Genomic mapping in outbred mice reveals overlap in genetic susceptibility for HZE ion- and γ-ray-induced tumors.

Cancer risk from galactic cosmic radiation exposure is considered a potential "showstopper" for a manned mission to Mars. Calculating the actual risks confronted by spaceflight crews is complicated by our limited understanding of the carcinogenic effects of high-charge, high-energy (HZE) ions, a radiation type for which no human exposure data exist. Using a mouse model of genetic diversity, we find that the histotype spectrum of HZE ion-induced tumors is similar to the spectra of spontaneous and γ-ray-induced tumors and that the genomic loci controlling susceptibilities overlap between groups for some tumor types. Where it occurs, this overlap indicates shared tumorigenesis mechanisms regardless of the type of radiation exposure and supports the use of human epidemiological data from γ-ray exposures to predict cancer risks from galactic cosmic rays.

[Post-myocardial infarction depression]. / La depresión tras el infarto agudo de miocardio.

Major depression is a common finding among patients recovering from a myocardial infarction. Additionally, clinically significant depressive symptoms are present in other patients whose symptom severity or duration does not meet established criteria for a diagnosis of major depression. Over the last decade, increasing evidence suggests that in addition to its effect on patient s quality of life, post-MI depression also deserves attention because of a reported relation to increased morbidity and mortality. This evidence report reviews the studies that have studied depression or depressive symptoms in patients after an MI and focuses on the prevalence, clinical significance, treatment, and methods of evaluating this condition. A large number of studies have evaluated various aspects of post-MI depression including prevalence, its association with mortality, and major adverse events, and treatment.

Bone marrow protection with amifostine in the treatment of high-risk malignant lymphoma.

Based on preclinical and clinical studies which suggested that amifostine can protect against haematological toxicity of cyclophosphamide, we conducted a clinical trial of amifostine and intermediate doses of cyclophosphamide in patients with high-risk malignant lymphoma. 40 patients were enrolled to receive amifostine (910 mg/m2) before cyclophosphamide (1500 mg/m2) for two cycles (10 patients); 20 patients were allocated to receive amifostine/cyclophosphamide only on one cycle (patients were their own control) and 10 patients received cyclophosphamide alone without amifostine protection. Patients who received amifostine had fewer days of severe granulocytopenia (grade III or IV) and infectious episodes, and delay on treatment was minimal. Amifostine was well tolerated; only 2 patients developed transient and mild hypotension. The complete response rate was 72% (29/40). We conclude that amifostine is a good protector against haematological toxicity of cyclophosphamide and did not interfere with tumour response. Clinical trials with increasing doses of cytotoxic drugs or combination chemotherapy are needed to define the role of this myeloprotector agent in the treatment of patients with malignant lymphoma.

High dose chemotherapy with G-CSF in refractory Hodgkin's disease.

This study analyzed the long-term results in patients with Hodgkin's disease (HD) who were resistant or refractory to conventional chemotherapy and who were treated with intensive, non-myeloablative chemotherapy with granulocyte colony-stimulating factor (G-CSF) as hematological support. The study population included 86 patients who were treated with combination chemotherapy with high doses: BCNU, 300 mg/m2, on day 1, vincristine 1.4 mg/m2, and bleomycin 10 mg/m2 on days 1, 7, 14 and 21; etoposide 500 mg/m2, i.v., on days 14 and 15; and ifosfamide 4 g/m2, and epirubicin 180 mg/m2, on day 29. G-CSF 5 ug/kg/day, was used to ameliorate severe myelosuppression on days 3 to 13, 16 and 26 and 29 to 38. If a complete response was observed, two cycles of IOPP (ifosfamide 1.5 g/m2, i.v., on days 1 and 8; vincristine 1.4 mg/m2, i.v. on days 1 and 8; prednisone 60 mg/m2, p.o., daily, days 1 to 14 and procarbazine 100 ng/m2, p.o., daily, days 1 to 14 vere given as consolidation therapy. At 8-years, the overall survival rate vas 58% (50 out of 86 patients) being 38 and 76% in patients whose initial complete response was shorter or longer that 12 months, respectively or in 44% of induction failures. Hematological toxicity grade III or IV was observed in all cycles. However hematological recovery was already evident (median on day 13). Only transitory delay in continuing therapy was observed (median 3.9 days). Twenty-two patients developed infection-related granulocytopenia but no therapy related deaths were observed. G-CSF was well tolerated. This study indicates that the hematopoetic growth factor, G-CSF, was sufficient to act as hematological support in patients who received intensive, but non-myeloablative chemotherapy. In our opinion intensive chemotherapy without autologous transplant procedures can be considered in patients with refractory Hodgkin's disease because complete response rate and overall survival times are similar to more aggressive but more toxic regimens.

