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J F Rossi

Publications and source records attributed to J F Rossi.

At least 37 records · Page 2Linked to original sources
PubMed1999

The Mi15 monoclonal antibody (anti-syndecan-1) is a reliable marker for quantifying plasma cells in paraffin-embedded bone marrow biopsy specimens.

Plasmocyte selective monoclonal antibodies (MAb) recognizing syndecan-1 have recently been described. They belong to a new cluster, CD138. Using the MAb MI15, we investigated the expression of syndecan-1 in routinely paraffin-embedded tissues. Nontumoral lymph nodes (25 cases) and bone marrow biopsy specimens (63 cases) showed strong membrane staining of plasma cells only, allowing accurate analysis of the nuclear structure. The MI15 positivity correlated with kappa and lambda light chain expression in the cytoplasm. The percentages of plasma cells calculated in bone marrow biopsy specimens after MI15 staining were, respectively, 2.1% (range, 1% to 4%) in normal bone marrows, 8.5% (range, 5 to 17) in reactive plasmocytosis, and 4.66% in monoclonal gammapathy of undetermined significance (MGUS) patients (range, 1 to 13), in the same range but slightly higher than those obtained on smears or on hematoxylin and eosin (H&E)-stained sections. In multiple myeloma (40 cases), all plasma cell types were marked, and Mi15 MAb gave additional information in 8 of 40 (20%) patients. In lymph nodes, Mi15 MAb reacted with Reed-Sternberg cells of classical Hodgkin's disease in 23 of 31 cases (74%) with variable intensity. In contrast, nodular lymphocyte predominance Hodgkin's disease (10 cases), most B cell lymphomas (88 of 107 cases) and all T cell lymphomas (30 cases) were negative. In B cell lymphomas, plasmocytomas (8 cases), plasmocytic lymphomas (2 cases), and 5 of 13 cases of immunoblastic lymphoma with plasmocytoid differentiation were stained. In lymphoplasmocytoid lymphomas (4 lymph nodes and 20 bone marrow biopsy specimens), only mature plasma cells were positive. Moreover, a wide distribution of syndecan-1 was observed in normal and tumoral epithelial tissues. Finally, Mi15 MAb appears to be a reliable marker for identifying and quantifying normal and tumoral plasma cells in paraffin-embedded bone marrow and lymph node samples.

Antibodies, Monoclonal↗
PubMed1999

Intensive sequential chemotherapy (ISC 95) with growth factors and blood stem cell support in high-intermediate and high-risk (IPI 2 and IPI 3) aggressive non-Hodgkin's lymphoma: an oligocentric report on 42 patients.

We previously reported feasibility and efficacy of a monocentric pilot study of intensive sequential chemotherapy (ISC) in poor-risk aggressive non-Hodgkin's lymphoma (NHL) in patients < 60 years. To validate these results on a large cohort of patients, we designed a new and oligocentric study. After a COP (cyclophosphamide (Cy), vincristine (Vcr), prednisone (Pred) debulking, patients received four courses of high-dose CHOP (Cy, doxorubicin (Doxo), Ver, Pred), with the addition of etoposide and cisplatin during the two last courses. G-CSF was delivered after each cycle, and peripheral blood stem cells (PBSC) were used to support the two last cycles. Total duration of chemotherapy was 13 weeks, with a planned dose-intensity (DI) of 1420 mg/m2/week and 23 mg/m2/week for Cy and Doxo, respectively. Radiotherapy (involved fields) was then delivered for patients with node size > or = 5 cm at diagnosis. Forty-two patients were enrolled in this study; 36 completed the treatment and received 75% or more of the planned DI for both Cy and Doxo. Median duration of grade 4 neutropenia was 14 days (range, 2 to 28) for the regimen as a whole, and median duration of rehospitalization for febrile neutropenia was 18 days (range, 4 to 41). Overall response rate was 83%, with 29 patients (69%) in complete response (CR). Six patients failed to respond and one died of toxicity. With a median follow-up of 22.5 months (range, 10 to 42), the 3-year event-free survival (EFS) is 55% (95% CI, 39-71), while disease-free survival (DFS) is 79% (95% CI, 63-95). Ambulatory ISC is accessible and feasible in an oligocentric study. PBSC allow repeated delivery of high-dose chemotherapy cycles, and result in encouraging CR, EFS, and DFS rates for poor-risk aggressive NHL's patients.

Adult↗
PubMed1999

Cytokines in metastatic renal cell carcinoma: is it useful to switch to interleukin-2 or interferon after failure of a first treatment? Groupe Français d'Immunothérape.

