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Biomedical subjects

T G Gross

Publications and source records attributed to T G Gross.

At least 37 records · Page 2Linked to original sources
PubMed1997

Successful correction of hemophagocytic lymphohistiocytosis with related or unrelated bone marrow transplantation.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation leading to widespread lymphocytic and hemophagocytic infiltration of vital organs. Apparent cure has only been achieved with allogeneic bone marrow transplantation (BMT). This report describes 20 consecutive patients, who underwent either matched sibling donor (n = 4) or unrelated donor (URD; n = 16) BMT. Age at the time of BMT was 0.4 to 5.3 years (median, 0.8 years). Central nervous system disease was present at diagnosis in 13 patients. At BMT, 14 patients were in a clinical remission, whereas 6 patients had active HLH. All patients were engrafted after cytoreduction with busulfan, cyclophosphamide, and etoposide. The probability of grade II-III acute graft-versus-host disease (GVHD) for all patients was 57% (95% confidence limit [CL], 0.28, 0.86), and 73% (95% CL, 0.44, 1.0) in URD patients. The overall probability of survival at 3 years was 45% (95% CL, 0.23, 0.67) and 44% (95% CL, 0.19, 0.68) when URD BMT was evaluated separately. Favorable BMT outcome was associated with clinical remission status at the time of BMT. The preparative regimen was well tolerated, and in the 9 surviving patients it provided durable engraftment and was effective at eradicating the underlying disease.

Adrenal Cortex Hormones↗
PubMed1997

Cytodifferentiation of a Wilms' tumor pulmonary metastasis: theoretic and clinical implications.

BACKGROUND: Complete maturation (cytodifferentiation) of treated metastatic Wilms' tumor is an infrequent occurrence. In a large series of reports, Wilms' metastases have generally contained malignant blastemic elements admixed with lesser amounts of cytodifferentiated mesenchyme. The authors describe a patient in whom complete maturation of a pulmonary metastasis was documented after intensive chemoradiotherapy. METHODS: A MEDLINE search was employed to identify pertinent cases from 1966 to the present. Key words used in the search included Wilms' tumor, relapse, therapy, metastasis, maturation, and cytodifferentiation. Four patients were identified as having completely mature cytodifferentiated pulmonary metastases of Wilms' tumor after chemotherapy; one had also undergone irradiation of the pulmonary metastasis. RESULTS: The primary tumor was an extremely necrotic blastemic Wilms' tumor devoid of maturation, as studied after irradiation and chemotherapy. The lung metastases (examined 13 years later) were represented by a scar and a nodule comprised of bland epithelium and tubules admixed with mature smooth muscle. Immunohistochemical stains, used to assess the proliferative rate of these cells, revealed a nearly negligible proliferation index. CONCLUSIONS: This report suggests that therapy (chemotherapy and/or irradiation) may effect, on occasion, complete cytodifferentiation of Wilms' tumor pulmonary metastasis. Although this would appear to be an uncommon event, its true incidence is unknown, because few patients with metastatic pulmonary Wilms' tumor are subjected to biopsy. The findings of this study suggest that for children with radiologically stable Wilms' lung metastases (as determined by imaging studies) who are yet undergoing intensive chemoradiotherapy, the notion of a surgical biopsy should be entertained to determine the true nature of the radiologic images. For some, this might result in the cessation of further therapy that would be unnecessary and not without complications.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

A yeast artificial chromosome (YAC) contig encompassing the critical region of the X-linked lymphoproliferative disease (XLP) locus.

X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability to Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia, or malignant lymphoma. Initially the XLP gene was assigned to a 10-cM region in Xq25 between DXS42 and DXS37. Subsequently, an interstitial, cytogenetically visible deletion in Xq25 was identified in one XLP family, 43. In this study we estimated the deletion in XLP patient 43-004 by dual-laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mb of DNA sequence. From a human chromosome Xq25-specific yeast artificial chromosome (YAC) sublibrary, five YACs containing DNA sequences deleted in patient 43-004 have been isolated. Sequence-tagged sites (STSs) from these YACs have been used to identify interstitial deletions in unrelated XLP patients. Three more families with interstitial deletions were found. Two of the patients (63-003 and 73-032) carried an interstitial deletion of 3.0 Mb overlapping the 43-004 deletion. In one XLP patient (30-011) who exhibited the characteristic postinfectious mononucleosis phenotype of XLP with hypogammaglobulinemia and malignant lymphoma, a deletion of approximately 250 kb was detected overlapping the deletion detected in patients 43-004, 63-003, and 73-032. A YAC contig of 2.2 Mb spanning the XLP critical region, whose orientation on chromosome X was determined by double-color fluorescence in situ hybridization and which consists of 15 overlapping YAC clones, has been constructed. A detailed restriction enzyme map of the region has been constructed. YAC insert sizes were determined by counter-clamped homogenous electric field gel electrophoresis. Chimerism of YACs was determined by FISH and restriction mapping. On the basis of lambda subclones, YAC end-derived plasmids, and STSs with an average spacing of 100 kb, a long-range physical map was constructed using 5 rare-cutter restriction enzymes. The STSs and lambda subclones were used in Southern hybridization and PCR analyses. The work presented here substantially refines the critical region for XLP. The YAC contig with the overlapping interstitial deletions constitutes the basis for the construction of a transcriptional map of the critical region and facilitates the identification of the XLP gene.

