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Biomedical subjects

J F Rossi

Publications and source records attributed to J F Rossi.

At least 73 records · Page 4Linked to original sources
PubMed1995

Treatment of Waldenstrom's macroglobulinemia with very low doses of alpha interferon.

Waldenström's macroglobulinemia (WM) is a differentiated B-cell malignancy which is usually less responsive to standard chemotherapy because of low-proliferating cells. Interferon alpha has been shown to possess a therapeutic action in numerous B-cell malignancies including the early stage of chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma and hairy cell leukemia. Fourteen patients with progressive WM were included in a pilot study using very low dose of interferon alpha-2a (1 Million Units 3 times a week). The mean duration of treatment was 10.3 months (range 2-44). Six of 14 (42%) patients presented an increase in the hemoglobin level (> or = 0.9 g/dL) and 4/14 (28%) had a substantial decrease of the monoclonal component (> or = 20% of reduction). Only two patients presented both types of response, while the others with an increase in the hemoglobin level had a slight decrease in the monoclonal component (MC) (1 patient), a stable MC (1 patient) or a slight increase of MC (1 patient). One additional patient had a 15% decrease of the MC with a stable hemoglobin level. Response was observed within 3 months with a median duration of 6 months. Treatment was stopped for 3 patients because of flu-like symptoms (2 patients), or thrombocytopenia (1 patient). Follow up was possible in 12 patients lasting up to a maximum of 30 months after discontinuing treatment. Seven patients died, including 4 with progressive disease, two of infection and one of cardiac failure. In the view of these results, very low dose of interferon alpha may constitute a new approach for treatment of some cases of WM.

Aged↗
PubMed1995

Chemoresistance and multiple myeloma: from biological to clinical aspects.

Resistance to chemotherapy represents a major cause for cancer treatment failure. Several biological mechanisms implicated in chemoresistance have been described, including multidrug resistance (MDR1/P-glycoprotein [P-gp] or p170), resistance-related proteins (p95 and p110), multidrug resistance-associated protein (p190), proteins implicated in cell detoxification such as glutathione S-transferase and genes affecting DNA structure (topoisomerases). MDR1 has been the most studied in hematological malignancies, particularly in lymphoma and multiple myeloma (MM), diseases generally considered as overexpressing such mechanisms in relapse. Overexpression of chemoresistance is generally an induced phenomenon caused or amplified by the drugs, as demonstrated by the development of drug-resistant cell lines in vitro. It may be defined as a profile of chemoresistance depending on the drug used for induction. This may have a potential implication for monitoring chemoresistance to modulate or to prevent its amplification. Several questions are always open to discussion, including the method of detection, the true prognostic impact of chemoresistance, the dynamic expression of such mechanisms, depending on the cell status, the host response and the mechanism of induction. In MM, the over-expression of MDR1/P-gp is usually less than 10% at diagnosis, leading to 59-80% at relapse, depending on the clinical status. The percentage of positivity depends on the cumulative dose of vincristine and/or doxorubicin. GST pi is (over)expressed in 10-70% of patients at diagnosis, and in 30% at relapse, but in small series, as well as for topoisomerases I and II which are concerned in 53% and 6%, respectively, at diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Human anti-mouse antibody response to the injection of murine monoclonal antibodies against IL-6.

We analysed human anti-mouse antibodies (HAMA) in 12 patients (six with multiple myeloma (MM) and six with metastatic renal cell carcinoma (MRCC) who were treated with B-E8, an IgG1 MoAb against IL-6. Efficiency of the treatment was evidenced by the drop in the serum levels of C-reactive protein (CRP), the in vivo production of which is under the control of IL-6. Three patients with MM and the six patients with MRCC became immunized to the injected MoAb. HAMA appeared between days 7 and 15 after the beginning of the treatment. The nine patients made IgG antibodies; four also made IgM. All immunized patients made anti-idiotype antibodies specific to B-E8. Two of them also developed HAMA directed to murine IgG1 isotype; in these two patients B-E8 MoAb cleared rapidly from the circulation with loss of treatment efficiency. In the patients who developed only anti-idiotype antibodies, serum levels of B-E8 remained unchanged and CRP production remained inhibited, indicating that treatment remained efficient in the presence of HAMA. Circulating B-E8 MoAbs were still able to bind to IL-6 and to inhibit IL-6-dependent proliferation despite the presence of anti-idiotypic HAMA. Therefore, in contrast to HAMA produced against MoAb directed against cellular targets, HAMA against anti-IL-6 MoAb idiotopes led neither to clearance nor to functional inactivation of the injected MoAb. This was further shown by resuming the B-E8 treatment with success in a patient who still had anti-idiotypic HAMA.

