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1.
Ann Oncol ; 29(9): 1932-1938, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30060083

RESUMEN

Background: Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL). Patients and methods: BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50-1200 mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. Results: Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3 months [95% confidence interval (CI) 10.4-NR], not yet reached, and 10.7 months (95% CI 4.3-21.0), respectively. Conclusions: This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL. Trial registered: Clinicaltrials.gov, NCT01594229.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma no Hodgkin/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa/métodos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Clorhidrato de Bendamustina/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Neutropenia Febril Inducida por Quimioterapia/epidemiología , Neutropenia Febril Inducida por Quimioterapia/etiología , Progresión de la Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Supervivencia sin Progresión , Rituximab/administración & dosificación , Rituximab/efectos adversos , Rituximab/farmacocinética , Terapia Recuperativa/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética
2.
Cancer Chemother Pharmacol ; 81(2): 347-354, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29234922

RESUMEN

BACKGROUND: Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients. PATIENTS/METHODS: After HDC, everolimus was dosed to serum trough levels (goal 3-15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL. RESULTS: 49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required. CONCLUSIONS: Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Everolimus/farmacocinética , Linfoma de Células B/tratamiento farmacológico , Quimioterapia de Mantención/métodos , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Transformación Celular Neoplásica , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Esquema de Medicación , Quimioterapia Combinada , Everolimus/administración & dosificación , Everolimus/uso terapéutico , Femenino , Humanos , Leucemia Linfoide/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Rituximab/efectos adversos , Resultado del Tratamiento
3.
Am J Transplant ; 11(6): 1140-7, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21645251

RESUMEN

The continuing organ shortage requires evaluation of all potential donors, including those with malignant disease. In the United States, no organized approach to assessment of risk of donor tumor transmission exists, and organs from such donors are often discarded. The ad hoc Disease Transmission Advisory Committee (DTAC) of the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) formed an ad hoc Malignancy Subcommittee to advise on this subject. The Subcommittee reviewed the largely anecdotal literature and held discussions to generate a framework to approach risk evaluation in this circumstance. Six levels of risk developed by consensus. Suggested approach to donor utilization is given for each category, recognizing the primacy of individual clinical judgment and often emergent clinical circumstances. Categories are populated with specific tumors based on available data, including active or historical cancer. Benign tumors are considered in relation to risk of malignant transformation. Specific attention is paid to potential use of kidneys harboring small solitary renal cell carcinomas, and to patients with central nervous system tumors. This resource document is tailored to clinical practice in the United States and should aid clinical decision making in the difficult circumstance of an organ donor with potential or proven neoplasia.


Asunto(s)
Neoplasias/etiología , Trasplante de Órganos/efectos adversos , Humanos , Medición de Riesgo
4.
Bone Marrow Transplant ; 43(6): 477-80, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18978825

RESUMEN

Graft failure after allogeneic blood or marrow transplantation, although generally uncommon, can be a devastating complication. This report includes the outcome of nine patients who received a salvage transplant for failure to engraft after one (n=8) or 2 (n=1) prior transplants. Eight patients received allografts from the original donor. All received fludarabine 30 mg/m(2) i.v. and alemtuzumab 20 mg i.v. daily from days -6 to -2. Daily CYA was begun on day -2, and the allograft was infused on day 0. The therapy was well tolerated with low toxicity, and all nine patients engrafted, recovering neutrophils at a median of 12 days after transplant. Four patients died: two of relapse, one of a fungal infection in the setting of GVHD and one of multiple sclerosis. The combination of fludarabine and alemtuzumab is an effective and well-tolerated salvage conditioning regimen for patients who experience graft failure after blood or marrow transplants.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Médula Ósea/métodos , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Femenino , Rechazo de Injerto , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Terapia Recuperativa/métodos , Resultado del Tratamiento , Vidarabina/administración & dosificación
5.
Hum Pathol ; 32(9): 963-9, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11567226

