[Radiologic contrast media. IX. Iodinated derivatives of 3-aminomethylphenylalkanoic acids].
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Chemistry, Pharmaceutical↗
Biomedical subjects
L Fumagalli
Publications and source records attributed to L Fumagalli.
Bovine pancreatic trypsin inhibitor and homologous polypeptide inhibitors in nephron cells.
Bovine pancreatic trypsin inhibitor (BPTI, aprotinin) is a fifty-eight amino acid polypeptide, which is present together with related molecular isoforms in various bovine organs. In the present study these protease inhibitors were isolated from bovine kidney by affinity chromatography on immobilized trypsin and a subsequent FPLC step. Due to their electrophoretic, structural, and inhibitory properties, the inhibitors were strictly similar to the polypeptides identified previously in other bovine organs. Immunohistochemical experiments showed a widespread localization of these polypeptides in nephron epithelial cells (proximal and distal tubules, loop of Henle, collecting tubules).
Amino Acid Sequence↗
Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients.
Malignant pleural mesothelioma is often unresectable at diagnosis, is refractory to cytotoxic agents and is frequently complicated by pleural effusion. The expected survival range for patients with or without involvement of visceral pleura is respectively 1-9 and 9-12 months; mesothelioma-related pleural effusion severely impairs the patients' quality of life and easily relapses after conservative treatments. Intrapleural administration of IL-2 is reported to be effective both in tumor-associated malignant pleurisy and on primary mesothelioma, whereas few data exist about IL-2 systemic administration. In order to assess the palliative and therapeutic activity of IL-2 in unresectable pleural malignant mesothelioma with pleural effusion, we performed a phase II study on 31 consecutive patients (M/F 16/15; median age 61 years, range 40-84; PS ECOG 0 n=7; ECOG 1 n=15; ECOG 2 n=9; stage IA n=13; IB n=9; II n=7; IV=2) who received first-line therapy with intrapleural repeated instillation of 9000000 I.U. IL-2 twice/weekly for 4 weeks, after needle thoracenthesis. In nonprogressing patients, 3000000 I.U. IL-2 were subcutaneously administered thrice weekly for up to 6 months. Toxicity (WHO criteria) with intrapleural IL-2 consisted of grade 3 fever in 6/31 (19%) patients and of cardiac toxicity (failure) grade 3 in one patient (3%); toxicity during subcutaneous treatment was mild to moderate, mainly a flu-like syndrome. In 28/31 (90%) of patients there was no further or minimal (asymptomatic) pleural fluid collection (according to Paladine criteria); pleurisy relapsed only in 1/28 patients after 19 months. Tumor objective response (WHO criteria), evaluated by CT, occurred in seven patients (one CR and six PR; ORR 22%); ten patients achieved SD and 14 patients progressed. Median overall survival was 15 months (range 5-39) in all patients. IL-2 intrapleural administration followed by low-dose IL-2 subcutaneously in pleurisy-complicated malignant mesothelioma is feasible and active both in palliation of pleural effusion and on primary tumor, with manageable toxicity. The overall survival observed in nonprogressing patients warrants further randomized studies with IL-2 aimed to the patient outcome.
Adult↗
Coexpression of mRNAs for P2X1, P2X2 and P2X4 receptors in rat vascular smooth muscle: an in situ hybridization and RT-PCR study.
The expression of mRNAs for three P2X receptor subtypes (PX21, P2X2, P2X4) in the rat vascular system was studied by in situ hybridization and RT-PCR. In heart sections mRNAs transcripts for all three receptors were colocalized in smooth muscle cells of coronary vessels, while no specific positivity was apparent in myocardium. Coexpression of P2X receptor mRNA transcripts were also observed in other peripheral vessels, including aorta, pulmonary artery, internal and external iliac arteries, renal artery and femoral artery. By contrast, no mRNA transcripts of the above receptors were found in the superior mesenteric artery. RT-PCR performed on microdissected tissues (coronary arteries, aorta and myocardium from various heart areas) confirmed the presence of P2X1, P2X2 and P2X4 receptor mRNAs. Furthermore, in the same tissues two splice variants of the P2X2 receptor were identified. These results reveal an important molecular heterogeneity of P2X receptors, thus substantiating the possibility of a heteropolymeric assembly of ATP-gated ion channels in the cardiovascular system.
Animals↗
A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates.
