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Background: An early serum tumor marker (TM) decline during chemotherapy was shown to independently predict survival in patients with poor-prognosis disseminated non-seminomatous germ-cell tumors (NSGCTs). The aim of this study was to assess whether a TM decline (TMD) also correlates with the outcome in the salvage setting. Patients and methods: Data regarding 400 patients with progressive or relapsed disseminated NSGCTs after firstline chemotherapy prospectively accrued onto two phase III clinical trials were obtained. Serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG) were assessed at baseline and after 6 weeks of chemotherapy. A total of 297 patients, 185 and 112 in the training and validation sets, with initially abnormal TMs for whom a change from baseline could be established were used for this analysis. Results: An unfavorable decline in either AFP or hCG was predictive of progression-free survival (PFS) [hazard ratio, HR = 2.15, (95% CI 1.48–3.11); P

To determine the value of gray-scale ultrasonography (US) and Doppler US in the prediction, diagnosis, and prognostic assessment of hepatic veno-occlusive disease (HVOD).One hundred patients (median age, 22 years; range, 18 months to 59 years) receiving total body irradiation or busulfan therapy as intensive treatment before hematopoietic stem cell transplantation were studied prospectively. Each patient underwent gray-scale and Doppler US examination before transplantation and weekly thereafter while hospitalized (about four examinations per patient). Seven gray-scale morphologic criteria and seven Doppler criteria were studied, yielding three individual scores: gray-scale score, Doppler score, and total score.Twenty-five patients developed HVOD; nine of these patients died. Positive predictive values of the 14 criteria were 31%-95%, and negative predictive values were 85%-96%. The three scores correlated with the clinical diagnosis of HVOD. Depending on the cutoff value, the positive predictive value of the total score was 44%-89% and the negative predictive value was 91%-98%. The gray-scale and Doppler criteria differed significantly between patients with HVOD and those with graft-versus-host disease of the liver (P = 10(-4)).Even if there is overlap in findings between patients with and those without HVOD, gray-scale and Doppler US are valid for positive and differential diagnosis and have predictive and prognostic relevance.

PURPOSE To evaluate growth, thyroid function, puberty, cardiac function, and the incidence of cataracts in children who received allogeneic bone marrow transplantation (BMT) for acute myeloblastic leukemia (AML) in first complete remission (CR) after a preparation with or without total-body irradiation (TBI). PATIENTS AND METHODS Among 45 children studied, 26 received busulfan-cyclophosphamide (Bu-Cy) in preparation for transplantation and 19 received TBI. TBI was fractionated in nine cases and delivered as a single dose in 10. Four children in the Bu-Cy group and none in the TBI group had received prior cranial radiation. The mean follow-up duration after BMT was 5.9 years for the whole group. RESULTS The mean cumulative changes in height SD score (SDS) were -0.86 at 3 years and -1.56 at 5 years in the TBI group, whereas these changes were only -0.05 and -0.17 in the Bu-Cy group (P < .01 at 3 and 5 years). The 6-year probability of hypothyroidism was 9% +/- 8% in the Bu-Cy group and 43% +/- 15% after TBI (P < .02). Pubertal development after Bu-Cy was assessable in two girls and five boys: both girls had primary ovarian failure, whereas Leydig cell function appeared to be preserved in the five boys. One child who had received anthracycline when he was less than 1 year old developed cardiac dysfunction 4 years after Bu-Cy. The 6-year probability of cataracts was 70% +/- 13% in the TBI group and 0% after Bu-Cy. CONCLUSION The use of Bu-Cy represents an alternative transplant cytoreductive regimen for children with AML in first CR, which can reduce the risk of posttransplant growth impairment, thyroid dysfunction, Leydig cell damage, and the incidence of cataracts.

PURPOSE To identify prognostic variables for response and survival in male patients with relapsed or refractory germ cell tumors treated with high-dose chemotherapy (HDCT) and hematopoietic progenitor cell support. PATIENTS AND METHODS Three hundred ten patients treated with HDCT at four centers in the United States and Europe were retrospectively evaluated. Univariate and multivariate analysis of patient, disease, and treatment characteristics were used for comparisons of response rates and failure-free survival (FFS). RESULTS The actuarial FFS rate was 32% at 1, 30% at 2, and 29% at 3 years. Multivariate analysis identified progressive disease before HDCT, mediastinal nonseminomatous primary tumor, refractory or absolute refractory disease to conventional-dose cisplatin, and human chorionic gonadotropin (HCG) levels greater than 1,000 U/L before HDCT as independent adverse prognostic variables for FFS after HDCT. These variables were used to identify patients with good, intermediate, and poor prognoses. In the good-risk category, the predicted FFS rate at 2 years was 51%, compared with 27% and 5% in the intermediate-risk and poor-risk categories (P < .001). The increased risk for treatment failure was due to both a significantly lower rate of favorable responses and a significantly higher rate of relapses. Within the prognostic categories, the particular HDCT regimen or higher dosages of carboplatin or etoposide did not have a significant influence on treatment outcome. CONCLUSION Prognostic variables for treatment response after HDCT can be identified. The proposed prognostic model might help to optimize the use of HDCT in germ cell tumors and warrants validation in future trials.

Objective To evaluate the safety of tracheotomy in neutropenic ventilated cancer patients, in terms of infectious and haemorrhagic complications. Design Retrospective study. Setting A medical-surgical intensive care unit in a Cancer-hospital.Patients and participants: 26 consecutive patients undergoing a tracheotomy in neutropenic period, from 1987 to 1990. Interventions Tracheotomy, performed at the bedside or in operating, room. Measurements and results In all neutropenic patients undergoing a tracheotomy, the characteristics and duration of both neutropenia and mechanical ventilation have been recorded. Stomal bleeding and infection, and infectious pneumonias and alveolar haemorrhage have been carefully reviewed. Platelets were transfused in 23 of the 26 patients at the time of the procedure; no local haemorrhage was observed. Neither stomal nor pulmonary infections secondary to traceotomy were noted. No respiratory worsening was attributable to the tracheotomy. Nineteen patients (73%) died in ICU, without direct link between tracheotomy and death. Conclusions These findings suggest that a tracheotomy can be safely performed in neutropenic patients requiring mechanical ventilation.