Adult↗
PubMed1993

Expression of P-glycoprotein and anionic glutathione S-transferase genes in non-Hodgkin's lymphoma.

Non-Hodgkin's lymphomas (NHL) are usually sensitive to chemotherapy. A certain percentage of patients are primarily or subsequently resistant to chemotherapeutic agents. Several biological mechanisms are implicated in this phenomenon, including multidrug resistance (mdr1) and glutathione S-transferase (GST pi). We investigated these two systems, using dot blot analysis, in 41 patients who presented NHL with advanced disease. There were 15 patients with low grade, 22 with intermediate grade, and 4 patients with high grade using the Working Formulation for Clinical Usage. Twenty-five patients had not been previously treated and 16 had been treated, including 13 with refractory disease. Eleven out of 25 (44%) patients overexpressed mdr1 mRNA at diagnosis as compared to 6/16 (38%) in relapse, corresponding to 6/13 (46%) refractory patients. Nine out of 25 (36%) patients overexpressed GST pi mRNA at the time of diagnosis, and 6/16 (50%) in relapse. These data indicate that overexpression of these two messengers is not acquired after treatment in NHL. Furthermore, there is no relationship between the stage or histological grade and the overexpression of these two markers. This study shows that mdr1 and GST pi gene expressions are independent of one another. With regard to the clinical response, our results also demonstrated a higher level of treatment failure in the group co-expressing the two transcripts, 6/8 (75%) patients died in progressive disease as compared to 9/15 (60%) patients without overexpression, and 2/8 (25%) vs 6/15 (40%) responded to treatment. On the other hand, overexpression of only one of the two mRNAs did not allow us to observe a difference in the clinical response. Since it seems that coexpression of the mechanisms of resistance present a better clinical impact, it would be of interest to analyse simultaneously different mechanisms involved in the resistance phenomenon in NHL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Overall interleukin-6 production exceeds 7 mg/day in multiple myeloma complicated by sepsis.

We previously reported that injection of anti-IL-6 monoclonal antibody (mAb) in a patient with multiple myeloma (MM) induced the circulation of high amounts of IL-6 in the form of IL-6/anti-IL-6 monomeric complexes. This made it possible to estimate overall daily IL-6 production in patients in vivo, which had not been achieved in animals or humans before. In this study, estimations are given for a patient with MM who developed Escherichia coli sepsis during anti-IL-6 mAb. During the first 12 days, the overall IL-6 production was estimated at 1.5 to 2.0 micrograms/day. On day 13, serum IL-6 concentration, in the form of IL-6/anti-IL-6 complexes, increased 1000-fold and was 1.7 x 10(6) pg/ml, in relation with the development of E. coli sepsis. Overall IL-6 production was estimated to be greater than 7 mg/day, i.e. 3500 times higher than before sepsis. Serum IL-6 levels in the form of monomeric immune complexes remained very high for 20 days after sepsis indicating the persistence of very high overall IL-6 production (100 to 3500-fold greater than pre-sepsis production). This study demonstrates a considerable and persistent potential for IL-6 production in this patient during and after sepsis.

Antibodies, Monoclonal↗
PubMed1992

Responsiveness of chronic lymphocytic leukemia B cells activated via surface Igs or CD40 to B-cell tropic factors.