RESUMEN

The tumor necrosis factor receptor-associated factor 1 (TRAF1) participates in the signal transduction of various members of the tumor necrosis factor receptor (TNFR) family, including TNFR2, CD40, CD30, and the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). In vitro, TRAF1 is induced by LMP1, and previous studies have suggested that expression of TRAF1 is higher in EBV-associated tumors than in their EBV-negative counterparts. To determine whether this was the case in posttransplant lymphoproliferative disease (PTLD) and related disorders, we used immunohistochemistry to analyze expression of TRAF1 in a total of 42 such lesions arising in a variety of immunosuppressive states. The specimens consisted of 22 PTLD lesions, 18 acquired immunodeficiency syndrome-associated lymphomas, including 6 primary central nervous system lymphomas, and 2 cases of Hodgkin disease. The presence of latent EBV infection was determined by EBER in situ hybridization, and expression of EBV-LMP1 was detected by immunohistochemistry. Latent EBV infection, as determined by a positive EBER signal, was detected in 36 of 42 tumors. Of the EBER-positive specimens, 30 of 36 also expressed LMP1. Twenty-four of 30 LMP1-positive tumors, including both Hodgkin disease specimens, expressed TRAF1, compared with only 3 of 12 LMP1-negative tumors. This difference was statistically significant (P <.005). These results show frequent expression of TRAF1 at the protein level in LMP1-positive PTLD and related disorders and suggest an important role for LMP1-mediated TRAF1 signaling in the pathogenesis of EBV-positive tumors arising in immunosuppressive states.


Asunto(s)
Linfoma Relacionado con SIDA/metabolismo , Trastornos Linfoproliferativos/metabolismo , Trasplante de Órganos , Proteínas/metabolismo , Proteínas Ribosómicas , Proteínas de la Matriz Viral/metabolismo , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Técnicas para Inmunoenzimas , Hibridación in Situ , Linfoma Relacionado con SIDA/patología , Linfoma Relacionado con SIDA/virología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/virología , Complicaciones Posoperatorias , Proteínas de Unión al ARN/análisis , Factor 1 Asociado a Receptor de TNF
6.
J Med Virol ; 65(1): 105-13, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11505451

RESUMEN

Epstein-Barr virus (EBV) has been identified in a wide range of neoplastic and non-neoplastic disorders. The EBV open reading frame BHRF1 encodes a protein with partial sequence and functional homology to the anti-apoptotic onco-protein Bcl-2 and may therefore have a role in the proliferation of EBV positive cells. We have developed a rat monoclonal antibody against pBHRF1, which can detect BHRF1 in paraffin sections. While a number of mutant versions of BHRF1 were recognised, the monoclonal did not detect the BHRF1 homologue encoded by Herpesvirus papio or two mutants with deletions in the BH2 region. This novel rat monoclonal antibody (6A9) was used to examine tissue sections from 39 cases of non-keratinising undifferentiated nasopharyngeal carcinoma (NPC), 6 cases of metastatic NPC, 7 cases of EBV-positive NPC with squamous differentiation from Chinese patients, 15 cases of EBV-positive post-transplant lymphoproliferative disorder (PTLD), 6 EBV-containing lymphoblastoid cell lines, and 2 cases of oral hairy leukoplakia (OHL). In 11 cases of undifferentiated NPC, RT-PCR data were available for comparison with the immunohistochemistry. Both cases of OHL and two cases of LCL were positive for BHRF1 but none of the PTLD showed positive staining. All cases of undifferentiated NPC were positive for Bcl-2 but only one BHRF1 positive cell was identified in 1 of 39 cases of primary undifferentiated NPC. The 6A9 antibody produced less background staining and no nuclear positivity compared with the commercially available mouse monoclonal 5B11. It is concluded that BHRF1 can not be detected by immunohistochemistry in NPC and therefore it appears not to play a significant anti-apoptotic role in the progression of this EBV-associated tumour. The 6A9 monoclonal appears to be superior to 5B11 for the detection of pBHRF1 in tissue sections.