Chromosomes, Artificial, Yeast↗
PubMed1997

Posttransplant eosinophilic gastroenteritis in children.

The cause of eosinophilic gastroenteropathy in older children and adults is unknown. In this report, two post-liver transplantation children treated with low-dose cyclosporine A and alternate-day low-dose prednisone are described who were administered a single bolus administration of a lympholytic dose of corticosteroids without taper and who developed intestinal symptomatology several weeks later. Histologic examination of mucosal biopsy specimens from various regions of the gastrointestinal tract showed an intense eosinophilic infiltration of the mucosa and lamina propria. The patients recovered after corticosteroid administration was tapered. Post-transplant gastroenteric eosinophilic inflammation may need to be considered in patients on immunomodulatory medications who have chronic intestinal symptomatology.

Anti-Inflammatory Agents↗
PubMed1997

Hematopoietic recovery after allogeneic blood stem-cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies.

PURPOSE: To compare hematopoietic recovery, duration of hospitalization, and 100-day survival in patients who received allogeneic-blood stem cells (BSC) or conventional allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: From December 1994 to August 1995, 21 patients participated in a phase II study of allogeneic BSC transplantation. Cells mobilized with granulocyte colony-stimulating factor (G-CSF; 5 micrograms/kg/ d) were collected from human leukocyte antigen (HLA)-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. G-CSF (10 micrograms/kg/d) was administered posttransplant. The outcomes were compared with 22 identically treated historical patients who received allogeneic BMT. RESULTS: The median infused CD34+ cell and granulocyte-macrophage colony-forming unit (CFU-GM) content were 7.73 x 10(4)/kg and 41.6 x 10(4)/kg, respectively. The median time to a neutrophil count greater than 500/ microL was 11 days after BSC and 16.5 days after BMT (P = .0003). A trend toward faster platelet and RBC recovery after BSC was observed. BSC patients received fewer platelet transfusions: 10 versus 19 (P = .015). The median length of hospitalization was shorter after BSC transplantation: 25 versus 31.5 days (P = .0243). The 100-day survival rates were similar: 83% after BSC and 75% after BMT (P = .3585). The incidence of acute GVHD grade II to IV was 57% and 45% for BSC and BMT, respectively (P = .4654). CONCLUSION: In comparison to BMT, allogeneic BSC transplantation may result in faster hematopoietic recovery, shorter hospital stay, and similar early survival. Whether allogeneic BSC are superior to bone marrow needs to be determined in randomized trials.

Adult↗
PubMed1996

Epstein-Barr virus-associated hemophagocytic syndrome and fatal infectious mononucleosis.

Virus-associated hemophagocytic syndrome (VAHS) has been thought to be a distinct clinical entity, characterized by intermittent fever, enlarged liver and spleen, and the appearance of hemophagocytosis. Hemopoietic cells are actively ingested by monocytes/macrophages in various organs, including lymph nodes, bone marrow, liver, and spleen. Epstein-Barr virus (EBV) is now thought to be one of the major causes for the development of this unique syndrome. Additionally, VAHS is often associated with fatal infectious mononucleosis (IM). The relationship between EBV-associated VAHS and fatal IM is discussed in this concise review.

Herpesvirus 4, Human↗
PubMed1996

Concurrent Epstein-Barr virus associated non-Hodgkin lymphoma and recurrent Hodgkin disease.

PURPOSE: Patients treated for Hodgkin disease (HD) are at increased risk for developing secondary neoplasms, including non-Hodgkin lymphoma (NHL). We present a patient who developed NHL (brain and lungs) as a second malignancy together with recurrent HD (bone marrow). Because HD and NHL have both been associated with Epstein-Barr virus (EBV), especially in the immunodeficient host, the tumor specimens were studied for the presence of EBV, and the possible role of immunodeficiency in the development of this second malignancy was assessed. METHODS AND RESULTS: Tumor specimens were analyzed by conventional histologic and immunohistochemical methods, EBV detection was determined by RNA in situ hybridization for EBV- encoded RNAs (EBERs). Histopathology showed diffuse large cell lymphoma of B-cell phenotype in specimens from lesions in the brain and lungs. These specimens were EBER+. HD specimens from all recurrences were evaluated and were EBER. CONCLUSIONS: This patient had received extensive chemoradiotherapy for recurrent HD, and presented with Pneumocystis pneumonia, a low absolute T-cell count, no response to mitogens in vitro, a second malignancy (EBV+NHL), and recurrent EBV-HD. We propose that the immunocompromised state of the patient played a significant role in the development of his second malignancy.

