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Richard F Ambinder

Publications and source records attributed to Richard F Ambinder.

At least 19 recordsLinked to original sources
PubMed2006

Infection of human B cells with Epstein-Barr virus results in the expression of somatic hypermutation-inducing molecules and in the accrual of oncogene mutations.

Infection of human B cells with Epstein-Barr virus (EBV) was seen to result in activation-induced cytidine deaminase (AID) and polymerase-eta (pol-eta) gene expression. AID and pol-eta are cellular gene products that play central roles in the DNA-modifying processes involved in immunoglobulin gene class switch recombination and somatic hypermutation. Errors in these processes can result in oncogene mutation/translocation, thereby contributing to lymphomagenesis. It was seen that EBV infected, AID, and pol-eta expressing B cells accumulated mutations in cellular proto-oncogenes (BCL-6 and p53) that are known to be involved in the genesis of B cell lymphoma. The nature of the mutations seen in these oncogenes was consistent with the known activity of AID and pol-eta. These findings indicate that EBV induced AID and pol-eta expression, and that this was associated with oncogene mutation, providing a novel means by which EBV infection of B cells may contribute to lymphomagenesis.

B-Lymphocytes↗
PubMed2006

Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions.

We retrospectively analyzed 83 consecutive recipients of donor lymphocyte infusions (DLI) after allogeneic transplantation for factors associated with disease response and graft-versus-host disease (GVHD). DLI was highly effective in relapsed chronic phase chronic myeloid leukemia (CML), with 71% of patients achieving durable complete remissions (CR). In relapsed acute myeloid leukemia, DLI led to durable CRs in 31% of patients; the rate was <20% in all other diseases. Achieving full donor chimerism and GVHD were predictive of CR. Grade II or higher acute or chronic GVHD occurred in 36 (43%) patients and contributed to death in 13 (16%). Even more patients, 33 (40%), died of their underlying malignancy, including 10 who developed active GVHD. In relapsed CML, most durable CRs occurred without clinically apparent GVHD, yet all responders achieved full donor chimerism, including 6 with coincident normal host hematopoiesis at the time of DLI. Thus, in CML, potent lymphohematopoietic graft-versus-host reactions occurred even in the absence of clinically apparent GVHD; this confirms the ability to dissociate these processes and argues against a leukemia-specific immunologic effect. DLI clearly has efficacy in the treatment of relapsed disease after allogeneic transplantation. However, with the exception of CML, most patients die of their underlying disease because of insufficient antitumor activity even with active GVHD.

Acute Disease↗
PubMed2006

Clinical outcome following autologous and allogeneic blood and marrow transplantation for relapsed diffuse large-cell non-Hodgkin's lymphoma.

High-dose chemotherapy followed by blood or marrow transplantation (BMT) is generally considered the best salvage option for patients with relapsed diffuse large-B-cell non-Hodgkin's lymphoma (DLCL). The relative roles for allogeneic and autologous BMT remain controversial. We reviewed the clinical outcome of 183 patients with relapsed DLCL who underwent BMT at Johns Hopkins University in 1985-2001. A total of 45 patients received T-cell-depleted HLA-matched allogeneic bone marrow (allo-BMT), and 138 patients received autologous marrow or peripheral blood stem cells (auto-BMT). The allo-BMT recipients had a higher proportion of patients with chemoresistant disease (P = .004) and had received more chemotherapy before BMT (P = .02). The auto-BMT recipients were older (P < .001) and were of more advanced-stage disease (P = .01). The 3-year overall survival (OS) was 23.7% (median survival, 129 days) after allo-BMT and 33.1% (median survival, 263 days), after auto-BMT (log-rank, P = .17). The 3-year OS for patients with sensitive disease was 51.9% after allo-BMT and 46.2% after auto-BMT (log-rank, P = .38). For patients with resistant disease, the 3-year OS was 12.1% after allo-BMT and 19.1% after auto-BMT (log rank, P = .08). In multivariate analysis, significant predictors of death were disease sensitivity (hazard rate [HR], 0.3; 95% confidence interval [CI] 0.2-04; P < .001), age >40 years (HR, 2.42; 95% CI, 1.7-3.4; P < .001), and stage at diagnosis (HR, 1.2; 95% CI, 1.0-1.4; P = .04). The 3-year event-free survival (EFS) for patients with sensitive disease was 52.7% after allo-BMT and 42.0% after auto-BMT (log-rank, P = .29). For patients with resistant disease, the 3-year EFS was 6.2% after allo-BMT and 19.4% after auto-BMT (log-rank, P = .1). The 3-year probability of relapse for chemosensitive patients was 30% after allo-BMT and 46.1% after auto-BMT (log-rank, P = .25). The 3-year relapse rate in patients with resistant disease was 75.0% after allo-BMT and 69.9% after auto-BMT (log-rank, P = .58). In multivariate analysis, only disease sensitivity status (HR, 0.4; 95% CI, 0.2-2.1; P < .001) and age >40 years (HR, 1.7; 95% CI, 1.1-2.9; P = .03) appear to have a significant impact on relapse. Transplant-related mortality (TRM) was the cause of death for 51.1% of allo-BMT recipients and 23.9% of auto-BMT recipients (P < .001). Mortality from lymphoma was 26.6% in allo-BMT recipients and 43.5% in auto-BMT recipients (P = .02). Auto-BMT and allo-BMT produced similar survival for patients with relapsed DLCL. For patients with sensitive disease, allo-BMT seemed to provide longer survival with less relapse; however, this was achieved at the cost of greater TRM.

