Lymphoreticular Malignancies Research Articles

CAMPATH 1H (ALEMTUZUMAB) IN RENAL TRANSPLANTATION: 5-YEAR COMPARATIVE FOLLOW UP.

O143* Aims: Alemtuzumab is a powerful lymphocyte depleting monoclonal antibody that is licensed for use in the treatment of lymphoreticular malignancy and is under evaluation in organ transplantation. This paper describes the 5-year follow up of our original study which comprised alemtuzumab followed by low dose ciclosporin monotherapy. Theses patients have been compared to contemporary controls. The only selection criteria for alemtuzumab was the giving of informed consent. Methods: Cadaveric renal transplant recipients (n = 33) were given two doses of 20mg alemtuzumab followed 48 hours later by low dose ciclosporin monotherapy. A cohort of patients (n = 66) transplanted in the same time period in the same centre and receiving conventional ciclosporin-based triple therapy (n = 61) or sirolimus, ciclosporin and prednisolone (n = 5) were selected for comparison. Patients receiving the transplant before and after a patient on alemtuzumab were selected, excluding living donor transplants and multi-organ transplants. Results: There were no significant differences between alemtuzumab and control groups. Follow up was complete in the alemtuzumab group and while 2 of the control group were lost to follow up at varying intervals post transplant; both had normal graft function at the time. Table 1 illustrates the outcomes for each group.FigureOne patient in the alemtuzumab group died from a post transplant lymphoproliferative disease. The other deaths were due to either ischaemic heart disease (n = 2) and calciphylaxis (n = 1) in the alemtuzumab group, or to ischaemic heart disease (n = 6), cerebrovascular disease (n=1), sepsis (n = 2), cerebral tumour (n = 1) and unknown (n=1) in the control patients. Notable events in alemtuzumab treated patients include one de novo autoimmune haemolytic anaemia and one ileocaecal TB infection. In spite of profound initial lymphocyte depletion in the alemtuzumab group, the total lymphocyte counts in both groups were similar by 6 months. Renal function remained similar in each group throughout. The incidence of acute rejection was also similar in both groups, but time of the first acute rejection episode occurred much later in alemtuzumab treated patients (median 170 days compared to 16 days in control). Conclusions: Alemtuzumab combined with low dose ciclosporin is a safe and effective regimen, but patients needed to be followed up closely for late acute rejection. The protocol is well tolerated and avoids corticosteroids and high dose CNI therapy.

Identification of two mutations for ataxia telangiectasia among the Druze community.

Ataxia telangiectasia (AT) is a rare autosomal recessive disease characterized by progressive cerebellar ataxia, immunodeficiency, susceptibility to lymphoreticular malignancies and cancer predisposition, hypersensitivity to ionic radiation and chromosomal instability. In this study, we report a founder effect of AT with two different mutations: 1339 C > T and 6672 del GG together with 6677 del TACG, found in four Israeli Druze clans originating from three different Druze centers in the Middle East (Lebanon, Syria and Jordan). The 1339 C > T mutation, which results in a stop codon at position 447 of the ATM protein, was observed in two unrelated clans originating from Lebanon and Jordan. The 6672 del GG/6677 del TACG mutation was observed in two unrelated clans originating from Syria and Lebanon. In the present study, simple and fast detection assays were developed for both mutations. The ability to identify AT carriers routinely provides a unique opportunity for prenatal diagnosis, genetic counseling as well as marriage guidance in the Druze community.

Nijmegen breakage syndrome in 13% of age-matched Czech children with primary microcephaly

