Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma.

BACKGROUND: Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS: Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS: Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS: m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.

UNICANCER-PEGASE 07 study: a randomized phase III trial evaluating postoperative docetaxel-5FU regimen after neoadjuvant dose-intense chemotherapy for treatment of inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel-5-fluorouracil (D-5FU) regimen after preoperative dose-intense (DI) epirubicin-cyclophosphamide (EC) and locoregional treatment in IBC patients. PATIENTS AND METHODS: PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m(2) and C 4000 mg/m(2) every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m(2), day 1 and 5FU 750 mg/m(2)/day continuous infusion, days 1-5 every 3 weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease-free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS). RESULTS: Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months [95% confidence interval (CI) 58.4-60.3] in arm A and 60.5 months (95% CI 58.3-61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9-64.7) in arm A and 55.5% (95% CI 44.3-65.3) in arm B [hazard ratio (HR) = 0.94 (0.61-1.48); P = 0.81]. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1-78.8) in arm A and 70% (95% CI 58.8-78.7) in arm B [HR = 0.93 (0.55-1.60); P = 0.814]. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival. CONCLUSION: The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC. CLINICAL TRIAL NUMBER: ClinicalTrials.gov identifier: NCT02324088.

Adjuvant radiotherapy for extremity and trunk wall atypical lipomatous tumor/well-differentiated LPS (ALT/WD-LPS): a French Sarcoma Group (GSF-GETO) study.

BACKGROUND: The role of adjuvant radiotherapy (RT) in the management of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WD-LPS) remains controversial. METHODS: Two hundred eighty-three patients with operable ALT/WD-LPS, no history of previous cancer, chemotherapy (CT) or RT, treated between 1984 and 2011 registered in the Conticabase database were included and described. Overall (OS), progression-free survival (PFS) and time to local relapse (TTLR) were evaluated from the time of first treatment. RESULTS: Three of 20 centers enrolled 58% of the patients. Median age at diagnosis was 61 (range 25-94) years, 147 patients (52%) were males, 222 (78%) patients had their primary tumor located in an extremity while 36 (13%) and 25 (9%) had tumors involving the girdle and the trunk wall, respectively. The median size of primary tumors was 17 cm (range 2-48 cm). Adjuvant RT was given to 132 patients (47%). Patients who received adjuvant RT had larger tumors (P = 0.005), involving more often the distal limbs (P < 0.001). Use of adjuvant RT varied across centers and along the study period. Other characteristics were balanced between the two groups. Median follow-up was 61.7 months. None of the patients developed metastasis during follow-up. The 5-year local relapse-free survival rates were 98.3% versus 80.3% with and without adjuvant RT, respectively (P < 0.001). Once stratified on time period (before/after 2003), adjuvant RT, tumor site and margin status (R0 versus other) were independently associated with TTLR. No OS difference was observed (P = 0.105). CONCLUSION: In this study, adjuvant RT following resection of ALT/WD-LPS was associated with a reduction of LR risk.

Gastrointestinal metastases in renal cell carcinoma: A retrospective multicenter GETUG (Groupe d'Étude des Tumeurs Uro-Génitales) study.

BACKGROUND: Among patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood. OBJECTIVES: To report clinical presentations, patient characteristics, therapeutic strategies, and prognosis of GIMs from RCC. METHODS: We retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021. RESULTS: We identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of patients already had other metastases. GIMs occurred after a median duration of 5.4 years (IC95%=[4.2-7.1]) and 1.9 years (IC95%=[1.2-3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. GIM management consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months. CONCLUSION: We report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether or not they are symptomatic.

Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. METHODS: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. RESULTS: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). CONCLUSION: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

Novel method of doxorubicin-SPION reversible association for magnetic drug targeting.

A new method of reversible association of doxorubicin (DOX) to superparamagnetic iron oxide nanoparticles (SPION) is developed for magnetically targeted chemotherapy. The efficacy of this approach is evaluated in terms of drug loading, delivery kinetics and cytotoxicity in vitro. Aqueous suspensions of SPION (ferrofluids) were prepared by coprecipitation of ferric and ferrous chlorides in alkaline medium followed by surface oxidation by ferric nitrate and surface treatment with citrate ions. The ferrofluids were loaded with DOX using a pre-formed DOX-Fe(2+) complex. The resulting drug loading was as high as 14% (w/w). This value exceeds the maximal loading known from literature up today. The release of DOX from the nanoparticles is strongly pH-dependent: at pH 7.4 the amount of drug released attains a plateau of approximately 85% after 1h, whereas at pH 4.0 the release is almost immediate. At both pH, the released drug is iron-free. The in vitro cytotoxicity of the DOX-loaded SPION on the MCF-7 breast cancer cell line is similar to that of DOX in solution or even higher, at low-drug concentrations. The present study demonstrates the potential of the novel method of pH-sensitive DOX-SPION association to design novel magnetic nanovectors for chemotherapy.