In order to investigate the biology of tumor cells which express MDR1 gene and to test the activity of different P-glycoprotein blocking agents in vivo, we established a nude mice model. Five Non Hodgkin's Lymphoma (NHL) tumor specimens were xenografted to nude mice. One of them, obtained from a chemotherapy-refractory patient gave rise to a mice transplantable model. This tumor xenograft model, IGR-NHL-90, showed overexpression of the human MDR1 gene. In this tumor model, histology, mitotic index, phenotypic and karyotypic traits remained stable at subsequent passages. The in vitro resistance of vincristine was reversed by verapamil for these NHL tumor cells, suggesting that the MDR1 resistance is a relevant mechanism in this model. In the absence of chemotherapy a higher biological aggressivity of the heterotransplanted NHL was noted in subsequent nude mice passages. This was associated with decreased passage time and higher MDR1 m-RNA transcript levels. Thus IGR-NHL-90 may represent a suitable material to study regulation of MDR1 gene transcription in vivo and also to test the activity of various P-glycoprotein reversing agents with concurrent chemotherapy.

Immunological control of acute leukemia may be achieved after allogeneic transplant. Despite promising preliminary results, the impact of immunotherapy with interleukin-2 (r-IL-2) on patients with acute leukemia (AL), in first complete remission (CR1) remains unclear. We conducted a prospective multicenter randomized trial to compare outcome in patients with AL in CR1, treated with autologous bone marrow transplantation (BMT) with or without postgraft r-IL-2. One hundred and thirty patients with AL in CR1 (myeloblastic (AML): N = 78; lymphoblastic (ALL): N = 52) were randomized at time of BMT to receive (N = 65) or not (N = 65) r-IL-2. r-IL-2 (RU 49637 from Roussel Uclaf) was started after hematological recovery, as a five cycle regimen (12 M IU/m2/day continuous infusion on day 1-5, 15-17, 29-31,43-45 and 57-59). The two groups were balanced for patient and transplant characteristics. Analysis was based on an intent to treat. Thirty-eight (59%) of the 65 patients randomized into the study group started r-IL-2 at a median of sixty-eight days (23-140) after transplant and received 77% (16-100) of the scheduled dosage. They received a median of 120 x 10(6) IU/m2 (25-156) over 10 (3-13) days during a total median period of 56 (3-78) days. With a median follow-up of 7 years (5.4-8.1 years), 79 patients relapsed (study group: 43 (66%); control group: 36 (55%): p = NS). Survival and leukemia-free survival estimates were 33% (23-45) versus 43% (22-52) and 29% (19-41) versus 36% (24-51) respectively for study and control groups (all p = NS). These results show that leukemic control after autologous BMT is not increased by r-IL-2 therapy. Further studies should investigate more appropriate r-IL-2 schedules and the possibilities offered by better antigen recognition and activated effector cells.

Resume Les resultats d'un protocole de traitement empirique de 223 episodes febriles chez le neutropenique montrent 1) que la frequence des septicemies inaugurales a germes a Gram positif atteint 50 %, 2) que l'indication de la vancomycine ne peut attendre la documentation bacteriologique, 3) qu'il est possible de donner une monoantibiotherapie par ceftazidime seule a la dose de 3g/j, mais 4) que les surinfections a germes a Gram negatif sont moins frequentes lorsqu'on l'associe a l'amikacine, et 5) que les surinfections a germe a Gram positif sont moins frequentes lorsqu'on associe la vancomycine a la ceftazidime.

Fludarabine was associated with a good response and was well tolerated in patients with follicular lymphoma in phase II trials and this treatment may be associated with less adverse events than treatment with CHVP plus interferon in elderly patients.One hundred thirty-one patients older than 59 years with a follicular lymphoma and poor prognosis were randomized between the association of CHVP (12 cycles in 18 months) plus interferon (5 MU TIW for 18 months) or fludarabine alone (25 mg/m2/d x 5 days for 6 cycles, then 20 mg/m2/day for 6 further cycles for 18 months). Poor prognosis was defined by the presence of a large tumor mass, poor performance status, the presence of B symptoms, above normal LDH level, oror = 3 mg/l beta-microglobulin level.Patients treated with CHVP plus interferon had a higher response to treatment, a longer time to progression and a longer survival than those treated with fludarabine alone (P0.05 for all analyses). With a median follow-up of 29 months, the 2-year failure-free survival was 63% for the CHVP-plus-interferon arm compared to 49% for the fludarabine arm and the two-year survival was 77% and 62%, respectively. This benefit was confirmed in a multivariate analysis including initial prognostic parameters. Fludarabine alone was associated with less neutropenia than CHVP plus interferon. Interferon was decreased or stopped in 39% of the patients because of severe fatigue.CHVP plus interferon over 18 months was associated with a better outcome, even though the combination of interferon plus chemotherapy was less well tolerated than fludarabine.