PURPOSE: Interleukin-2 (IL-2) and interferon alfa-2a (IFNalpha2a) have some antitumor activity in metastatic renal cell carcinoma either alone or in combination. To determine whether either of these cytokines might be efficient after failure of the other, we analyzed a series of patients treated with either IL-2 or IFNalpha2a as second-line treatment after failure of the other cytokine. PATIENTS AND METHODS: We recently performed a large multicenter study to determine the respective efficacy of IL-2, IFNalpha2a, or combined treatment in renal cell carcinoma. In this study, patients who progressed on the single-arm treatment could receive the other cytokine in a cross-over trial. IL-2 was administered as a continuous intravenous infusion for 5 days (18 x 10(6) IU/m(2)/d), and IFNalpha2a was administered three times weekly at 18 x 10(6) IU. RESULTS: A total of 113 patients with progressive disease after first-line treatment received either IFNalpha2a (n = 48) or IL-2 (n = 65). Toxicity during second-line treatment was similar to that observed during first-line treatment. Only four partial responses were observed (one with IFNalpha2a and three with IL-2). All partial responders had a performance status of 0 and lung metastases. Moreover, three of these four patients had stable disease or had responded to first-line therapy. Only one patient with confirmed disease progression after receiving IL-2 subsequently responded to IFNalpha2a. CONCLUSION: Cross-over after failure of IL-2 or IFNalpha2a is poorly efficient in metastatic renal cell carcinoma, especially when progression has been clearly documented.

Adult↗
PubMed1999

Interleukin-10 and Gp130 cytokines in human multiple myeloma.

Interleukin (IL)-10 is a critical cytokine involved in the terminal differentiation of B cells into plasma cells. IL-10 is also involved in multiple myeloma, a malignant plasma cell disorder. IL-6 and, more generally the cytokines activating the gp130 IL-6 transducer, are major survival and proliferation factors of myeloma cells. IL-10 is also a growth factor of malignant plasma cells, produced by myeloma cells from about half the patients and is detected in the plasma of patients with plasma cell leukemia or solitary plasmacytoma. The myeloma cell growth activity of IL-10 is mediated through a gp130 cytokine, oncostatin M (OSM), that is frequently produced by myeloma cells. Myeloma cells fail to express OSM receptors but IL-10, by inducing it, confers on them the sensitivity to OSM.

Animals↗
PubMed1999

Tumor necrosis factor is a survival and proliferation factor for human myeloma cells.

Interleukin-6 (IL-6) is a major survival factor for malignant plasma cells. In patients with multiple myeloma (MM), cell lines whose survival and proliferation are dependent upon addition of exogenous IL-6 have been obtained. We show here that tumor necrosis factor-alpha (TNF-alpha) is also a survival factor for myeloma cell lines, although less potent than IL-6. The survival activity of TNF-alpha is not affected by anti-IL-6 or anti-gp130 monoclonal antibodies (mAbs). TNF-alpha also induces myeloma cells in the cell cycle and promotes the long-term growth of malignant plasma cell lines. As TNF-alpha is produced in patients with MM and associated with a poor prognosis, these results suggest that anti-TNF-alpha therapies could be useful in this disease.

Antibodies, Monoclonal↗
PubMed1998

IFN-alpha is a survival factor for human myeloma cells and reduces dexamethasone-induced apoptosis.

IFN-alpha is used as a maintenance therapy in patients with multiple myeloma, but its benefit is a matter of controversy. In vitro studies show that IFN-alpha can both stimulate and inhibit myeloma cell proliferation. We have tested the effect of IFN-alpha on the survival of myeloma cell lines and primary plasma cells. IFN-alpha significantly reduced the apoptosis induced by removal of IL-6 in four IL-6-dependent myeloma cell lines. It also reduced the level of apoptosis induced by dexamethasone in these cell lines as well as in purified primary myeloma cells from seven patients. IFN-alpha promoted the survival of myeloma cells, which, following removal of IL-6, were blocked in G1 and died. However, unlike IL-6, IFN-alpha-treated cells remained mainly blocked in the G1 phase of the cycle. While the effects of IL-6 are mediated through stimulation of its gp130 receptor subunit, the IFN-alpha-induced survival of myeloma cells was independent of gp130 transducer activation (as demonstrated using a neutralizing anti-gp130 Ab). However, the signal transduction cascades activated by these two cytokines share at least some common elements, since stimulation with either IFN-alpha or IL-6 resulted in STAT3 phosphorylation. These results indicate that IFN-alpha promotes the survival, but not the proliferation, of myeloma cells, preventing the apoptosis induced by removal of IL-6 or addition of dexamethasone. This survival factor activity may explain the conflicting reports on the effects of IFN-alpha on myeloma cell proliferation.

