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Allogeneic blood transfusions have immunomodulatory effects and have been associated with activation of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) in vitro and of HIV in small pilot studies. Retrospective studies suggest that transfusions adversely affect the clinical course of HIV. Data in selected non-HIV-infected patients requiring blood transfusion have suggested clinical benefit with leukocyte-reduced red blood cells (RBCs).To compare the effects of leukoreduced and unmodified RBC transfusions on survival, complications of acquired immunodeficiency syndrome, and relevant laboratory markers in HIV-infected patients.Double-blind randomized controlled trial conducted in 11 US academic medical centers from July 1995 through June 1999, with a median follow-up of 12 months (24 months in survivors).A total of 531 persons infected with HIV and CMV, aged 14 years or older, who required transfusions for anemia; 259 received leukoreduced transfusions and 262 received unmodified transfusions (10 did not receive the planned transfusion).Survival and change in plasma HIV RNA level 7 days after transfusion, compared by type of transfusion.At entry, the groups were similar in demographic, clinical, and relevant laboratory characteristics. A total of 3864 RBC units were transfused. Two hundred eighty-nine deaths occurred (151 with leukoreduced transfusion; 138 with unmodified transfusion); median survival was 13.0 and 20.5 months, respectively (relative hazard [RH], 1.20; 95% confidence interval [CI], 0.95-1.51; log-rank P =.12). Analyses adjusted for prognostic factors suggested possible worse survival with leukoreduction (RH, 1.35; 95% CI, 1.06-1.72). There was no difference in time to new opportunistic event/death or frequency of transfusion reactions. No changes in plasma HIV RNA level were seen in either group at days 7, 14, 21, or 28, even in patients not taking antiretroviral drugs. There were no differences in trends between groups in CMV DNA, CD4 cell counts, activated (CD38% or human leukocyte antigen-DR) CD8 cell counts, or plasma cytokine levels.We found no evidence of HIV, CMV, or cytokine activation following blood transfusion in patients with advanced HIV infection. Leukoreduction provided no clinical benefit in these patients. These data demonstrate the importance of conducting controlled studies of effects of leukoreduction in different patient populations, since smaller studies in other patient populations have suggested leukoreduction may be beneficial.

The importance of plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA in pregnant women in relation to the other factors known to influence the risk of transmission of infection to their infants is incompletely defined. We studied the relation of maternal plasma HIV-1 RNA levels to the risk of perinatal transmission and the timing of transmission.We measured plasma HIV-1 RNA serially in 552 women with HIV-1 infection who had singleton pregnancies. The status of infection in their infants was assessed by culture of blood and further classified as early (if a culture of blood obtained within the first two days of life was positive) or late (if a culture of blood obtained in the first seven days of life was negative but subsequent cultures were positive). The rates of transmission at various levels of maternal plasma HIV-1 RNA were analyzed by tests for trend, with adjustment for covariates by stratification and logistic regression.Increasing geometric mean levels of plasma HIV-1 RNA were associated with increasing rates of transmission: the rate was 0 percent among women with less than 1000 copies per milliliter (0 of 57), 16.6 percent among women with 1000 to 10,000 copies per milliliter (32 of 193), 21.3 percent among women with 10,001 to 50,000 copies per milliliter (39 of 183), 30.9 percent among women with 50,001 to 100,000 copies per milliliter (17 of 55), and 40.6 percent among women with more than 100,000 copies per milliliter (26 of 64) (P0.001). The treatment status of one woman was unknown. The highest rate of transmission was among women whose plasma HIV-1 RNA levels exceeded 100,000 copies per milliliter and who had not received zidovudine (19 of 30 women, 63.3 percent). Neither higher HIV-1 RNA levels early in pregnancy nor higher levels late in pregnancy were associated with the timing of infection in the infants.In pregnant women with HIV-1 infection the level of plasma HIV-1 RNA predicts the risk but not the timing of transmission of HIV-1 to their infants.