The Nijmegen breakage syndrome is a rare autosomal recessive chromosomal instability disorder characterized by early growth retardation, congenital microcephaly, immunodeficiency, borderline mental development, and a high tendency to lymphoreticular malignancies. Most Nijmegen breakage syndrome patients are of Slavonic origin, and all of them known so far carry a founder homozygous 5 nucleotide deletion in the NBS1 gene. Microcephaly was present in 100% of Nijmegen breakage syndrome patients in a recent large international cooperative study. The frequency of Nijmegen breakage syndrome among children with primary microcephaly was not known. Early correct diagnosis of the syndrome is crucial for appropriate preventive care and therapy. We tested 67 Czech patients of different ages with simple microcephaly for the presence of the most common mutation in the NBS1 gene. Three new Nijmegen breakage syndrome cases were detected in this cohort, representing 4.5% of the cohort. All these newly diagnosed Nijmegen breakage syndrome patients were younger than 10 months at the time of diagnosis. They were all born within a 2.5-year period. Twenty-three of the 67 children in the cohort were born within this 2.5-year period, representing a 13% incidence of Nijmegen breakage syndrome. Frequency of Nijmegen breakage syndrome heterozygotes among infants in the Czech Republic is 1: 130-158 and the birth rate is 90,000 per year, therefore in the time span of 2.5 years, three new Nijmegen breakage syndrome homozygotes are expected to be born. Therefore we assume that by DNA testing of Czech primary microcephalic children it is possible to detect all Nijmegen breakage syndrome patients to be expected. The age at correct diagnosis was lowered from 7.1 years at the time before DNA testing, to well under 1 year of age. All new Nijmegen breakage syndrome patients could receive appropriate preventive care, which should significantly improve their life expectancy and prognosis.

The clinical epidemiology of pulmonary cryptococcosis in non-AIDS patients at a tertiary care medical center.

Cryptococcus neoformans is a ubiquitous saprophytic fungus with worldwide distribution. It has been found in nature, primarily in association with bird droppings, but nonavian sources have been described as well (10). Although the lungs are thought to be the portal of entry for cryptococcus, pulmonary infection is uncommon. The organism is trophic to the central nervous system and the vast majority of recognized infections involve meningitis. Before the acquired immunodeficiency syndrome (AIDS) epidemic (1980), cryptococcosis was a rare infection, and pulmonary disease was described in 10%–45% of patients with cryptococcal meningitis (2). However, the true incidence of pulmonary cryptococcosis (PC) was not known, but was much lower than meningitis. Most PC cases were identified histologically and often at autopsy, with only about 20% diagnosed by culture (2, 3, 13). In recent years, many of the reports of cryptococcal infection have been in the human immunodeficiency virus (HIV)-positive population, and little is known of the disease in non-AIDS patients, particularly pulmonary involvement. At our institution, a tertiary care medical center with a large transplant program, sporadic cases of PC have occurred in solidorgan transplant recipients as well as in patients with a variety of different medical conditions. The purpose of our study was to investigate the epidemiology of PC in non-AIDS patients, and to determine predictors of outcome among these patients.

Invasive candidiasis stimulates hepatocyte and monocyte production of active transforming growth factor beta.

Candida albicans is an opportunistic fungal pathogen and a major cause of morbidity and mortality in patients with compromised immune function. The cytokine response to tissue invasion by C. albicans can influence the differentiation and function of lymphocytes and other mononuclear cells that are critical components of the host response. While the production of transforming growth factor beta (TGF-beta) has been documented in mice infected with C. albicans and is known to suppress phagocyte function, the cellular source and role of this cytokine in the pathogenesis of systemic candidiasis are not well understood. We have investigated the source of production of TGF-beta by immunohistochemical studies in tissue samples from patients with an uncommon complication of lymphoreticular malignancy, chronic disseminated candidiasis (CDC), and from a neutropenic-rabbit model of CDC. Liver biopsy specimens from patients with documented CDC demonstrated intense staining for extracellular matrix-associated TGF-beta1 within inflammatory granulomas, as well as staining for TGF-beta1 and TGF-beta3 within adjacent hepatocytes. These results correlate with the immunolocalization of TGF-beta observed in livers of infected neutropenic rabbits, using a neutralizing antibody that recognizes the mature TGF-beta protein. Human peripheral blood monocytes incubated with C. albicans in vitro release large amounts of biologically active TGF-beta1. The data demonstrate that local production of active TGF-betas by hepatocytes and by infected mononuclear cells is a component of the response to C. albicans infection that most probably contributes to disease progression in the immunocompromised host.

Mycosis fungoides in identical twins

J Am Acad Dermatol 2001;44:532-3.

Café au lait spots: the pediatrician's perspective.

