Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients.

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.

Evidence of genetic susceptibility to infectious mononucleosis: a twin study.

Infectious mononucleosis is a clinical manifestation of primary Epstein-Barr virus infection. It is unknown whether genetic factors contribute to risk. To assess heritability, we compared disease concordance in monozygotic to dizygotic twin pairs from the population-based California Twin Program and assessed the risk to initially unaffected co-twins. One member of 611 and both members of 58 twin pairs reported a history of infectious mononucleosis. Pairwise concordance in monozygotic and dizygotic pairs was respectively 12·1% [standard error (s.e.)=1·9%] and 6·1% (s.e.=1·2%). The relative risk (hazard ratio) of monozygotic compared to dizygotic unaffected co-twins of cases was 1·9 [95% confidence interval (CI) 1·1-3·4, P=0·03], over the follow-up period. When the analysis was restricted to same-sex twin pairs, that estimate was 2·5 (95% CI 1·2-5·3, P=0·02). The results are compatible with a heritable contribution to the risk of infectious mononucleosis.

A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors.

The critical 8p22 tumor suppressor deleted in liver cancer 1 (DLC1) is frequently inactivated by aberrant CpG methylation and/or genetic deletion and implicated in tumorigeneses of multiple tumor types. Here, we report the identification and characterization of its new isoform, DLC1 isoform 4 (DLC1-i4). This novel isoform encodes an 1125-aa (amino acid) protein with distinct N-terminus as compared with other known DLC1 isoforms. Similar to other isoforms, DLC1-i4 is expressed ubiquitously in normal tissues and immortalized normal epithelial cells, suggesting a role as a major DLC1 transcript. However, differential expression of the four DLC1 isoforms is found in tumor cell lines: Isoform 1 (longest) and 3 (short thus probably nonfunctional) share a promoter and are silenced in almost all cancer and immortalized cell lines, whereas isoform 2 and 4 utilize different promoters and are frequently downregulated. DLC1-i4 is significantly downregulated in multiple carcinoma cell lines, including 2/4 nasopharyngeal, 8/16 (50%) esophageal, 4/16 (25%) gastric, 6/9 (67%) breast, 3/4 colorectal, 4/4 cervical and 2/8(25%) lung carcinoma cell lines. The functional DLC1-i4 promoter is within a CpG island and is activated by wild-type p53. CpG methylation of the DLC1-i4 promoter is associated with its silencing in tumor cells and was detected in 38-100% of multiple primary tumors. Treatment with 5-aza-2'-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B led to demethylation of the promoter and reactivation of its expression, indicating a predominantly epigenetic mechanism of silencing. Ectopic expression of DLC1-i4 in silenced tumor cells strongly inhibited their growth and colony formation. Thus, we identified a new isoform of DLC1 with tumor suppressive function. The differential expression of various DLC1 isoforms suggests interplay in modulating the complex activities of DLC1 during carcinogenesis.

Immunologic recovery following autologous stem-cell transplantation with pre- and posttransplantation rituximab for low-grade or mantle cell lymphoma.

BACKGROUND: Rituximab may improve transplant outcomes but may delay immunologic recovery. PATIENTS AND METHODS: Seventy-seven patients with low-grade or mantle cell lymphoma received autologous stem-cell transplantation (ASCT) on a phase II study. Rituximab 375 mg/m(2) was administered 3 days before mobilization-dose cyclophosphamide, then weekly for four doses after count recovery from ASCT. Immune reconstitution was assessed. RESULTS: Sixty percent of transplants occurred in first remission. Actuarial event-free survival (EFS) and overall survival (OS) were 60% and 73%, respectively, at 5 years, with 7.2-year median follow-up for OS in surviving patients. Median EFS was 8.3 years. Older age and transformed lymphomas were independently associated with inferior EFS, whereas day 60 lymphocyte counts did not predict EFS or late infections. Early and late transplant-related mortality was 1% and 8%, with secondary leukemia in two patients. B-cell counts recovered by 1-2 years; however, the median IgG level remained low at 2 years. Late-onset idiopathic neutropenia, generally inconsequential, was noted in 43%. CONCLUSION: ASCT with rituximab can produce durable remissions on follow-up out to 10 years. Major infections do not appear to be significantly increased or to be predicted by immune monitoring.