To determine differences in rates of reactivity to purified protein derivative (PPD) tuberculin and of skin test anergy in relationship to serostatus, immune status, demographic characteristics, and other risk factors in women infected with or at high risk for infection with HIV-1; and to compare the usefulness of three different antigens in assessing delayed type hypersensitivity.Cross-sectional analysis of baseline data in a multicenter prospective cohort study of 1343 HIV-1-seropositive and 390 seronegative but at-risk women recruited from sites of HIV primary care and through community-based outreach for a longitudinal cohort study.4.7% of the 1343 HIV-1-seropositive women and 15.4% of the 390 HIV-seronegative women were tuberculin-positive (p.001). A lower threshold in millimeters of induration for tuberculin reactivity among HIV-seropositive women resulted in a smaller difference between the seropositive and the seronegative groups. Even when a 2-mm threshold was used in HIV-seropositive respondents, with a 10-mm threshold among seronegative participants, the difference between the seropositive (6.9% reactive) and the seronegative (15.4% reactive) groups remained statistically significant (p.001). Limiting analysis to women who responded to the non-PPD antigens did not eliminate the differences in PPD reactivity between the HIV-seropositive and HIV-seronegative women. In multivariate analysis, tuberculin reactivity was associated with HIV-negative serostatus, a history of tuberculosis infection or disease, geographic site, and CD4 count200 cells/mm3 in the HIV-seropositive women. In all, 41% of HIV-seropositive women and 12% of seronegative women were anergic (p.001). Candida antigen had the lowest response rates. In multivariate analyses, only HIV-serostatus and CD4 cell counts in HIV-seropositive women were significantly associated with anergy.In this community-based cohort of HIV-seropositive and HIV-seronegative women, we found significant differences between the seronegative and seropositive women even with a lower threshold of induration defining PPD reactivity among seropositive women and among women not anergic to the non-PPD antigens. Prevalence of PPD reactivity was higher than in previously described in cohorts of homosexual men, but lower than in cohorts of predominantly male injection drug users. Rates of anergy were similar to those in most previously described cohorts.

To determine the seroprevalence of, and risk factors for, HTLV-I and HTLV-II infection among HIV-infected women and women at high risk for HIV infection.Cross-sectional analysis of baseline data for women enrolled in the prospective Women's Interagency HIV Study (WIHS).From October 1994 through November 1995, 2657 women from five metropolitan areas in the United States (Chicago, Los Angeles, New York City [two sites], Northern California, and Washington DC) were enrolled in WIHS. An interview-based survey collected data on demographics, behavior, and medical history. HTLV-I and HTLV-II determinations were made using a combined HTLV-I/HTLV-II indirect immunofluorescent antibody (IFA) screening test, an IFA titration specificity test, and individual HTLV-I and HTLV-II confirmatory Western blots. Fisher's exact tests and logistic regression were used to determine univariate and multivariate independent predictors for HTLV-II infection.Of 2625 women enrolled in WIHS with confirmed HIV results, 2487 (95%) were tested for HTLV-I and HTLV-II. Of these, 241 (10%) were HTLV-II-seropositive and 13 (0.5%) were HTLV-I-seropositive. On multivariate analysis, independent predictors of HTLV-II infection included injection drug use (OR = 5.2; p.001), black race (OR = 3.6; p0.001), age35 years (OR = 3.3; p.001) and a history of sex with a male injecting drug user (OR = 1.9; p.001). Among women infected with HIV, the seroprevalence of HTLV-II was 11% compared with 6% for women at risk for HIV but not infected (p.001). However, HIV was not an independent predictor of HTLV-II infection in multivariate analysis.This cross-sectional analysis confirms that HTLV-II is found commonly in HIV-infected women and uninfected women at risk for HIV in major urban areas throughout the United States and that HTLV-II is far more common than HTLV-I in these populations. Although injecting drug use is most strongly associated with HTLV-II infection, sexual transmission likely contributes to the high HTLV-II seroprevalence in this cohort.