Asunto(s)
Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/metabolismo , Leucoplasia Vellosa/virología , Trastornos Linfoproliferativos/virología , Neoplasias Nasofaríngeas/virología , Proteínas Virales/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Apoptosis/fisiología , Western Blotting , Línea Celular Transformada , Transformación Celular Viral , Formaldehído , Humanos , Inmunohistoquímica , Ratones , Datos de Secuencia Molecular , Adhesión en Parafina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Fijación del Tejido , Proteínas Virales/química , Proteínas Virales/genética , Proteínas Virales/inmunología
7.
J Natl Cancer Inst Monogr ; (28): 38-43, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11158205

RESUMEN

Post-transplant lymphoproliferative disorders (PTLDs) comprise a histologic spectrum, ranging from hyperplastic-appearing lesions to frank non-Hodgkin's lymphoma or multiple myeloma histology. Multiple clones may coexist, each representing a discrete lymphomagenic event, a situation that is unique to immunodeficiency states. The incidence varies from 1% in renal recipients to 5% in heart recipients, but can be markedly increased by the use of anti-T-cell therapies or by T-cell depletion in bone marrow transplantation. PTLD continues to arise, even many years after transplantation, and late T-cell lymphomas have recently been recognized. Pretransplant Epstein-Barr virus (EBV) seronegativity increases risk to as high as 30%-50%. PTLD has a highly variable clinical picture; certain patterns are, however, seen. Reversibility of PTLD with reduction in immunosuppressives has long been recognized. Predicting reversibility has been difficult. The presence or absence of bcl-6 mutations has recently been identified as being of predictive value. Surgical resection can be curative. Cytotoxics, although problematic, can also be curative. Long-term remission has been achieved with anti CD21 and CD24 antibodies; efficacy has been reported for interferon alfa and for rituximab. In vitro expanded EBV-specific T cells have been effective as treatment and as prophylaxis in the setting of bone marrow transplantation. EBV viral load measured in blood appears to associate with the emergence of PTLD and may facilitate prophylactic studies. PTLD is a model of immunodeficiency-related EBV lymphomagenesis. Pathogenetic, therapeutic, and prophylactic insights gained from the study of PTLD are likely to be applicable to the acquired immunodeficiency syndrome setting.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Trastornos Linfoproliferativos/etiología , Neoplasias/etiología , Complicaciones Posoperatorias , Trasplante , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales/sangre , Antineoplásicos/uso terapéutico , Terapia Combinada , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/transmisión , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/patogenicidad , Herpesvirus Humano 8/patogenicidad , Humanos , Huésped Inmunocomprometido , Terapia de Inmunosupresión/efectos adversos , Linfoma Relacionado con SIDA/etiología , Linfoma Relacionado con SIDA/inmunología , Linfoma de Células B/etiología , Linfoma de Células B/virología , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/terapia , Neoplasias/inmunología , Sarcoma de Kaposi/etiología , Sarcoma de Kaposi/virología , Linfocitos T/trasplante , Trasplante/efectos adversos , Infecciones Tumorales por Virus/complicaciones , Infecciones Tumorales por Virus/transmisión , Viremia/virología
8.
Diagn Mol Pathol ; 10(4): 255-64, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11763317

RESUMEN

Epstein-Barr virus (EBV) is associated with several benign and malignant diseases, and blood tests for EBV viral load show promise as markers of disease burden in affected patients. A commercial quantitative PCR method (BioSource International) was recently introduced to facilitate measuring viral load. It relies on coamplification of EBV DNA and a spiked competitor in plasma or serum, followed by semiautomated product detection on enzyme-linked immunosorbent assay (ELISA) plates. In the current study, analytic performance characteristics were assessed, and the authors describe several methodologic improvements to facilitate laboratory implementation. Rapid DNA extraction was accomplished using commercial silica spin columns, heat-labile uracil-N-glycosylase was used to inhibit amplicon contamination, and inexpensive agarose gels were used to screen for polymerase chain reaction products requiring ELISA plate quantitation. Accuracy and precision were verified using EBV DNA standards derived from two cell lines and plasmid containing viral sequences. The assay was sensitive to as few as five template copies per polymerase chain reaction and was linear across four orders of magnitude (correlation coefficient 0.995). When applied to matched plasma and serum samples from 15 patients with nasopharyngeal carcinoma, both sample types yielded similar viral load results. This commercial EBV viral load assay provides sensitive and quantitative detection of EBV DNA using equipment already available in many molecular diagnostic laboratories.