The same but different: autologous hematopoietic stem cell transplantation for patients with lymphoma and HIV infection.

In an earlier era, high-dose therapies were thought to be contraindicated in HIV-infected patients. Patients with HIV fared somewhat better with reduced-dose lymphoma therapies and salvage of relapsed patients was rarely possible. With more than a decade of effective antiretroviral therapy, full-dose lymphoma therapies have become standard, and high-dose therapy with autologous hematopoietic stem cell rescue for those who fail frontline therapy or who are judged to have very high risk disease has been pursued with very encouraging results. Transplant-related mortality is less than 5%. With prophylaxis for pneumocystis and herpesvirus infections, deaths due to opportunistic infections are distinctly unusual. Most deaths have been associated with veno-occlusive disease or lymphoma progression. There is no need for quarantine of patients or special isolation procedures. Most patients with responsive lymphoma remain lymphoma free several years after high-dose therapy. CD4(+) cell count and HIV load seem not to be adversely affected in the long term. Much like diabetes, HIV infection should be regarded as a problem that requires special attention during high-dose therapy rather than a contraindication to high-dose therapy in patients with lymphoma who would otherwise be judged transplant candidates.

Salvage transplantation for allograft failure using fludarabine and alemtuzumab as conditioning regimen.

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.

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation.

Identification of tumor suppressor genes (TSG) silenced by methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic tumor markers for early cancer detection. Both nasopharyngeal carcinoma (NPC) and esophageal carcinoma are major tumors in Southern China and Southeast Asia. Through expression subtraction of NPC, we identified Deleted in Liver Cancer 1 (DLC1)/ARHGAP7 (NM_006094)--an 8p22 TSG as a major downregulated gene. Although expressed in all normal tissues, DLC1 was silenced or downregulated in 11/12 (91%) NPC, 6/15 (40%) esophageal, 5/8 (63%) cervical and 3/9 (33%) breast carcinoma cell lines. No genetic deletion of DLC1 was detected in NPC although a hemizygous deletion at 8p22-11 was found by 1-Mb array-CGH in some cell lines. We then located the functional DLC1 promoter by 5'-RACE and promoter activity assays. This promoter was frequently methylated in all downregulated cell lines and in a large collection of primary tumors including 89% (64/72) NPC (endemic and sporadic types), 51% (48/94) esophageal, 87% (7/8) cervical and 36% (5/14) breast carcinomas, but seldom in paired surgical marginal tissues and not in any normal epithelial tissue. The transcriptional silencing of DLC1 could be reversed by 5-aza-2'-deoxycytidine or genetic double knock-out of DNMT1 and DNMT3B. Furthermore, ectopic expression of DLC1 in NPC and esophageal carcinoma cells strongly inhibited their colony formation. We thus found frequent epigenetic silencing of DLC1 in NPC, esophageal and cervical carcinomas, and a high correlation of methylation with its downregulation, suggesting a predominant role of epigenetic inactivation. DLC1 appears to be a major TSG implicated in the pathogenesis of these tumors, and should be further tested as a molecular biomarker in patients with these cancers.

Lytic viral replication as a contributor to the detection of Epstein-Barr virus in breast cancer.