Antigens, CD↗
PubMed1998

A gp130 interleukin-6 transducer-dependent SCID model of human multiple myeloma.

Agonist antihuman gp130 transducer monoclonal antibodies (MoAbs) were used in SCID mice to grow myeloma cells whose survival and proliferation is dependent on gp130 transducer activation. The agonist anti-gp130 MoAbs neither bound to murine gp130 nor activated murine cells and, as a consequence, did not induce interleukin-6 (IL-6)-related toxicities in mice. They have a 2-week half-life in vivo when injected in the peritoneum. The agonist antibodies made possible the in vivo growth of exogenous IL-6-dependent human myeloma cells as well as that of freshly explanted myeloma cells from 1 patient with secondary plasma cell leukemia. Tumors occurred 4 to 10 weeks after myeloma cell graft and weighed 3 to 5 g. They grew as solid tumors in the peritoneal cavity and metastasized to the different peritoneal organs: liver, pancreas, spleen, and intestine. Tumoral cells were detected in blood and bone marrow of mice grafted with the XG-2 myeloma cells. Tumoral cells grown in SCID mice had kept the phenotypic characteristics of the original tumoral cells and their in vitro growth required the presence of IL-6 or agonist anti-gp130 MoAbs. Myeloma cells from 4 patients with medullary involvement persisted for more than 1 year as judged by detectable circulating human Ig. However, no tumors were detected, suggesting a long-term survival of human myeloma cells without major proliferation. These observations paralleled those made in in vitro cultures as well as the tumor growth pattern in these patients. This gp130 transducer-dependent SCID model of multiple myeloma should be useful to study various therapeutical approaches in multiple myeloma in vivo.

Animals↗
PubMed1998

Clinical-grade functional dendritic cells from patients with multiple myeloma are not infected with Kaposi's sarcoma-associated herpesvirus.

Bone marrow dendritic cells (DC) from patients with multiple myeloma (MM) were recently reported to be infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Because immunotherapy strategies using DC are very promising in this disease, we looked for KSHV DNA in clinical-grade DC generated in vitro from MM patients. Adherent apheresis cells from MM patients were maintained for 7 days in clinical-grade X-VIVO 15 culture medium supplemented with granulocyte-macrophage colony-stimulating factor, interleukin-4, or interleukin-13. Tumor necrosis factor alpha was added for the last 2 days. We obtained a cell population with a DC phenotype able to endocytose fluorescein isothiocyanate (FITC)-dextran and efficiently activate resting allogenic T lymphocytes. To detect KSHV DNA, we used polymerase chain reaction (PCR) followed by Southern blotting of PCR product with a sensitivity detecting a few copies of viral DNA. All the PCR were repeated in a blinded fashion three times, on 1 mug and 0.2 mug of genomic DNA, in two different laboratories. Clinical-grade DC from 10 (91%) of 11 patients were not infected with KSHV. The apheresis cells and the purified CD34(+) cells from the same patients were also negative. A very weak PCR band was detected with DC from one patient, but the initial apheresis cells were negative. The detection of KSHV infection in 1 (9%) of 11 MM patients probably represents background seroprevalence. It seems likely that functional and clinical-grade DC from MM patients can safely be used in clinical trials.

Blood Component Removal↗
PubMed1998

Phase-I/II radio-immunotherapy study with Iodine-131-labeled anti-CEA monoclonal antibody F6 F(ab')2 in patients with non-resectable liver metastases from colorectal cancer.