Asunto(s)
Herpesvirus Humano 4/aislamiento & purificación , Reacción en Cadena de la Polimerasa , Carga Viral/métodos , ADN Viral/análisis , Ensayo de Inmunoadsorción Enzimática , Herpesvirus Humano 4/genética , Humanos , Juego de Reactivos para Diagnóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Células Tumorales Cultivadas
9.
Curr Treat Options Oncol ; 2(4): 301-8, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12057110

RESUMEN

Post-transplant lymphoproliferative disorder is a curable disease in which a wide range of treatment strategies has met with a degree of success. Both the disease and the organ transplant setting in which it occurs are highly variable. A sequential approach to treatment is preferred, starting with reduction in immunosuppressives. Rituximab or interferon alfa can be tried next, in the hope of avoiding chemotherapy. Rituximab has significant activity and has shown no additional toxicities in transplant recipients. It may be appropriate to add rituximab to the initial treatment in critically ill patients. Cytotoxic chemotherapy is effective but significantly more toxic in this patient population. Effective therapy should be instituted before progressive disease results in declining performance status and multi-organ dysfunction. The goal of treatment is complete and durable remission. Adoptive T-cell therapy is an effective and promising alternative for allogeneic bone marrow transplant recipients.


Asunto(s)
Linfoma no Hodgkin/etiología , Trasplante/efectos adversos , Adulto , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , Niño , Métodos Epidemiológicos , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/transmisión , Herpesvirus Humano 4/crecimiento & desarrollo , Humanos , Huésped Inmunocomprometido , Terapia de Inmunosupresión/efectos adversos , Inmunoterapia Adoptiva , Incidencia , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/terapia , Linfoma no Hodgkin/virología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/terapia , Complicaciones Posoperatorias/virología , Inducción de Remisión , Riesgo , Resultado del Tratamiento , Activación Viral
10.
Semin Oncol ; 27(4): 402-8, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10950366

RESUMEN

Post-transplant lymphoproliferative disorders (PTLD) share many of the features of human immunodeficiency virus (HIV)-related lymphomas, although important differences exist. PTLD ranges from hyperplastic lesions to aggressive lymphoma or multiple myeloma histology. The coexistence of multiple clones, and the strong association with the Epstein-Barr virus (EBV), represent a uniquely different mechanism for lymphomagenesis when compared with de novo lymphoma. The risk of PTLD increases as the duration of immunodeficiency lengthens, with unusual, newly described entities arising after prolonged immunosuppression. The risk is also strongly influenced by the specific anti-T-cell therapies used to prevent graft rejection, providing insight into the nature of immune surveillance. The presence or absence of bcl-6 mutations may be predictive of the reversibility of the PTLD with reduction in immunosuppressive therapy. The use of cytotoxic agents has been complicated by problems similar to those encountered with HIV-related lymphomas, but can nonetheless be very effective. Long-term remission has been achieved with anti-CD21 and anti-CD24 antibodies, although these have not been equally effective for all categories of PTLD. In vitro-expanded EBV-specific T cells have been effective both as treatment and as prophylaxis in the setting of PTLD occurring after marrow transplantation. EBV viral load measurement correlates with the emergence of PTLD, and may make clinical trials of screening, prophylaxis, or early intervention possible.