The Women's Interagency HIV Study comprises the largest U.S. cohort to date of human immunodeficiency virus (HIV)-seropositive women (N = 2,058) with a comparison cohort of seronegative women (N = 568). The methodology, training, and quality assurance activities employed are described. The study population, enrolled between October 1994 and November 1995 through six clinical consortia throughout the United States (totaling 23 sites) represents a typically hard-to-reach study population. More than half of the women in each cohort were living below the federally defined levels of poverty. The women ranged in age from 16 to 73 years; approximately one-quarter self-identified as Latina or Hispanic, over one-half as African-American not of Hispanic origin, and less than 20% as white, non-Hispanic origin. Self-reporting of HIV exposure risk included injection drug use by 34% of the seropositive women and 28% of the seronegative women, heterosexual contact (42% vs 26%), transfusion risk (4% vs 3%) and no identified risk (20% vs 43%). Demographic and HIV exposure risk characteristics of the seropositive cohort were comparable with characteristics of nationally reported AIDS cases in U.S. women. This well characterized cohort of HIV-seropositive and high-risk seronegative women represents a rich opportunity for future studies of HIV disease progression and pathogenesis.

To assess changes in lymphocyte subsets during pregnancy and 1 year postpartum in human immunodeficiency virus (HIV)-infected women.Changes in CD4+ and CD8+ cell counts, CD4 and CD8 percent, CD4/CD8 ratio, and total lymphocyte count and percent were assessed in each of 226 HIV-infected women followed during pregnancy and 1 year postpartum, and for each of 100 nonpregnant HIV-infected woman during 1 year. Trends over time were compared between pregnant women with and without several covariates. Postpartum changes over a 1-year period were compared to a 1-year period in the nonpregnant cohort.There was a mean increase of 2.76 per week in the CD4+ cell count during pregnancy (P = .04). No other characteristics changed significantly during pregnancy. The mean CD4+ and CD8+ cell counts, the CD8 percent, and the total lymphocyte count and percent increased immediately postdelivery. During the first postpartum year, there were statistically significant declines in the absolute CD4+ and CD8+ cell counts, the relative CD4 and CD8 percentages, and the total lymphocyte count and percentage. The rate of change for CD4+ and CD8+ counts, but not for CD4 percent, was less during 1 year in the nonpregnant cohort than in the first postpartum year, and the CD8 percent increased in the nonpregnant women. A wide variability in trends of all measurements during pregnancy was seen.During pregnancy, CD4 and CD8 percentages remain stable. There are no clinically significant changes during pregnancy or postpartum in any lymphocyte parameter we assessed. Postpartum changes in lymphocytes and lymphocyte subsets most likely represent a return to baseline from the physiologic changes of pregnancy and the immediate postpartum period.

There are only limited data on human immunodeficiency virus type 1 (HIV-1) RNA in perinatally infected infants. Understanding the dynamics of HIV-1 infection and its relation to disease progression may help identify opportunities for effective antiviral treatment in infected infants.We obtained plasma samples from 106 HIV-infected infants at birth; at 1, 2, 4, 6, 9, 12, 15, and 18 months of age; and subsequently every 6 months. HIV-1 RNA was assayed by means of a reverse-transcription polymerase chain reaction. The infants were born between 1990 and 1993, and only 21 percent of the infants' mothers received any treatment with zidovudine during pregnancy.Plasma HIV-1 RNA levels increased rapidly after birth, peaked at 1 to 2 months of age (median values at 1 and 2 months, 318,000 and 256,000 copies per milliliter, respectively), and then slowly declined to a median of 34,000 copies per milliliter at 24 months. Newborns with a first positive HIV-1 culture within 48 hours after birth had significantly higher HIV-1 RNA levels, although only during the first two months of life, than those with a first positive culture seven or more days after birth. Infants with a rapid progression of disease had higher peak HIV-1 RNA levels in the first two months of life than those without rapid progression (median value, 724,000 vs. 219,000 copies per milliliter; P=0.006), as well as a higher geometric mean value during the first year of life (median value, 330,000 vs. 158,000 copies per milliliter, P=0.001).In perinatally infected infants, HIV-1 RNA levels are high and decline only slowly during the first two years of life. Infants with very high viral loads in the first months of life are at increased risk for a rapid progression of disease, which suggests that early treatment with antiretroviral agents may be indicated for these infants.