Experimental studies in nude mice with human colon-carcinoma grafts demonstrated the therapeutic efficiency of F(ab')2 fragments to carcinoembryonic antigen (CEA) labeled with a high dose of 131Iodine. A phase I/II study was designed to determine the maximum tolerated dose of 131I-labeled F(ab')2 fragments (131I-F(ab')2) from anti-CEA monoclonal antibody F6, its limiting organ toxicity and tumor uptake. Ten patients with non-resectable liver metastases from colorectal cancer (9 detected by CT scan and 1 by laparotomy) were treated with 131I-F(ab')2, doses ranging from 87 mCi to 300 mCi for the first 5 patients, with a constant 300-mCi dose for the last 5 patients. For all the patients, autologous bone marrow was harvested and stored before treatment. Circulating CEA ranged from 2 to 126 ng/ml. No severe adverse events were observed during or immediately following infusion of therapeutic doses. The 9 patients with radiologic evidence of liver metastases showed uptake of 131I-F(ab')2 in the metastases, as observed by single-photon-emission tomography. The only toxicity was hematologic, and no severe aplasia was observed when up to 250 mCi was infused. At the 300-mCi dose, 5 out of 6 patients presented grade-3 or -4 hematologic toxicity, with a nadir for neutrophils and thrombocytes ranging from 25 to 35 days after infusion. In these 5 cases, bone marrow was re-infused. No clinical complications were observed during aplasia. The tumor response could be evaluated in 9 out of 10 patients. One patient showed a partial response of one small liver metastasis (2 cm in diameter) and a stable evolution of the other metastases, 2 patients had stable disease, and 6 showed tumor progression at the time of evaluation (2 or 3 months after injection) by CT scan. This phase-I/II study demonstrated that a dose of 300 mCi of 131I-F(ab')2 from the anti-CEA Mab F6 is well tolerated with bone-marrow rescue, whereas a dose of 200 mCi can be infused without severe bone-marrow toxicity.

Adult↗
PubMed1998

Evaluation of endometrial inflammation by quantification of macrophages, T lymphocytes, and interleukin-1 and -6 in human endometrium.

PURPOSE: Our purpose was to determine the impact of endometrial inflammation on fertility. METHODS: The study population included 49 women: 5 women bearing an intrauterine device, 33 sterile patients, and 11 fertile women. Endometrial biopsies were performed between day 17 and day 21 of the cycle. Immunostaining was performed with an ABC kit. Monoclonal antibodies were CD68 for macrophages, CD3 for T lymphocytes, and B-E8 for interleukin (IL)-6; IL-1 alpha and IL-1 beta were stained with polyclonal antibodies. A double immunofluorescence staining was performed to identify endometrial cells. Macrophage and lymphocyte rates were defined as the percentage of stained cells by field. Double staining was compared among macrophages, T lymphocytes, and anti-IL antibodies in each group. RESULTS: The macrophage rate was high for women bearing an intrauterine device, intermediate for sterile patients, and low for fertile women (P = 0.03). There was a lack of double staining between activated T lymphocytes and anti-IL-6 antibody in tubal sterility and endometriosis. Endometrial macrophages were stained with anti-IL antibodies for all groups. CONCLUSIONS: Endometrial macrophages seem to be an interesting parameter for evaluating endometrial inflammation. In tubal infertility and endometriosis, the lack of expression of IL-6 in T lymphocytes could participate in impaired embryo implantation.

Adult↗
PubMed1998

The myeloma cell antigen syndecan-1 is lost by apoptotic myeloma cells.

Syndecan-1 is a cell membrane proteoglycan that binds extracellular matrix components and various growth factors. It is expressed only on malignant plasma cells in bone marrow samples from patients with multiple myeloma (MM). Several reports have suggested that syndecan-1 was present only on a part of the myeloma cells. By using either IL-6-dependent myeloma cell lines or primary myeloma cells stained by annexin V, we report here that syndecan-1 was rapidly lost by myeloma cells undergoing apoptosis. In the same experimental conditions, expression of other cell membrane antigens such as CD38, HLA class-I or CD49d on apoptotic myeloma cells was not affected. In addition, we show that syndecan-1 loss was independent of activation of the gp130 IL-6 transducer. Dexamethasone induced a strong apoptosis of myeloma cells associated with the loss of syndecan-1. Finally, by using freshly-explanted tumoural samples, we show that syndecan-1 rapidly disappeared from myeloma cells in association with induction of apoptosis. In conclusion we showed that syndecan-1 is a marker for viable myeloma cells which is rapidly lost by apoptotic cells. These results emphasize the usefulness of anti-syndecan-1 antibodies to purge tumoural cells from haemopoietic grafts or to purify these cells for further manipulations for immuno or gene therapies.

ADP-ribosyl Cyclase↗
PubMed1998

Interleukin-1 in multiple myeloma: producer cells and their role in the control of IL-6 production.