Asunto(s)
Herpesvirus Humano 4/fisiología , Tolerancia Inmunológica , Linfoma Relacionado con SIDA/etiología , Trastornos Linfoproliferativos/etiología , Trasplante de Órganos/efectos adversos , Humanos , Linfoma Relacionado con SIDA/inmunología , Linfoma Relacionado con SIDA/patología , Linfoma Relacionado con SIDA/virología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/terapia , Trastornos Linfoproliferativos/virología , Modelos Biológicos
11.
Transplantation ; 69(11): 2446-8, 2000 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-10868657

RESUMEN

BACKGROUND: Bronchioloalveolar carcinoma (BAC) is a well-differentiated lung adenocarcinoma that has a tendency to spread chiefly within the confines of the lung by aerogenous and lymphatic routes and may therefore be amenable to local therapy. However, a high rate of local recurrence after lung transplantation was recently reported. We describe two patients with unresectable and recurrent extensive BAC limited to the lung parenchyma who underwent lung transplantation with curative intent. METHODS: Patients were chosen to receive lung transplants for BAC if they met the following criteria: (1) recurrent or unresectable BAC limited to the lung parenchyma without nodal involvement and (2) suitable candidate for lung transplantation. RESULTS: The first patient relapsed in the lungs at 9 months after transplantation. The pattern of disease suggested contamination of the new lungs at the time of implantation. Repeat lung transplantation was performed, with cardiopulmonary bypass and irrigation of the remaining upper airway. This patient has had no evidence of local or systemic tumor recurrence at more than 4 years since the second transplantation. The second patient underwent transplantation using the modified technique and expired 16 months after transplantation of other causes. An autopsy showed no evidence of recurrent BAC in the lungs or of metastatic lesions at any site. CONCLUSIONS: Lung transplantation may be an option for unresectable or recurrent BAC confined to the lungs. Isolation of the diseased lungs and the use of cardiopulmonary bypass during surgery may be important in this disease and should be studied further.


Asunto(s)
Adenocarcinoma Bronquioloalveolar/cirugía , Neoplasias Pulmonares/cirugía , Trasplante de Pulmón , Adenocarcinoma Bronquioloalveolar/diagnóstico por imagen , Adulto , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugía , Radiografía Torácica , Tomografía Computarizada por Rayos X
12.
Ann Oncol ; 11 Suppl 1: 45-8, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10707778

RESUMEN

Immunodeficiency-related B-cell disorders are seen after organ transplantation and in congenital and acquired immunodeficiency states. Post-transplant lymphoproliferative disorders (PTLD) comprise a histologic spectrum ranging from hyper-plastic appearing lesions to frank non-Hodgkin's lymphoma or multiple myeloma histology. Multiple clones may co-exist, representing a uniquely different mechanism for lymphomagenesis. The incidence varies from 1% in renal recipients to 8% in lung recipients, but can be markedly increased by the use of anti-T-cell therapies, or by T-cell depletion in bone marrow transplantation. Pre-transplant EBV seronegativity increases risk to as high as 30%-50%. More than 90% of tumors are EBV-associated. Mechanisms for viral lymphomagenesis remain incompletely defined; LMP-1 may function as an oncogene and coprecipitates with TRAF, BCL-2 overexpression has also been identified. A possible direct tumorigenic effect has recently been suggested for cyclosporine. PTLD has a highly variable clinical picture, certain patterns are however seen. Reversibility of PTLD with reduction in immunosuppressives has long been recognized. Predicting reversibility has been difficult. The presence or absence of BCL-6 mutations has recently been identified as being of predictive value. Surgical resection can be curative. Cytotoxics, although problematic, can also be curative. Long term remission has been achieved with anti CD21 and CD24 antibodies; efficacy has been reported anecdotally for interferon alpha and for rituximab. In vitro expanded EBV-specific T cells have been effective as treatment and as prophylaxis in the setting of bone marrow transplantation. EBV viral load measured in blood appears to correlate with the emergence of PTLD and may facilitate prophylactic studies. PTLD is a model of immunodeficiency related EBV lymphomagenesis. Pathogenetic, therapeutic, and prophylactic insights gained from the study of PTLD are likely to be applicable to other immunodeficiency states and to EBV-related lymphoid neoplasia in general.


