Phase I-II study of two consecutive courses of high-dose epipodophyllotoxin, ifosfamide, and carboplatin with autologous bone marrow transplantation for treatment of adult patients with solid tumors.

We describe a phase I-II study of two consecutive 5-day courses of a three-drug regimen of ifosfamide (IFM), carboplatin (CBDCA), and either etoposide (VP-16) (regimen 1) or teniposide (VM-26) (regimen 2) in high doses together with autologous bone marrow transplantation (ABMT), for previously treated patients with ovarian carcinoma (OC), germ cell tumors (GCT), gestational trophoblastic disease (GTD), or oat cell carcinoma (OCC). Forty-four patients entered the study. Two patients with OC received regimen 1, and 22 were given regimen 2. Sixteen patients with GCT, two with GTD, and two with OCC were treated with regimen 1. Six patients (13%) died of toxicity. Nephropathy and esophagitis were the dose-limiting toxic effects. The maximum-tolerated doses (MTDs) were 1,500 and 200 mg/m2/d for 5 days for IFM and CBDCA, respectively, in combination with VP-16 250 mg/m2/d for 5 days (regimen 1), and 150, 1,500, and 200 mg/m2/d for 5 days for VM-26, IFM, and CBDCA, respectively (regimen 2). The response rate of patients with OC was 78% (complete response [CR], 14%). For patients previously resistant to chemotherapy, the response rate was 70%. There were no long-term disease-free survivors among patients with OC. The response rate of patients with GCT was 60% (CR, 33%). All responders with GCT were resistant to previous chemotherapy. Unmaintained CRs lasted 2, 6, 8+, 27+, and 37+ months. Of the two patients with GTD, one with previous resistance to chemotherapy attained a CR of 18+ months. One patient with OCC attained a CR lasting 6 months. The regimen possesses great antitumor activity. It produced CRs of long duration in a number of patients with GCT and GTD who were previously resistant to chemotherapy.

Homograft replacement of the mitral valve. Graft selection, technique of implantation, and results in forty-three patients.

UNLABELLED: Because of experience gained in reconstructive mitral valve surgery, we have reevaluated the implantation of cryopreserved homografts in the mitral position. Forty-three patients, aged 11 to 69 years (mean 34 years), underwent mitral valve replacement with cryopreserved mitral homografts. The indications for the procedure were acute endocarditis (n = 14), rheumatic stenosis (n = 26), systemic lupus endocarditis (n = 2), and marasmic endocarditis (n = 1). All homografts were obtained from hearts explanted in the course of transplantation and were cryopreserved at -160 degrees C in 10% dimethyl sulfoxide solution without antibiotics. Appropriate sizing was based on morphologic study of the homografts and preoperative echocardiographic assessment of the recipient valve. In 82 homografts analyzed, the height of the anterior leaflet was 25 +/- 3 mm and the distance from the anulus to the apex of the anterior papillary muscle was 21 +/- 3 mm. The morphologic features of the papillary muscles were classified according to four types of increasing complexity. Nine valves with complex (type IV) papillary muscle abnormalities were discarded. Echocardiographic measurements of the valve were matched with those of the homograft identification cards and a slightly larger homograft was selected (measurements + 3 mm). Partial homograft replacement was done in case of a localized lesion (abscess or calcification) (n = 21). Total homograft replacement was undertaken in the presence of diffuse lesions (n = 22). Two hospital deaths occurred as a result of poor cardiac output. One patient required reoperation on the tenth postoperative day after a dehiscence on the valvular suture line. After a mean follow-up of 14 months, there has been one late death caused by a bronchial neoplasm and one reoperation for residual stenosis (partial replacement). The remaining patients were in either New York Heart Association class I (n = 25) or II (n = 13). Thirty-three patients were in sinus rhythm. Follow-up echocardiography has revealed no mitral regurgitation (n = 20), minimal mitral regurgitation (n = 13), and mild mitral regurgitation (n = 5). Surface valve area has been calculated at 2.5 +/- 0.4 cm2 in partial homograft reconstruction and 2.7 +/- 0.3 cm2 in total homograft replacement, with a transvalvular gradient of 3 +/- 4 mm Hg. CONCLUSION: In a selected group of patients, the use of mitral homografts significantly extended the present limitations of reparative surgery of the mitral valve.