We studied the role of interleukin (IL)-1beta in patients with multiple myeloma. By in situ hybridization and immunochemistry, myeloid and megakaryocytic cells expressed high levels of the IL-1beta gene and produced IL-1beta. Myeloma cells less potently expressed the IL-1beta gene and IL-1beta protein. IL-1beta gene expression was not constitutive since it was detected in the bone marrow myeloma cells of two patients, unlike circulating tumoural cells. In addition, nine myeloma cell lines failed to express the IL-1beta gene and this expression could not be induced by 12 different cytokines. We demonstrated that IL-1 was mainly responsible for IL-6 production in the tumoural environment through a PGE2 loop. In fact, an IL-1 receptor antagonist (IL-1RA) blocked PGE2 synthesis and IL-6 production by 80%; this blockage could be reversed by adding synthetic PGE2. Similar findings were found with indomethacin, an inhibitor of cyclooxygenase that blocks PGE2 synthesis. Taken together, these data emphasize the possibility of blocking IL-1 by using IL-1RA or other antagonists in order to block IL-6 production, which is a major tumoural survival and proliferation factor.

Adult↗
PubMed1998

MBR rearrangement and P-glycoprotein expression are not independent prognostic factors like p53 protein in malignant lymphoma.

Non-Hodgkin's lymphomas (NHL) are B-cell malignancies which generally present molecular abnormalities, such as bcl-2 translocation t(14; 18) predominantly in the follicular subgroup. Other molecular events have been described in NHL, including p53 gene mutation and overexpression of one chemoresistance mechanism, the multidrug resistance system, P-glycoprotein (MDR 1/P-gp). In this study, we analysed samples from 44 NHL patients with the presence of the bcl-2 major breakpoint region (MBR) rearrangement in 29 and without in 15. Immunochemical analysis revealed that 39 samples were positive for bcl-2 protein expression in tumoral cells (88.6%). Seventeen (38.6%) patients expressed P-gp and 9 (20.5%) expressed p53 proteins. Eleven patients expressed both bcl-2 and P-gp proteins, four expressed bcl-2 and p53 proteins whereas four expressed bcl-2, p53 and P-gp proteins. Our results confirm the importance of p53 expression as a key prognostic factor, and no objective response (OR) was found in patients with p53 positivity. MBR rearrangement was not associated with poor response to chemotherapy (62.1% OR in MBR positive patients v. 60% OR in MBR negative patients). The clinical impact of P-gp cannot be identified because no relationship was observed between P-gp expression and prognosis (58.8% OR in P-gp positive patients v. 63% OR in P-gp negative patients).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial.

PURPOSE: To compare progression-free survival (PFS), overall survival (OS), and toxicity of a doxorubicin-containing regimen administered alone or in combination with interferon alfa-2b (IFNalpha) in patients with low-grade follicular lymphoma (FL) and poor prognostic factors. PATIENTS AND METHODS: Two hundred sixty-eight patients with advanced-stage FL received cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) monthly for 6 months, then every 2 months for 12 months. After randomization, 242 patients were evaluated for efficacy: 119 received CHVP alone, and 123 also received IFNalpha at a dose of 5 million units three times weekly for 18 months. RESULTS: After a 6-year median follow-up, the patients treated with CHVP + IFNalpha showed significantly longer median PFS than those who received CHVP alone (2.9 years v 1.5 years, respectively; P = .0002) and significantly longer median OS (not reached v 5.6 years, respectively; P = .008). Although some side effects, which included neutropenia, asthenia, fever, elevated serum transaminase levels, flu-like symptoms, and thrombocytopenia, were more frequently observed in patients who received the combination regimen, these reactions were moderate. IFNalpha was withdrawn because of toxicity in 10% of the patients, and a dosage reduction or temporary suspension was required in 28%. CONCLUSION: With long-term follow-up of 6 years, these results confirm that the addition of IFNalpha to a doxorubicin-containing regimen for patients with advanced-stage and clinically aggressive FL not only increased PFS, as in most other similar trials, but also prolonged OS. Toxicity was moderate. The beneficial effects of this combined chemotherapy and IFNalpha regimen on OS probably reflect the selection of FL patients with poor prognostic factors.

Antineoplastic Agents↗
PubMed1998

C-reactive protein serum level is a valuable and simple prognostic marker in non Hodgkin's lymphoma.

