximab) followed by G-CSF (filgrastim 600 microg/day) subcutaneous daily, the serum CRP level rose to a maximum of 5.6 mg/dl, with a maximum fever elevation of 38.9 degrees C. In the other case, after the subject was given CHASE therapy followed by subcutaneous treatment with G-CSF (filgrastim 75 microg/day) daily, the maximum serum CRP level was 12.2 mg/dl along with a maximum fever of 38.9 degrees C. Although no infection was found in either case, multiple antibacterial agents were ineffective;after discontinuation of G-CSF, fever dissipated and the serum CRP level became negative. G-CSF induces the proliferation and differentiation of neutrophils and also causes the mobilization of mature neutrophils from hematopoietic tissues. With the increasing propensity to G-CSF, we must keep in mind the possibility of such adverse reactions so as to serve the overall best interests of the patient.     

Macrophage-histiocytes in malignant lymphoma, small lymphocytic type (well-differentiated lymphocytic lymphoma)

The authors studied the occurrence of Ricinus communis agglutinin (RCA)-binding macrophage-histiocytes in paraffin-embedded tumor tissue of 38 patients with malignant lymphoma, small lymphocytic type, a tumor of low-grade malignancy. Thirty-one patients (82%) had an indolent clinical course and were free of disease for a minimum follow-up period of 24 months. However, seven patients (18%) died within 24 months of biopsy, and six of the seven patients died of rapid progression of their tumor despite intensive treatment. Histologically, the tumors of these six short-term survivors were indistinguishable from those of the long-term survivors. RCA staining of paraffin-embedded tumor tissue of the 38 cases revealed three groups of tumors: (1) tumors with numerous (greater than 10/high-power field [HPF]) stromal macrophage-histiocytes (4 patients); (2) tumors with a moderate number (4-9/HPF) of macrophage-histiocytes (5 patients); (3) tumors with rare or no (0-3/HPF) macrophage-histiocytes, or only thin, anuclear variants (29 patients). Each of the six short-term survivors had readily demonstrable RCA-binding macrophage-histiocytes in their tumor; these were numerous in four and moderate in two. In contrast, macrophage-histiocytes were either rare or absent, or were anuclear variants, in 29 of the 31 patients who had an indolent clinical course. These observations suggest that in small lymphocytic type malignant lymphoma there is a subgroup characterized by an increased number of stromal macrophage-histiocytes and aggressive behavior of the tumor. Tumors of this subgroup can be detected by RCA staining.     

116例携带乙肝病毒的淋巴瘤患者化疗后发生肝功能损害的临床分析

背景与目的:有研究显示,携带慢性乙型肝炎病毒(hepatitisBvirus,HBV)的恶性肿瘤患者化疗后肝功能损害发生率及相关死亡率明显增加。本研究探讨携带慢性HBV的淋巴瘤患者接受化疗后,肝功能损害的发生情况及其临床后果,并进一步探讨临床相关的高危因素。方法:1985年1月至2002年1月在我院门诊及住院的携带HBV的116例淋巴瘤患者,回顾性分析其接受化疗后肝功能损害的发生情况、临床后果及其相关高危因素。结果:60例(51.7%)患者化疗后出现肝功能损害,按WHO肝脏毒性标准,Ⅰ度4例(3.4%)、Ⅱ度14例(12.1%)、Ⅲ度15例(12.9%)、Ⅳ度27例(23.3%)。经对症治疗后11例(9.5%)患者按期化疗,27例(23.3%)化疗延期,16例(13.8%)终止化疗,6例(5.2%)死亡。应用二值多元logistic回归模型,应用激素是化疗后发生肝炎的高危因素。结论:携带HBV的淋巴瘤患者化疗后肝功能损害发生率高,化疗后肝功能损害会导致患者化疗延迟,甚至死亡。应用激素是其发生的高危因素。     

Continuous treatment of non-Hodgkin's malignant lymphoma with prednimustine (Leo 1031)

The effect of Prednimustine was evaluated in 37 patients with generalised non-Hodgkin's lymphomas. The patients were divided into three groups according to dosage and previous treatment. Totally, in all three groups, 22 complete and 10 partial remissions were observed. During follow-up, five of the complete responders and all partial responders have relapsed. Leucopenia and thrombocytopenia were induced in several patients, but were always moderate and reversible after withdrawal of the drug. In some patients with a history of peptic ulcer or diabetes mellitus, these conditions were aggravated.     

恶性淋巴瘤患者血流感染情况及病原菌耐药性分析

目的 分析恶性淋巴瘤患者血流感染情况及病原菌耐药性.方法 选取310例恶性淋巴瘤患者,检测血流感染的病原菌分布情况,以纸片扩散法进行药敏反应试验.结果 310例恶性淋巴瘤患者中,发生血流感染29例,感染率为9.35％.29例发生血流感染的恶性淋巴瘤患者中共分离出25株病原菌,其中革兰阳性菌15株,占60.00％;革兰阴...     

乙肝表面抗原阳性淋巴瘤患者19例利妥昔单抗联合化疗肝功能损害分析

目的探讨利妥昔单抗（商品名：美罗华）联合化疗对乙肝表面抗原阳性（HBsAg^＋）淋巴瘤患者肝功能的影响。方法回顾性分析2001年6月至2007年8月病理确诊B细胞非霍奇金淋巴瘤伴HBsAg^＋的19例住院患者的临床资料。所有患者均接受利妥昔单抗联合化疗,参照WHO不良反应评价标准对治疗后肝功能损害进行分析。同时检测了部分患者的HBV—DNA,并分析其与治疗后肝功能损害的关系。结果19例患者中有12例（63．2％）发生了,肝功能损害。4例（21．1％）患者发生了Ⅰ度肝功能损害,6例（31．2％）患者发生了Ⅱ度肝功能损害,2例（10．5％）患者发生了Ⅲ度肝功能损害。无一例患者发生Ⅳ度肝功能损害？治疗前HBV—DNA〉10^7copy／ml的患者6例中有5例（83．3％）发生了肝功能损害,而治疗前HBV—DNA〈10^4copy／ml的患者5例中有3例（60％）发生了肝功能损害。结论HBsAg^＋淋巴瘤患者接受利妥昔单抗联合化疗后发生肝功能损害的概率较高：HBsAg^＋淋巴瘤患者应用利妥昔单抗时应该慎重,并进行抗乙肝病毒的治疗.