Asunto(s)
Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/terapia , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Trasplante de Tejidos/efectos adversos , Humanos , Terapia de Inmunosupresión/efectos adversos , Terapia de Inmunosupresión/métodos , Incidencia , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/etiología , Masculino , Mieloma Múltiple/epidemiología , Mieloma Múltiple/etiología , Pronóstico , Factores de Riesgo , Tasa de Supervivencia
13.
Clin Cancer Res ; 5(11): 3394-402, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10589750

RESUMEN

Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Citarabina/uso terapéutico , Neoplasias Meníngeas/tratamiento farmacológico , Neoplasias Meníngeas/secundario , Metotrexato/uso terapéutico , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Citarabina/administración & dosificación , Preparaciones de Acción Retardada , Progresión de la Enfermedad , Femenino , Humanos , Inyecciones Espinales , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Melanoma/tratamiento farmacológico , Neoplasias Meníngeas/mortalidad , Metotrexato/administración & dosificación , Persona de Mediana Edad , Neoplasias/patología , Estudios Prospectivos , Tasa de Supervivencia , Sobrevivientes
14.
Semin Oncol ; 26(5 Suppl 14): 21-5, 1999 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-10561014

RESUMEN

Epstein-Barr virus-associated B-cell lymphoproliferations are a serious complication of organ or bone marrow transplantation whose incidence is strongly influenced by a number of risk factors. The disease represents a model of Epstein-Barr virus-driven lymphoid neoplasia in the setting of immunodeficiency. The incidence and pathogenesis of posttransplant lymphoproliferations are examined in relation to the nature of the transplanted organ, the Epstein-Barr virus infection, and the use of specific immunosuppressive regimens. Pathologic classifications and molecular mechanisms for neoplasia are reviewed. Clinical manifestations, pathologic features, and diagnostic considerations are summarized, with emphasis on those aspects that differ significantly from classic non-Hodgkin's lymphoma. Existing data regarding treatment are reviewed, including reduction in immunosuppression, surgery, radiation, chemotherapy, interferon-alpha, monoclonal anti-B-cell antibodies, and T-cell therapy. A basis for the selection of therapeutic options is suggested.


Asunto(s)
Infecciones por Herpesviridae/etiología , Herpesvirus Humano 4 , Trastornos Linfoproliferativos/etiología , Trasplante/efectos adversos , Infecciones Tumorales por Virus/etiología , Transformación Celular Neoplásica , Humanos , Terapia de Inmunosupresión , Trastornos Linfoproliferativos/terapia , Trastornos Linfoproliferativos/virología , Factores de Riesgo
15.
Am J Pathol ; 155(2): 619-25, 1999 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10433954

RESUMEN

The Epstein-Barr virus (EBV) major latent promoter C drives the expression of viral nuclear proteins important in lymphocyte immortalization and as targets for immune surveillance by cytotoxic T cells. Hypermethylation of the C promoter silences its transcription. This promoter is methylated and silent in Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma, and nasal lymphoma. However, it is never methylated in the EBV-immortalized lymphoblastoid cell lines that serve as a model for EBV-associated lymphoproliferative disease. We have analyzed C promoter methylation in iatrogenic EBV-associated B-cell lymphoproliferative disease, mainly posttransplant lymphoma, using a sensitive polymerase chain reaction-based C promoter methylation assay. Our results showed heterogeneity in lymphoproliferative disease with methylation of viral DNA in specimens from 3 of 13 patients. In specimens from two of these patients, only methylated viral DNA was detected and viral nuclear antigen expression was correspondingly restricted. Heterogeneity in C promoter methylation and expression of associated transcripts may be an important determinant of the growth properties of lymphoproliferative lesions and may provide an explanation for the failure of some tumors to respond to withdrawal or reduction of immunosuppressive therapy.