To determine the prognostic factors and outcome of first-line induction failure Hodgkin's disease patients who were treated with a salvage regimen of high-dose chemotherapy and autologous stem-cell transplantation, and to compare them with matched, conventionally treated patients.We retrospectively analyzed data relating to 86 Hodgkin's disease patients who underwent autologous stem-cell transplantation after failure of the first chemotherapy regimen, either because they did not enter a complete remission and experienced progression of disease less than 3 months after the end of their first-line treatment or because they showed evidence of disease progression during first-line therapy. Graft patients were matched with 258 conventionally treated patients (three controls per case) for age, sex, clinical stage, B symptoms, and time at risk; patient data were obtained from international databases.Among the 86 graft patients, the median age at diagnosis was 29 years (range, 14 to 57 years). Thirty-nine percent of patients had stage II disease, 23% had stage III disease, and 38% had stage IV disease. Seventy percent of the patients received chemotherapy and 30% received combined modality therapy; 60% of the patients received a seven- or eight-drug regimen. After this first-line treatment, 91% had disease progression and 9% had a brief partial response. Eighty patients received a second-line treatment; pretransplantation status was as follows: 24% of patients had a complete remission, 38% had a partial remission (PR), 14% had stable disease, and disease progression occurred in 24%. With a median follow-up of 22 months (range, 4 to 105 months) from diagnosis, the 5-year event-free survival and overall survival rates from transplantation were 25% and 35% (95% confidence intervals, 15 to 36 and 23 to 49), respectively. In multivariate analysis, the pretransplantation disease status after salvage therapy was the only significant prognostic factor for survival (PR: relative risk = 2.8, P = .017; progressive disease: relative risk (RR) = 5.26, P.001). From diagnosis, the 6-year overall survival rates of the graft patients and 258 matched conventionally treated patients were 38% and 29%, respectively (P = .058).Autologous stem-cell transplantation represents the best therapeutic option currently available for patients with primary induction failure and is associated with acceptable toxicity. Response to second-line treatment before high-dose chemotherapy is the only prognostic factor that can be correlated with survival.

From 1986 to 1992, the Febrile Aplasia Study Group conducted a series of studies involving severely neutropenic patients. The average duration of neutropenia was 21 days, following chemotherapy for leukaemia, or chemotherapy/radiotherapy as part of a conditioning regimen for autologous or allogeneic bone marrow transplantation. A total of 591 evaluable febrile episodes were randomized to treatment with either ceftazidime 3 g daily + amikacin (the reference regimen; n=246), ceftazidime alone (n=98), ceftazidime + vancomycin (n=77), ceftazidime + ciprofloxacin (n=64) or piperacillin/tazobactam + amikacin (n=106). Only three patients treated with the reference dose of ceftazidime died or suffered serious morbidity from infections caused by Gram-negative bacteria. Piperacillin/tazobactam + amikacin was the only antibiotic regimen to have an effect significantly different from the reference regimen. Piperacillin/tazobactam + amikacin produced a higher rate of defervescence at 72 h (P=0.003), fewer days of fever (P < 0.001), fewer superinfections (P=0.018), a less frequent requirement for addition of vancomycin (P=0.01) and a higher incidence of treatment judged to be a 'complete success' (enduring defervescence without a change in antibiotics) (P=0.04). Despite the improved control of Gram-positive microorganisms, the infection-related death rate remained unchanged from 1987 to 1992. An increase in disseminated aspergillosis compensated for the reduction in lethal Gram-positive septicaemia.

A great amount of scientific information, accumulated over recent years on the biology of Multiple Myeloma (MM), has fuelled speculation about the origin of malignant plasma cells, about a purported critical role played by the bone marrow stroma, and further still, on cytokine interactions and in particular that of IL-6 and its relationship with the immune system. Among the growth factors secreted by stroma cells, IL-6 is a potent stimulator of myeloma cells in vitro but does not induce a malignant phenotype in normal plasma cells. Many efforts have been produced to identify the stem cell in MM and probably memory B lymphocytes are the best candidates. The demonstration of a Graft vs Myeloma effect in the allogeneic setting strongly supports the immunotherapy in MM. Recent data also suggest that a virus (Kaposi-associated herpes virus, HHV-8) may be significantly associated with the development of MM. In parallel, progress has been achieved in the treatment of this incurable disease with well defined prognostic factors, more efficient supportive care and its corollary, improved quality of life and dose-intensified chemo-radiotherapy followed by autologous hematopoietic stem cell support. Improving the quality of grafts with the selection of CD34 positive cells is another approach aimed at reducing plasma cell contamination without impairing haematological recovery. An EBMT randomized study assessing the role of CD34 selection has been initiated by our group Increasingly efficient first-line therapy, better quality autografts and improved post-remission treatment with, for example, anti-idiopathic vaccination are the most promising future directions.

To further delineate the cytokine involvement in human acute graft-versus-host disease (GVHD), we analyzed cytokine expression in peripheral blood mononuclear cells (PBMC) from patients who developed acute GVHD after allogeneic bone marrow transplantation and from those who did not.We used a highly quantitative and sensitive polymerase chain reaction assay based on the coamplification of an internal standard, with the cDNA derived from the mRNA of interest. Results are expressed in copy numbers, after normalization to a fixed amount of actin, allowing comparison between different samples. After a myeloablative regimen, 22 patients with hematological diseases received an unmanipulated allograft from a matched sibling. They were subsequently submitted to prophylactic immunosuppression. We examined the transcription of genes encoding cytokines in PBMC and skin biopsies. We selected T helper 1 (interferon ([IFN]gamma, interleukin [IL]-2), T helper 2 (IL-4, IL-10), and inflammatory (IL-1, IL-6) cytokines.Four weeks after bone marrow transplantation, the bulk of the PBMC population exhibited an increased expression of IL-1 and IL-6, with no major difference between GVHD+ and GVHD- patients. In addition, although IL-2 expression was not detected, increased levels of IFNgamma mRNA were observed in allografted patients, with higher levels in GVHD+ patients. In skin biopsies sampled at the beginning of GVHD, although low expression of IL-1 and IL-6 could be observed, neither type 1 (IL-2, IFNgamma) nor type 2 (IL-4, IL-10) cytokines could be detected.These studies suggest that the occurrence of human GVHD does not seem to be clearly associated with a T helper 1-type cytokine pattern.