Adolescent↗
PubMed2006

Body size, physical activity, and risk of Hodgkin's lymphoma in women.

Few studies have examined the associations of body size and physical activity with the development of Hodgkin's lymphoma (HL) in women. In data from a population-based case-control study in women ages 19 to 79 years, we assessed the relation of self-report height, weight, body mass index (BMI), and strenuous physical activity to HL risk in 312 cases with diagnostic re-review and 325 random-digit dialed controls using logistic regression. Analyses were stratified by age group and tumor cell presence of EBV. After adjustment for social class measures, taller childhood and adult height were associated with higher HL risk. In women ages 19 to 44 years, HL risk was elevated for higher, but healthy, BMI values, whereas in women ages 45 to 79 years, associations with BMI were inverse. The odds of developing HL were lower with participation (versus nonparticipation) in strenuous physical activity in the past year [odds ratio (OR), 0.58; 95% confidence interval (95% CI), 0.39-0.87 in women 19-44 years; OR, 0.45; 95% CI, 0.19-1.06 in women 45-79 years] and throughout adult life, and with sports team membership (versus nonmembership) in high school and/or at ages 18 to 22 years. Results were similar in cases (n = 269) with and without tumor-cell EBV compared with controls, although the inverse association with physical activity was somewhat stronger for women with EBV-positive disease. These findings show that in women, body size and strenuous physical activity, both modifiable characteristics, are associated with HL risk in adult life possibly through immunologic, infectious, or genetic mechanisms.

Adult↗
PubMed2005

Epstein-Barr virus as a marker of survival after Hodgkin's lymphoma: a population-based study.

PURPOSE: Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) cells has been considered as a prognostic marker for this heterogeneous disease, but studies have yielded mixed findings, likely because of selected patient series and failure to acknowledge an effect of age on outcome. This study assessed survival after HL in a population-based cohort large enough to examine the joint effects of EBV with other factors including age, sex, and histologic subtype. PATIENTS AND METHODS: Included were 922 patients with classical HL diagnosed between mid-1988 and 1997 in the Greater San Francisco Bay Area, with archived biopsy specimens assayed for EBV with immunohistochemistry and in situ hybridization. Vital status was followed through December 30, 2003 (median follow-up time, 97 months). Overall and disease-specific survival were analyzed with the Kaplan-Meier method and Cox proportional hazards regression models. RESULTS: In children less than 15 years old, EBV presence was suggestively associated (P = .07) with favorable survival. In adults aged 15 to 44 years, EBV did not affect HL outcome, although a protective effect was suggested. In older adults (45 to 96 years), EBV presence nearly doubled the risk of overall and HL-specific mortality but only for patients with nodular sclerosis (NS) histologic subtype (hazard ratio for death = 2.5; 95% CI, 1.5 to 4.3). CONCLUSION: In HL, EBV tumor cell presence is associated with better survival in young patients and poorer survival in older patients with NS, independent of other factors. Variation in outcome by age and histology could indicate biologically distinct disease entities. Evidence that EBV is a meaningful prognostic marker may have therapeutic relevance.

Adolescent↗
PubMed2005

Exposure to childhood infections and risk of Epstein-Barr virus--defined Hodgkin's lymphoma in women.

