Mononuclear phagocytes exhibit complex interactions with cancer cells and might contribute to fib... more Mononuclear phagocytes exhibit complex interactions with cancer cells and might contribute to fibrin formation associated with malignancy through the production of procoagulant activity (PCA). We have studied the PCA of peritoneal macrophages in 8 patients with advanced (stages III or IV) ovarian cancer and of macrophages from regional lymph nodes in 14 patients with limited (stages I or II) uterine cancer; peritoneal and lymph-node macrophages from patients with benign gynecological tumors were used as reference cell populations. In all patients, PCA of blood monocytes was also studied. Peritoneal and lymph-node macrophages obtained from patients with ovarian and uterine cancer, respectively, expressed far higher levels of basal PCA than the corresponding cell populations from patients with benign tumors (p <0.001). PCA of blood mononuclear cells from patients with ovarian, but not with uterine cancer, was significantly higher (p <0.001) than that of control cells. High levels of D-dimer, a specific product derived from plasmin-induced degradation of stabilized fibrin, were found in all ascitic fluids and in all plasma samples but one from patients with ovarian cancer. In contrast, all controls and all uterine cancer patients but one had normal plasma D-dimer. Our findings suggest that local activation of host macrophages for PCA production might contribute to fibrin formation within the tumoral mass. In advanced cancer, blood monocytes may also be activated to produce PCA and thus contribute to activation of intravascular coagulation and, possibly, to thrombo-embolic complications frequently associated with disseminated malignancy.
Retinoids exhibit a wide spectrum of activities, including antiinflammatory properties. We have i... more Retinoids exhibit a wide spectrum of activities, including antiinflammatory properties. We have investigated the effect of retinoic acid (RA) and retinyl acetate (RAc) on the production of reactive oxygen metabolites and the release of lysosomal enzymes by human polymorphonuclear leukocytes (PMN). Incubation of PMN with RAc or RA (1–100 μM) caused a dose-dependent inhibition (upto 90%) in O 2− production and chemiluminescence induced by phorbol myristate acetate (PMA), N-formyl-methionylleucyl-phenylanaline (fMLP), opsonized zymosan or ionophore A23187. Both retinoids (1–100 μM) also inhibited, in a dose-dependent way, degranulation induced by fMLP (upto 85% at the highest concentration of RA). These inhibitory effects appear irreversible, since they persist after the drugs are removed and the cells washed before stimulation. Inhibitors of cyclo-oxygenase activity such as acetylsalicylic acid and indomethacin did not influence the effects of RAc. In contrast, BW755, an inhibitor of both cyclooxygenase and lipoxygenase, reversed the inhibitory action of RAc, suggesting that the effect of retinoids occurs possibly through the mediation of lipoxygenase products. The modulation of PMN oxidative metabolism and degranulation might help explain the antiinflammatory properties of retinoids.
Ten patients in first or second relapse with Philadelphia chromosome acute lymphoblastic leukaemi... more Ten patients in first or second relapse with Philadelphia chromosome acute lymphoblastic leukaemia, ineligible for allogeneic sibling marrow transplantation, were treated with an intensive chemotherapy regimen including idarubicin, intermediate-dose arabinosylcytosine, etoposide and G-CSF. Peripheral blood stem cells were collected by leukapheresis during initial early WBC recovery from chemotherapy-Induced aplasia. In 5/10 patients all metaphases in leukapheresis products were found to be Philadelphia-chromosome-negative and they have been used as autotransplants after conditioning with TBI/etoposide/cyclophosphamide (or idarubicin) and G-CSF. All five patients showed sustained engraftment and one of them is alive and well Philadelphia-chromosome-negative 18 months after transplant. These preliminary results suggest that it is possible to recover Philadelphia-chromosome-negative blood stem cells after intensive chemotherapy, even in advanced patients, and to perform autografting with these cells.