Effect of granulocyte colony-stimulating factor in patients with diffuse large cell lymphoma treated with intensive chemotherapy.

We investigated whether Granulocyte colony-stimulating factor (G-CSF) could prevent myelotoxicity or accelerate hematopoietic recovery after intensive chemotherapy in previously untreated patients with diffuse large cell lymphoma (DLCL). Forty-two patients were included in a prospective clinical trial in which alternating chemotherapy ESAP (etoposide, Solu-Medrol, cytosine arabinoside, cis-platinum), m-BECOD (low doses methotrexate, bleomycin, epirubicin, cyclophosphamide, vincristine, dexamethasone), MVPP-Bleo (mitoxantrone, vincristine, prednisone, procarbazine, bleomycin) were administered by 9 cycles. Each cycle was followed by 10 days of G-CSF (5 micrograms/kg/day) started five days after chemotherapy compared to a control group which received chemotherapy without G-CSF support. Leucocytes and granulocytes were significantly higher in patients receiving G-CSF compared to the control group. The total number of days of leukopenia (WBC counts below 2.0 x 10(9)/L and absolute granulocytes below 1.0 x 10(9)/L) were longer in the patients without G-CSF compared to those who received G-CSF (14.1 days versus 1.9 days). Delays in treatment were most frequent in the control group: 38% versus 4% in all cycles. Infection episodes occurred in 41 out of 168 cycles (25%) in the control group compared to 7 out of 172 (4%) in the G-CSF arm. Complete response was achieved in 12 out of 22 (54%) in the control group compared to 16 out 20 (80%) in the patients who received G-CSF. Toxicity secondary to G-CSF was mild. G-CSF can be administered safely to patients with DLCL and results in improved hematologic recovery after intensive chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Value of serum beta 2 microglobulin as an indicator of early relapse in diffuse large cell lymphoma.

In patients with diffuse large cell lymphoma treated with chemotherapy the presence of high levels of serum beta 2 microglobulin has been considered as a bad prognostic factor. Until now, attempts to detect early relapse in patients with diffuse large cell lymphoma have been sparse. To address this issue we began a prospective clinical trial to evaluate the role of different clinical, laboratory and radiographic tests in the detection of early relapse in non-Hodgkin's lymphoma (NHL). Only serum beta 2 microglobulin levels had clinical significance and 26 of 53 patients (49%) had abnormal levels, 3 to 23.1 months (mean 8.5 months) before evident relapse. Elevated serum lactic dehydrogenase (LDH) levels and beta 2 microglobulin were observed in six patients and all relapsed, suggesting that the combination of these two tests should be considered in future prospective clinical trials in order to define the utility of both tests to detect early relapse. This information may allow us to begin chemotherapy when the tumor mass is still low thereby making the probability of achieving a long second remission more likely.

GM-CSF instead of hematological support during high-dose chemotherapy for refractory malignant lymphoma.

Patients with refractory malignant lymphoma (RML) have a poor prognosis when treated with conventional chemotherapy. The use of high-dose chemotherapy has been limited by secondary myelosuppression. We report the use of intensive and short-duration chemotherapy in patients with RML who received granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of hematological support and salvage with bone marrow transplantation or infusion of peripheral blood stem cells. Thirty-one patients with RML were treated with cyclophosphamide: 7 g/m2, iv on day 1, followed by GM-CSF: 5 micrograms/kg/day, subcutaneously until hematological recovery (granulocytes > 1.8 x 10(9)/L) started on day 2. Methotrexate, 5 g/m2, was also given when the granulocytes and platelets counts were normal, followed by leucovorin rescue. Epirubicin, 180 mg/m2, iv, was given on day 29 if the granulocyte count was normal, and GM-CSF was started on day 30. Complete response was obtained in 21 out of 31 patients (67%) and partial response in 4 more, thus an overall response was achieved in 80% of the treated patients. Time to treatment failure was 24+ months, and the overall survival was 28+ months. Hematological toxicity grade IV, according to the WHO criteria was observed in all cycles, however hematological recovery was already evident on day 13 +/- 2. Eleven patients developed infection related to the treatment, but no therapy related death was observed. GM-CSF was well tolerated with minimal toxicity. Is evident that GM-CSF can act as hematological support after high-dose chemotherapy in patients who cannot undergo bone marrow transplantation programs.(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance therapy with interferon alfa 2b in Hodgkin's disease.