The role of Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) etiology remains unresolved as EBV is detected in only some HL tumors and few studies have tried to reconcile its presence with factors suggesting viral etiology (e.g., childhood social class, infection history). In a population-based case-control study of San Francisco Bay area women, we analyzed interview data by tumor EBV status. Among 211 young adult cases, EBV-positive HL (11%) was associated with a single vs. shared bedroom at age 11 (OR = 4.0, 95% CI 1.1-14.4); risk was decreased for common childhood infections (OR = 0.3, 95% CI 0.1-1.0), including measles before age 10, but not with prior infectious mononucleosis (IM), which is delayed EBV infection. No study factors affected risk of young adult EBV-negative HL. Among 57 older adult cases, EBV-positive HL (23%) was unrelated to study factors; EBV-negative HL was associated with a single bedroom at age 11 (OR = 3.6, 95% CI 1.5-9.1) and IM in family members (OR = 3.1, 95% CI 1.1-9.0). Thus, delayed exposure to infection may increase risk of EBV-positive HL in young adults, but risk patterns differ in younger and older women for both EBV-positive and -negative HL. Late EBV infection does not appear relevant to risk, suggesting that other pathogens impact HL etiology in affluent female populations. Inconsistency of findings with prior studies may reflect failure of study risk factors to proxy meaningful exposures, risk differences by gender, or selection or misclassification bias. Null findings for EBV-negative HL indicate that etiologic models should be reconsidered for this common form.

Adult↗
PubMed2005

Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010.

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy results in significant improvement in clinical outcome for individuals with non-HIV-associated aggressive B-cell lymphoma. To assess the potential risks and benefits of the addition of rituximab to CHOP for HIV-associated non-Hodgkin lymphoma (HIV-NHL) 150 patients receiving CHOP for HIV-NHL were randomized (2:1) to receive 375 mg/m(2) rituximab with each chemotherapy cycle (n = 99) or no immunotherapy (n = 50) in a multicenter phase 3 trial. The complete response rate (CR + CRu) was 57.6% for R-CHOP and 47% for CHOP (P = .147). With a median follow-up of 137 weeks, time to progression, progression-free survival, and overall survival times were 125, 45, and 139 weeks, respectively, for R-CHOP and 85, 38, and 110 weeks, respectively, for CHOP (P = not significant, all comparisons). Treatment-related infectious deaths occurred in 14% of patients receiving R-CHOP compared with 2% in the chemotherapy-alone group (P = .035). Of these deaths, 60% occurred in patients with CD4 counts less than 50/mm(3). Progression-free survival was significantly influenced by CD4(+) count (P < .001) and International Prognostic Index score (P = .022), but not bcl-2 status. The addition of rituximab to CHOP in patients with HIV-NHL may be associated with improved tumor responses. However, these benefits may be offset by an increase in infectious deaths, particularly in those individuals with CD4(+) lymphocyte counts less than 50/mm(3).

Adult↗
PubMed2005

Outcomes of autologous and allogeneic blood or marrow transplantation for mantle cell lymphoma.

To evaluate high-dose therapy and autologous or allogeneic blood or marrow transplantation (BMT) for mantle cell lymphoma, patients receiving BMT for newly diagnosed or relapsed mantle cell lymphoma were identified through the registry at Johns Hopkins. The pathologic diagnostic criteria were reviewed, and details of the presentation, transplant procedure, and survival outcomes were determined. Fifty-eight patients were identified, of whom 64% underwent transplantation in first remission and 12% had primary induction failure. Nineteen patients (one third) received an allograft. Preparative regimens consisted of cyclophosphamide in combination with either busulfan or total body irradiation. On multiple regression analysis, transplantation after 1 or more relapses (hazard ratio, 2.98; P = .02), primary induction failure (hazard ratio, 5.39; P = .002), and allogeneic transplantation (hazard ratio, 3.03; P = .007) were associated with an inferior event-free survival (EFS). However, EFS curves were not statistically different for autologous and allogeneic BMT performed in first remission, with an estimated 3-year EFS approaching or equaling 70%. Primary induction failure and residual bone marrow involvement were the only statistically significant predictors of relapse on multiple regression analysis. At 3 years, the estimated EFS for the entire cohort after BMT was 51%, the probability of relapse was 31%, and the overall survival was 59%. The benefit of autologous or allogeneic BMT for mantle cell lymphoma is thus most apparent when transplantation is performed in first remission. Whether allogeneic BMT ultimately confers an advantage because of a graft-versus-lymphoma effect remains to be determined.