Epstein-Barr virus (EBV) has an accepted association with the epithelial malignancy nasopharyngeal carcinoma and has also been reported in other more controversial carcinoma settings. Evaluation of EBV association with epithelial carcinomas such as breast cancer would benefit from a better understanding of the outcome of EBV infection of these cells. Cell-free preparations of a green fluorescent protein-expressing virus, BX1, were used to infect breast cancer cell lines, which were then examined for EBV gene expression and viral genome copy number. Reverse transcription-PCR analyses revealed that the cells supported a mixture of latency II and lytic EBV gene expression. Lytic Zta and BMRF1 protein expression was detected by immunohistochemistry, and DNA PCR analyses estimated an EBV copy number of 300 to 600 genomes per infected cell. Evidence for lytic EBV expression was also found in breast tissue, where reverse transcription-PCR analyses detected lytic Zta transcripts in 7 of 10 breast carcinoma tissues and 4 of 10 normal tissues from the same patients. Scattered cells immunoreactive for Zta protein were also detectable in breast carcinoma. Quantitative real-time PCR analysis of EBV-positive breast carcinoma tissues suggested that less than 0.1% of the cells contained viral genomes. We suggest that sporadic lytic EBV infection may contribute to PCR-based detection of EBV in traditionally nonvirally associated epithelial malignancies.

Phase I study of escalating doses of low-dose-rate, locoregional irradiation preceding Cytoxan-TBI for patients with chemotherapy-resistant non-Hodgkin's or Hodgkin's lymphoma.

PURPOSE: In patients in whom bone marrow transplantation (BMT) fails, recurrence often occurs at sites known to have contained disease before initiating BMT. The purpose of this study was to find the maximal tolerable dose of locoregional irradiation (LRT) between 1000 and 2000 cGy that could be integrated with our Cytoxan-total body irradiation (TBI) BMT conditioning regimen in the treatment of lymphoma. METHODS AND MATERIALS: Patients had Hodgkin's or non-Hodgkin's lymphoma in chemotherapy-refractory relapse. All patients received LRT to a maximum of three sets of fields encompassing either all current or all previously known sites of disease. Cytoxan-TBI consisted of cyclophosphamide 50 mg/kg daily for 4 days followed by TBI of 1200 cGy given in four fractions. RESULTS: Twenty-one patients were enrolled. Radiation Therapy Oncology Group Grade 3 in-field acute toxicity was observed in 1 patient at each dose level up to 1500 cGy and in 3 of 6 patients receiving 2000 cGy. Clinically evident late toxicities were limited to hypothyroidism and one second malignancy occurring outside the LRT fields. CONCLUSION: Low-dose-rate, LRT with concurrent Cytoxan-TBI before BMT has acceptable rates of in-field toxicity for doses up to 1500 cGy in five fractions. This regimen safely permits the use of a total combined radiation dose of up to 2700 cGy during 2 weeks, with encouraging in-field response rates in treatment-refractory patients.

Gemcitabine as first-line therapy in patients with metastatic breast cancer: a phase II trial.

OBJECTIVES: This phase II study was conducted to evaluate the efficacy and safety of gemcitabine in patients with metastatic breast cancer (MBC). METHODS: Women with histologically or cytologically confirmed bidimensionally measurable MBC not amendable to curative surgery or radiation were eligible. Prior chemotherapy for metastatic disease was not permitted. Patients received gemcitabine 1,200 mg/m(2) on days 1, 8 and 15 for 3 weeks every 28 days for a maximum of 8 cycles. RESULTS: Thirty-nine patients, with a median age of 58 years, were enrolled. The overall response rate for the 35 evaluable patients was 37.1% (95% confidence interval [CI], 21.5-55.1%), with 2 complete responses and 11 partial responses. Median time to progression and survival were 5.1 months (95% CI, 3.5-8.8 months) and 21.1 months (95% CI, 11.0-26.9 months), respectively. Chemotherapy was well tolerated, with a median of 4 cycles completed. Grade 4 toxicities were 1 infection and 1 abnormal pulmonary function. Grade 3 neutropenia and thrombocytopenia occurred in 30.3% and 6.3% of patients, respectively. The most common grade 3 non-hematologic toxicity was nausea/vomiting (10.3%). Five of 21 patients had improved Karnofsky performance status (KPS) scores. CONCLUSION: Single-agent gemcitabine is active and well tolerated as first-line treatment in patients with MBC.

Long-term results of blood and marrow transplantation for Hodgkin's lymphoma.

PURPOSE: To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients

Frequent expression of the tumor necrosis factor receptor-associated factor 1 in latent membrane protein 1-positive posttransplant lymphoproliferative disease and HIV-associated lymphomas.