Child↗
PubMed1996

Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry.

Seven male patients in the David T Purtilo International X-linked Lymphoproliferative Disease (XLP) Registry have undergone allogeneic hematopoietic stem cell transplantation (HSCT). All patients received HSCT from HLA-identical donors: sibling BM, five; unrelated BM, one; and sibling umbilical cord blood, one. Ages at time of HSCT ranged from 5 to 30 years. Pre-HSCT clinical course varied, but four boys had a significant history of chronic and/or serious infections. Conditioning regimens varied: TBI containing regimens, four, chemotherapy only, three. All patients engrafted. Six developed grade I-II acute GVHD but no chronic GVHD. Four are alive and well with normal immune function greater than 3 years following HSCT. Three died within 100 days: disseminated adenovirus, one; polymicrobial sepsis, one; and multiple organ system failure and bleeding diathesis, one. No EBV-associated post-transplant complications were observed, even though all donors except the umbilical cord blood were EBV-seropositive. Unsuccessful HSCT was associated with age at HSCT (> 15 years), TBI-containing regimen and significant history for pre-HSCT infections. These results provide evidence that HSCT performed during childhood with HLA-identical sibling donors, regardless of EBV serostatus, offers the only curative therapy for XLP.

Adolescent↗
PubMed1996

Immunologic phenotype and function in human bone marrow, blood stem cells and umbilical cord blood.

The T cell-mediated antineoplastic activity observed following allogeneic transplantation and the suggestion of improved therapeutic efficacy by autologous peripheral stem cell transplantation (PSCT) as compared to autologous bone marrow transplantation (ABMT) for non-Hodgkin's lymphoma (NHL) stimulated our interest in the immunologic competence of stem cell products. We report the immune phenotype and function of normal peripheral blood (PB) cells, bone marrow (BM) cells from normal donors and cancer bearing patients, GM-CSF-mobilized and apheresed blood mononuclear cells from NHL patients, unmobilized apheresed mononuclear cells from normal volunteers and umbilical cord blood (CB). The analyses include three-color fluorescent cytometry of the major hematologic and immunologic phenotypes as well as natural killer (NK) activity, natural suppressor (NS) activity, and phytohemagglutinin (PHA) and pokeweed (PWM) mitogenesis. These studies demonstrated an increased frequency of T cells in apheresis products as compared to BM and CB products. Specifically, the mobilized PSC had significant increases in CD3+, CD4+, CD45RO+ and CD56+ cells relative to BM cells. In addition, the frequency of TCR gamma/delta + cells in all the stem cell products, with the exception of CB, were also increased compared to normal peripheral blood leukocytes (PBL). However, all the stem cell products had a significant depression in T (PHA mitogenesis) and B (PWM mitogenesis) cell function. The depression in immune cell functionality, in the PSC products was perhaps due to the high frequency of monocytes which appeared to be increased due to both mobilization and apheresis. The frequency of the NK cell phenotype (CD56) but not function was increased in the mobilized PSC products, while the NK cell function in the BM products from cancer patients but not normal donors was depressed as compared to normal PBL. In summary, there are significant differences in the cellular phenotypes and immunologic competence among the various stem cell products with potential therapeutic implications.

Bone Marrow↗
PubMed1996

Molecular epidemiology of deletions and mutations of the latent membrane protein 1 oncogene of the Epstein-Barr virus in posttransplant lymphoproliferative disorders.

Latent membrane protein 1 (LMP1) is a protooncogene of the Epstein-Barr virus (EBV) that is expressed in most EBV-positive posttransplant lymphoproliferative disorders (PTLD). Small deletions in the carboxy-terminal domain of LMP1 have been recently described in Hodgkin's disease, nasopharyngeal carcinoma, and non-Hodgkin's lymphoma. We characterized the deletions and point mutations of LMP1 in 32 PTLD and 8 reactive lymphoid cases found to contain EBV by one or more methods, including LMP1 immunohistochemistry, EBV-encoded RNA in situ hybridization, LMP1 DNA amplification, or Southern blot analysis. Our goal was to study the relationship of LMP1 deletions and mutations with the PTLD morphology, clonality, EBV strain subtype, and survival of patients. We found a 30-bp deletion (Del-LMP1) in 13 of 32 (41%) PTLD cases and a similar incidence of Del-LMP1 and point mutations in 3 of 8 (38%) reactive EBV cases (rho = 0.87). The presence of the Del-LMP1 in the PTLD cases was not highly associated with a high-grade morphology or clonal immunoglobulin gene rearrangements compared with the wild-type LMP1. We found that 100% of B-strain isolates, compared with 30% of A-strain isolates, harbored the Del-LMP1. There was no significant difference in the survival of PTLD patients with or without Del-LMP1 (rho = 0.83). We conclude that the incidence of Del-LMP1 in PTLD may be reflective of the incidence of this EBV substrain in the regional population and that the Del-LMP1 sequence has no prognostic significance in PTLD.