It has been suggested that a positive diagnostic test for human immunodeficiency virus type 1 (HIV-1) during the first 48 h of life is indicative of intrauterine transmission, whereas negative tests during the first week with positive tests later indicate intrapartum transmission. On the basis of data from all 140 infected infants in the Women and Infants Transmission Study (WITS), the probability was estimated that an HIV-1 culture would be positive for the first time at each day of life if cultures were performed daily. The estimated probabilities (+/-SE) by days 0, 2, 4, 7, 9, 16, and 30 of life are 27.4% (+/-6.4%), 27.4% (+/-13.0%), 45.3% (+/-20.5%), 45.3% (+/-22.5%), 65.3% (+/-20.0%), 88.4% (+/-7.8%), and 89.3% (+/-7.0%), respectively. The initial 27% probability is consistent with the hypothesis that transmission usually occurs during the intrapartum period. However, the distribution of age at first positive culture does not separate clearly into two distinct intervals. More definitive methods for determining the timing of transmission are needed.

A substantial proportion of perinatally acquired infections with the human immunodeficiency virus type 1 (HIV-1) occur at or near delivery, which suggests that obstetrical factors may have an important influence on transmission. We evaluated the relation of such factors and other variables to the perinatal transmission of HIV-1.The Women and Infants Transmission Study is a prospective, observational study of HIV-1-infected women who were enrolled during pregnancy and followed with their infants for three years after delivery. We studied obstetrical, clinical, immunologic, and virologic data on 525 women who delivered live singleton infants whose HIV-1-infection status was known as of August 31, 1994.Among mothers with membranes that ruptured more than four hours before delivery, the rate of transmission of HIV-1 to the infants was 25 percent, as compared with 14 percent among mothers with membranes that ruptured four hours or less before delivery. In a multivariate analysis, the presence of ruptured membranes for more than four hours nearly doubled the risk of transmission (odds ratio, 1.82; 95 percent confidence interval, 1.10 to 3.00; P = 0.02), regardless of the mode of delivery. The other maternal factors independently associated with transmission were illicit-drug use during pregnancy (odds ratio, 1.90; 95 percent confidence interval, 1.14 to 3.16; P = 0.01), low antenatal CD4+ lymphocyte count (29 percent of total lymphocytes) (odds ratio, 2.82; 1.67 to 4.76; P0.001), and birth weight2500 g (odds ratio, 1.86; 1.03 to 3.34; P = 0.04).The risk of transmission of HIV-1 from mother to infant increases when the fetal membranes rupture more than four hours before delivery.

To determine the sensitivity and specificity of anti-human immunodeficiency virus (HIV) IgA in identifying infected infants at or before 6 months of age among the offspring of HIV-infected mothers.Prospective comparison of anti-HIV IgA measurement performed in 2 different laboratories by 2 different methods with the criterion standard of blood culture.Five centers in the United States and Puerto Rico.Population-based sample of 156 infants of HIV-infected mothers in the Women and Infants Transmission Study.Results of anti-HIV IgA test in relation to the infection status of the infants as measured by blood culture.Six-month plasma or serum samples were first tested in the 2 laboratories. The sensitivity and specificity of anti-HIV IgA in detecting infected infants at this age by laboratories 1 and 2 were 69% and 63% and 100% and 99%, respectively. A look-back study of samples obtained at birth, 1, 2, and 4 months was then performed on all infected children and a matched set of uninfected children. The performance of the test at birth was unsatisfactory in both laboratories (sensitivity 44% and 33%, specificity 43% and 60%), whether peripheral or cord blood was examined. At 1, 2, and 4 months, the sensitivity of the test was lower than at 6 months, but specificity was high. A modest correlation of absent anti-HIV IgA antibody and low percentage of CD4 cells in peripheral blood was seen at 6 months of age.The anti-HIV IgA test has moderate sensitivity and high specificity for the diagnosis of HIV infection at 6 months of age in the offspring of infected mothers.

