Cytogenetic and molecular studies of the Philadelphia translocation t(9;22) observed in a patient with myelodysplastic syndrome.

We report here the case of a patient with refractory anemia with excess of blasts (RAEB) which evolved into RAEB in transformation. The standard Philadelphia (Ph) chromosome was found by cytogenetic study at diagnosis and during evolution. Southern blot analysis showed breakpoint cluster region (bcr) rearrangement as observed in chronic myelogenous leukemia (CML).

Efficacy of a five-drug combination including ritonavir, saquinavir and efavirenz in patients who failed on a conventional triple-drug regimen: phenotypic resistance to protease inhibitors predicts outcome of therapy.

OBJECTIVE: to assess the safety and efficacy of a combination of ritonavir, efavirenz and two recycled nucleosides in patients who failed on a conventional triple-drug regimen including indinavir or ritonavir. METHODS: An open label study of ritonavir (100 mg twice daily), saquinavir (1000 mg twice daily), efavirenz (600 mg per day) and nucleoside analogues in 32 saquinavir- and efavirenz-naive protease inhibitor-experienced patients. Patients were included on the basis of plasma levels of HIV RNA above 5000 copies/ml while on conventional antiretroviral therapy. Phenotypic resistance and genotypic resistance mutations to saquinavir were assessed at baseline. Peak and trough plasma levels of saquinavir were monitored throughout the study. RESULTS: Median CD4 cell counts and median plasma HIV RNA at baseline were 258 x 10(6)/l and 4.31 log10 copies/ml, respectively. The plasma viral load decreased by a median of 1.20 log10 copies/ml and the CD4 cell count increased by a median 60 x 10(6) cells/l at week 24 of therapy. Seventy-one per cent of the patients achieved a plasma viral load < 500 copies/ml and 45% achieved a viral load < 50 copies/ml. Patients exhibiting phenotypic resistance to saquinavir at baseline experienced a median decrease in HIV RNA of 0.91 log10 copies/ml at week 24 of therapy, as compared with a decrease of 1.52 log10 copies/ml in those exhibiting sensitive viral strains (P = 0.03). Genotypic resistance to saquinavir was not predictive of virologic failure. CONCLUSION: Our results indicate that the combination of ritonavir, saquinavir and efavirenz is safe and effective at 24 weeks in over two-thirds of patients who previously failed on highly active antiretroviral therapy, and that the determination of phenotypic resistance may be of greater value than the detection of resistance mutations to predict the outcome of salvage therapy in this setting.

Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease.

OBJECTIVES: To determine the clinical, virological and immunological outcome in a cohort of unselected patients receiving triple combination therapy for more than 1 year. METHODS: Prospective follow-up of a cohort of 162 unselected, protease inhibitor-naive, antiretroviral-experienced patients with advanced HIV disease, treated with indinavir combined with two nucleoside analogues. RESULTS: The mean CD4 cell count and plasma HIV RNA level in the study group at baseline were 69+/-5 x 10(6)/l and 4.75+/-0.07 log10 copies/ml, respectively. Five per cent of patients died prematurely or were lost to follow-up. Fifty-seven per cent of patients responded to therapy, as assessed by a sustained increase in CD4 cell counts above 50 x 10(6)/l and a decrease in plasma HIV RNA greater than 1 log10 copies/ml, throughout 12.1 months of follow-up. Seventeen per cent of patients were immunological and virological non-responders. Twenty-one per cent of patients exhibited discrepant virological and immunological responses to treatment, of whom one-half failed to exhibit significant increases in CD4 cells despite a virological response to therapy and one-half exhibited increased CD4 cell counts in the absence of significant decrease in plasma viral load. The incidence of AIDS-defining events in the latter group of patients was similar to that of responder patients, whereas their incidence was higher in patients who failed to exhibit a virological and immunological response and those who failed to increase CD4 cells despite a significant decrease in viral load. CONCLUSION: Our observations of discrepant immunological and virological responses to treatment raise the issue of the significance of persistent elevated levels of plasma HIV RNA and of the relevance of measurements of plasma viral load for assessing the efficacy of antiretroviral therapy in patients whose CD4 cell counts increase despite the absence of significant decrease in plasma HIV viral load.

A prime-boost approach to HIV preventive vaccine using a recombinant canarypox virus expressing glycoprotein 160 (MN) followed by a recombinant glycoprotein 160 (MN/LAI). The AGIS Group, and l'Agence Nationale de Recherche sur le SIDA.