We performed a randomized clinical trial to assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with advanced Hodgkin's disease in complete remission (CR) after conventional chemotherapy. One hundred and thirty-five patients (stage IIIB-IV B) were initially treated with EBVD (epirubicin, bleomycin, vinblastine, dacarbazine). IF CR was achieved they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU three times a week for one year or no further treatment (control group). Clinical and laboratory characteristics at diagnosis were quite similar in both groups. After a median follow-up of 74.3 months (range 49 to 108), 61 out of 68 patients (91%; 95% confidence interval (CI): 76% to 97%) remain in first complete remission in the IFN-treated group compared to 38 out of 67 (58%; 95% CI: 49% to 71%) in the control group (p<.01). Overall survival was also better in the IFN treated group: 62 patients (92%; 95% CI: 82% to 97%) are alive free of disease at 7-years compared to 40 patients (67%, 95%: 55% to 76%) in the control group (p<.01). Toxicity secondary to IFN administration was mild and no dose modification was necessary during treatment. All patients received the planned dose of IFN. This was not an intent-to treat analysis. IFN administration as maintenance therapy was appears to be the only cause of improvement in outcome in these patients. We feel that IFN should be considered as maintenance therapy in patients with advanced Hodgkin's disease because this treatment improves the final outcome without the excessive toxicities of more aggressive therapeutic approaches such as bone marrow transplantation during first CR. We hope that IFN will be considered in future randomized clinical trials in order to define it's role in the treatment of Hodgkin's disease.

Late lethal events in patients with diffuse large B cell lymphoma: a review of 714 patients treated in a single centre.

Presence of late lethal events has been recognized as a complication in patients with malignant lymphoma. We reviewed 714 cases of patients treated during 1975-1995 with a long term follow-up (>4 years) in an attempt to identify all late events secondary to malignant lymphoma, either to the treatment or those which are unrelated. Forty-three patients died, and of these 21 (2.8%) were secondary to relapse and tumor progression; deaths associated with second neoplasm and cardiac events were increased 9.6 fold and 26.4 fold respectively compared to the general population. The risk factors for these complications did not differ from those in previous reports and included alkylating agents and/or radiotherapy for second neoplasms and anthracycline therapy and radiotherapy for cardiac toxicity. Moreover, 10 patients died secondary to non-related events. Nevertheless, at 10 years overall survival was 94% (95% confidence interval (CI): 82% to 98%) and event free survival was 97.1% (95% CI: 81% to 98%), for these patients. Thus, second events, fatal in most cases, will be considered as an expected risk in the treatment of patients with malignant lymphoma. The proposed modifications of therapy many indeed be useful to avoid or diminish these complications in the future.

Is Surgery Necessary in the Treatment of Primary Gastric Non-Hodgkin Lymphoma?

Fifty-two patients with primary gastric lymphoma were randomly assigned to two different surgical approaches. Twenty-eight cases were diagnosed by endoscopy and treated with chemotherapy CHOP-Bleo (cyclophosphamide, adriamycin, vincristine, prednisone and bleomycin) alternating with CMED (cyclophosphamide, metothexate, etoposide and dexamethasone). Twenty four cases underwent debulking surgery (partial or total gastrectomy) followed by the same chemotherapy. No differences were observed in relapse free disease or survival in resected or unresected patients. Complications were more frequent and severe in patients who underwent surgery. We believe that surgery is not necessary in the treatment of patients with primary gastric lymphoma.

Beta 2 microglobulin level as an indicator of prognosis in diffuse large cell lymphoma.

We report results of our investigation of prognostic factors for patients with diffuse large cell lymphoma (DLCL) who were entered on the same treatment protocol and who had known pretreatment serum beta 2 microglobulin levels. Serum beta 2 microglobulin, bone marrow involvement, performance status and lactic dehydrogenase (LDH) levels were associated with a poor prognosis in univariate analysis. However, only beta 2 microglobulin remained of prognostic significance in a multivariate analysis with statistical differences at different cut off levels. We believe that beta 2 microglobulin levels accurately separate patients into low-, intermediate- and high-risk patients. It is concluded that serum beta 2 microglobulin is the most significant prognostic factor currently available for DLCL and should be incorporated in the initial staging in order to provide a basis for designing the therapeutic approach in these cases.