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.

Epstein-Barr virus associated lymphoproliferations in the AIDS setting.

Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that is associated with a variety of malignancies. In vivo infection of B lymphocytes is initially associated with the broad expression of immunodominant viral latency genes and proliferation of infected cells. Ultimately, a viral reservoir is established in resting B cells with restricted expression of viral latency genes and no expression of immunodominant viral genes. Among the tumours associated with EBV that are relevant to a consideration of EBV in HIV-associated malignancies are posttransplant lymphoproliferative disease, Burkitt's lymphoma (BL) and Hodgkin's disease (HD). BL carries whereas EBV in only a minority of cases whereas HD in patients infected with HIV is virtually always EBV-associated. EBV-directed T cell therapies have proven effective in posttransplant lymphomas in bone marrow transplantation patients. In patients with HIV infection, primary central nervous system (CNS) and immunoblastic lymphomas show similarities with posttransplant lymphoproliferative disease. EBV detection studies in cerebrospinal fluid are useful diagnostically in primary CNS lymphoma. T cell therapies may be useful in the treatment of EBV-associated lymphomas. Thus, a better understanding of the relationship between EBV and these tumours will not only help to clarify their pathogenesis, but may facilitate the development of new diagnostic and therapeutic strategies.

Expression of the tumour necrosis factor receptor-associated factors 1 and 2 in Hodgkin's disease.

The tumour necrosis factor receptor-associated factors (TRAFs) 1 and 2 participate in the signal transduction of various members of the tumour necrosis factor receptor (TNFR) family, including TNFR1, TNFR2, CD40, CD30, and the Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP1). Previous in situ hybridization studies have demonstrated TRAF1 transcripts in the malignant cells of the majority of Hodgkin's disease (HD) tumours, where the expression of TRAF1 was higher in EBV-associated tumours than in their EBV-negative counterparts. In order to determine whether TRAF1 and also TRAF2 were expressed at the protein level in HD and whether there was any relationship to EBV status, immunohistochemistry has been used to detect these proteins in a series of HD specimens. TRAF1 protein was detected more frequently in Hodgkin/Reed-Sternberg (HRS) cells from EBV-positive tumours than in their EBV-negative counterparts. This difference was statistically significant (p=0.01). In contrast, TRAF2 expression by HRS cells appeared to be independent of EBV status. Using a sequential labelling approach, co-localization of LMP1 with either TRAF1 or TRAF2 was also demonstrated in HRS cells from EBV-positive tumours.

Induction of Epstein-Barr virus kinases to sensitize tumor cells to nucleoside analogues.

The presence of Epstein-Barr virus (EBV) in the tumor cells of some EBV-associated malignancies may facilitate selective killing of these tumor cells. We show that treatment of an EBV(+) Burkitt's lymphoma cell line with 5-azacytidine led to a dose-dependent induction of EBV lytic antigen expression, including expression of the viral thymidine kinase (TK) and phosphotransferase (PT). Azacytidine treatment for 24 h modestly sensitized the cell line to all nucleosides tested. To better characterize EBV TK with regard to various nucleoside analogues, we expressed EBV TK in stable cell clones. Two EBV TK-expressing clones were moderately sensitive to high doses of acyclovir and penciclovir (PCV) (62.5 to 500 microM) and to lower doses of ganciclovir (GCV) and bromovinyldeoxyuridine (BVdU) (10 to 100 microM) compared to a control clone and were shown to phosphorylate GCV. Similar experiments in a transient overexpression system showed more killing of cells transfected with the EBV TK expression vector than of cells transfected with the control mutant vector (50 microM GCV for 4 days). A putative PT was also studied in the transient transfection system and appeared similar to the TK in phosphorylating GCV and conferring sensitivity to GCV, but not in BVdU- or PCV-mediated cell killing. Induction of EBV kinases in combination with agents such as GCV merits further evaluation as an alternative strategy to gene therapy for selective killing of EBV-infected cells.