1. Mustafa Tekin, MD* 2. Joann N. Bodurtha, MD, MPH† 3. Vincent M. Riccardi, MD‡ 1. 2. *Clinical Genetics Fellow. 3. 4. †Associate Professor of Human Genetics, Pediatrics, Obstetrics and Gynecology, Virginia Commonwealth University/Medical College of Virginia Hospitals, Richmond, VA. 5. ‡President, The Neurofibromatosis Institute, La Crescenta, CA. Objectives After completing this article, readers should be able to: 1. Define cafe au lait spots typical of neurofibromatosis type 1 (NF1) and describe their frequency and variability in the normal population. 2. List three or more genetic disorders other than NF1 that are associated with cafe au lait spots. 3. Summarize three or more clinical manifestations and molecular bases of NF1 and NF2. 4. List the diagnostic criteria for NF1. 5. Summarize clinical findings of genetic disorders other than NF1 associated with cafe au lait spots. Every pediatrician faces the challenge of deciding if a patient who has cafe au lait (CAL) spots has an underlying genetic condition. CAL spots typical of neurofibromatosis type 1 (NF1) are discrete, round or oval, uniformly hyperpigmented skin patches. Their color varies from light to dark brown, and the border may be smooth or irregular. They usually are smaller in newborns, enlarge as children get older, and are less prominent in adults. The histologic basis of CAL spots is increased melanin content, with the presence of giant melanosomes in both melanocytes and basal keratinocytes and no melanocytic proliferation. The giant melanosomes in CAL spots are not unique to NF1; they can be seen in unaffected skin of adults who have NF1 and occasionally in normal skin of healthy individuals. Therefore, the presence of giant melanosomes is not helpful for diagnosing NF1. The frequency and number of CAL spots vary in the general population according to ethnic background and age. Sometimes otherwise healthy children who have red hair and often are of Irish or Welsh background have multiple areas of patchy hyperpigmentation. Similarly, multiple patchy areas of hyperpigmentation can occur in healthy children who have mixed ethnic backgrounds in which two parents have very different skin colors. CAL spots were noted in 0.3% of Caucasians and 18% of African-Americans …

Two Different Extramammary Neoplasms Metastatic to the Breast

Two Different Extramammary Neoplasms Metastatic to the Breast

Nonmammary malignancies of the breast: Ultrasound, CT, and MRI

The three major categories of nonmammary malignancies of the breast include primary and secondary lymphoreticular malignancy, primary and secondary sarcoma, and hematogenous metastasis. This article describes the imaging features of 35 nonmammary malignancies of the breast and axilla with histopathologic confirmation. These include primary and secondary breast lymphoma, primary axillary nodal lymphoma, metastatic acute lymphatic leukemia, metastatic plasmacytoma, granulocytic sarcoma, primary angiosarcoma, metastatic rhabdomyosarcoma, hematogenous metastasis from primary lung, ovarian, cervical, thyroid, and colonic carcinoma, malignant melanoma, carcinoma of the nasal cavity, and adenocarcinoma of unknown primary. Wherever possible, correlation between mammography and ultrasound, computed tomography (CT), and/or magnetic resonance (MR) imaging is made.

POLAND'S SYNDROME WITH LUNG CANCER

Poland's syndrome, a rare congenital anomaly characterized by pectoralis muscle defect, has been reported in association with lymphoreticular malignancies and some solid tumors. Lung cancer associated with Poland's syndrome has not been previously described. We present the first report of a case of Poland's syndrome associated with lung cancer and demonstrate the CT findings.

HEMATOLOGIC ASPECTS OF SYSTEMIC MASTOCYTOSIS

Systemic mast cell disease is characterized by bone marrow involvement by mast cells and frequently by peripheral blood cytopenias. The coexistence of hematologic disorders, such as myeloproliferative or myelodysplastic syndromes, or of lymphoreticular malignancies with SMCD is common. Overt mast cell leukemia is rare. In general, patients who coexhibit a severe hematologic disorder tend to have a more compressed clinical course and a worse prognosis. Hemorrhage can be a result of heparin release from stimulated mast cells.