The safety and the immunogenicity of a recombinant canarypox live vector expressing the human immunodeficiency virus type 1 (HIV-1) gp160 gene from the MN isolate, ALVAC-HIV (vCP125), followed by booster injections of a soluble recombinant hybrid envelope glycoprotein MN/LAI (rgp160), were evaluated in vaccinia-immune, healthy adults at low risk for acquiring HIV-1 infection. Volunteers (n = 20) received vCP125 (10(6) TCID50) at 0 and 1 month, followed randomly by rgp160 formulated in alum or in Freund's incomplete adjuvant (FIA) at 3 and 6 months. Local and systemic reactions were mild or moderate and resolved within the first 72 hr after immunization. No significant biological changes in routine tests were observed in any volunteer. Two injections of vCP125 did not elicit antibodies. Neutralizing antibodies (NA) against the HIV-1 MN isolate were detected in 65 and 90% of the subjects after the first and the second rgp 160 booster injections, respectively. Six months after the last boost, only 55% were still positive. Seven of 14 sera with the highest NA titers against MN weakly cross-neutralized the HIV-1 SF2 isolate; none had NA against the HIV-1 LAI or against a North American primary isolate. Specific lymphocyte T cell proliferation to rgp 160 was detected in 25% of the subjects after vCP125 and in all subjects after the first booster injection and 12 months after the first injection. An envelope-specific cytotoxic lymphocyte activity was found in 39% of the volunteers and characterized for some of them as CD3+, CD8+, MHC class I restricted. The adjuvant formulation did not influence significantly the immune responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytogenetic study in a bone marrow metastatic Merkel cell carcinoma.

We report an additional cytogenetic study of a metastatic Merkel cell carcinoma. Even though the cells analyzed were from a metastatic lesion, chromosomal abnormalities were not complex. Similarities between cytogenetic findings described in small-cell lung carcinoma and the present case are observed. However, further studies are needed to define the relationship between these two neuroendocrine small-cell malignancies.

Similar cytogenetic abnormalities in two cases of plasma cell leukemia.

Plasma cell leukemia (PCL) is a very rare disease. We report two cases of PCL with complex chromosomal abnormalities: long arm trisomy and short arm partial monosomy of chromosome 1, a marker derived from chromosome 8, and monosomy 13 were found in both cases; other additional chromosome abnormalities were also present in each case. Bastard et al. reports two similar cases in this issue. Cytogenetic studies in PCL have seldom been reported in the literature: chromosomal abnormalities are most often complex: chromosomes 1, 8, 11, 13, and 14 are those most frequently involved. Such cytogenetic findings are observed in advanced multiple myeloma. Cytogenetic, clinical, and immunological findings observed in PCL and the advanced stage of multiple myeloma are arguments for the single origin of pathogenesis.

Refractory anemia with excess of blasts in transformation. Clinical, hematologic, and cytogenetic findings in nine patients.

Clinical, hematologic, and cytogenetic data of nine patients with refractory anemia with excess of blasts in transformation (RAEB-t), classified according to the French-American-British Cooperative Group for myelodysplastic syndrome (MDS), are reported. At diagnosis, eight out of nine cases, had chromosomal abnormalities and three out of nine developed acute leukemia. Karyotype studies allowed individualization of two groups of patients: five with nonrandom major karyotype abnormalities (MAKA) including hypodiploidy, chromosomes 5 and 7 involvement, at least four other abnormalities, and a poor prognosis (survival always under 3.5 months); and four patients with either normal karyotypes or minor karyotype abnormalities (MIKA) (no more than three abnormalities) and a better prognosis (survival from 14 to 38 months). Karyotype appears to be a major prognostic factor among RAEB-t.

Survival with intraperitoneal cisplatin in advanced ovarian cancer after second-look laparotomy.

We studied survival in 36 patients with Stage III/IV ovarian cancer who received intraperitoneal high-dose cisplatin (200 mg/m2) alone or in combination with cytarabine (2 g), after intravenous (i.v.) cisplatin-based chemotherapy followed by second-look laparotomy. Complete responders were scheduled for three courses of IP chemotherapy, and others for six. Eight patients (22%) did not complete treatment (6 catheter failures and 2 renal failures). Peritoneal cytology remained positive in 6 patients (17%). Median overall and progression-free survival after second-look laparotomy were 44 and 37 months, respectively, for 13 complete responders to i.v. chemotherapy; 24 months and 11 months for patients with residual tumors less than 2 cm (17 cases); 15 and 12 months with tumors greater than 2 cm (6 cases). There was a significant difference in overall (p = 0.05) and progression-free (p = 0.001) survival between complete responders to i.v. chemotherapy and patients whose tumor was less than 2 cm. We find no evidence that high-dose cisplatin-based intraperitoneal chemotherapy given after second-look laparotomy will enhance survival in advanced ovarian cancer with zero or minimal residual disease.