Spindle cell conversion by Kaposi's sarcoma-associated herpesvirus: formation of colonies and plaques with mixed lytic and latent gene expression in infected primary dermal microvascular endothelial cell cultures.

Angiogenic Kaposi's sarcoma (KS) skin lesions found in both AIDS and non-AIDS patients are universally associated with infection by the presumed causative agent, known as KS-associated herpesvirus (KSHV) or human herpesvirus 8. KSHV genomes expressing latent state virus-encoded mRNAs and the LANA1 (latent nuclear antigen 1) protein are consistently present in spindle-like tumor cells that are thought to be of endothelial cell origin. Although the KSHV lytic cycle can be induced in rare latently infected primary effusion lymphoma (PEL) cell lines, the ability to transmit or assay infectious KSHV has so far eluded investigators. Here, we demonstrate that infection with supernatant virions derived from three different tetradecanoyl phorbol acetate-induced PEL cell lines can induce cultured primary human dermal microvascular endothelial cells (DMVEC) to form colonies of proliferating latently infected spindle-shaped cells, all of which express the KSHV-encoded LANA1 protein. Although their initial infectivity varied widely (JSC1 > > BC3 > BCP1), virions from all three cell lines produced distinctive spindle cell colonies and plaques without affecting the contact-inhibited cobblestone-like phenotype of adjacent uninfected DMVEC. Each infected culture could also be expanded into a completely spindloid persistently infected culture displaying aggregated swirls of spindle cells resembling those in KS lesions. Formation of new colonies and plaques was inhibited in the presence of phosphonoacetic acid or gangciclovir, but these antiherpesvirus agents had little effect on the propagation of already latently infected spindloid cultures. In persistently infected secondary cultures, patches of up to 10% of the spindloid cells constitutively expressed several early viral lytic cycle proteins, and 1 to 2% of the cells also formed typical herpesvirus DNA replication compartments, displayed cytopathic rounding effects, and expressed late viral antigens. We conclude that de novo KSHV infection induces a spindle cell conversion phenotype in primary DMVEC cultures that is directly associated with latent state expression of the LANA1 protein. However, these cultures also spontaneously reactivate to produce an unusual combination of both latent and productive but slow lytic cycle infection. The formation of spindle cell colonies and plaques in DMVEC cultures provides for the first time a quantitative assay for directly measuring the infectivity of KSHV virion preparations.

Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy.

PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART. PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir. RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL. CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.

Epstein-Barr virus and survival after Hodgkin disease in a population-based series of women.

BACKGROUND: Epstein-Barr virus (EBV) positive Hodgkin disease (HD), as defined by the presence of EBV genes or gene products in the malignant cells, differs epidemiologically from EBV negative HD. However, survival patterns for EBV-defined HD have not been well studied. To determine if EBV status influenced survival time after HD, the authors investigated a large, population-based series of female patients. METHODS: For 311 female patients living in the Greater San Francisco Bay Area who were aged 19-79 years with HD diagnosed between mid-1988 and 1994, histopathologically rereviewed archived biopsy specimens were assayed for EBV with immunohistochemistry and in situ hybridization. The 53 subjects with EBV positive and the 258 with EBV negative HD were observed for vital status through 1998; overall survival was analyzed with Kaplan-Meier and Cox proportional hazards regression methods. RESULTS: Epstein-Barr virus positive HD patients were older, received diagnosis at a later stage, and were less likely to have nodular sclerosis histology than EBV negative patients. Deaths were reported for 21 (40%) EBV positive and 37 (14%) EBV negative patients. No survival differences were observed between EBV positive and negative women aged 19-44 years, but survival was significantly poorer in women aged 45-79 years with EBV positive HD. Regression analysis confirmed this strong negative effect of EBV positive status on survival (hazard ratio for death, 3.0; 95% confidence interval, 1.5-6.2) as unrelated to age, stage at diagnosis, or tumor histology. CONCLUSIONS: This study found a marked survival disadvantage for EBV positive HD in older but not young adult women. These findings suggest influences of both EBV status and age on HD survival, as well as pathogenesis.