Malnutrition as an adverse prognostic factor in patients with diffuse large cell lymphoma.

To assess the usefulness of nutritional status at diagnosis, we studied a group of 87 adult patients with diffuse large cell lymphoma (DLCL) in a prospective clinical trial. Nutritional status (NS) was measured by the combination of triceps skinfold, arm circumference and serum determinations of albumin and transferrin. Normal values were considered if the nutritional index was < 40, malnutrition was considered when the nutritional index was > 40. Fifty one (58%) of the patients presented with malnutrition at diagnosis with a nutritional index > 40. Malnourished patients had a significantly poorer outcome than well-nourished patients because overall survival was better: 57+ months (mean) in well-nourished patients compared to only 14 months (mean) in malnourished patients. Disease-free survival was also better in the patients with normal NS: 48% compared to 10% in patients with abnormal NS. Chemotherapy was better tolerated in the well-nourished cases with less delay in treatment schedule, less episodes of severe myelosuppression and infection and more dose intensity than patients with nutritional index > 40. Multivariable analysis indicates that malnutrition was a poor prognostic factor independent of other prognostic factors. We believe that malnutrition itself might be included as an adverse prognostic factor in patients with DLCL and studies to improve this clinical situation will be conducted.

Hodgkin's disease and acute leukemia. Is it a true association?

The incidence of secondary malignancy was assessed in 537 patients with Hodgkin's disease treated with radiotherapy (128 patients), chemotherapy alone (156 patients), or in combined modality therapy (253 patients) between January 1973 to September 1985 with a median follow-up of 7.5 years. The dose of radiation therapy, dose of cytotoxic drugs and sequence of treatment was carefully analyzed. No cases of acute leukemia or other secondary malignant disease were identified in these cases. No differences in clinical laboratory features or treatments were identified in relation to previous reports. Racial difference is the unique feature which seems to avoid the development of this complication in patients treated for Hodgkin's disease. We hope that other reports in Latin America can contribute to the identification of race as the difference.

Biological modifiers (etretinate (changed from etetrinate) and alfa 2a) in the treatment of refractory cutaneous T-cell lymphoma.

To assess the efficacy and toxicity of biological modifiers in combination etetrinate, 0.8 mg/kg/day, po and interferon alfa 2a 9.0 MU, three times at week) in the treatment of refractory cutaneous T-cell lymphoma (CTLC) we began a clinical study on 12 heavily treated patients. After 1 year on treatment 10/12 patients (83%) achieved complete response. Two patients were considered failures with disease progression. After a median follow-up of 3 years, seven patients (56%) remained in complete remission. Toxicity was mild. All patients received 93% of the planned dose of etetrinate and interferon. We feel that biological modifiers, as etetrinate and interferons, are agents with limited hematological toxicity even in higher doses. The combination of two agents, with different mechanisms of action, could improve the outcome in patients with refractory CTCL. Controlled trials are necessary to define the roles of this type of therapy as first line of treatment.

Evaluation on a six-dose treatment of anti CD 20 monoclonal antibody in patients with refractory follicular lymphoma.

Treatment of refractory follicular lymphoma with monoclonal antibody CD 20 has been proven to be a good therapeutic option. However, most studies used four weekly doses and time to treatment failure (TTF) and overall survival (OS) could be considered very short: 11.0 and 13.6 months respectively. We started a pilot study to evaluate if six infusions at the same doses and schedule could improve the outcome in these patients. Seventeen patients with refractory follicular lymphoma heavily treated with chemotherapy (> 2 regimens), radiotherapy and biological modifiers were enrolled in a pilot study. They received 6 weekly doses, at 375 mg/m2, of monoclonal anti CD 20. In an intent to treat analysis, overall response was 76%, of which 47% (8 patients) were complete response and 5 patients were partial response. With a median follow-up of 28.6 months, 7 complete responders remain alive, free of disease, and 2 partial responses remain stable without additional treatment. Median to TTF has not been reached; yet, actuarial curves showed that at 3 years, 53% of patients are alive. The four patients who were failure died secondary to tumor progression. Overall survival (OS) at 3-year was 76%. Toxicity was mild, all patients completed the schedule on time and doses. The addition of two doses of anti CD 20 clearly improved OS and TTF in a group of patients with refractory follicular lymphoma heavily treated and with poor prognostic factors. However, the number is too short to draw definitive conclusions; more clinical trials are necessary to determine if 4 or 6 doses of anti CD 20 therapy are better in this setting of patients.