Adult↗
PubMed2005

High-dose therapy and blood or marrow transplantation for non-Hodgkin lymphoma with central nervous system involvement.

The role of autologous or allogeneic blood or marrow transplantation (BMT) remains undefined in patients with central nervous system (CNS) involvement by lymphoma. The records of all adult and pediatric non-Hodgkin lymphoma patients receiving BMT at Johns Hopkins from 1980 to 2003 were reviewed, and 37 patients were identified who had CNS involvement that was treated into remission by the time of BMT. The chief histologies were diffuse large B-cell lymphoma and T-cell lymphoblastic lymphoma/leukemia. Twenty-four percent received intrathecal chemotherapy alone, and 70% received intrathecal chemotherapy and CNS irradiation before BMT. The main preparative regimens were cyclophosphamide/total body irradiation and busulfan/cyclophosphamide. Forty-one percent received an allogeneic transplant. Lymphoma relapsed after BMT in 14 patients (38%), and at least 5 had documented or suspected CNS relapse. In multivariate models, age > or =18 years at diagnosis, resistant systemic disease, busulfan/cyclophosphamide conditioning, and lack of intrathecal consolidation after BMT were statistically significant predictors of inferior survival. The 5-year actuarial event-free survival was 36%, and overall survival was 39%. After BMT, long-term survival is thus achievable in a subset of patients with a history of treated CNS involvement by non-Hodgkin lymphoma. The survival rates are not dissimilar to those typically seen in other high-risk lymphoma patients undergoing BMT. These data suggest that patients with lymphomatous involvement of the CNS who achieve CNS remission should be offered BMT if it is otherwise indicated.

Adolescent↗
PubMed2005

AIDS-related primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) can develop in the setting of profound immunosuppression, including late-stage infection with HIV. The management of such patients has yet to be defined optimally and differs substantially from that of immunocompetent patients who have PCNSL. The clinical features, diagnosis, and management of AIDS-related PCNSL are reviewed. The authors focus on commonly encountered diagnostic and therapeutic dilemmas and explore some promises and pitfalls of Epstein-Barr virus-directed therapies.

Central Nervous System Neoplasms↗
PubMed2004

Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494).

PURPOSE: To determine the effectiveness of an infusional chemotherapy regimen in patients with HIV-associated lymphoma treated before and after the use of highly active antiretroviral therapy (HAART) in routine clinical practice. PATIENTS AND METHODS: Ninety-eight assessable patients with HIV-associated intermediate- or high-grade non-Hodgkin's lymphoma received cyclophosphamide 200 mg/m(2)/d, doxorubicin 12.5 mg/m(2)/d, and etoposide 60 mg/m(2)/d (CDE) given by continuous intravenous infusion for 4 days (96 hours) every 4 weeks plus filgrastim. Concurrent antiretroviral treatment consisted of the nucleoside analog didanosine in the first 43 patients enrolled before December 1996 (pre-HAART group), or HAART in the remaining 55 patients enrolled after that time (HAART group). RESULTS: Complete response occurred in 44 patients (45%; 95% CI, 35% to 55%). Failure-free survival and overall survival (OS) at 2 years was 36% (95% CI, 26% to 46%) and 43% (95% CI, 33% to 53%), respectively. At the time of the analysis, 30% in the pre-HAART group were alive compared with 47% in the HAART group; when adjusted for varying length of follow-up, patients in the HAART group had improved OS (P =.039). Patients in the HAART group experienced less grade 4 nonhematologic toxicity (22% v 42%; P =.037), thrombocytopenia (31% v 52%; P =.033), and anemia (9% v 27%; P =.021), and had fewer treatment-associated deaths (0% v 10%; P =.013). CONCLUSION: Infusional CDE is an effective and potentially curative regimen for patients with HIV-associated lymphoma. Patients treated in the HAART era have less chemotherapy-associated toxicity and improved survival.

Adult↗
PubMed2004

Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors.