Allogeneic BMT for patients with acute myeloid leukemia (AML) is presently a reference therapy. The indications for this therapy mainly rely upon prognostic factors, and their importance is constantly reassessed. To examine the impact of time from diagnosis to transplant on survival and leukemia-free survival (LFS), we analyzed 109 patients from the database of the SFGM comprising patients who had all received an HLA-identical allogeneic BMT for a diagnosis of AML in first complete remission (CR1) between January 1987 and December 1992. All patients were conditioned with cyclophosphamide (CY) and total body irradiation (TBI) (CYTBI), and methotrexate (MTX) + cyclosporin A (CsA) were used as graft-versus-host disease (GVHD) prophylaxis. Patient characteristics were: age = 33 +/- 9, M/F = 64/45, white blood cell count (WBC) at diagnosis = 27 +/- 42 x 10(9)/l, FAB distribution: M1 and M2 = 55; M3 = 15, M4 and M5 = 33, M0, M6 and M7 = 6. Karyotyping was carried out for 64 patients: 32 had a normal karyotype, 16 had good prognosis abnormalities (t(8;21), t(15;17), inv 16) and 16 patients had other abnormalities. Eleven patients needed two courses of induction to achieve CR. Time between diagnosis and BMT was 120 (64-287) days. Forty-nine patients developed gradeor = 2 acute GVHD (actuarial probability = 46%). With a median follow-up of 50 months (27-100), the 5-year probabilities for transplant-related mortality (TRM), relapse, overall survival and LFS are respectively 25%, 26%, 59% and 55%. A multivariate analysis showed that survival is adversely influenced by three independent factors: time to transplant (120 days vsor = 120 days), acute GVHD (grade 2-4 vs grade 0-1) and age (33 vsor = 33). LFS is only influenced by the first two of these factors. The favorable impact of a shorter time from diagnosis to transplant should lead to performing the transplant as early as possible. Practically speaking, this means that when such therapy is chosen for a patient with CR1 AML, the search for an allogeneic donor should begin immediately and transplant be performed as soon as possible.

We conducted a randomized multicenter study to compare the efficacy and safety of two antibiotic regimens (cefepime [2 g b.i.d.] plus amikacin or ceftazidime [2 g t.i.d.] plus amikacin) as first-line therapy for fever in patients with hematologic malignancies and neutropenia. A total of 353 patients were randomized according to a 2:1 (cefepime:ceftazidime) ratio. Two hundred-twelve patients in the cefepime group and 107 in the ceftazidime group (90% of all patients) were evaluable for efficacy. The polymorphonuclear neutrophil count was100/mm3 on enrollment for 70% of the patients. The mean duration of neutropenia was 26 days. The efficacy in both study arms was comparable, although a trend in favor of cefepime was seen in terms of therapeutic success (response rate, 27% vs. 21% for the ceftazidime group). The overall response rate after glycopeptides were added to the regimens was 60% for the cefepime group and 51% for the ceftazidime group; the bacterial eradication rates were 81% vs. 76%, respectively, and the rates of new bacterial infections were 14% vs. 18%, respectively. We conclude that the combination cefepime/amikacin is at least as effective as the reference regimen of ceftazidime/amikacin in this setting.

A 36-year-old women with chronic myelogenous leukemia in first chronic phase received a bone marrow transplant from her HLA-identical brother. The preparatory regimen consisted of total body irradiation (10 Gy) and cyclophosphamide (60 mg/kg for 2 days). Full engraftment was achieved and the woman was monitored as an outpatient after discharge from hospital on day 35. One year after BMT, while she was on cyclosporin A and steroids because of chronic graft-versus-host disease, the patient developed protein-losing gastropathy associated with cytomegalovirus infection (with no gastrointestinal symptoms), which regressed spontaneously in 4 weeks.

Fifty-one patients with primary refractory or relapsed malignant lymphoma (47 non-Hodgkin's lymphoma and four Hodgkin's disease) were treated with a new chemotherapeutic regimen (cisplatinum, methyl GAG, bleomocyin, methyl prednisolon). Among these 51 patients, 41 had measurable disease. Three of these 41 patients achieved complete remissions (7.3%) and 17 showed partial response (41.5%). The low hematological toxicity of this chemotherapeutic combination allowed us to give the full dose at the planned cycle date in 90% of the cycles. No major toxicity were observed (two minor neurological toxicities, one ototoxicity associated with oral mucositis toxicity, 6 febrile episodes) during 164 courses. With a median follow-up of 12 months, 18% of patients were alive without disease. We conclude that in this particular population of malignant lymphomas, Cis-BMP is an effective therapy with minimal toxicity.

Etoposide, bleomycin, and cisplatin based combination chemotherapy (BEP) and the surgical removal of residual disease is the standard treatment of metastatic germ cell tumors (GCT). Standard treatment including three cycles of BEP for good risk patients and four cycles of BEP for poor risk patients allows 95 and 65% cure rates in these groups respectively. However, about 10% of patients achieving CR after first line therapy eventually relapse. Conventional second line treatment (VeIP) includes a combination of vinblastin, ifosfamide and cisplatin or (VIP) with etoposide replacing vinblastin for patients pretreated by noncontaining etoposide chemotherapy regimens. These protocols induce a 60% CR rate and a 20-30% long term nonevolutive disease (NED) rate. Trials with high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (AHSCT) have been undertaken during the past decade. The main experiences were obtained with combinations of etoposide, platin derivatives, and either cyclophosphamide or ifosfamide. The majority of studies concerned heavily pretreated patients. Few studies have included HDCT and AHSCT as part of consolidation first line treatment for poor risk patients. A randomized multicenter French trial showed no significant benefit of this procedure (Droz, ASCO 1992). In refractory patients, HDCT and AHSCT induces a potential of 10% NED rate and this appears to be the maximum effect that can be obtained. An analysis of prognostic factors at first salvage chemotherapy revealed four adverse factors: high serum levels of HCG (10,000 mIU/ml) or AFP (1,000 g/ml); extragonadal origin; presence of lung metastases at salvage; and an incomplete response to first line treatment. Three prognostic groups have been defined according to a combination of these variables (Droz, Kramar, ASCO 1993). The use of HDCT followed by AHSCT as consolidation salvage treatment seems more promising since 25-45% of patients have long-term NED. It can be assumed that this procedure may increase the long term NED rate by 20% and produce a success rate up to 40%, but further studies are warranted in this setting. In order to evaluate HDCT with AHSCT rescue, an international randomized study has been undertaken in relapsed or first partial remission GCT patients. Randomization is stratified according to the three prognostic groups previously defined. Salvage regimens for eligible patients include two cycles of PEI or VeIP and in case of response, two more cycles of the same protocol (arm A) or one more cycle of PEI or VeIP followed by HDCT (CarboPEC: carboplatin, etoposide, and cyclophosphamide) (arm B).(ABSTRACT TRUNCATED AT 400 WORDS)