Long-term human blood cultures: application to circulating progenitor cell autografting.

Peripheral blood cells collected by cytapheresis from patients with acute leukemia following induction therapy or with multiple myeloma off-therapy, were maintained in a one-stage long-term liquid culture system. The data indicate that: (1) blood-derived granulopoietic proliferation can be sustained for up to 8 weeks with generation of CFU-GM in a way similar to bone marrow cells; and (2) this normal hematopoiesis can be sustained in spite of the absence of any development of a substantial stromal adherent layer, which suggests that, unlike hematopoiesis from bone marrow, the blood-derived non-adherent cell population is a self-sustaining compartment. While autologous transplantation with peripheral progenitor cells is gaining importance as an alternative to autologous bone marrow transplantation, this study suggests that circulating progenitor cells may have a different behavior from marrow cells. This observation may be relevant to the understanding of cases of defective hematopoietic reconstitution.

Mitral valve replacement using a cryopreserved mitral homograft.

Mitral valve replacement, using a cryopreserved mitral homograft, was performed in a 49-year-old patient with calcified mitral stenosis. Postoperative course was uneventful. Transesophageal echocardiography performed 6 months later showed normal function of the mitral homograft.

The role of autologous blood stem cells in support of high-dose therapy for multiple myeloma.

During the last few years, high-dose therapy with hemopoietic stem cell support has become a well-admitted therapeutic option for young patients with MM. The role of allogeneic or autologous graft and of blood rather than bone marrow as the source of hemopoietic stem cells must be further investigated. Autologous PBSC transplantation has, however, both practical and theoretic advantages over allogeneic and autologous BMT: (1) It can be applied to most patients, especially if blood stem cells are collected early in the course of therapy. (2) It usually induces relatively rapid hematologic reconstitution. (3) In comparison with autologous BMT, it appears to minimize the hazard of the reinfusion of malignant cells.

Homograft replacement of the mitral valve in young recipients: mid-term results.

OBJECTIVE: Mitral homograft (MH) can represent an interesting alternative for valve replacement in the young. However, concerns have been expressed about the durability of valve allografts in children. We report our experience with MH replacement in young patients. METHODS: From 1993 to 1997, 13 young patients aged 3-25 years (mean 15+/-6 years) underwent total mitral valve (MV) replacement with a cryopreserved homograft (CH). All but one had previously undergone one or more cardiac operations. The indications were rheumatic disease (6), acute and subacute endocarditis (2), congenital heart disease (4), and systemic lupus endocarditis (1). RESULTS: No in hospital deaths are reported. Discharge echocardiogram showed a well-functioning MH in all but one patient. One patient was lost to follow-up. Follow-up ranged from 0.7 to 6.6 years (4.1+/-2.2). On follow-up two patients were doing well. Two patients died without reoperation and both had MV stenosis. Seven patients (54%) required reoperation: mean delay 4.17 years (0.7-7). In all cases, thickening, shrinking and calcification of the allograft were present. None of these seven had contributive histopathologic changes. One patient presenting recurrent MV insufficiency will require a reoperation. CONCLUSION: MV homograft is a safe and reproducible technique, but does not provide durable results and should not be used in young patients.

Evaluation of cryopreserved arteries as alternative small vessel prostheses.

Biologic or synthetic grafts have had limited success in small vessel applications. Studies were initiated to assess the potential use of cryopreserved (CP) arteries as coronary artery bypass conduits. Sheep carotid arteries (internal diameter: 4 mm; length: 10 cm) were cryopreserved in a nutrient media containing 10% DMSO and were stored in a nitrogen vapor at -150 degrees C. After thawing, histological, enzyme-histochemical and functional studies showed slight histological alterations, preservation of enzymal activities and an abolition of the contractile response. In a sheep model, arterial substitution of a 10 cm segment of carotid artery was realised by implantation of fresh autografts ( n = 4); fresh allografts (n = 9) and CP allografts (n = 9). After 3 months, all autografts were patent with slight histological alterations. Fresh and CP allografts showed similar modifications: patency rate was 7/9 in both groups. Intimal thickening with cell proliferation was seen in fresh (3/7) and CP (4/8) arteries; loss of smooth muscle medial cells was constant. Adventitia was always involved by a marked inflammatory reaction. One characteristic of CP allografts was the frequent presence of large dystrophic calcifications. In conclusion, morphologic and functional arterial changes occurred after freezing and thawing. In spite of vascular rejection, the patency rate of allografts after 3 months of implantation in arterial circulation remained high and does not seem influenced by cryopreservation.