A new four-color flow cytometric assay to detect apoptosis in lymphocyte subsets of cultured peripheral blood cells

Human peripheral blood lymphocytes kept in culture after isolation die by an apoptotic process. Detection of apoptosis with labeled Annexin V to demonstrate loss of plasma membrane asymmetry is sensitive, specific, and easy using flow cytometry. This is true in lymphoblastic cell lines when combining Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI). However, measurement of apoptosis by flow cytometry in isolated human lymphocytes using Annexin V-FITC/PI is disturbed by the presence of a variable percentage of erythrocytes in the isolated lymphocyte population. To overcome this problem, we have developed and tested a new four-color flow cytometric assay to detect apoptosis in lymphocyte subsets of cultured peripheral blood cells. Peripheral blood lymphocytes are isolated by density gradient centrifugation. Nucleus-containing cells are selected using CD45-phycoerythrin (PE). The lymphocyte subset of interest is selected using CD4, CD8, or CD19 energy-coupled dye (ECD) labeling. Apoptosis is detected using Annexin V-FITC with 7-amino-Actinomycin-D (7-AAD) to distinguish early apoptotic from late apoptotic lymphocytes. We have developed a new technique to detect apoptosis in isolated human peripheral blood lymphocyte subsets with good reproducibility, coefficient of variation < 17%. We now have a validated tool to study apoptosis in subsets of isolated human lymphocytes to increase our knowledge of pathogenesis and therapies in lymphoreticular malignancies.

The histologic pattern of non-Hodgkin's lymphomas in Ethiopians

Non-Hodgkin's lymphomas (NHLs) are among the malignancies that can arise in advanced stages of infection in patients with human immunodefiency virus (HIV). However, the pattern of this malignancy has not been reported in Ethiopia. A sixteen year retrospective review has been carried out to determine the trend, age, sex distribution, and histological types of non-Hodgkin's lymphoma from January 1982 to December 1997. A total of 544 cases of non-Hodgkin's lymphoma were available for analysis. An increasing trend is observed from 1995 onwards. The male-to-female ratio was 2.8:1 and the peak occurence was in the age group of 50-54 years. The most frequent histologic grade was high grade accounting for 237 (43.6%) followed by 162 (29.9%) low grade and intermediate grade of 139 (25.5%). Diffuse growth pattern was seen in 96% of cases and follicular in only 4%. The most frequent histological type was immunoblastic (30.3%) followed by small lymphocytic lymphoma (26.5%). Extranodal involvement was observed in one fourth (24.6%) of cases. This study showed that NHLs are a heterogeneous collection of lymphoreticular malignancies having a wide age coverage and various peculiar histological types. Unlike in the Western Countries, follicular NHLs are much less common here. A properly designed prospective study is recommended to observe the stage, prognostic markers, and treatment outcome of various types of non-Hodgkin's lymphoma. (Ethiopian Journal of Health Development, 2000, 14(3): 345-352)

In VitroChromosomal Radiosensitivity in Common Variable Immune Deficiency

Common variable immune deficiency (CVID) is characterized by low immunoglobulin levels and recurrent infections in patients with a period of normal immune function several years after birth. It is associated with diarrhea, malabsorption, bronchiectasis, and lymphoreticular malignancies. Radiation-induced chromosome instability may contribute to the high degree of susceptibility to neoplasia. Peripheral blood lymphocyte cultures were obtained from six patients with CVID and the healthy control group matched by age and sex. The groups did not differ in the frequency of spontaneous chromosome aberrations. After exposure to X-ray radiation, mitotic indices were found to be significantly low and incidence of chromosomal alterations were high in the CVID group. We conclude that chromosomes of cells from patients with CVID are significantly more radiosensitive than those of controls. Thus these patients must be protected from unnecessary X-ray examinations and in case of radiosensitive tumour, the dose of irradiation should be carefully monitored.

Solid tumor DNA ploidy analysis.

Flow cytometric DNA content analysis of human neoplasia provides quantitative information on DNA ploidy, clonal DNA heterogeneity, and proliferative activity. These submicroscopic features are important for the biological and clinical evaluation of tumors as demonstrated in clinical studies of a wide spectrum of human lymphoreticular and solid malignancies (, , , , , , , , , , , , , , , , , , , , , , , ). Although valuable, such information should not be used in isolation from other conventional diagnostic and biological parameters in the risk assessment of cancer patients.

Transfusion- and community-acquired cytomegalovirus infection in children with malignant disease: a prospective study.