Patterns of relapse in poor-prognosis germ-cell tumours in the GETUG 13 trial: Implications for assessment of brain metastases.

BACKGROUND: The GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13. METHODS: We conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain. RESULTS: With a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy. CONCLUSIONS: Brain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2-3 months of chemotherapy.

High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group.

The optimum treatment of primary CNS lymphoma (PCNSL) is not yet determined. The objective of this study was to assess the safety and efficacy of initial methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) in patients with newly diagnosed PCNSL. Twenty-five patients received two courses of initial chemotherapy combining methotrexate, etoposide, carmustine and methylprednisolone, and one course of ifosfamide-cytarabine followed by peripheral stem cell collection. Seventeen responsive patients then received HDT using carmustine, etoposide, cytarabine and melphalan with autologous stem cell rescue. After ASCT for responding patients or after salvage therapy for non-responders, whole brain radiation therapy at a dose of 30 Gy was delivered. The objective response rate to the induction chemotherapy was 84%. Four of the 21 responding patients did not have ASCT because of toxicity or refusal. With a median follow-up time of 34 months, the projected event free survival rate is 46% at 4 years. Projected overall survival is 64% at 4 years. Sixteen patients are actually in continuous complete response. No evidence of late treatment-related toxicity was observed. This treatment approach appears feasible in newly diagnosed PCNSL with encouraging results.

Post-operative sequential high-dose chemotherapy with haematopoietic stem cell support as front-line treatment in advanced ovarian cancer: a phase II multicentre study.

In spite of multimodal management including aggressive surgery and chemotherapy, the prognosis of advanced ovarian cancer (AOC) remains poor. Multicycle high-dose chemotherapy (HDC) with haematopoietic stem cell (HSC) support has been shown to be a promising procedure in various cancers including AOC. We conducted a phase II multicentre study to evaluate feasibility, toxicity and efficacy of post-operative front-line sequential HDC with HSC support in AOC. Thirty four patients with stage IIIC/IV received a post-operative sequential combination of high-dose cyclophosphamide/epirubicin (D1, D21) with HSC harvesting, high-dose carboplatin (D42, D98) followed by HSC infusion, and dose-dense paclitaxel (D63, D77, D119, D133). Rh-G-CSF (filgrastim) was administered following all cycles. Primary endpoint was pathological complete response rate (pCR). Thirty patients received at least 7 of the scheduled 8 cycles. Haematological toxicity was significant but manageable. Grade 3/4 extra-haematopoietic toxicities were relatively uncommon and reversible. No toxicity-related death was observed. The observed pCR was 37% and did not reach the initial endpoint. Post-operative front-line sequential HDC in AOC is feasible and safe in a multicentre setting. The observed pCR does not support a clear advantage over conventional treatment. This approach remains an experimental strategy to further optimise and validate.

Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II.

Tyrosine phosphorylation plays a crucial role in cell proliferation and cell transformation which suggests that tyrosine kinase-specific inhibitors might be used as anticancer agents. When the cytotoxic effect of the potent tyrosine kinase inhibitor genistein on various cell lines was studied, we observed that 9-hydroxyellipticine-resistant Chinese hamster lung cells (DC-3F/9-OH-E) were markedly more resistant to genistein than the parental cell line (DC-3F). The DC-3F/9-OH-E cells have been shown to have an altered DNA topoisomerase II activity. We therefore examined the effects of genistein on DNA topoisomerase II-related activities of nuclear extracts from DC-3F cells as well as on purified DNA topoisomerase II from calf thymus. Our results show that genistein (a) inhibits the decatenation activity of DNA topoisomerase II and (b) stimulates DNA topoisomerase II-mediated double strand breaks in pBR322 DNA on sites different from those of 4'-(9-acridinylamino)methanesulfon-m-anisidide, etoposide, and 2-methyl-9-hydroxyellipticinium. Structure-activity studies with six chemically related compounds show that only genistein has an effect on the cleavage activity of DNA topoisomerase II in the concentration range studied. Finally, genistein treatment of DC-3F cells results in the occurrence of protein-linked DNA strand breaks as shown by DNA filter elution. Viscometric (lengthening) studies demonstrate that genistein is not a DNA intercalator. Genistein is therefore an interesting compound because it induces cleavable complexes without intercalation. Taken together, our results show that genistein is an inhibitor of both protein tyrosine kinases and mammalian DNA topoisomerase II. This could be accounted for by the sharing of a common structure sequence between the two proteins at the ATP binding site.