Recent studies performed in the laboratory have established that interleukin-4 (IL-4) used in combination with anti-CD40 monoclonal antibody (MoAb) 89 presented on Ltk- mouse fibroblasts stably expressing human Fc gamma RII/CDw32 (referred to as the CD40 system) sustains long-term proliferation of normal human B cells. In the present study, B-cell chronic lymphocytic leukemias (B-CLLs) activated through slgs or CD40 were examined for their capacity to proliferate and differentiate in response to various cytokines. Our results indicate that the outcome of IL-4 stimulation on the in vitro growth of B-CLL depends on the signalling pathway used for their activation. Whereas IL-4 did not display any growth-stimulatory effect on B-CLL activated by Ig cross-linking agents, it could stimulate DNA synthesis and enhance the viable cell recovery when leukemic B cells were cultured in the CD40 system. Most B-CLL samples were induced for IgM synthesis upon Staphylococcus aureus strain Cowan I stimulation. This Ig response was potentiated by IL-2 and antagonized by IL-4. Anti-CD40 MoAb used alone or in combination with cytokines (IL-1 alpha to IL-6, interferon gamma, tumor necrosis factor gamma, and transforming growth factor beta) failed to induce Ig secretion from B-CLL cells. No evidence for Ig isotype switching was obtained with the cytokines listed above, regardless of the mode of activation. Taken together, our results suggest that B-CLL cells can be partially released from their apparent maturation block by IL-2 and Ig cross-linking agents. In contrast, combinations of IL-4 and cross-linked anti-CD40 antibodies induced entry of B-CLL cell into cycle, but poorly stimulated their differentiation into Ig secreting cells.

Adult↗
PubMed1992

Antiproliferative effects of interleukin-4 on freshly isolated non-Hodgkin malignant B-lymphoma cells.

The pattern of in vitro growth response of freshly isolated non-Hodgkin malignant lymphoma B cells (NHML) to cytokines was investigated. Ten tumor specimens of low- or intermediate-grade malignancy were selected for study. To assess their proliferative capacity in vitro, B-lymphoma cells were activated through ligation of their surface Ig receptor with insolubilized anti-IgM antibodies or Staphylococcus aureus strain Cowan I (SAC). In the great majority of cases, interleukin-2 (IL-2) was the sole factor that significantly and reproducibly stimulated DNA synthesis in NHML activated through their surface Igs. Other B-cell tropic factors, including IL-4, IL-5, IL-6, and tumor necrosis factor-alpha (TNF-alpha), failed to elicit a growth response in most of the IL-2-responsive neoplastic samples. However, one specimen among 10 exhibited the opposite pattern of response and proliferated following culture with IL-4 and anti-Ig reagents, but not after IL-2 stimulation. Three specimens could also be induced for DNA synthesis on cross-linking of their surface Igs in the absence of exogenous growth factors. Although IL-4 could not support the in vitro growth of the majority of NHML cases, it strongly suppressed the proliferative signals delivered to these cells by anti-Ig reagents used alone or in combination with IL-2. Our data suggest that, in most cases, IL-4 essentially provides growth-inhibitory signals to NHML when they are activated through their surface Ig receptors and as such may be considered to be a valid candidate for future therapy of this type of mature B-cell malignancy.

Antibodies, Anti-Idiotypic↗
PubMed1992

Doxorubicin and doxorubicinol plasma concentrations and excretion in parotid saliva.

The pharmacokinetics of doxorubicin (DOX) and doxorubicinol (DOXol) was studied in six patients with various advanced neoplastic diseases who received 28-72 mg/m2 DOX (nine courses). Plasma and parotid saliva were collected over a 48-h period, and DOX and DOXol were quantified by high-performance liquid chromatography with fluorescence detection. As reported previously, a wide range of plasma levels were found among our patients. It appears that in addition to being quickly cleared from the plasma, both DOX and DOXol are excreted in detectable amounts in parotid saliva, a route of elimination that has been given little attention, if any. Excretion in the saliva exposes the mucosa of the upper gastrointestinal tract to drug and may play a role in causing stomatitis in patients receiving DOX by the i.v. route. Since huge interindividual and pronounced intraindividual differences were found in S/P ratios that mostly were not systematically related to the plasma drug concentration, the concentration in parotid saliva was not useful in predicting the level of free DOX and DOXol in plasma. For the parent drug and its metabolite, the S/P ratios increased significantly with time during the 48-h period after dosing.