The use of cytomegalovirus (CMV)-"safe" blood has been recommended for CMV seronegative patients with newly diagnosed malignant disease for whom bone marrow transplantation is a future option. To evaluate this policy, 76 CMV-seronegative children with lymphoreticular malignancies or solid tumors were randomly assigned to receive either blood components that were not screened for CMV antibody or CMV-seronegative red cell (RBC) and platelet units. Subjects were followed for evidence of CMV infection by the use of enzyme-linked immunosorbent assays and virus isolation. Follow-up continued long after the blood transfusions to determine the risk of community-acquired CMV infection. No cases of transfusion-acquired CMV infection were documented. The prevalence of CMV IgG and IgM antibody in blood donors was 40.5 and 0.9 percent, respectively. Patients assigned to receive standard blood components and CMV-negative components were given a median (range) of 7 (1-30) and 9 (1-38) RBC units and 11 (0-123) and 14 (0-71) platelet units, respectively. The risk of transfusion-acquired CMV infection is estimated to be less than 1 in 698 donor exposures. Two patients developed asymptomatic community-acquired CMV infection, for an incidence of 1.7 percent per patient-year of follow-up. The risk of transfusion-acquired CMV infection in this population is low, largely because of the patients' low level of exposure to seropositive blood and the use of relatively white cell-reduced components for purposes other than CMV prevention. Such children at this center therefore continue to receive standard blood components. Strategies to prevent CMV seroconversion in these children should include parental education to minimize the risk of community-acquired infection.

Azathioprine-Induced Lymphoma Manifesting as Fulminant Hepatic Failure

Azathioprine-Induced Lymphoma Manifesting as Fulminant Hepatic Failure

Successful treatment of primary cutaneous Aspergillus flavus infection of the hand with oral itraconazole

Primary cutaneous Aspergillus flavus infections of the hand are exceedingly rare. Usually, these infections are present in severely immunocompromised patients suffering from lymphoreticular malignancies. The majority of cases result in invasive systemic infections and often culminate in death. We report a case of primary cutaneous A. flavus infection in the hand of a patient immunocompromised only by non-insulin-dependent diabetes, who ultimately was cured of this infection with oral itraconazole.

Lymphome non hodgkinien Ki-1 positif révélé par des ulcérations cutanéomuqueuses et une glomérulonéphrite

Malignant lymphoma particularly of T phenotype can be associated with specific or non specific cutaneous lesions. These cutaneous manifestations can occur at the onset of the disease being sometimes the revealing sign or they can appear during the course of the lymphoreticular malignancies. Glomerulonephritis was also described in lymphoma. Ki-1 positive large cell lymphoma was recently identified. A new case is reported with lymphadenopathy and intestinal localisation revealed by cutaneous and mucosal ulcerations principally in the mouth and a focal segmental glomerulonephritis with endo- and extracapillary proliferation. The absence of lymphoma in cutaneous and renal lesions and the clinical presentation support the hypothesis of paraneoplastic manifestations, may be related to a vasculitis.

A Case of Cryptococcosis involving Lung and CNS without Underlying Disease

Cryptococcosis is a systemic mycosis that most often involves the lungs and central nervous system and, less frequently, the skin, skeletal system, and prostate gland. Cryptococcus neoformans, the causative organism, is a yeastlike round or oval fungus, 4 to in diameter, which is surrounded by a polysaccharide capsule and reproduces by budding and found in soil and other environmental areas, especially those contaminated by pigeon droppings. Humans and animals acquire infection after inhalation of aerosolized spores. Condition or factors that predispose to cryptococcosis include corticosteroid therapy, lymphoreticular malignancies, HIV infection, and sarcoidosis etc. We discribed a case of cryptococcosis involving lung and CNS coincidently without specific underlying disease and the literature on subject were reviewed. A fifty-six year-old previously healthy female presented with headache of 3 months of duration. She had no history suggesting immunologic suppression and we could not find any abnormal laboratory findings including blood sugar, serum immunoglobulin and complement level, HIV antibody, and T cell subsets. Chest roentgenogram and CT scan showed a solitary soft tissue mass in LUL with distal pneumonitis. Brain MRI showed granulomatous lesion in cerebellum and parasagittal cortex of right frontal lobe. The diagnosis was made by bronchoscopic brushing cytology, transthoracic fine needle aspiration, and sputum KOH mount and culture. She was treated 6 weeks course of Amphotericin B and switched to oral fluconazole therapy for 3 months. Her symptoms and X-ray findings were improved gradually and she is now under regular clinical follow up.