[Mitral valve replacement with cryopreserved mitral homograft]. / Remplacement valvulaire mitral par homogreffe mitrale cryopréservée.

Mitral valve replacement using a cryopreserved mitral homograft was performed in a 49 year old patient with calcified mitral stenosis. The surgical technique is described. The postoperative course was uneventful. Transoesophageal echo performed 4 months later showed a normal function of the mitral homograft.

[Transplantation of cryopreserved carotids in the rabbit: effect of cryoprotective agents]. / Transplantation de carotides cryopréservées chez le lapin: effet des agents cryoprotecteurs.

The cryopreservation of blood vessels has been carried out for some decades with variable results. In order to study the behaviour of cryopreserved allografts by using new technique of cryopreservation a study on the ultrastructure arterial tissue consequences by microscopic techniques has been carried. The graft has been harvested from carotid artery of donor rabbit, implanted to a carotid artery of a recipient rabbit and extracted at 1, 3 and 5 months after the operation. An intimal thickening and a cellular loss in the media have been observed. However, good patency has been observed in all cryopreserved allografts. Manifestations of rejection are delayed in groups with polyethylene glycol.

Cryopreserved aortic allograft replacement of infected prosthetic grafts in man: processing and clinical results.

Aortic allografts preserved at 4 degrees C have been used successfully for the replacement of infected prosthetic grafts, but have a limited storage duration and this does not allow for rigourous security of the allograft. Original cryopreservation protocol has been developed, characterized by the use of polyethylene glycol 20,000 30 g/l associated with 12.5% DMSO, high concentration of antibiotics (lincomycin 300 mg/l, vancomycin 125 mg/l), controlled freezing rate, and storage in the vapour phase of liquid nitrogen (-150 degrees C). Cryopreserved arterial allografts were used for the replacement of infected prostheses in 22 patients. In 2 patients, allograft-related dysfunction was observed, 3 patients died in the early postoperative period from non-allograft-related causes, and, 17 patients were cured of infection without any dysfunction of the allograft. These results are comparable to replacement by fresh allograft, but cryopreservation allows for better microbiological security, long-term storage, and, thus, better management of the available allografts.

Separation of living red blood cells by gravitational field-flow fractionation.

The field-flow fractionation technique, using the earth's gravitational field, has been applied to peripheral blood cell populations. A more or less symmetrical, gaussian-like, elution peak is generally observed for the red cell population. The bimodal cell population obtained after a massive transfusion is shown to result in a shoulder on the red blood cell elution profile. In one case where a similar shouldering peak was obtained from a non-transfused donor, the existence of an immunological double population has been demonstrated. This suggests that field-flow fractionation has some potential for complementary biomedical diagnosis.

Autologous bone marrow transplantation in Hodgkin's disease.

The outcome of advanced Hodgkin's disease has improved since the use of MOPP and ABVD. However 50% of these patients will relapse. Conventional salvage therapy can yield a complete response rate of 50%. However, only 5 to 30 percent can expect to be cured. Autologous bone marrow (ABMT) in reported publications can reach 50 to 80% remission rate in refractory patients with a disease free survival of 40 to 80%. Adverse prognostic factors are: tumor burden, number of prior chemotherapies, response to latest therapy and performance status. At the present time, ABMT is discussed in relapse of poor prognosis with initially stage I to IIIA. Twenty-six patients underwent ABMT at Saint-Louis Hospital. Fifteen were sensitive relapses of poor prognosis, 11 initially refractory disease. After ABMT, 19 were in complete remission including 14 relapses. Disease free survival was 80% for relapsing patients, again 50% for refractory patients (P = 0.001). ABMT should be a tool for refractory patients and relapses of poor prognosis.