In a series of patients transplanted with HLA-matched allogeneic bone marrow grafts (alloBMT), we previously showed that a few T-cell receptor (TCR) V alpha and V beta gene segment transcripts were overexpressed in skin compared with blood at the time of acute graft-versus-host disease (aGVHD). Here, in one selected patient with overexpressed V beta 16 and V alpha 11 transcripts in skin, we analyzed the junctional variability of these transcripts in donor blood, patient blood, and skin collected at aGVHD onset. A unique junctional region sequence accounted for 81% of in frame V beta 16 transcripts (13 of 16) in skin and 59% (13 of 22) in patient blood. Similarly, two recurrent junctional region sequences were found in skin V alpha 11 transcripts, one accounting for 66% (21 of 32) and the other for 16% (5 of 32). These recurrences were also found in patient blood (36% and 15% of V alpha 11 transcripts, respectively). To extend our analysis, a polymerase chain reaction (PCR)-based method was used to precisely determine TCR beta transcript length in run-off reactions using uncloned bulk cDNA samples. All V beta-C beta PCR products analyzed in donor blood, as well as the majority of those analyzed in patient blood, included transcripts with highly diverse junctional region sizes. As expected from the sequence data, most V beta 16-C beta PCR products in skin and patient blood were of the same size (ie, same junctional region). In addition, V beta 3, V beta 5, and V beta 17 transcripts in skin were shown to display highly restricted size variability. The clonality of the V beta 16-C beta and V beta 17-C beta transcripts was further supported by the results of run-off reactions using 13 J beta specific primers. We have identified several recurrent TCR transcripts in skin, some of them also present in patient blood. These data support the view that several T-cell subpopulations are clonally expanded in vivo at the time of aGVHD onset in this case of related HLA-matched alloBMT.

Burkitt's lymphoma and L3-ALL are different forms of the same disease: B-cell disease. Therapeutic improvement has been considerable over the past 10 years. In France, four consecutive multicentre LMB studies of the SFOP greatly contributed to this improvement. An overall cure rate of 90% can now be achieved in children with a short intensive risk adapted polychemotherapy regimen based on high-dose fractionated CPM, HD MTX (3 g/m2), Ara-C in continuous infusion. For patients with ALL or with CNS involvement, the addition of CNS-directed therapy with a higher dose of MTX (8 g/m2), HD Ara-C (3 g/m2 x 4), VP 16, triple intrathecal injections and cranial irradiation greatly improved survival: 87% for ALL and 73% for patients with CNS involvement. In adults, the application of the paediatric protocol is possible with acceptable toxicity and a retrospective study of 41 cases treated according to a LMB protocol showed a cure rate of 71%. Such a regimen should now be proposed to adults and studied prospectively.

The authors report a case of protein losing gastropathy associated with cytomegalovirus. This form which is extremely rare in adults occurred alone after allogenic bone marrow transplantation and become apparent by a hypoalbuminaemia causing oedema of the lower limbs. Gastrocopy showed large red folds of approximately a centimetre covered in a whitish hypersecretion coating. Biopsy demonstrated active gastritis which appeared on a hypertrophic and hypersecretive gastritis. Outcome was favourable within 3 months without treatment.

We conducted a randomized trial with ceftazidine alone or associated with amikacin or vancomycin to investigate the efficacy of the daily 3 g dosage of ceftazidime and the efficacy of monotherapy with ceftazidime and to determine if vancomycin should be added empirically.Patient inclusion criteria were: age over 10 years, therapeutically-induced neutropenia and fever for at least three hours above 38.5 degrees C in absence of a clear non-infectious aetiology. Patients were randomized into three groups: group C, ceftazidime alone 3 g/day; group CA, ceftazidime 3 g/day plus amikacin 15 mg/kg/day; or group C, ceftazidime 3 g/day plus vancomycin 1.5 g/day.Results from one hundred and two episodes of fever were analyzed. The underlying diseases were haematological malignancies (89 patients) and solid tumours (13 patients). The median duration of neutropenia (0.5 x 10(9) PMN/L) was 18 days and the minimum duration of 7 days. The main criterion for the analysis of efficacy was the onset of a major infectious event, i.e. death related to documented or suspected infection and any infectious event considered life-threatening or hindering future treatment of the underlying disease. Eight (22%) patients in group C developed major infectious events compared with four (13%) in group CA and none in group CV (p0.01). Major infectious events were mainly due to Gram-positive organisms, particularly Streptococcus species.We conclude that: 1) ceftazidime alone and in association with amikacin is effective in preventing Gram-negative major infectious events; and 2) vancomycin should not be added only when a Gram-positive infection is documented, but used empirically.

Four out of 23 consecutive patients treated with high-dose Ara-C for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, pulmonary edema, acute renal failure, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during Ara-C infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose Ara-C may be associated with cytokine release.

The results of high-dose chemotherapy and autologous bone marrow transplantation in 388 patients with germ-cell tumors have been reported. It is clear that one or two cycles of various combinations of etoposide, cyclophosphamide, ifosfamide, cisplatin, and carboplatin can be administered with acceptable toxicity, and it appears that high doses of etoposide and oxazophosphorine derivatives increase the cure rate. Cyclophosphamide may be preferable to ifosfamide, because it seems less toxic. The need for and the dose and mode of administration of carboplatin remain in question. In patients with refractory disease, the long-term results of high-dose therapy and marrow transplantation are poor, with cure rates of 8% to 20%, but there is no clear alternative. As consolidation treatment after conventional salvage chemotherapy, early results suggest benefit, but randomized trials are needed. As first-line treatment in patients with high-risk disease, the results to date demonstrate no benefit over available therapy.