The survival of patients with Hodgkin's disease has dramatically improved over the past 30 years because of advances in treatment. However, concern for the risk of long-term complications has resulted in a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. One major consequence of successful treatment of Hodgkin's disease is the development of second malignant neoplasms. We sought to determine the factors most important for development of second tumors in pathologically staged and treated Hodgkin's disease patients followed for long intervals to provide background information for future clinical trials and guidelines for routine patient follow-up. Between April 1969 and December 1988, 794 patients with laparotomy staged (PS) IA-IIIB Hodgkin's disease were treated with radiation therapy (RT) alone or combined radiation therapy and chemotherapy (CT). There were 8,500 person-years of follow-up (average of 10.7 person-years per patient). Age and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed to expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. Seventy-two patients have developed a second malignant neoplasm. Eight patients developed acute leukemia, 10 had non-Hodgkin's lymphoma (NHL), and 53 patients developed solid tumors at a median time of 5 years, 7.25 years, and 12.2 years, respectively, after Hodgkin's disease. One patient developed multiple myeloma 16.5 years after Hodgkin's disease. The relative risk (RR) of developing a second malignancy was 5.6. The absolute excess risk per 10,000 person-years (AR) of developing a second malignancy was 69.6 (7.0% excess risk per person per decade of follow-up). The highest RR occurred for the development of leukemia (RR = 66.2), however because of the low expected risk, the AR was only 9.3. The RR of solid tumors after Hodgkin's disease was lower (4.7); however, the AR was greater (49) than for acute leukemia. Among the solid tumors, breast, gastrointestinal, lung, and soft tissue cancers had the highest absolute excess risks. The risk for developing breast cancer after Hodgkin's disease was greatest in women who were under the age of 25 at treatment. The most significant risk factor for the development of both leukemia and solid tumors was the combined use of radiation therapy and chemotherapy. The RR following RT alone was 4.1 (AR = 51.1); for RT + CT (initially or at relapse) the RR was 9.75 (P0.05, nonoverlapping confidence limits, AR = 123.9). Survival following development of a second malignancy was poor in patients with leukemia, gastrointestinal tumors, lung cancer, and sarcoma. Survival from other malignancies including NHL and breast cancer was more encouraging. Second malignant neoplasms are a major cause of late morbidity and mortality following treatment for Hodgkin's disease. The most significant risk factor for the development of second tumors is the extent of treatment for Hodgkin's disease. Recommendations are presented for both prevention and early detection of these tumors.

Despite dramatic improvements in the survival of patients with Hodgkin's disease attributable to advances in treatment over the past 30 years, concern for the risk of treatment-related deaths has led to a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. We determined the causes of death in a group of patients with pathologically staged and intensively treated Hodgkin's disease who were followed for long intervals.Between April 1969 and December 1988, 794 patients with laparotomy-staged IA to IIIB Hodgkin's disease were treated with radiation therapy alone or combined radiation therapy and chemotherapy. There were 8700 person-years of follow-up (average, 10.95 person-years/ patient). Causes of mortality were grouped into the categories Hodgkin's disease, second malignant tumors, cardiovascular, infection, and miscellaneous. Age- and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed-to-expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years.Of 124 patients who died, 56 died of Hodgkin's disease, 36 of second malignant neoplasms, 15 of cardiac causes, 9 of infection, and 8 of miscellaneous causes. The 20-year actuarial survival rate for all patients in this study is 73%. Age 40 years or older, mixed cellularity/lymphocyte-depleted histologic type, and stage-III disease were adverse independent predictors of survival. The largest differences were seen by age. The 20-year actuarial rates of survival were 78%, 78%, and 46%, respectively, for patients aged 16 or less, 17 to 39, and 40 years or older at diagnosis. Hodgkin's disease diagnosed at age 40 or older was a significant risk factor for all causes of death. The use of combined chemotherapy/ radiotherapy was a significant risk factor for second tumor and infection-related mortality. The excess risk of death from all causes, including Hodgkin's disease, remained constant with time from treatment and was approximately 1.2% per year over the first 20 years. Deaths from Hodgkin's disease decreased with time from treatment, with no patients dying after 15 years. This decrease, combined with an increased excess mortality risk with time from other causes, especially second tumors, accounted for the constant excess mortality with time after Hodgkin's disease.Hodgkin's disease followed by second tumors, cardiac events, and infections remain the major causes of death after treatment of Hodgkin's disease. Our findings suggest the importance of both maintaining a high disease-free survival and reducing long-term complications in designing treatments of Hodgkin's disease.