High-dose therapy followed by autografting can cure patients with aggressive Hodgkin&amp;amp;... more High-dose therapy followed by autografting can cure patients with aggressive Hodgkin&amp;amp;amp;amp;amp;amp;#39;s disease (HD) refractory or with early relapse to first-line combination chemotherapy. On the other hand, the eradication of the disease is rarely achieved in heavily pretreated patients. It has been suggested that patients with HD with very high risk characteristics at diagnosis, often relapse despite appropriate therapy with 7-8 drugs combination. Thus it seems to us that such patients are potential candidates for early autografting during first remission. Twelve years ago, we initiated a pilot study to investigate whether patients with very high risk characteristics, would benefit from early autografting. The application of early autografting was compared with our historical group of patients in complete remission after receiving MOPP/ABVD, who had the same negative prognostic characteristics, refused autografting and who did not receive other treatment after achieving complete remission. Among the 22 consecutive patients entered into the pilot study and autografted, 18 are alive and 17 (77%) remain alive in unmaintained remission at a median of 86 months. One patient (4%) died of interstitial pneumonitis in the transplantation group. Only 8/24 (33%) patients, who did not receive an autograft, are currently alive and disease free at a median of 89 months. In conclusion, the early application of autografting appears to improve the outcome in patients with very high risk HD who achieved remission with MOPP/ABVD.
Twenty-five adults with previously treated acute leukemia were treated with 4-demethoxydaunorubic... more Twenty-five adults with previously treated acute leukemia were treated with 4-demethoxydaunorubicin (Idarubicin) with a daily dose of 8 mg/m2 for 3 days intravenously. Complete remission was achieved in 3 of 18 patients with acute nonlymphoblastic leukemia (ANLL) and 2 of 6 with lymphoblastic leukemia. Complete remissions were observed in two of eight ANLL patients refractory to cytarabine, anthracycline, and m-Amsa (amsacrine), indicating a lack of cross-resistance between these drugs and Idarubicin. The median duration of remission was 8 weeks. The main major toxicity of Idarubicin therapy, severe myelosuppression, cannot be considered a toxic effect because it was desired in this case list. Our preliminary results indicate that Idarubicin has significant activity against refractory adult acute leukemia.
Twenty-seven patients with chronic myelogenous leukemia (CML)—17 in the chronic phase and 10 in t... more Twenty-seven patients with chronic myelogenous leukemia (CML)—17 in the chronic phase and 10 in the accelerated phase—were treated with an intensive chemotherapy regimen consisting of idarubicin, arabinosylcytosine, and etoposide. All patients were ineligible for bone marrow transplantation (BMT) and showed little or no cytogenetic response to interferon alpha (IFN-α). Blood hemopoietic cells (BHC) were collected by leukapheresis in all patients during early recovery from chemotherapy-induced aplasia. In 13/27 patients (48%), all metaphases were Ph-negative (Ph−); in another five patients, the percentage of Ph-positive (Ph+) metaphases decreased to less than 50%. Complete Ph+ disappearance was found in 66% of the patients treated within two years of diagnosis and in only 30% of those treated later. The collected Ph− cells have been used as autotransplants in nine patients: seven have shown sustained engraftment, and five are alive and well, with Ph− at 3+, 4+, 7+, 11+, and 19+ months after transplant It is remarkable that one patient, now Ph− at 19 months after transplant, is also PCR negative. These results suggest that it is possible to collect Ph− hemopoietic cells even years after diagnosis and to perform autologous transplants with these cells.
Forty consecutive adult patients under the age of 50 with acute non-lymphoblastic leukemia (ANLL)... more Forty consecutive adult patients under the age of 50 with acute non-lymphoblastic leukemia (ANLL) in first complete remission, underwent autologous bone marrow transplantation (ABMT) between March 1984 and April 1990. The conditioning regimen employed ...
13 patients with refractory or relapsed acute lymphoblastic leukemia (ALL) and 7 patients with ac... more 13 patients with refractory or relapsed acute lymphoblastic leukemia (ALL) and 7 patients with acute myeloid leukemia (AML) were treated with a regimen that included idarubicin 12 mg/m2 intravenously daily for 3 d plus cytarabine 2 g/m2 by infusion over 3 hours daily for 3 d. There were 10 remissions (ALL:7; AML:3) in the 15 relapsed patients and 4 (ALL:3) in the 5 patients with primary refractory disease. Severe myelosuppression was observed in all patients. Toxicity of this regimen caused nausea and vomiting, stomatitis, infections and/or liver enzymes increase. Cardiac toxicity was not observed. 2 patients died in aplasia of Gram-negative septicemia and brain hemorrhage. In conclusion, the combination of idarubicin and intermediate-dose cytarabine (IDARA-C) seems to be highly effective and sufficiently well-tolerated for the treatment of refractory and relapsed acute leukemias.