Management and prognosis of malignant peripheral nerve sheath tumors: The experience of the French Sarcoma Group (GSF-GETO).

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are a rare subtype of soft tissue sarcoma. They can arise in irradiated fields, in patients with type 1 neurofibromatosis (NF1), or sporadically. MPNST exhibit an aggressive behaviour, and their optimal management remains controversial. An unsolved issue is whether NF1-related and sporadic forms of MPNST have a different prognosis, and should be managed differently. MATERIAL AND METHODS: Adult and paediatric patients with histologically confirmed MPNST treated between 1990 and 2013 in French cancer centres of the GSF/GETO network, were included in this retrospective study. RESULTS: A total of 353 patients (37% with NF1 and 59% with sporadic tumours) were analysed. Median age at diagnosis was 42 years (range 1-94). The majority of tumours developed in the limbs, were deep-seated and of high grade. Two hundreds and ninety four patients underwent a curative intent surgery. Among them, 60 patients (21%) had neoadjuvant treatment (mainly chemotherapy), and 173 (59%) had adjuvant treatment (mainly radiotherapy). For operated patients, median progression free and overall survival (OS) were 26.3 months and 95.8 months, respectively. In multivariate analysis, poor-prognosis factors for OS were high grade, deep location, locally advanced stage at diagnosis, and macroscopically incomplete resection (R2). NF1 status was not negatively prognostic, except in the recurrence or metastatic setting, where NF1-related MPNST patients treated with palliative chemotherapy showed worse survival than patients with sporadic forms. CONCLUSION: To our knowledge, our series is the largest study of patients with MPNST reported to date. For operated patients, we showed a worse prognosis for NF1-related MPNST, due to different clinical features at diagnosis, more than NF1 status itself. The French sarcoma group is now conducting correlative analyses on these patients, using the latest molecular tools.

VAD-PECC regimen in the treatment of advanced-stage multiple myeloma.

PURPOSE: This prospective study was undertaken to evaluate the efficacy of combination chemotherapy with alternating cycles of vincristine, doxorubicin, and dexamethasone (VAD) and prednisone, vindesine, carmustine, and cyclophosphamide (PECC) in poor-risk multiple myeloma (MM). PATIENTS AND METHODS: Forty-four patients were previously untreated; 36 had been pretreated with an alkylating agent-containing regimen and had refractory or relapsed MM. All previously untreated patients had a high tumor burden at inclusion (stage III according to the Durie and Salmon classification). Logistic regression and the Cox proportional hazards models were used to assess the association between patient characteristics and response rate and survival, respectively. RESULTS: The overall response rate was 68% for previously untreated patients, compared with 54% for previously treated patients (P = .16). The median survival time for all patients was 28 months: 53 months in previously untreated patients, and 18 months in previously treated patients. Univariate analysis showed that the predictive factors that had a significant affect on survival in the newly diagnosed patients were age, therapeutic response to VAD-PECC, low pretreatment Karnofsky score, high baseline serum beta 2-microglobulin (beta 2M) level, bone marrow impairment, and renal insufficiency at the start of treatment. When these parameters were used as continuous variables in multivariate analysis, three were found to correlate with survival: serum beta 2M, followed by therapeutic response and Karnofsky score. In the previously treated group, only Karnofsky score entered the Cox model. CONCLUSION: These results indicate that combination VAD-PECC chemotherapy is an effective treatment that results in high response rates and long-term survival in advanced MM.

Subcutaneous interleukin-2, interferon alfa-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: a multicenter phase II trial. Groupe Français d'Immunothérapie.