This study was designed to examine the efficacy and toxicity of high-dose cyclophosphamide (CY), and to evaluate the potential added effect of vincristine (VCR) given at a theoretic time of malignant cell stimulation in a group of patients with multiple myeloma, refractory to or relapsing after, treatment with standard doses of chemotherapy.Patients were randomly assigned to receive CY 2400 mg per M2 as a single-day dose and VCR 1.4 mg per M2 given on Day 1 or Day 9 after the CY.There were 108 cases suitable for analysis. No difference in objective response (17.6%, 23.5%), subjective response, remission duration, or survival was observed in the two treatment arms.The authors conclude that a single, high dose of cyclophosphamide is more toxic and provides equal or less response than the equivalent dose given over 4 consecutive days and that no improved effect was detected using timed-sequential therapy with VCR.

Cisplatin, 5-fluorouracil, and leucovorin (PFL) have demonstrated synergistic activity in preclinical models. Continuous infusion of these agents maximizes the potential for synergistic interaction and forms the basis of the PFL regimen.Sixty-one patients with advanced (Stages IIIB and IV) non-small cell lung cancer were entered into the study. Thirty-one were treated with cisplatin 25 mg/m2/day on days 1-5, 5-fluorouracil 800 mg/m2/day on days 2-6, and calcium leucovorin 500 mg/m2/day on days 1-6. Because of severe mucositis, the final 30 patients were treated with the same dosage of cisplatin but with the deletion on day 6 of leucovorin and 5-fluorouracil. Cycles were repeated every 28 days. Response was assessed after two cycles. Responding patients received an additional two cycles. Patients with Stage IIIB disease received radiation therapy to the mediastinum and sites of involved disease.PFL had an overall response rate of 41%. Median survival was 8.1 months, and median time to treatment failure was 4.2 months. Importantly, 68% (17 of 25) of responses were maximal after just two cycles of chemotherapy. Notable toxicities included mucositis (43%or = Grade 3) and myelosuppression. Response, time to failure, or survival did not differ between the two schedules. Mucositis was less severe with 4-day PFL.PFL as given in this manner is an active regimen for the treatment of patients with advanced non-small cell lung cancer. The rapidity of response makes it a regimen for incorporation into protocols for Stage IIIA disease. A neoadjuvant study using PFL is underway.