For 30 months we have treated 115 non-pretreated non-seminomatous germ cell tumour (NSGCT) patients with poor risk characteristics. Patients were allocated randomly to either arm A: NCI regimen with vinblastine, etoposide (E), bleomycin and double dose cisplatin (P2) (PVeBV) 3 or 4 cycles Q3W, or arm B: modified PVeBV protocol (bleomycin in continuous infusion) Q4W than a cycle of high-dose E + cyclophosphamide + P2 (PEC) and autologous bone marrow transplantation (ABMT). 114 patients are evaluable: 81 testicular, 18 mediastinal and 15 retroperitoneal primaries.Arm A 57 patients: 7 patients did not complete the treatment. There were 15 failures, 9 PR, 33 CR. Seven patients relapsed. The 2-year survival is 82%. Arm B 57 patients: 16 patients did not complete the treatment. There were 26 failures, 7 PR and 24 CR. Nine patients relapsed. The 2-year survival is 60%. Both CR rates and survival are not statistically different. This trial fails to show any benefit of early intensified chemotherapy + ABMT to increase the CR and survival rates in poor risk NSGCT.

The prognosis of Burkitt's lymphoma is generally considered to be poor, particularly in the advanced stages of the disease. Although recent chemotherapy protocols have given high rates of cure in children, there are few such reports concerning adults. We therefore conducted a retrospective analysis of the results for treatment of 46 adults in the Institut Gustave Roussy (IGR) between 1978 and 1987, in order to establish an effective treatment strategy for use in a prospective trial. The median age of the patients was 31 years and the majority were Caucasians of European origin. The clinical symptoms and course of the disease were similar to those in the pediatric situation and corresponded to the so-called non endemic forms observed in Europe and the United States. Presentation was generally extra-nodal, usually with abdominal manifestations. As a rule, the disease progressed rapidly and showed a high affinity for the central nervous system in the absence of specific prophylaxis, despite systemic therapy with highly active agents, particularly in the advanced stages. According to Murphy's classification, there were 6 stage I, 11 stage II, 19 stage III and 10 stage IV patients (3 of whom had CNS involvement). Treatment was heterogenous, although all the patients received polychemotherapy including anthracyclins. The best results were obtained from eleven patients treated according to the French Multicenter Protocols for pediatric Burkitt's lymphoma (LMB-84 and LMB-86). Kaplan-Meier 5-year relapse free survival rate among the 46 patients was 42% (stage I: 83%; stage II: 67%; stage III: 30%; stage IV: 30%). In order to standardize our therapeutic approach, we started a prospective study in 1988 using the unmodified pediatric protocol for our adult patients.

Allogeneic bone marrow transplantation (BMT) is currently an established therapy for hematological malignancies. Twenty years of experience has demonstrated that curability comes from both tumor ablation due to conditioning regimen and immunological therapy from the allogeneic graft [1]. This allogeneic effect, called graft-versus-leukemia effect, has been individualized in retrospective studies looking at the impact of graft-versus-host disease on patient outcome [2]. Furthermore, experience with T cell depletion of the graft has been successful in abolishing graft-versus-host disease but has been associated with a high rejection and relapse rate [3]. This experience has confirmed the immunological nature of the graft-versus-leukemia effect and the importance of T cells in the mechanism. Besides toxicity, allogeneic BMT is limited by the lack of suitable donors. This is the reason why autologous BMT has been frequently proposed as an alternative.

Twenty-eight patients with poor prognosis, advanced metastatic non seminomatous germ cell tumors (NSGCT) were treated with early high dose chemotherapy and autologous bone marrow transplantation (ABMT) rescue. The primary tumor was testicular in 19 patients and extragonadal in nine patients. For 19 patients with a testicular primary, the median probability of complete remission (CR) was 0.05 according to our prognostic mathematical model based on pretreatment levels of serum HCG and AFP. The same prognostic model was used for extragonadal primaries. Treatment consisted of two cycles of a modified double dose of cisplatin, vinblastine, bleomycin, VP-16 regimen (mPVeBV) followed by a high dose cisplatin-etoposide-cyclophosphamide regimen (PEC) followed by ABMT. Of the 28 patients, 17 (61%) achieved CR, one of which was surgical CR (sCR), five died of rapidly progressive disease early during the first cycle of mPVeBV, two had treatment-related deaths, three did not respond and one patient refused treatment. Of the 17 patients initially in CR, three relapsed after 4, 4 and 7 months respectively and have subsequently died. Two other patients died while still in CR: one committed suicide and one died of an infectious complication due to transfusion-related AIDS. Twelve patients are alive in CR after a median follow-up of 66 months (range 7-72 months). The non parametric 3-year survival rate is 40%. To demonstrate the effect of intensive chemotherapy with ABMT, a randomized multicenter French study was set up to evaluate the PVeBV regimen with or without high dose treatment and ABMT in poor risk NSGCT patients.

Fractionated total body irradiation was given to a patient with chronic myeloid leukemia as part of a conditioning regimen for bone marrow transplantation. The radiation treatment was discontinued after the third fraction (total dose: 385 cGy) and no bone marrow graft was given because of the patient's refusal. Peripheral blood lymphocyte levels were monitored for 3 months and lymphocyte subsets up to 50 days post-irradiation. Lymphocyte numbers reached the nadir 48 h after the last fraction and lymphopenia was still present 3 months later. All lymphocyte subsets (T, B, CD4 and CD8 cells) showed a similar decrease except for natural killer cells which exhibited a larger decline. The regenerative capacity of T cells, CD4 subset and natural killer cells was less than that of B cells and CD8 lymphocyte subsets.

Prolymphocytic leukemia is an entity characterized by morphologic, immunologic, clinical and behavioral features which allows its keeping apart from chronic lymphoid leukemia. Careful analysis of blood smear is the main step for its diagnosis. Our purpose is to remind this particular chronic lymphoproliferative syndrome which requires energetic initial treatment. Prolymphocytic leukemia de novo as well as a possible transformation of chronic lymphoid leukemia to prolymphocytic leukemia are discussed.