Mononuclear phagocytes exhibit complex interactions with cancer cells and might contribute to fib... more Mononuclear phagocytes exhibit complex interactions with cancer cells and might contribute to fibrin formation associated with malignancy through the production of procoagulant activity (PCA). We have studied the PCA of peritoneal macrophages in 8 patients with advanced (stages III or IV) ovarian cancer and of macrophages from regional lymph nodes in 14 patients with limited (stages I or II) uterine cancer; peritoneal and lymph-node macrophages from patients with benign gynecological tumors were used as reference cell populations. In all patients, PCA of blood monocytes was also studied. Peritoneal and lymph-node macrophages obtained from patients with ovarian and uterine cancer, respectively, expressed far higher levels of basal PCA than the corresponding cell populations from patients with benign tumors (p <0.001). PCA of blood mononuclear cells from patients with ovarian, but not with uterine cancer, was significantly higher (p <0.001) than that of control cells. High levels of D-dimer, a specific product derived from plasmin-induced degradation of stabilized fibrin, were found in all ascitic fluids and in all plasma samples but one from patients with ovarian cancer. In contrast, all controls and all uterine cancer patients but one had normal plasma D-dimer. Our findings suggest that local activation of host macrophages for PCA production might contribute to fibrin formation within the tumoral mass. In advanced cancer, blood monocytes may also be activated to produce PCA and thus contribute to activation of intravascular coagulation and, possibly, to thrombo-embolic complications frequently associated with disseminated malignancy.
Retinoids exhibit a wide spectrum of activities, including antiinflammatory properties. We have i... more Retinoids exhibit a wide spectrum of activities, including antiinflammatory properties. We have investigated the effect of retinoic acid (RA) and retinyl acetate (RAc) on the production of reactive oxygen metabolites and the release of lysosomal enzymes by human polymorphonuclear leukocytes (PMN). Incubation of PMN with RAc or RA (1–100 μM) caused a dose-dependent inhibition (upto 90%) in O 2− production and chemiluminescence induced by phorbol myristate acetate (PMA), N-formyl-methionylleucyl-phenylanaline (fMLP), opsonized zymosan or ionophore A23187. Both retinoids (1–100 μM) also inhibited, in a dose-dependent way, degranulation induced by fMLP (upto 85% at the highest concentration of RA). These inhibitory effects appear irreversible, since they persist after the drugs are removed and the cells washed before stimulation. Inhibitors of cyclo-oxygenase activity such as acetylsalicylic acid and indomethacin did not influence the effects of RAc. In contrast, BW755, an inhibitor of both cyclooxygenase and lipoxygenase, reversed the inhibitory action of RAc, suggesting that the effect of retinoids occurs possibly through the mediation of lipoxygenase products. The modulation of PMN oxidative metabolism and degranulation might help explain the antiinflammatory properties of retinoids.
Ten patients in first or second relapse with Philadelphia chromosome acute lymphoblastic leukaemi... more Ten patients in first or second relapse with Philadelphia chromosome acute lymphoblastic leukaemia, ineligible for allogeneic sibling marrow transplantation, were treated with an intensive chemotherapy regimen including idarubicin, intermediate-dose arabinosylcytosine, etoposide and G-CSF. Peripheral blood stem cells were collected by leukapheresis during initial early WBC recovery from chemotherapy-Induced aplasia. In 5/10 patients all metaphases in leukapheresis products were found to be Philadelphia-chromosome-negative and they have been used as autotransplants after conditioning with TBI/etoposide/cyclophosphamide (or idarubicin) and G-CSF. All five patients showed sustained engraftment and one of them is alive and well Philadelphia-chromosome-negative 18 months after transplant. These preliminary results suggest that it is possible to recover Philadelphia-chromosome-negative blood stem cells after intensive chemotherapy, even in advanced patients, and to perform autografting with these cells.