PURPOSE: A phase II trial was designed to determine the efficacy and the tolerance of interleukin-2 (IL-2), interferon alfa-2a (IFNalpha), and fluorouracil (5-FU) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: One hundred eleven patients were included. Patients received subcutaneous IL-2 9 x 10(6) IU daily for 6 days and IFNalpha 6 x 10(6) IU on days 1, 3, and 5 every other week for 8 weeks. 5-FU was administered through a continuous infusion at 600 mg/m2 for 5 consecutive days for 1 week every 4 weeks. RESULTS: The response rate was 1.8% (95% confidence interval [CI], 0% to 4.3%) with only two partial responses (PRs). Toxicity was moderate with 3.6% grade 4 events and two deaths related to treatment. CONCLUSION: This regimen of IL-2, IFNalpha, and 5-FU in patients with metastatic renal cell carcinoma was ineffective. The results raise the question of the dose and schedule of subcutaneous cytokines that must be used in metastatic renal carcinoma.

Long-term cultures to evaluate engraftment potential of CD34+ cells from peripheral blood after mobilization by chemotherapy with and without GM-CSF.

In this study we used a long-term culture system to evaluate engraftment potential of human peripheral blood (PB) cells mobilized by chemotherapy (CT) associated or not with granulocyte-macrophage colony-stimulating factor (GM-CSF). In six patients who underwent blood cell transplantation, PB CD34+ cells were cultured after mobilization and were compared to CD34+ cells in steady state from PB and bone marrow (BM). Qualitative differences were shown between PBC samples obtained after CT with and without GM-CSF. Despite similar CFU-GM counts at culture initiation, GM-CSF-mobilized CD34+ cells might contain a lower proportion of primitive stem cells, as suggested by the significant decrease in CFU-GM numbers produced beyond week 5 compared to CT-mobilized CD34+ cells (p = 0.033). Likewise, the percentage of CFU-GM produced beyond week 5 in relation to initial input was significantly lower than steady-state PB (p = 0.039) and than CT-mobilized CD34+ cells (p = 0.033). However, this CFU-GM production with GM-CSF-mobilized PB CD34+ cells was not different from cultures with BMC CD34+ cells. These results suggest that GM-CSF can mobilize CFU-GM in the blood mainly by differentiation at the expense of the primitive stem cell compartment. It appears valuable to define clearly for each mobilizing procedure a particular threshold of CFU-GM which reflects sufficient numbers of primitive stem cells to ensure long-term engraftment.

Mechanisms of action in NIH-3T3 cells of genistein, an inhibitor of EGF receptor tyrosine kinase activity.

Genistein has been shown to inhibit specifically in vitro the epidermal growth factor (EGF)-receptor tyrosine protein kinase activity (Akiyama et al., J Biol Chem 262: 5592-5597, 1987). When the effects of genistein on NIH-3T3 cells were studied, a cytostatic effect was observed at low concentration (less than 40 microM) and a cytotoxic effect at higher concentration (greater than 40 microM). Genistein was able to block the mitogenic effect mediated by EGF on NIH-3T3 cells (IC50 = 12 microM) or by insulin (IC50 = 19 microM). Genistein was also able to block the mitogenic effect mediated by thrombin (IC50 = 20 microM) although the thrombin receptor does not involve a protein tyrosine kinase activity. Genistein at cytostatic concentration (less than 40 microM) did not prevent the induction of c-myc mRNA synthesis caused by the activation of EGF receptor by EGF. Therefore the cytostatic effect of genistein on NIH-3T3 cells did not appear to be mediated by EGF receptor tyrosine kinase inhibition. This hypothesis was also supported by the absence of effect of genistein on the EGF-stimulated phosphorylation of several proteins and particularly of a cytosolic 80 kD protein. The stimulation of S6 kinase activity of cells treated by EGF was prevented by genistein. The stimulation by EGF of in situ S6 phosphorylation was also prevented by genistein. In addition, S6 kinase extracted from cells treated by EGF was inhibited by genistein. These effects occur at similar doses and maximal inhibition of S6 kinase was obtained at about 15 microM.

Acute hepatitis B after autologous stem cell transplantation in a man previously infected by hepatitis B virus.

We report a case of acute hepatitis B after autologous stem cell transplantation (ASCT) in a patient with low-grade non-Hodgkin's lymphoma. At diagnosis of the hematological disease, the patient had the characteristic serology of a previous hepatitis B infection, being Ag HBs negative, hepatitis B virus core antibody positive (anti-HBC) and hepatitis B virus surface antibody weakly positive. He developed fatal hepatitis B after autologous stem cell transplantation, suggesting reactivation consequent to immunosuppression.

Sensitivity of human CFU-GM to mafosfamide: analysis of the factors affecting individual variations.

