A common polymorphism in the 3' untranslated region of the stromal cell-derived factor 1 (also called pre-B-cell-stimulating factor) beta gene transcript, termed SDF1-3'A, has been associated with an ...increased risk of non-Hodgkin's lymphoma (NHL) in HIV-1-infected, but not in uninfected, individuals. Because the gene variation is located within the 3' untranslated region, the SDF1-3'A may influence the abundance of SDF-1 mRNA, possibly up-regulating the chemokine expression especially in the presence of HIV-1. In the current study, we investigated the levels of SDF-1 mRNA in peripheral blood mononuclear cells and HIV-1 viral load in 84 HIV-1-infected children (0.7 to 18 years of age; median, 5.8), including 12 children who developed NHL during their illnesses (AIDS-NHL group; 8 with SDF1-3'A, 4 with SDF1-wild-type). High level SDF-1 expression was observed in 15 of 34 children with SDF1-3'A as compared with 10 of 50 with wild type (P < 0.03). More notably, the children with AIDS-NHL had significantly elevated levels of SDF-1 mRNA in peripheral blood mononuclear cells, obtained at the time of presentation in 10 children and 8.5 to 19.4 months before (median, 15 months) in 7 children, as compared with the children in the non-NHL group (P < 0.00001). The amounts of cell-associated HIV-1 DNA and singly spliced HIV-1 mRNA were significantly greater in children with AIDS-NHL than those with non-NHL AIDS (P = 0.0052 and 0.011, respectively; stratified by antiretroviral treatment regimen), whereas their serum HIV-1 RNA levels were comparable. Overexpression of SDF-1 and aberrant HIV-1 expression in circulating lymphocytes appear to be linked to the development of AIDS-lymphoma. Additional studies are required to determine whether excessive SDF-1, together with virally encoded factors, is directly involved in the pathogenesis of AIDS-lymphoma.
Recently we have observed an increased incidence of opportunistic infections in patients treated with intensive chemotherapy for cancer. Because T-cell depletion is associated with similar clinical ...events in human immunodeficiency virus infection and after bone marrow transplantation, we have analyzed peripheral blood lymphocyte populations in a series of patients during treatment with intensive chemotherapy for cancer. Although neutrophil, monocyte, and platelet numbers consistently recovered to greater than 50% of pretreatment values after each sequential cycle of therapy, lymphocyte numbers did not recover within the same time period. B cells decreased rapidly from a mean value of 149 ± 46/mm3 before chemotherapy to 4 ± 1/mm3 during chemotherapy (P = .011. CD4+ T cells decreased from a mean of 588 ± 76/mm3 before chemotherapy to 105 ± 28/mm3 during chemotherapy (P= .0002) and CD8+ T cells decreased from a mean of 382 ± 41/mm3 before chemotherapy to 150 ± 46/mm3 during chemotherapy (P = .0009). Natural killer cell numbers did not show significant declines (171 ± 30/ mm3 before, 114 ± 24/mm3 during, P = .19). Based on the history of opportunistic complications in patients with other disorders who display similar degrees of CD4+ T-cell lymphopenia and preliminary observations in this population, immune incompetence could surface as a dose-limiting toxicity for highly dose-intensive chemotherapy regimens.
This is a US government work. There are no restrictions on its use.
To evaluate long-term survivors of high-grade non-Hodgkin's lymphomas (NHLs) for late effects and to attempt to assess the relative contributions of the primary treatment modalities to these late ...effects.
Of 103 young survivors followed up for 1 to 20 years, 74 patients were interviewed and underwent various investigations, and an additional 12 patients were interviewed only. Of the 86 patients, 65 had previously suffered from small non-cleaved-cell lymphoma, 16 from lymphoblastic lymphoma, and five from large-cell lymphoma.
Left ventricular dysfunction was identified in eight of 57 (14.0%) patients who had received doxorubicin (DOX) in doses greater than 200 mg/m2, of whom four were symptomatic and four were asymptomatic. A ninth patient required a pacemaker. Of the 86 patients, 23 (26.7%) reported pregnancies, 18 of whom had 30 children. Two of the 86 (2.3%) patients developed second cancers. Other major late effects included posttransfusion viral hepatitis, eight patients; CNS toxicity, two patients; endocrine impairment, 14 patients; vitamin B12 deficiency, two patients; esophageal stricture, one patient; urinary tract problems, two patients; and musculoskeletal defects, three patients. Major late effects occurred in 11 of 21 (52.4%) patients who had received radiation as well as chemotherapy, eight of 22 (36.4%) patients who had surgical resections as well as chemotherapy, and 17 of 74 (23.0%) patients who had received chemotherapy alone.