High-dose therapy followed by autografting can cure patients with aggressive Hodgkin&amp;amp;... more High-dose therapy followed by autografting can cure patients with aggressive Hodgkin&amp;amp;amp;amp;amp;amp;#39;s disease (HD) refractory or with early relapse to first-line combination chemotherapy. On the other hand, the eradication of the disease is rarely achieved in heavily pretreated patients. It has been suggested that patients with HD with very high risk characteristics at diagnosis, often relapse despite appropriate therapy with 7-8 drugs combination. Thus it seems to us that such patients are potential candidates for early autografting during first remission. Twelve years ago, we initiated a pilot study to investigate whether patients with very high risk characteristics, would benefit from early autografting. The application of early autografting was compared with our historical group of patients in complete remission after receiving MOPP/ABVD, who had the same negative prognostic characteristics, refused autografting and who did not receive other treatment after achieving complete remission. Among the 22 consecutive patients entered into the pilot study and autografted, 18 are alive and 17 (77%) remain alive in unmaintained remission at a median of 86 months. One patient (4%) died of interstitial pneumonitis in the transplantation group. Only 8/24 (33%) patients, who did not receive an autograft, are currently alive and disease free at a median of 89 months. In conclusion, the early application of autografting appears to improve the outcome in patients with very high risk HD who achieved remission with MOPP/ABVD.
Twenty-five adults with previously treated acute leukemia were treated with 4-demethoxydaunorubic... more Twenty-five adults with previously treated acute leukemia were treated with 4-demethoxydaunorubicin (Idarubicin) with a daily dose of 8 mg/m2 for 3 days intravenously. Complete remission was achieved in 3 of 18 patients with acute nonlymphoblastic leukemia (ANLL) and 2 of 6 with lymphoblastic leukemia. Complete remissions were observed in two of eight ANLL patients refractory to cytarabine, anthracycline, and m-Amsa (amsacrine), indicating a lack of cross-resistance between these drugs and Idarubicin. The median duration of remission was 8 weeks. The main major toxicity of Idarubicin therapy, severe myelosuppression, cannot be considered a toxic effect because it was desired in this case list. Our preliminary results indicate that Idarubicin has significant activity against refractory adult acute leukemia.
Twenty-seven patients with chronic myelogenous leukemia (CML)—17 in the chronic phase and 10 in t... more Twenty-seven patients with chronic myelogenous leukemia (CML)—17 in the chronic phase and 10 in the accelerated phase—were treated with an intensive chemotherapy regimen consisting of idarubicin, arabinosylcytosine, and etoposide. All patients were ineligible for bone marrow transplantation (BMT) and showed little or no cytogenetic response to interferon alpha (IFN-α). Blood hemopoietic cells (BHC) were collected by leukapheresis in all patients during early recovery from chemotherapy-induced aplasia. In 13/27 patients (48%), all metaphases were Ph-negative (Ph−); in another five patients, the percentage of Ph-positive (Ph+) metaphases decreased to less than 50%. Complete Ph+ disappearance was found in 66% of the patients treated within two years of diagnosis and in only 30% of those treated later. The collected Ph− cells have been used as autotransplants in nine patients: seven have shown sustained engraftment, and five are alive and well, with Ph− at 3+, 4+, 7+, 11+, and 19+ months after transplant It is remarkable that one patient, now Ph− at 19 months after transplant, is also PCR negative. These results suggest that it is possible to collect Ph− hemopoietic cells even years after diagnosis and to perform autologous transplants with these cells.
Forty consecutive adult patients under the age of 50 with acute non-lymphoblastic leukemia (ANLL)... more Forty consecutive adult patients under the age of 50 with acute non-lymphoblastic leukemia (ANLL) in first complete remission, underwent autologous bone marrow transplantation (ABMT) between March 1984 and April 1990. The conditioning regimen employed ...
13 patients with refractory or relapsed acute lymphoblastic leukemia (ALL) and 7 patients with ac... more 13 patients with refractory or relapsed acute lymphoblastic leukemia (ALL) and 7 patients with acute myeloid leukemia (AML) were treated with a regimen that included idarubicin 12 mg/m2 intravenously daily for 3 d plus cytarabine 2 g/m2 by infusion over 3 hours daily for 3 d. There were 10 remissions (ALL:7; AML:3) in the 15 relapsed patients and 4 (ALL:3) in the 5 patients with primary refractory disease. Severe myelosuppression was observed in all patients. Toxicity of this regimen caused nausea and vomiting, stomatitis, infections and/or liver enzymes increase. Cardiac toxicity was not observed. 2 patients died in aplasia of Gram-negative septicemia and brain hemorrhage. In conclusion, the combination of idarubicin and intermediate-dose cytarabine (IDARA-C) seems to be highly effective and sufficiently well-tolerated for the treatment of refractory and relapsed acute leukemias.
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Papers by Domenico Giordano