A study of CFU-GM sensitivity to mafosfamide was carried out in 67 candidates for ABMT. A lethal dose 95 (LD95) was calculated from the dose-response curve. Despite standardized treatment conditions of marrow buffy-coat cells, LD95 values that were normally distributed (median 100 micrograms/ml; mean +/- SEM 95.6 +/- 4.0 micrograms/ml) varied considerably from patient to patient (range 30-160 micrograms/ml). Three independent factors appeared to confer greater sensitivity of CFU-GM: low patient age, low CFU-GM rate in treated cells and prolonged delay of CFU-GM sensitivity test from last chemotherapy course. In contrast, sex, pathology, disease status, number of previous chemotherapies and use of CY before the test did not influence CFU-GM sensitivity. Forty-six patients were autografted with mafosfamide-treated marrows according to their LD95. The mean percentage of CFU-GM effectively recovered after graft purging was 3.96 +/- 2.09%. All patients engrafted well and their peripheral blood cell recoveries were correlated with graft CFU-GM content evaluated before purging but not after purging or after freezing. In multivariate analysis, this parameter remained the only factor predicting hematopoietic recovery among other patient variables such as sex, age, pathology, disease status, previous chemotherapies or TBI in conditioning regimens. In a subgroup of 39 patients with lymphoid malignancies compared with 25 patients autografted for non-Hodgkin's lymphomas with unpurged marrows, the delay in days (medians) was similar for leukocytes > 1 x 10(9)/l (19 vs 17 days) and for neutrophils > 0.5 x 10(9)/l (18 vs 17 days) while it was longer for platelets > 50 x 10(9)/l (34 vs 128 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Granulocyte-macrophage colony-stimulating factor accelerates hematopoietic recovery after autologous bone marrow or peripheral blood progenitor cell transplantation and high-dose chemotherapy for lymphoma.

The use of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) as an adjunct to autologous bone marrow transplantation (ABMT) or peripheral blood progenitor cell (PBPC) transplantation was evaluated in 59 lymphoma patients. Patients were divided into three groups. In group I (n = 21) patients received rhGM-CSF (5 micrograms/kg daily) at the time of PBPC collection and during the recovery phase post-infusion. In group II (n = 12) patients received rhGM-CSF as an adjunct to ABMT. In group III (n = 26) they were grafted with bone marrow without rhGM-CSF. Administration of rhGM-CSF (groups I and II) significantly reduced the time to myeloid engraftment, the number of febrile days and the median duration of antibiotics administration and of hospital stay when compared with the group in which patients did not receive rhGM-CSF. The only difference between ABMT and PBPC, given with rhGM-CSF support, was observed in the duration of hospitalization (group I > group II, P < 0.05). These data show that rhGM-CSF is highly effective in reducing the duration of aplasia following BMT and PBPC transfusion, and there appears to be little difference in efficacy between these techniques, provided that patients also receive rhGM-CSF.

Structural rearrangements of chromosome 13 as additional abnormalities in Burkitt lymphoma and type 3 acute lymphoblastic leukemia.

We report three cases of chromosome 13 rearrangements as additional abnormalities in two patients with Burkitt lymphoma (BL) and one with type 3 acute lymphoblastic leukemia (ALL). Involvement of chromosome 13 has been reported most often as 13q+, without identification of the supplementary chromosomal material; in our three cases with 13q+, we identified two duplications: dup(13)(q13q22) and dup(13)(q21q22).

Simultaneous occurrence of acute myelogenous leukemia and seminoma of the testis.

Simultaneous tumors are rarely encountered during the course of acute leukemias. We report on a case of seminoma of the testis that occurred during the evolution of acute myelogenous leukemia. To our knowledge, this simultaneous association has not previously been described, but a causal relationship was not apparent in the present case. The likelihood of a common carcinogenesis existed, but direct exposure to carcinogens could not be established. Although the results of a physical examination and echography were normal at the time of diagnosis, we cannot exclude the presence of microscopic cancer of the testis. Since the dissemination pattern of seminoma is usually slower than that observed in this case and the disease remains limited to the lymph nodes for long periods following dissemination, the rapid development of the present case might have been attributable to the immunosuppression and the scrotal sepsis that occurred during the induction therapy. Immunosuppression might have stimulated the progression of a primary microscopic seminoma and the development of metastasis, whereas the scrotal sepsis and inflammation might have favored the occurrence of metastasis through bypass of the lymphatic barrier.