Adolescent↗
PubMed1995

X-linked lymphoproliferative disease: twenty-five years after the discovery.

The X-linked lymphoproliferative disease (XLP), one of six described X-linked immunodeficiencies, stems from a mutation at Xq25 which renders males impotent to mount an effective immune response to the ubiquitous EBV. Purtilo, who first observed this disease in 1969, established a Registry in 1980 to serve as a worldwide resource for the diagnosis, treatment, and research of this condition. Since Purtilo's death in late 1992, the Registry and research unit have not only continued to function as a worldwide consultative service, but have contributed the following. First, the number of affected boys has continued to grow; some 272 among 80 kindreds have been identified. Second, some boys (10%) who inherit the mutated XLP gene are immunologically abnormal even before evidence of EBV exposure. Third, the search for the XLP gene has been narrowed to a small region on Xq25. Its identification is near at hand; once cloned, this gene may well illustrate how the body orchestrates the complex immune response to EBV. Therein lies the justification for the quest for this gene, not only for the benefit of the few surviving boys and those to be born to female carriers, but also for defining its role in defending the body against a ubiquitous DNA virus.

Child↗
PubMed1994

Fatal eosinophilic disease following autologous bone marrow transplantation.

A 15-year-old girl developed massive, fatal eosinophilic disease following autologous bone marrow transplantation (BMT) for Hodgkin's disease (HD). Prior to autologous BMT, the erythrocyte sedimentation rate (ESR) was elevated, with active HD, but eosinophilia was absent. Post-autologous BMT, ESR and peripheral eosinophilia were observed to correlate with respiratory symptoms. Initial evaluation revealed no recurrent tumor, infection or other identifiable etiology. A diagnosis of chronic eosinophilic pneumonia was made following lung biopsy. A complete response was initially achieved with steroid therapy; however, when steroid therapy was tapered, the eosinophilia and elevated ESR recurred with worsening respiratory symptoms. Terminally, severe pulmonary disease developed and recurrent HD was found in lung, lymph nodes and bone marrow. During episodes of eosinophilia, the patient's serum stimulated her bone marrow as well as control marrow to produce predominantly eosinophilic colonies. Eosinophilic colony production was not observed with patient's sera obtained prior to or during autologous BMT or with control sera. This patient died of eosinophilic inflammatory disease following autologous BMT. The etiology of this disease was not definitely identified but appeared to be due to an eosinophilic-stimulating factor which developed after autologous BMT.

Adolescent↗
PubMed1990

Differential cellular susceptibility to Epstein-Barr virus infection in a patient with X-linked lymphoproliferative disease.

Epstein-Barr virus (EBV) is often associated with lethal lymphoproliferative diseases in immunologically compromised individuals. Recently, we have studied a 20-month-old boy with X-linked lymphoproliferative disease (XLP) who had succumbed to infectious mononucleosis (IM) complicated by fulminant hepatitis and virus-associated hemophagocytic syndrome following EBV infection. EBV genomes were detected in peripheral blood lymphocytes (PBL), cervical and mesenteric lymph nodes, liver, spleen, thymus, and bone marrow. According to restriction endonuclease analyses, the EBV-DNA pattern was similar in all samples except for the EBV-DNA from the bone marrow. Additionally, circular EBV-DNA (suggesting a latent infection) predominated in spontaneously established lymphoblastoid cell lines (LCLs) derived from both the lymph node and cord lymphocytes co-cultured with PBL. In contrast, both circular and linear EBV-DNA (suggesting a lytic infection) were noted in spontaneously established LCLs derived from his PBL. Furthermore, LCLs derived from both the lymph node and cord lymphocytes co-cultured with PBL expressed fewer reactive cells for early antigen (EA) and viral capsid antigen (VCA) than spontaneous LCLs from his PBL, thus providing evidence for different B cellular susceptibility to EBV infection in this patient with XLP. Finally, defective EBV-specific cytotoxic T cell activity was observed in this patient. Latent EBV infected cells may easily escape immunosurveillance by the host. These findings may explain the fatal course of EBV infection in this patient.

Antigens, Viral↗