A total of 62 patients with high-risk acute lymphoblastic leukemia (ALL) were treated with fractionated total body irradiation, high-dose cytosine arabinoside and melphalan followed by bone marrow transplantation (BMT). Thirty-six patients received allogeneic and 26 autologous BMT. Eight patients were treated in CR1, 36 in CR2 (first relapse occurring on therapy for 32), seven in further CR, 10 in relapse (five early first relapse, four second relapse and one fourth relapse) and one with refractory ALL. Severe toxicity occurred in 26 of the 62 patients (42%) and 14 died (22.5%) from non-leukemic causes. The actuarial event-free survival at 3.6 years was 28% after autologous BMT and 52% after allogeneic BMT with actuarial relapse rates of 62% and 35%, respectively. The results of this pilot study seem promising for this group of poor risk ALL, but the relapse rate remains high after autologous BMT and needs to be improved.

Between october 1985 and january 1988, 32 patients with heavily pretreated refractory or relapsing non seminomatous germ cell tumors were included in a phase II trial using etoposide, ifosfamide and high dose cisplatin (VIhP). Eight of 30 evaluable patients (29 per cent) achieved complete response with VIhP treatment alone or followed by surgical excision of residual lesions. Five patients in complete remission relapsed at 3, 4, 5.5 and 7 months, and 3 patients remained continuously free of disease at 17, 21 and 22 months. Severe myelosuppression with a WBC nadir less than 500/mm3 and a platelet nadir less than 20,000/mm3 was observed in 73 per cent of the patients, and renal toxicity (WHO grade 2 or 3) in 29 per cent. The VIhP regimen for salvage therapy gives the same rate of long term survivors than the regimen with conventional cisplatin dosage (VIP) but is much more toxic and cannot be recommended.

In recent years, the prognosis of non-seminomatous germ-cell tumors has been greatly improved by the use of novel chemotherapeutic regimens including platinum derivatives. However, the prognosis remains poor for a certain proportion of these patients. We have therefore developed an intensive chemotherapy protocol (PEC) followed by bone marrow autografting: cisplatin (40 mg/m2/day x 5 d), etoposide (350 mg/m2/day x 5 d), cyclophosphamide (1,600 mg/m2/day x 4 d). Forty-four poor-prognosis patients were thus treated. The results can be stratified into 3 categories, as follows: I: 12 refractory patients: 3 CR, 6 PR, 2 failures, 1 unevaluable. Median survival was short (7 months, range 2-16 months); II: 6 patients with sensitive relapse: 5 CR, 1 unevaluable. Four patients remained in CR at 42, 45, 46 and 48 months; III: 26 patients who received PEC as consolidation therapy in the first CR-PR after courses of conventional chemotherapy and who were selected at the time of diagnosis on the basis of factors of poor prognosis: 16 CR, 3 PR, 7 unevaluable. Two-year disease-free survival (Kaplan-Meier) is 60%. The median duration of neutropenia (less than 0.5 x 10(9)/l) was 15 d (range 6-37) and that of thrombocytopenia (less than 20 x 10(9)/l), 13 d (range 3-32). The most significant non-hematologic toxicity was of the gastrointestinal tract; in particular severe mucositis. Four iatrogenic deaths occurred (2 candidiasis, 1 aspergillosis and 1 hemorrhage). Pharmacokinetic studies were used to determine the optimum time for reinfusing the marrow and provided information on the mechanism of the mucositis. In conclusion, PEC protocol showed a high efficacy with 94% response rate (68.5% CR) among the 35 evaluable pts. Patients refractory to conventional treatment did not appear to benefit from this intensive chemotherapy. However, it appears that it may be useful for patients with relapses sensitive to salvage therapy. Encouraging results were obtained with the PEC protocol administered as early consolidation for patients with identifiable risk factors at diagnosis. A multicenter, randomized trial is currently underway in France to compare this approach with standard conventional chemotherapy.

Chemotherapy has dramatically improved the prognosis of non-seminomatous germ cell tumors (NSGCT). However, some patients relapse and others are refractory to first line chemotherapy. We studied a salvage chemotherapeutic regimen with etoposide 75 gm/m2/day, and cisplatin 40 mg/m2/day, days 1-5 and Ifosfamide 3 g/m2/day, days 1 and 2 (VIhP regimen) in 32 patients. We observed 8 complete remissions with 4 long-term NED patients. Hematological, neurological and renal complications were frequent. In 16 other cases, a protocol using high dose chemotherapy, followed by autologous bone marrow rescue was studied. We observed 8 complete remissions with 4 long-term NED patients. These observations support a dose/effect relationship. A French randomized trial testing high dose chemotherapy, followed in some cases by an autologous marrow graft in poor risk advanced NSGCT, has recently been activated.

Seventy-five patients were treated for short periods with BCG either per os (7), by aerosols (2), i.d. with needles, i.d. with heaf-gun, on one or four scarification areas, i.v., or intratumorally. Two hundred and seventy-seven were treated for more than 3 years by BCG applied scarifications. The local reactions after application on scarification are negligible, the most frequent being pruritus and adenopathies. The systemic reactions are due to the BCG septicemia which is induced and which has been proved by the search for liver granulomas. Some reactions are of an allergic nature (e.g., choroiditis), but most are direct manifestations of the septicemia (fever, hepatomegaly, splenomegaly). One death was observed after tumoral injection in a terminal patient, otherwise there were no deaths, even in the patients under long-term treatment with the other metabolites. Deterioration of immune reactions may be induced either by the method of BCG application which is followed by a (probably) very small penetration (on scarified area in allergics), or by the penetration of high doses (four scarified areas in anergics and intravenous injections in anergics and in allergics).