Treatment of refractory Hodgkin's disease with modified Stanford V program.

This study analyzes the results using an Stanford V modified program in the treatment of refractory Hodgkin's disease (RHD). We used cyclophosphamide instead of mechloretamine, and epirubicin instead of doxorubicin to avoid the risk of acute and late side effects associated with this drugs. Seventy-one patients with RHD were treated. All were at an advanced stage at therapy and had associated adverse prognostic factors. The complete response (CR) rate was 84% (60 patients; 95% confidence interval [CI]: 72-91%). At 5 yr, actuarial overall survival (CS) is 71% (95% Cl: 59-78%) and event-free survival (EFS) is 70% (95% CI: 59-79%). Only the duration of the initial complete response (> 12 mo) influenced the duration of EFS and OS. Toxicity was mild. Granulocyte colony-stimulating factor to ameliorate the presence of severe myelosuppression was used only in a few patients. Cardiac function was not affected and, until now, late side effects has not been observed. Thus, the use of this modified Stanford program retains the usefulness of the original scheme both with less frequent and less severe acute and late side effects. A controlled clinical trial in untreated patients comparing the Stanford program with standard chemotherapy is warranted to define the role of this therapeutic option in patients with Hodgkin's disease.

[Comparative study of high doses vs conventional doses of cytosine arabinoside combined with cisplatin and dexamethasone in patients with refractory lymphoma]. / Estudio comparativo de dosis altas vs dosis convencionales de arabinósido de citosina en combinación con cisplatino y dexametasona en pacientes con linfoma refractario.

Forty-three patients with advanced malignant lymphoma resistant to previous chemotherapy were randomized in two groups: one received a high dose versus a low-dose cytosine arabinoside, in combination with dexamethasone and cisplatinum. Ten of 24 patients (41%) in the low-dose regimen achieved response: six complete remission (CR) and four partial remission (PR), compared with 5 of 19 (30%) (three CR and two PR). Survival was better in the low dose regimen: 39 versus 23 weeks. Toxicity was most frequent and severe in the high dose schedule. These results suggests that the use of cytosine arabinoside and cisplatinum is useful in the treatment of refractory lymphoma, and that the low-dose would be a better alternative than a high dose.

[The role of radiotherapy in the early stages of Hodgkin's disease]. / El papel de la radioterapia en las etapas tempranas de la enfermedad de Hodgkin.

The outcome of treatment for a first relapse in early stages (IA and IIA) of Hodgkin's disease after primary radiotherapy was analyzed in 86 patients. They received total nodal radiotherapy (TNR) as the primary treatment. Survival was used as the major endpoint. Median follow-up was 13.1 years. Duration of first complete remission was 60% for patients in stage IA and 39% for patients in stage IIA (p < .01). At 10-years, the survival for patients in stage IA was 78% and only 55% for patients in stage IIA (p < .01). A risk factor analysis showed that the presence of stage IIA and bulky disease (adenopathy > 7 cm) were associated with a worse prognosis. We believe that the use of TNR as initial treatment in early stages of Hodgkin's disease should be considered in patients in stage IA and without bulky disease. Patients in stage IIA and risk factors, such as bulky disease, should be treated with more aggressive therapeutic regimens.

[Prognostic importance of beta-2-microglobulin in multiple myeloma]. / Importancia pronóstica de la beta 2-microglobulina en mieloma múltiple.

Beta 2 microglobulin is a low molecular weight protein found on the surface of all nucleated cells: it is the light chain of the HL-A histocompatibility complex. The increased levels of serum beta 2 microglobulin in patients with multiple myeloma have been associated with a poor prognosis. Pretreatment levels of serum beta 2 microglobulin were estimated in 70 previously untreated patients with multiple myeloma. In a multivariate analysis, serum beta 2 microglobulin levels and stage were the most significant prognostic factors for survival independent of other risk factors associated with a worse prognosis. There was a clear difference in survival duration observed between the patients with a high pretreatment level of beta 2 microglobulin and stage III (none alive at 5 years) compared with patients with normal levels and stage I (80% alive at five years) (p less than .001). We conclude that pretreatment-beta 2 microglobulin level is one of the most useful prognostic factors in patients with multiple myeloma.