[Chemotherapy in cancer of colon. General review]. / La chimiothérapie dans le cancer du côlon. Revue générale.

The results of surgery as sole treatment of colon cancer are summarized before dealing with those of chemotherapy. Curative or palliative chemotherapy remains controverted. The results of single drug treatments and of the conventional protocols with 5-fluorouracil and nitrosoureas have been disappointing. A promising approach is modulation of 5-fluorouracil by folinic acid, with a response rate of up to 45 p 100, and potentiation of 5-fluorouracil by cisplatin. Intra-arterial chemotherapy has been, and still is, an interesting method in liver metastases, but recent studies and the experience acquired with prolonged follow-ups have thrown doubts on some of its results, notably survival. Adjuvant chemotherapy is even more controversial than curative chemotherapy; however, a recent controlled study has yielded favourable results, and the best drug combinations have not yet been tested. It is concluded that cancers of the colon have shown some chemosensitivity, even though it has not reached the same level as that of cancers of other organs.

[Functioning of implantable catheters of intraperitoneal chemotherapy]. / Fonctionnement des cathéters implantables de chimiothérapie intrapéritonéale.

Intraperitoneal chemotherapy with a totally implantable catheter was performed in 42 patients with advanced ovarian cancer who received 178 courses of chemotherapy administered in 2 l of solution. Major complication was inflow obstruction due to fibrosis around the catheter observed in 10 patients, 23.8% of the cases. Other complications were: leakage 3 (7.1%), pain 3 (7.2%), infection 3 (7.1%) and rectal perforation 1 (2.4%). Overall, these complications occurred in 15 patients (35.7%) and were the cause of treatment interruption in 7 (16.7%). Outflow obstruction which occurred in 23 patients (54.8%), did not create discomfort and could not be considered as a complication. Despite the problems, intraperitoneal chemotherapy with a totally implantable catheter appeared feasible in at least 80% of the patients.

[Results of intraperitoneal chemotherapy of ovarian cancer]. / Résultats de la chimiothérapie intrapéritonéale du cancer de l'ovaire.

We studied a series of 42 patients with advanced ovarian cancer who received intraperitoneal chemotherapy post second-look laparotomy. High-dose cisplatin (200 mg/m2) alone or in combination with cytarabine (2 g) achieved 47% response rate. Median overall survival from second-look laparotomy was 44 months with cisplatin (36 cases), 15 months with carboplatin (600 mg/m2, 5 cases) and not reached at 3 yrs with mitoxantrone (25 mg/m2, 8 cases). Median overall and progression-free survival from second-look laparotomy were 44 and 39 months respectively in complete responders (15 cases), 20 months and 9 months where residual tumor less than 2 cm (21 cases), 22 and 12 months where tumor greater than 2 cm (6 cases). There was a significant difference in survival (P = 0.01) and progression-free survival (P = 0.002) between complete responders and patients whose tumor was less than 2 cm. Toxicity was acceptable except for carboplatin with constant grade 4 leukocytes or platelets toxicity. It was not demonstrated that high-dose intraperitoneal chemotherapy given post second-look laparotomy will improve survival in advanced ovarian cancer. Further studies of polychemotherapy or early administration are needed.

[Prognosis in ovarian cancer as a function of the results of the second-look laparatomy]. / Pronostic des cancers de l'ovaire en fonction des résultats du second look.

Second-look laparotomy (SLL) was performed after chemotherapy in 106 patients with epithelial ovarian cancer. Thirteen were stage I and II and 93 stage III and IV. Seventy-eight patients received cisplatin-based regimens. Median follow-up was 60 months. Negative SLL was found in 32 patients who had a 5-year survival rate of 43.4% after SLO. Microscopy residual disease was present in 9 patients whose 5-year survival rate was 25%. Maximum residual tumor of 2 cm or less was found in 13 patients with 5-year survival rate of 30%. Residual tumor larger than 2 cm after secondary cytoreduction was present in 21 patients, their 3-year survival rate was 18.3%. Eighteen patients with bulky residual disease who did not have cytoreduction were all dead within 17 months. Patients with initial residual tumor at first laparotomy less than 2 cm had a near significant advantage in survival rate over patients with residual disease greater than 2 cm and stage IV (p = 0.07). Non-responders to initial chemotherapy had a survival rate similar to that of partial-responders. These findings justify discontinuation of conventional systemic chemotherapy for patients showing residual disease after SLL and secondary tumor removal in case of residual tumor at SLL. Therapeutic trials are needed in advanced ovarian cancer testing initial aggressive surgery or early debulking to avoid bulky residual disease and consolidation therapy in patients who achieved complete pathological response or minimal residual intraperitoneal disease.