Asunto(s)
Herpesvirus Humano 4/genética , Linfoma de Células B/etiología , Linfoma de Células B/virología , Reacción en Cadena de la Polimerasa/métodos , Regiones Promotoras Genéticas , Linfoma de Burkitt/virología , Carcinoma/virología , Línea Celular , Enfermedad de Hodgkin/virología , Humanos , Terapia de Inmunosupresión/efectos adversos , Linfoma/virología , Metilación , Modelos Genéticos , Neoplasias Nasofaríngeas/virología , Células Tumorales Cultivadas
16.
Chest ; 116(6 Suppl): 470S-473S, 1999 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-10619511

RESUMEN

Simian virus 40 (SV40) causes mesotheliomas, osteosarcomas, ependymomas, choroid plexus tumors, and lymphomas in hamsters. In humans, SV40 has been detected in tumors of the first four types. Using the polymerase chain reaction (PCR), we tested 29 non-Hodgkin's lymphomas (intermediate and high-grade), 25 posttransplant lymphoproliferative disorders, and 5 AIDS lymphomas for SV40 DNA. PCR analysis revealed that 3 of 29 lymphomas, 6 of 25 posttransplant lymphoproliferative disorders, and 2 of 5 AIDS lymphomas contained SV40 sequences corresponding to the retinoblastoma (RB)-pocket binding domain of SV40 tumor antigen (Tag). However, among positive samples, only one posttransplant lymphoproliferative disorder and one AIDS lymphoma contained the SV40 regulatory region, which suggest a higher viral load in these patients. In parallel experiments, 8 of 12 mesotheliomas tested positive for SV40 for both the RB-pocket binding domain of Tag and the SV40 regulatory region. These data confirm the presence of SV40 in most United States mesotheliomas and indicate that in human non-Hodgkin's lymphomas, the prevalence of SV40 is low.


Asunto(s)
Linfoma no Hodgkin/virología , Mesotelioma/virología , Infecciones por Papillomavirus/diagnóstico , Virus 40 de los Simios/aislamiento & purificación , Infecciones Tumorales por Virus/diagnóstico , Animales , Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Neoplasias del Plexo Coroideo/virología , Cricetinae , Ependimoma/virología , Humanos , Linfoma Relacionado con SIDA/virología , Trastornos Linfoproliferativos/virología , Osteosarcoma/virología , Reacción en Cadena de la Polimerasa , Prevalencia , Virus 40 de los Simios/genética , Virus 40 de los Simios/inmunología , Carga Viral
17.
Am J Pathol ; 153(3): 1001-4, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9736049

RESUMEN

A new member of the gamma-herpesvirus family, HHV-8 (also known as Kaposi's sarcoma (KS)-associated herpesvirus), has been linked to KS and body cavity-based lymphoma. Other members of this family, eg, Epstein-Barr virus, were originally thought to have only one strain, but subsequent analysis revealed different strains correlating to cellular patterns of infectivity and geographical location. To determine whether multiple strains of HHV-8 exist, we compared DNA sequences among KS and body cavity-based lymphoma-derived HHV-8 and examined differences in HHV-8 subgroups between American and Saudi Arabian iatrogenic KS patients. Samples were analyzed by polymerase chain reaction using multiple primer sets to five different open reading frames from HHV-8, and DNA sequencing was performed. HHV-8 DNA was present in all of our KS and body cavity-based lymphoma samples by polymerase chain reaction. HHV-8 DNA was detected in each body cavity-based lymphoma sample using a majority of the primers, whereas only two primer sets consistently amplified HHV-8 DNA derived from KS lesions. DNA sequencing within open reading frames 26 and 27 indicate the existence of at least three variants of HHV-8, with the majority of iatrogenic KS patients in Saudi Arabia containing unique nucleotide changes that may define a distinct, previously unidentified subgroup we term SA, whereas those from America were of Group A or B. Thus, although the sequencing data within open reading frames 26 and 27 did not permit discrimination between patients with lymphoma versus KS disease processes, HHV-8 derived from Saudi Arabian KS lesions were shown to have a distinct nucleotide sequence not seen in any of the other clinical samples examined.