[Determination of plasma hemoglobin in fresh plasma for therapeutic use by the TMB (3,3',5,5'-tetramethylbenzidine) method]. / Dosage del'hémoglobine plasmatique dans les plasmas frais à utilisation thérapeutique par la méthode à la T.M.B. (3,3'-5,5 tétraméthylbenzidine).

The maximum level of plasma hemoglobin in standard fresh frozen plasma before freezing has been mixed at 50 mg/l by french regulations. As no reference method is specified by the standards, we have adapted a technique where pseudo-peroxydasic activity of the hemoglobin is revealed by 3,3'-5,5', tetramethylbenzidine, a non carcinogenic chromogen derivate from benzidine. A 4 points reference scale is plotted for each plasma to be tested, thus reducing eventual interferences between pseudo-peroxydasic activity of the hemoglobin and other plasma proteins. We compared our modified technique to other existing ones: Vanzetti's extraction technique [8] whose main drawbacks are the use of flammable solvents and carcinogenic chromogen. Standefer's technique [10] involving plasma preincubation in H2O2 solution, which reveals protein interferences but is imprecise as it relies on only one reference point and does not show whether chromogen saturation is present. The level fixed by regulations is higher than the mean level indicated by our method, based on 118 samples of fresh plasma obtained by double centrifugation of whole blood collected on CPD as anticoagulant. It is also higher than the level indicated by the same method for plasma samples drawn from continuous or discontinuous flow cytapheresis (IBM 2997; Haemonetics V 50) using ACD - A or ACD - AA 16 as anticoagulant. Our method measures with precision low levels in plasma. Furthermore it is cheap, simple and easy to run in a blood transfusion center.

Production of lymphocyte activating factor in the absence of endogenous pyrogen by rabbit or human leukocytes stimulated by a muramyl dipeptide derivative.

N-acetylmuramyl-L-alanyl-D-isoglutamine or MDP is a synthetic immunoadjuvant capable of inducing a febrile response in the rabbit and of eliciting production of endogenous pyrogen (EP) in vivo and in vitro. It was also shown to stimulate in vitro lymphocyte activating factor (LAF) release. After conjugation to a synthetic carrier, the pyrogenic effect of MDP is strongly enhanced. Recently, adjuvant active derivatives of MDP devoid of pyrogenicity such as MDP(Gln)-OnBu (AcMur-L-Ala-D-Gln-alpha-nbutyl ester) have become available. In the present study, their stimulating properties on rabbit peritoneal exudate cells or human peripheral blood mononuclear cells were simultaneously evaluated by testing lymphocyte activating property and pyrogenic effect of the culture supernatant. In both types of cell cultures, whereas MDP elicited dual effects, the nonpyrogenic analog MDP(Gln)-OnBu produced LAF without detectable pyrogenicity even when a very sensitive assay (intracerebroventricular administration) was used. In contrast, conjugated MDP was capable of inducing the production of endogenous pyrogen in rabbit cell cultures with no or little LAF release. These results argue against the possibility that a single factor is responsible for both LAF and EP activities.

High dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma.

We report the results of peripheral blood stem cell (PBSC) collection performed after priming with a semi-intensive CHOP regimen in 70 patients with aggressive multiple myeloma (MM). Forty-one of the 44 previously untreated patients compared to 17 of the 26 patients with a refractory disease yielded stem cells enough for autotransplantation. Phenotypic and genotypic studies of collected mononuclear cells, even performed after depletion of monocytes and/or of T lymphocytes, did not reveal contamination by tumor plasma cells or clonal B cell precursors in any studied case. Forty-eight of the 58 patients with successful PBSC collection have been presently treated by high dose therapy followed by autologous blood stem cell transplantation (ABSCT). Among the 43 patients who received a regimen including total body irradiation, four died within six months after the autograft. All remainders responded and most often achieved an impressive tumor mass reduction. Ten relapsed and four died from disease progression. Nine to 70 months (median: 35 months) after blood stem cell collection, 29 patients are either in apparent complete remission or with a state of stable residual disease, most often minimal. Blood stem cell autograft was successful in all evaluable patients and the kinetic of hematologic recovery was roughly related to the amount of reinfused CFU-GM (2.1 to 50 x 10(4)/kg). Median delays for granulocytes greater than 500/mm3 and platelets greater than 25,000/mm3 were 15 days and 20 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)