Adult↗
PubMed1992

Non-Hodgkin's lymphoma associated with primary Sjögren's syndrome.

OBJECTIVES: To evaluate the prevalence, the incidence and clinical presentation of non-Hodgkin's lymphoma associated with primary Sjögren's syndrome. METHODS: Sixty-two patients with primary Sjögren's syndrome were analyzed retrospectively in an open investigation. RESULTS: Of 62 patients with primary Sjögren's syndrome, 4 of them (6.4%) developed non-Hodgkin's lymphoma (6.9 cases per 1000 per year). All of them were women. Non-Hodgkin's lymphoma always developed after the onset of primary Sjögren's syndrome with a time interval ranging from 3 to 27 years. Pathological findings showed two diffused mixed small and large cell cleaved lymphomas and two diffused large cell cleaved lymphomas. Three cases had extra-nodular localizations. All of these 4 patients are still alive and in complete remission 2 to 8 years after the diagnosis of non-Hodgkin's lymphoma. CONCLUSION: This study confirms the association of non-Hodgkin's lymphoma in primary Sjögren's syndrome. These non-Hodgkin's lymphomas frequently had extra-nodal localizations. Good sensitivity to treatment, when necessary, provided good prognosis.

Adult↗
PubMed1991

Bayesian estimation of doxorubicin pharmacokinetic parameters.

Doxorubicin was given by brief i.v. infusion (doses ranging from 25 to 72 mg/m2) to 28 patients for 2-7 successive courses of chemotherapy (68 courses studied in all). A Bayesian approach was developed to determine the individual pharmacokinetic parameters of doxorubicin. Statistical characteristics of the population pharmacokinetic parameters were first evaluated for 19 patients and a total of 30 courses, which, when combined with 4 individual plasma concentrations of drug, led to a Bayesian estimation of individual pharmacokinetic parameters for the remaining 38 courses. The estimated parameters for the elimination phase (A3/V1 and t1/2 elimination) and the residual plasma level at 48 h as computed by Bayesian estimation on this reduced sub-optimal sampling protocol were compared with a maximal likelihood estimation of these parameters. No statistically significant differences were found. Performance of the developed methodology was evaluated by computing bias and precision. The mean errors were -0.0315 x 10(-4) l-1 for A3/V1, 0.0839 h for t1/2 elimination, and -0.22 ng/ml for c(48 h). The precision of the prediction of these three parameters (0.304 x 10(-5) l-1, 3.34 h, and 0.659 ng/ml, respectively) remained lower than the interindividual standard deviation (1.42 x 10(-4) l-1, 14.9 h, and 4.54 ng/ml, respectively). This procedure enables the estimation of individual pharmacokinetic parameters for doxorubicin at minimal cost and minimal disturbance of the patient.

Bayes Theorem↗
PubMed1991

Osteoclast cytomorphometry demonstrates an abnormal population in B cell malignancies but not in multiple myeloma.

Increased bone resorption in the vicinity of myeloma cells is mediated by local stimulating factors. Other malignancies of the B cell lineage are also able to produce resorbing factors responsible for increased bone resorption. We have studied three groups of subjects: 10 patients with overt multiple myeloma, 10 patients with a B cell malignancy, and 10 healthy human subjects as controls. Patients were studied at the time of diagnosis and had a transiliac bone biopsy. Osteoclasts were evident on histological sections by their acid phosphatase activity. A software was developed on an automatic image analyzer (Leitz TAS+) for measuring the maximal Feret's diameter (Oc.Le) of each osteoclast (corresponding to the osteoclast length). The histogram of Oc.Le frequency distribution was supplied in each group. In myeloma patients, the Oc.Le frequency distribution was similar to that in normal subjects and showed the histogram to be asymetric with a positive skew (maximum peak at 20-25 microns). With a graphical analysis, this distribution was shown to follow a lognormal distribution corresponding to a homogeneous osteoclast population. In other B cell malignancies, Oc.Le displayed a bimodal distribution with a peak at 20-25 microns and a lower peak at 10-15 microns. The graphical analysis showed that small (mononucleated?) osteoclasts are present in B cell malignancies with normal osteoclasts. This might reflect the secretion of different soluble factors by malignant cells of the B lymphocyte lineage.