Asunto(s)
ADN Viral/análisis , Herpesvirus Humano 8/genética , Sarcoma de Kaposi/virología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/virología , Composición de Base , Secuencia de Bases , Cartilla de ADN/química , ADN Viral/genética , Variación Genética , Humanos , Enfermedad Iatrogénica , Linfoma de Células B/virología , Datos de Secuencia Molecular , Sistemas de Lectura Abierta/genética , Reacción en Cadena de la Polimerasa , Estudios Retrospectivos , Arabia Saudita , Análisis de Secuencia de ADN , Células Tumorales Cultivadas
19.
Hematol Oncol Clin North Am ; 11(5): 963-73, 1997 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9336725

RESUMEN

First described in organ transplant recipients in 1968, post-transplant lymphoproliferative disorder (PTLD) remains an often devastating complication of immunosuppression. Similar, if not identical, Epstein-Barr virus (EBV)-associated B lymphoproliferations have since been described in congenital and other acquired immunodeficiency states. Although PTLD is often morphologically indistinguishable from aggressive non-Hodgkin's lymphoma, the pathogenesis, presentation, clinical course, and management options differ significantly from those of classic NHL.


Asunto(s)
Terapia de Inmunosupresión/efectos adversos , Linfoma no Hodgkin/terapia , Complicaciones Posoperatorias/terapia , Trasplante/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones por Herpesviridae/epidemiología , Herpesvirus Humano 4/crecimiento & desarrollo , Herpesvirus Humano 4/patogenicidad , Humanos , Huésped Inmunocomprometido , Inmunoterapia , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Linfoma no Hodgkin/etiología , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/virología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/patología , Complicaciones Posoperatorias/virología , Proteínas Recombinantes , Infecciones Tumorales por Virus/epidemiología , Activación Viral
20.
Leuk Lymphoma ; 28(1-2): 89-101, 1997 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9498708

RESUMEN

A frequently fatal complication of organ transplantation, post-transplant lymphoproliferative disorder (PTLD) develops in 2%-6% of cardiac recipients. Treatment remains poorly defined. Reduction in immunosuppression is effective in a proportion of cases, but mortality in the order of 80% is reported for patients requiring chemotherapy. The reason for such poor outcomes is unclear, but may be partly due to the concomitant use of immunosuppressives. An update report is provided on nineteen consecutive cardiac recipients with PTLD, studied retrospectively in terms of clinical features and outcome. Patients were managed according to a uniform treatment approach. Initial therapy was a trial of reduced immunosuppression with concomitant acyclovir followed, if unsuccessful, by aggressive combination chemotherapy. The regimen used was predominantly ProMACE-CytaBOM. Six patients with phenotypically polyclonal PTLD presented <6 months after transplantation (median 6 weeks). Only 1/4 (25%) treated patients responded to reduced immunosuppression; the remainder died of multiorgan failure. Thirteen patients presented with phenotypically monoclonal disease > or =6 months after transplantation. In 8/12 (75%) treated patients initial therapy was reduction in immunosuppression. None achieved CR; 2 experienced fatal rejection. Two patients achieved durable surgical CR. The remaining 8 patients received chemotherapy; 2/8 (25%) died during treatment, 6/8 (75%) achieved CR. None have relapsed, at a median duration of follow-up of 64 months. Neutropenic sepsis, and subclinical doxorubicin cardiotoxicity at a mean cumulative dose of 63 mg/m2 were the principal toxicities. Our data indicate that aggressive chemotherapy is feasible and can produce very durable remissions in phenotypically monoclonal PTLD refractory to reduced immunosuppression. ProMACE-CytaBOM is well suited to cardiac recipients, minimizing doxorubicin exposure and obviating the need for concurrent immunosuppressives.


Asunto(s)
Aciclovir/administración & dosificación , Antimetabolitos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Corazón , Inmunosupresores/efectos adversos , Trastornos Linfoproliferativos/tratamiento farmacológico , Adulto , Femenino , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/uso terapéutico , Inyecciones Intravenosas , Trastornos Linfoproliferativos/etiología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento
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