The records and initial bone marrow studies of 106 patients with newly diagnosed acute myelogenous leukemia (AML) were analyzed retrospectively to determine whether bone marrow dysplasia was predictive of a previous myelodysplastic disorder or correlated with remission rate and survival.Bone marrow aspirates and biopsy specimens were reviewed in a blinded fashion; dysplasia was assessed in as objective a manner as possible by numerically scoring nine specific findings: erythrocyte multinuclearity, nuclear fragmentation, megaloblastic characteristics, leukocyte granulation abnormalities and nuclear malformations, Pelger-Huet cells, and megakaryocytic dysplasia (mononuclear megakaryocytes, micromegakaryocytes, and megakaryocytes with multiple distinct nuclei).Dysplasia of the megakaryocytic line was seen in 34% of patients; 70% of the patients had erythrocyte dysplasia; and 68% had leukocyte dysplasia. Pelger-Huet cells were seen in bone marrow of 35% of the patients. Overall dysplasia score and specific dysplastic findings such as Pelger-Huet cells did not correlate with a known history of myelodysplasia (P = 0.47), cytogenetic abnormalities (P = 0.35), prior chemotherapy treatment with or without alkylating agents (P = 1.00), previous malignant disorders such as polycythemia vera (P = 1.00), remission rate (P = 0.93), or survival (P = 0.42). Multivariate analysis confirmed known independent risk factors for remission in this patient population, including age (P = 0.04), history of prior chemotherapy (P = 0.04), abnormalities in chromosomes 5, 7, or 8 (P = 0.02), and type of antileukemia therapy (P0.001).Bone marrow dysplasia is common in patients with AML and does not correlate with a history of myelodysplasia or predict outcome when patients are treated with standard intensive AML therapy.

Cisplatin and etoposide combination chemotherapy is the most commonly used regimen for advanced non-small cell lung cancer (NSCLC). 5-Fluorouracil (5-FU) is an agent with little intrinsic activity against NSCLC: However, there is increasing evidence that 5-FU is synergistic with cisplatin and vice versa. In an effort to improve on the traditional chemotherapeutic approach to NSCLC, a treatment regimen consisting of cisplatin, 5-FU, and etoposide (PFE) was developed.Thirty-five patients with advanced NSCLC were treated with the PFE regimen (cisplatin 25/mg/m2/d and 5-FU 1000 mg/m2/d by continuous infusion and etoposide 60 mg/m2/d, each for 4 days). The cycles were repeated every 28 days.The patients received a mean of 2.8 cycles of PFE. Ten patients had a partial response to chemotherapy for an overall response rate of 28.6%. The median survival was 7.0 months. Toxicities included myocardial infarction (2 of 35), congestive heart failure (2 of 35), fatal pulmonary embolus (1 of 35), and a cerebrovascular accident (1 of 35). The incidence of Grade 4 neutropenia (5.7%) and thrombocytopenia (8.5%) was acceptable.The response rate, duration of response, and survival in this group of 35 patients treated with PFE was similar to that reported for cisplatin and etoposide. The increased cardiovascular toxicity may be the result of the infused 5-FU.

This study aims to identify factors that predict outcome after salvage therapy for patients with Hodgkin disease (HD) in first relapse.Between 1969 and 1985, 627 patients with Pathologic Stage IA-IIIB HD were treated at the Joint Center for Radiation Therapy. With a median follow-up time for survivors of 135 months, 138 patients (22%) have experienced relapse. One hundred twenty-seven of these were retreated with curative intent and form the basis of this report.The complete response (CR) rate after retreatment was 79%. The 10-year actuarial freedom from second relapse (FSR) was 53%, and the 10-year survival rate from the time of first relapse was 57%. For patients experiencing relapse after initial radiation therapy (RT) alone (n = 110), the 10-year FSR and overall survival rates were 58% and 62%, respectively. Histologic type was the single most important prognostic factor for second CR rate, FSR, and survival. Patients with nodular sclerosis or lymphocyte predominant (NS/LP) histologic type had a 91% second CR rate, 67% 10-year FSR rate, and 75% 10-year survival rate, compared with 66%, 44%, and 43%, respectively, for patients with mixed cellularity or lymphocyte depleted (MC/LD) histologic type. For patients who experienced relapse after initial combined modality therapy (CMT; n = 17), the 10-year FSR and overall survival rates were 13% and 24%, respectively.This study demonstrates that patients who experience relapse after RT alone can be effectively salvaged with combination chemotherapy. The implications of these results for clinical decision making are discussed.