Acid Phosphatase↗
PubMed1991

Characterization of proliferative cells in malignant melanomas and their inflammatory infiltrates.

Distinct changes in the antigenic phenotypes of mononuclear cells infiltrating primary and metastatic malignant melanomas (MM) have been shown to characterize distinct steps of melanoma progression. The purpose of our study is to establish whether the growth fraction of malignant melanoma cells is related to the mononuclear cell subtypes. Using monoclonal antibody Ki67, the presence of a nuclear antigen in proliferating cells of both tumor and inflammatory infiltrate cells was established in 20 primary recurrent and metastatic cutaneous melanomas. Monoclonal antibodies against lymphocyte and macrophage subsets were also applied in situ. Numerous CD8 and CD4 positive cells and natural killer (NK) cells were detected in all the infiltrates. A low CD4+/CD8+ ratio was observed in most tumors with a high proliferative activity. The presence of positive CD1+ cells seemed also to be correlated with a high activity. Our data suggest a correlation between inflammatory cell subsets and proliferative activity of MM.

Antigens, CD↗
PubMed1991

Maintenance treatment with recombinant alpha interferon after autologous bone marrow transplantation for aggressive myeloma in first remission after conventional induction chemotherapy.

Twenty patients (median age 57 years) with high tumor mass myeloma in first remission after conventional chemotherapy received a two-phase treatment: autologous bone marrow transplantation (ABMT) using a preparative regimen of high dose melphalan plus total body irradiation followed by maintenance treatment with recombinant alpha interferon. Before ABMT all patients were in partial remission, while after ABMT 10 (50%) achieved complete remission, and 10 remained in partial remission (with a 90% decrease in measurable paraprotein in 7/10). With a median follow-up of 19.8 months (12.2-33.5) after diagnosis and 13 months (4-25) after ABMT, the Kaplan-Meier 2-year post-ABMT probability of progression-free survival was 85% (95% CI = 58.7-95.8%). None of the 10 patients in complete remission has relapsed. No toxic death occurred. Alpha interferon was introduced early after ABMT (2.7 months) and was well tolerated. This strategy may represent an advance in the management of aggressive myeloma.

Adult↗
PubMed1990

Doxorubicin and doxorubicinol: intra- and inter-individual variations of pharmacokinetic parameters.

Doxorubicin was given by short i.v. infusion (dose range 25-72 mg/m2) to 18 patients who underwent three to seven successive courses of chemotherapy (total, 57 courses). Plasma levels of doxorubicin and its major metabolite doxorubicinol were determined by high-performance liquid chromatography over a 48-h period after the infusion. Pharmacokinetic parameters for the parent drug and its metabolite were calculated for each course of treatment. The results show considerable inter- and intraindividual variations for most parameters. The coefficients of variation (CV) ranged from 37% to 93% (inter-individual) and from 6% to 59% (intra-individual). Nevertheless, we observed a good stability over successive courses for terminal half-life in six patients (CV, 6%-25%) and for clearance and AUC in four subjects (CV, 10%-22%). The ratio of the AUCs for doxorubicinol: doxorubicin averaged 0.514. The pharmacokinetic pattern of doxorubicinol was biphasic in plasma of the majority of patients. We propose a model for curve-fitting of these metabolite plasma concentrations that is based on two successive releases of the compound in the plasma compartment, separated by a lag time.

Adult↗