PURPOSE: To determine whether therapy with a DNA methyltransferase inhibitor is effective in achieving demethylation and gene re-expression in tumor DNA in patients. METHODS: Biopsy specimens were obtained from patients with Epstein-Barr virus-associated tumors, enrolled on a clinical trial of 5-azacitidine, within 72 hours of the conclusion of the last infusion of the first cycle of therapy, and compared to pretreatment specimens. Methylation-specific polymerase chain reaction, bisulfite genomic sequencing, and immunohistochemistry were used to assess demethylation and gene re-expression. RESULTS: Substantial degrees of demethylation were detected in all latent and lytic Epstein-Barr virus promoters examined. Immunohistochemistry suggested activation of a previously silent viral antigen expression in one instance. CONCLUSION: Pharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients.

Antigens, Viral, Tumor↗
PubMed2004

Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin's lymphoma.

Epigenetic inactivation of RASSF1A, a putative tumor suppressor with proapoptotic activity, is frequently observed in a number of solid tumors, including a variety of epithelial cancers, but has not been described in hematopoietic tumors. We have analysed the expression and methylation status of RASSF1A in Hodgkin's lymphoma (HL)-derived cell lines, primary HL tumors and serum samples from HL patients. RASSF1A transcription was detectable in only 2/6 HL cell lines. Methylation-specific PCR and bisulfite genomic sequencing revealed that the RASSF1A promoter was hypermethylated in all four RASSF1A-nonexpressing cell lines. 5-aza-2'-deoxycytidine treatment resulted in demethylation of the promoter and RASSF1A expression in these lines. Hypermethylation of RASSF1A was also detected in 34/52 (65%) primary HL tumors and in 2/22 serum samples from these patients. Microdissection of Hodgkin/Reed-Sternberg (HRS) cells from several of these cases confirmed that the RASSF1A hypermethylation we detected in the analysis of whole tumor originated from the tumor cell population. Although hypermethylation of RASSF1A was detected in 5/6 non-Hodgkin's lymphoma (NHL)-derived cell lines, only rare primary NHL (1/10 of Burkitt's lymphoma, 1/12 of post-transplant lymphoma, 1/12 diffuse large B-cell lymphoma, 0/27 of nasal lymphoma, 0/8 follicular center cell lymphoma, 0/4 mantle cell lymphoma, 0/4 anaplastic large cell (Ki-1+) lymphoma, 0/2 MALT lymphoma) showed hypermethylation of the promoter. No methylation was detected in any of the 14 normal PBMC. These results point to an important role for epigenetic silencing of RASSF1A in the pathogenesis of HL. Inactivation of RASSF1A could be one mechanism by which HRS cells escape the apoptosis that should occur following nonproductive immunoglobulin gene rearrangements.

Apoptosis↗
PubMed2004

Smoking and Hodgkin lymphoma risk in women United States.

OBJECTIVE: Smoking has received little consideration as a risk factor for Hodgkin lymphoma (HL) in women, despite recent significant findings in men and gender differences in HL incidence. We investigated the association of HL with lifetime cigarette smoking and household environmental tobacco smoke (ETS) exposure in women. METHODS: In data from a population-based case-control study in women ages 19-79, we analyzed HL risk associated with self-reported smoking and household ETS exposure in 312 diagnostically re-reviewed cases and 325 random-digit dialing controls using logistic regression. Epstein-Barr virus (EBV) presence was determined in tumors of 269 cases. RESULTS: In 253 cases compared to 254 controls ages 19-44, risks of HL overall, and of nodular sclerosis and EBV-negative HL, were increased 50% with ETS exposure in childhood; for 11 cases of mixed cellularity (MC) HL, current smoking and adult ETS exposure also increased risk; for 24 cases of EBV-positive HL, risk was elevated for current smoking, greater smoking intensity and duration, and ETS exposure. In 59 cases and 71 controls ages 45-79, most smoking characteristics did not appear to affect risk. CONCLUSIONS: Apparent effects of current smoking on risks of MC HL and EBV-positive HL and of household ETS on risk of all HL in young adult females may broaden the evidence implicating tobacco smoke exposures in HL etiology.

Adult↗
PubMed2004

Inter- and intra-observer reliability of Epstein-Barr virus detection in Hodgkin lymphoma using histochemical procedures.