Interleukin-6 plays a central role in normal B-cell maturation and in proliferation of some B-cell malignancies including multiple myeloma and some non Hodgkin's lymphomas (NHL). Furthermore, this cytokine also plays a major role in acute phase response by mediating synthesis of acute phase proteins such as C-reactive protein (CRP). In order to evaluate the exact role of CRP serum level as a simple prognostic factor, we analyzed CRP and IL-6 serum levels in 39 patients with NHL. Eleven patients had low grade NHL, 15 intermediate grade NHL, and 13 high grade NHL. Thirty percent of the patients presented detectable IL-6 serum levels (mean+/-SD: 33.6+/-95.2 U/ml, range: 0 to 500). Increased serum CRP levels were found in 42% of the patients with a mean of 29.2+/-41.97 mg/l] (range: 0 to 129). Thirty seven patients were studied for both markers. Three groups of patients were determined. One with low IL-6 and CRP serum levels (N=21), a second with high level of both markers (N=10), and the third with high serum CRP levels alone (N = 5). Only one patient had high level of serum IL-6 with no detectable CRP. The correlation of serum IL-6 and CRP levels with patient survival was investigated. Median survival in the group with low IL-6 level was not reached. 67% of patients of this group were still alive at 32 months from diagnosis. The group of patients with detectable IL-6 had a median of survival of 12 months (p<0.025). The survival of patients with a CRP<10 mg/l was not reached. 75% of patients survive at 32 months from diagnosis, whereas the group with higher CRP level reached a median survival at 8.5 months (p<0.009). As expected, on univariate analysis, there is a significant relationship between CRP and IL-6 levels (p<0.00017), and CRP levels and B symptoms (p<0.001). Furthermore there is a significant relationship between CRP and LDH levels (p<0.042).These results indicated that CRP may be considered as a valuable and easy prognostic biomarker of NHL.

Biomarkers, Tumor↗
PubMed1997

Generation of virtually pure and potentially proliferating dendritic cells from non-CD34 apheresis cells from patients with multiple myeloma.

Defects in immune response are often reported in patients with multiple myeloma (MM). Because dendritic cells (DCs) are key effectors in promoting cellular immunity and are potential vectors for immunotherapy, we have evaluated the ability of MM patients' apheresis cells to generate DCs in short-term cultures. We report here the obtaining of a virtually pure population of DCs (89.7% +/- 6%, n = 18) after culturing adherent apheresis cells for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF ) and interleukin-4 (IL-4). These cells exhibited all the phenotypic characteristics (CD1a+, HLA-DR+, CD80+, CD40+, CD14-) and the MLR stimulating capacity of mature DCs. The number of DCs reached 12. 1% of the initial apheresis cell number put into culture. As DC precursors involved in this model were CD34(-) cells, the unabsorbed cells resulting from clinical-grade CD34 purification were a reliable source of DCs, even after freezing. The proliferation of DC precursors could be increased 10-fold by adding IL-3 and tumor necrosis factor-alpha together with GM-CSF and IL-4. Thus, CD34- apheresis cells from patients with MM offer an interesting source for generating pure, functional, and potentially proliferating DCs.

Antigens, CD34↗
PubMed1997

Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma.

We investigated the possible causative role of interleukin 6 (IL-6) in the paraneoplastic inflammatory syndrome and in paraneoplastic cholestasis (Stauffer syndrome) associated with renal-cell carcinoma in a series of 119 patients with metastases. IL-6 levels were found significantly higher in patients with paraneoplastic fever and weight loss. Patients with detectable serum IL-6 (n = 90, 76%) had significantly higher serum CRP, haptoglobin, and serum alkaline-phosphatase and gammaglutamyl-transferase levels. Platelets, polymorphonuclear neutrophil (PMN) and monocyte counts were also significantly higher in patients with detectable serum IL-6; in contrast, hemoglobin levels were significantly lower in patients with serum IL-6 over 80 pg/ml. Three of these patients were included in a phase-II trial of an anti-IL-6 monoclonal antibody given daily during 21 days. Reductions of CRP, haptoglobin and serum alkalin phosphatases were observed in all 3 patients during anti-IL-6 administration, with a subsequent increase up to or above pre-treatment levels after the end of anti-IL-6. Decrease of platelets, PMN and monocyte counts were also observed in the 3 patients during anti-IL-6 administration, with a normalization of cell counts in a patient with increased platelets, PMN and monocyte counts. Hemoglobin concentration, serum albumin concentration and lymphocyte counts remained stable in the 3 patients during and after anti-IL-6 administration. Serum IL-6, as evaluated by IRMA, decreased in the 3 patients during anti-IL-6 administration, but increased above pre-treatment levels after the end of anti-IL-6 administration. These results demonstrate that IL-6 is involved in the physiopathology of paraneoplastic syndromes observed in patients with metastatic renal-cell carcinoma, in particular CRP and haptoglobin increase, paraneoplastic cholestasis, also paraneoplastic thrombocytosis, neutrophilia and monocytosis.

Alkaline Phosphatase↗