The predominant major late effects observed were late cardiac toxicity related to DOX therapy and hepatitis C virus infection that presumably resulted from blood product transfusions administered before the introduction of screening for the hepatitis C virus. Fertility was not greatly impaired, and second malignancies were uncommon. No patient had clinically significant impairment of growth. Radiation appeared to increase the likelihood of late effects.
Of 120 patients with small noncleaved-cell lymphoma who were entered sequentially on four National Cancer Institute (NCI) protocols, 29 (24%) had CNS involvement at some time in their clinical ...course. Seventeen had initial CNS involvement, and 12 developed CNS involvement at the time of first relapse. All 29 patients had extensive disease at presentation. The median serum lactate dehydrogenase (LDH) levels at presentation were 1,150 IU/L for patients with initial CNS involvement and 1,083 IU/L for patients with CNS involvement at relapse. CNS disease was significantly associated with serum LDH levels (P less than .0001), bone marrow involvement (P less than .0001), and jaw involvement (P = .018), but not involvement of the abdomen. There were nine long-term survivors among the 29 patients (31%). CNS disease did not appear to confer a worse prognosis on these patients than on patients without CNS involvement who had similar degrees of serum LDH elevation or who had bone marrow involvement, suggesting that extensive disease rather than CNS involvement was responsible for the poor prognosis. Event-free survival for patients with serum LDH levels above 500 IU/L was not different whether CNS disease was present or not (P = .29), nor was event-free survival different for patients with stage IV disease, whether CNS disease was present or not (P = .92). Although some patients had CNS radiation, there was no evidence that this was of therapeutic benefit. Intrathecal (IT) chemoprophylaxis effectively prevented spread to the CNS in patients without initial CNS involvement. Five of 18 patients (28%) who received no IT prophylaxis had CNS relapse (four isolated to the CNS), but only seven of the 85 patients (8%) who received IT prophylaxis had CNS relapse (two isolated to the CNS). The differences in overall and isolated CNS relapse rates were statistically significant (P = .034 and P = .008, respectively).
We have retrospectively examined the outcome of 41 patients with high grade non-Hodgkin's lymphomas (NHL) and central nervous system (CNS) involvement who were treated with and without radiation at a ...single institution. Group I consisted of 25 patients with CNS involvement at presentation and Group II, of 16 with CNS involvement at first relapse. All 41 had systemic disease at diagnosis and received systemic and intrathecal chemotherapy. Response to therapy did not differ whether patients received concomitant radiation or no CNS radiation. Thirteen of 16 non-irradiated (81%) and 8 of 9 irradiated Group I patients (89%) achieved complete responses. Three of 4 non-irradiated (75%) and 7 of 12 irradiated (58%) Group II patients achieved complete responses. CNS relapse patterns were similar whether or not patients were irradiated, and regardless of radiation dose. Most patients (18) failed systemically; there were few (6) isolated CNS relapses. Survival was not improved by the addition of radiation. Of the 15 patients who achieved long term survival, 13 remained disease-free throughout their clinical course: 7 of these 13 patients (all Group I) did not receive CNS radiation and 6 (4 Group I, 2 Group II) did. In this series, in which 44% of patients who presented with CNS disease and 13% of those who relapsed with CNS became long term disease-free survivors, there was no discernable benefit from radiation, but increased toxicity was observed.
Summary
Prior to the introduction of the International Network for Cancer Treatment and Research (INCTR) protocol INCTR 03‐06, survival of patients with Burkitt lymphoma at four tertiary care centres ...in equatorial Africa was probably no more than 10–20%. The results reported here for 356 patients have demonstrated marked improvement in survival through the use of a uniform treatment protocol consisting of cyclophosphamide, methotrexate, vincristine, and intrathecal therapy, and the introduction of non‐cross resistant second‐line (salvage) therapy, consisting of ifosfamide, mesna, etoposide and cytarabine, when patients failed to achieve a complete response to first‐line therapy or relapsed early. Overall survival rates of 67% and 62% were observed at 1 and 2 years (relapse is rare after 1 year of remission). Of interest was the small impact of cerebrospinal fluid (CSF) and bone marrow involvement on outcome. However, the presence or absence of abdominal involvement clearly defined two prognostic groups. An additional finding was the association between CSF pleocytosis and orbital tumours, suggesting that spread of tumour cells to the central nervous system may sometimes occur via direct involvement of cranial nerves in the orbit. Survival rates may be increased in patients with abdominal involvement by combining first‐ and second‐line therapy, but verification will require a further clinical study.
PDF