EBER in situ hybridization (EBER) and LMP-1 immunohistochemistry (LMP-1) are widely used for identifying Epstein-Barr virus (EBV) within tumor cells of Hodgkin lymphoma (HL), but measurement error has never been formally evaluated. To determine assay reliability, 40 HL tumors with known EBV status were stained for both EBER and LMP-1 by two laboratories and reviewed twice by four hematopathologists. Inter- and intra-observer agreement were good to excellent, with kappas above 0.78 overall and above 0.60 for most subgroup analyses. However, reliability varied by histologic subtype, preparing laboratory, reviewer and EBV status determined on consensus review. For EBER, inter-observer agreement was high for nodular sclerosis HL but somewhat lower for EBV-negative mixed cellularity HL. For LMP-1, agreement was excellent for mixed cellularity HL but somewhat less reliable for EBV-positive nodular sclerosis HL. Agreement was good for EBER and LMP-1 applied to the same specimens but differed by consensus EBV status. The variability in assay interpretation justifies caution in comparing EBV association results across HL studies and underscores the need for interpretation guidelines.

Herpesvirus 4, Human↗
PubMed2004

Oral valacyclovir as prophylaxis against herpes simplex virus reactivation during high dose chemotherapy for leukemia.

Reactivation of herpes simplex virus is a common event in patients undergoing dose-intensive remission induction or consolidation chemotherapy of acute leukemia, for which either intravenous or oral acyclovir provides effective prophylaxis. This drug's short serum half-life and low oral bioavailability make frequent dosing necessary, however, and we therefore sought to determine if the pro-drug valacyclovir, which has improved bioavailability, could be successfully substituted for this indication. Eighty-one patients with leukemia were randomized to receive either 500 mg or 1,000 mg of valacyclovir orally every 8 h and followed clinically, as well as with serial surveillance cultures. Over a total of 1,979 days on study between the groups, and 380 throat cultures, no documented episodes of herpes simplex reactivation were noted. Valacyclovir was tolerated well with no evident drug-related toxicities. We conclude that valacyclovir at either of the two doses studied can be safely substituted for oral or intravenous acyclovir, and that it provides effective prophylaxis against reactivation of herpes simplex virus in this patient population.

Acyclovir↗
PubMed2004

Hodgkin's lymphoma: evolving concepts with implications for practice.

Hodgkin's lymphoma is a unique neoplasm of B lymphocytes. Recent data provide new understandings of the pathogenesis and options for staging and therapy of the disease. Three specific topics are addressed in this chapter. In Section I, Dr. Richard Ambinder reviews implications of the relationship of Epstein-Barr virus (EBV) and Hodgkin's lymphoma. This relation includes varying geographic epidemiologic associations, including varying associations with the clinical syndrome of infectious mononucleosis. There are plausible mechanisms, including processes initiated by viral proteins, by which EBV might lead to tumorigenesis. These mechanisms include promotion of genetic instability and alteration of normal processes of apoptosis. In addition to an epidemiologic association and potential role in pathogenesis, viral antigens may pose theoretical targets for anti-cancer therapies, including vaccination. In Section II, Dr. Sigrid Stroobants describes the potential role of positron emission tomographic (PET) scanning. By assessing differences in the metabolic activities of cancer cells, PET scanning may be superior to computerized tomographic scanning, which is limited to showing structural anatomical abnormalities. In patients with Hodgkin's and non-Hodgkin's lymphoma, PET scanning has been tested as an initial staging tool, to assess the rate of therapeutic response from a prognostic perspective, and to differentiate residual tumor from fibrotic masses in patients who have completed therapy. Particularly in assessing the nature of a residual mass seen with other post-therapeutic imaging modalities, PET scanning may provide unique information; very high negative predictive values have been reported. However, before this technology can be recommended for incorporation into standard management, properly conducted prospective trials are required to better evaluate the clinical utility of PET with respect to eventual patient outcomes. In Section III, Dr. Ralph Meyer reviews current data regarding the management of patients with limited-stage Hodgkin's lymphoma. Over the past decade, standard treatment has evolved to consist of combined-modality therapy that includes an abbreviated course of chemotherapy and involved-field radiation. As this therapy continues to include radiation therapy, patients will remain at risk of long-term toxicities that include the development of second cancers and cardiovascular events. These "late-effects" now account for more deaths than those attributed to progressive Hodgkin's lymphoma. Comparative data testing the role of chemotherapy alone are now available and demonstrate that omission of radiation therapy results in small but statistically significant reduction in disease control, but no detectable differences in overall survival. Further follow-up will clarify whether chemotherapy alone is the preferred treatment option; at present patients should be informed of the trade-offs involved in choosing between this option and combined modality therapy.

Combined Modality Therapy↗