Vindesine is a derivative of vinblastine and of vincristine. A high proportion of remissions were obtained in acute lymphoid leukaemia (6 complete and 1 incomplete remissions in 15 patients), in blastic crisis of chronic myeloid leukaemia, and a few responses have been registered in lymphosarcoma and Hodgkin's disease. Permanent 48 h i.v. infusion may include a remission where i.v. pusch of the same dose has failed. The most remarkable characteristic of vindesine is the absence of cross-resistance with vincristine as documented in acute lymphoid leukaemia.

Two non randomized therapeutic trials have been conducted in oat cell carcinoma of the lung with limited disease. The first protocol combined chemotherapy (adriamycin, cyclophosphamide, VM 26, procarbazine) with mediastinal and supra-clavicular radiotherapy in classical fractionation (40 grays in 4 weeks). The second combined a more intensive chemotherapy (adriamycin, VP 16, methotrexate, cyclophosphamide) with an alternating radiotherapy (3 series of 15 grays). All patients received prophylactic brain irradiation. Preliminary results show a 9 month survival rate of 34 per cent and 62.5 per cent respectively. In addition, all patients in the second protocol presented a complete response at the end of the induction treatment. These preliminary data encourage proceeding with this kind of combined treatment.

Sixty three patients with limited small cell lung carcinoma were entered into a pilot study alternating monthly cycles of combination chemotherapy (doxorubicin, VP16213, cyclophosphamide and methotrexate (group A) or cis platinum (group B) with 3 courses of mediastinal radiotherapy. The total mediastinal dose was 45 Gy for the first 28 patients (group A) and 55 Gy for the remaining 35 (group B). The complete response rate was 86% in group A (median survival 14 months) and 91% in group B (median survival 20 months). Local control at two years was 61% in group A and 82% in group B, while relapse-free 2 year survival rates were 32% and 37% respectively. The acceptable toxicity and high response rate of this combined modality therapy lead us to further research in maintenance therapy.

The present study is a retrospective analysis of 54 patients with hematological malignancies who were treated by total body irradiation (TBI) and allogenic bone-marrow transplantation from 1982-1986. Patients were not randomly assigned to receive either single dose total body irradiation (STBI) (10 Gy x 1-4 cGy/min-lung dose 8 Gy) or hyperfractionated total body irradiation (HTBI) (1,20 Gy x 11-3 fractions/day-lung dose 9 Gy). Thirty one patients received STBI and 23 a HTBI regimen. Despite the presence of a large proportion of patients with a high risk of leukemic relapse in the HTBI group, the incidence of relapse did not differ significantly in the two groups: STBI (16%), HTBI (21%). Lung and liver toxicity were predominant in the STBI group. Interstitial pneumonitis occurred in 45% of the STBI patients versus 13% in the HTBI group. This difference remains significant when adjusted to the incidence of graft versus host disease (GVHD) in the two groups. Three cases of veino-occlusive disease were observed (10%), but only in the STBI group. Even when differences in age and the frequency of GVHD are considered in the two groups, these findings suggest that HTBI is at least as effective as STBI and that toxicity is reduced with this schedule.

We have studied here cytotoxic function of three cloned cell lines--TC12, 48, and 50--derived from circulating lymphocytes that were potentially able to eliminate residual tumor cells in a patient transplanted for treatment of acute lymphocytic leukemia. These cloned cells, which have both phenotypic and functional characteristics of natural killer lymphocytes, were tested in chromium release assays against a panel of 16 uncultured populations of leukemia cells. In addition, their activity was compared with that of cloned and uncloned NK cells from normal individuals. It was found that TC clones induced a much weaker degree of killing against fresh tumor cells compared with conventional NK target cell lines such as K562 or MOLT 4. In addition, there was great heterogeneity in their individual lytic capacity against the various leukemia blasts (TC12, 48, and 50 cells killed in a significant fashion, respectively 7, 1, and 4 of the 16 leukemias), reflecting the functional diversity of normal NK cell populations. Thus, for a fraction of leukemias, there was no correlation between lytic ability of TC cells and that of uncloned lymphokine-activated large granular lymphocytes from normal peripheral blood. Together, these results support the view that direct identification of patients' cytotoxic lymphocytes screened against in vivo relevant tumor cells is necessary to evaluate potentially beneficial immunologic responses in the context of bone marrow transplantation.

In 1962, we started a controlled study (the principle of which was based on our experimental data) [19] to compare active systemic immunotherapy (AI) with no treatment for patients with acute lymphoid leukemia (ALL) after stopping their rerhission chemotherapy. The difference in remission duration and survival in favor of AI became significant so rapidly [21] that, for obvious ethical and juridical reasons, we were not authorized to introduce more patients than the 30 already in the trial, nor to perform another trial with controls left without treatment. We recently published two critical discussions of this trial [20, 22].

Cell surface modifications after vibrio cholerae neuraminidase treatment were investigated using three different tritiated lectins: Concanavalin A, Ricinus sanguineus agglutinin (R.S.A.) and Robinia pseudoacacia lectin. Lectin binding measurements were performed on untreated and enzyme treated cells. The cells used were from chronic and acute leukemic donors. After neuraminidase treatment, a significant increase in the number of receptor sites, from 1 to 3 times, was found in all cases tested and for all three lectins utilized with only one exception. The affinity constant was generally decreased after neuraminidase treatment. The increase in number lectin binding sites, indicating extensive modification of the cell surface, is completely consistant with the known importance of sialic acid in determining immunogenicity.

Dose-effect relationships of high-dose melphalan were evaluated in 37 patients with measurable relapsed or refractory acute leukemias. Thirteen patients (Group 1) received 70-100 mg/m2 of melphalan without marrow rescue and 24 patients (Group 2) received 140-180 mg/m2 of melphalan followed by marrow transplantation. Patients in both groups were comparable with respect to age, sex, diagnosis, and status of the leukemia. The complete remission rate was 23% in Group 1 versus 75% in Group 2 (P less than 0.01). Hematological recovery of remission patients was not statistically different in either group. Nonhematological toxicity was comparable in the two dose ranges examined. These results demonstrate the existence of a dose-response effect of high-dose melphalan regimens in relapsed acute leukemias, without marked increases in nonhematological toxicity with these doses.