The etiology of Hodgkin disease remains uncertain. Patterns of presentation of Hodgkin disease are analyzed by histologic subtype with implications for etiology and pathogenesis.The authors performed a detailed analysis of anatomic sites of involvement, histopathologic findings, and clinical features in 719 patients with Hodgkin disease who underwent staging laparotomy with splenectomy between April 1969 and December 1986. The presence of disease in each of 17 sites of potential nodal involvement was determined for each patient from a combination of clinical and surgical staging. Association among nodal sites was assessed in 2 x 2 tables by estimating the odds ratio and testing the significance with the chi-square test. A strict significance level (P = 0.01) was used. Log-linear models were used for assessing association in 2 x 2 tables while adjusting for other factors.The mediastinum, left side of neck, and right side of neck were the most common sites involved for patients with nodular sclerosing (NS) or mixed cellularity (MC) histologic subtypes. Each of these sites was involved 60% of the time. These sites were four or more times as common as other nodal sites above or below the diaphragm. In contrast, the mediastinum was involved in only 8% of patients with lymphocyte predominance (LP) histologic subtype. Significant associations were found between mediastinal disease and low cervical/supraclavicular lymph node disease, mediastinal disease and NS histologic subtypes, peripheral nodal disease and LP histologic subtypes, and between splenic disease and mixed cellularity/lymphocyte depletion (MC/LD) Hodgkin disease. The age at onset and sex of patients with Hodgkin disease and the patterns of nodal distribution were somewhat different for NS and MC/LD histologic subtypes. Even greater differences were seen between LP and other histologic subtypes.This study supports the conclusion that NS and MC Hodgkin disease spread by continguity, most often originating in the neck or mediastinum, and is consistent with evidence suggesting an infectious agent in the pathogenesis of these subtypes of Hodgkin disease. In contrast, LP Hodgkin disease is characterized by different sites of presentation and patterns of spread. This suggests that two or perhaps three clinicopathologic subtypes of Hodgkin disease exist. Implications for etiology and pathogenesis are discussed.

Cisplatin and 5-fluorouracil have noted synergy in preclinical systems. The authors combined methotrexate with infusional cisplatin and 5-fluorouracil in an attempt to produce a regimen with improved activity in advanced NSCLC:Twenty-six ambulatory patients with previously untreated non-small cell lung cancer were treated with continuous-infusion cisplatin (25 mg/m2/day for 5 days), 5-fluorouracil (800 mg/m2/day for 5 days), and intermediate-dose methotrexate (200 mg/m2 on days 15, 22), followed by leucovorin rescue (PFM regimen).Patients received a median of four cycles of therapy. Two patients had a complete response, and 10 had a partial response (overall response rate, 46.2% or 12 of 26). The median time to treatment failure was 22.5 weeks; the median survival was 55 weeks from the start of chemotherapy. There were no toxic deaths attributed to chemotherapy. Thrombocytopenia was the only Grade 4 toxicity (27%). Grade 1/4 and 2/4 peripheral neuropathy occurred in 17 of 26 patients (66%) and was associated with a cumulative cisplatin dose of more than 300 mg/m2.PFM (using continuous-infusion cisplatin) produced a high response rate but resulted in an high incidence of low-grade peripheral neuropathy.

A retrospective review of the Eastern Cooperative Oncology Group adjuvant chemotherapy studies EST 5177 and EST 6177 was performed in order to ascertain the first indicator of relapse in women with breast cancer and pathologically positive axillary lymph nodes. Of 856 evaluable patients, 208 have relapsed. In 175 patients who relapsed, the first indicator could be clearly identified: symptoms, 36%; patient self-examination, 18.3%; physical examination by the physician, 19.4%; abnormal blood chemistries, 12%; bone scans, 8%; chest x-rays, 5.1%; and mammograms, 1.1%. Although 74% of recurrences are therefore detected clinically, in a sizable proportion (26%), the ancillary tests were the earliest indicators of relapse. The manner of detection was not influenced by nodal, estrogen receptor (ER), or menopausal status. These results suggest that the follow-up schedule currently employed by ECOG appears reasonable.