Chemotherapy with 5-fluorouracil (5-FU) and folates represents the first-line standard therapy for metastatic colorectal cancer, whereas at present there is no conventional second-time treatment. Because of its importance in generating an effective anticancer immune response, interleukin-2 (IL-2) could constitute a new promising therapy of advanced colon cancer. Generally, IL-2 may determine tumor regressions in colon cancer only when it is given at high toxic doses. Our preliminary studies have shown that the pineal hormone melatonin may amplify IL-2 activity, which becomes active also at low doses in several tumor histotypes. On the basis, we have performed a clinical trial to evaluate the impact of low-dose IL-2 plus melatonin on the survival time in metastatic colon cancer, which progressed in response to 5-FU plus folates. The study included 50 metastatic colorectal cancer patients, who did not respond or progressed after initial response to first-line chemotherapy with 5-FU and folates. Patients were randomized to receive supportive care alone or low-dose subcutaneous IL-2 (3 million IU/day for 6 days/week for 4 weeks) plus melatonin (40 mg/day orally). No spontaneous tumor regression occurred in patients receiving supportive care alone. A partial response was achieved in 3/25 patients treated with immunotherapy. Percent survival at 1 year was significantly higher in patients treated with immunotherapy than in those treated with supportive care alone (9/25 vs. 3/25, p < 0.05). This study suggests that low-dose subcutaneous IL-2 plus melatonin may be effective as a second-line therapy to induce tumor regression and to prolong percent survival at 1 year in metastatic colorectal cancer patients progressing under 5-FU and folates.
Adult↗
A biological study on the efficacy of low-dose subcutaneous interleukin-2 plus melatonin in the treatment of cancer-related thrombocytopenia.
The production of cytokines involved in platelet generation, including interleukin (IL)-3, IL-6 and IL-11, is stimulated by IL-2. However, the platelet number has been shown to decrease on IL-2 cancer therapy, and this side effect depends on the enhanced peripheral platelet destruction following the activation of the macrophage system by IL-2 itself. Our previous studies showed that IL-2-induced macrophage activation may be counteracted by the pineal hormone melatonin (MLT). On this basis, a pilot study with IL-2 plus MLT was performed to evaluate its influence on the platelet number in cancer patients with persistent thrombocytopenia. The study included 20 advanced solid tumor patients, who received IL-2 at 3 million IU/day s.c. for 6 days/week for 4 weeks in association with MLT (40 mg/day orally). A normalization of the platelet number was achieved in 14/20 (70%) patients. This pilot study shows that the therapy with low-dose IL-2 plus MLT, in addition to its previously described antitumor activity, may also be effective in the treatment of cancer-related thrombocytopenia.
Adult↗
Preoperative interleukin-2 subcutaneous immunotherapy may prolong the survival time in advanced colorectal cancer patients.
It has been demonstrated that surgery may induce immunosuppression. This finding could influence the clinical course of surgically treated cancer patients. Moreover, preliminary experimental studies have shown that a preoperative injection of IL-2, whose importance in generating the antitumor immune response is well known, may neutralize surgery-induced immunosuppression. At present, however, it is still unknown whether preoperative IL-2-induced immune improvement in the postoperative period may influence the prognosis of surgically treated cancer patients. The present study was performed to evaluate the prognostic impact of IL-2 presurgical therapy in advanced colorectal cancer patients. The study included 50 colorectal cancer patients, Dukes' stage D, who were randomized to be treated with or without IL-2 preoperatively (18.10(6) IU/day subcutaneously for 3 consecutive days). After surgery, all patients underwent chemotherapy with 5-FU and folates until disease progression. Postoperative mean numbers of lymphocytes, T lymphocytes, natural killer cells and activated lymphocytes were significantly higher in IL-2-treated patients than in controls. Moreover, the percent of lymphocytic and/or eosinophilic tumor infiltration was significantly higher in IL-2 group than in controls. Finally, both survival curve and the percent of survival at 1 year were significantly greater in patients pretreated with IL-2 than in controls. This clinical trial demonstrates that preoperative IL-2-induced neutralization of postoperative lymphocytopenia is associated with a prolonged survival time in advanced colorectal cancer patients.
Adult↗
Circulating immature and mature dendritic cells in relation to lymphocyte subsets in patients with gastrointestinal tract cancer.
Cancer-related deficiency in circulating dendritic cells (DC), whose important anticancer role is well established, has been proven to be associated with lymphocytopenia. This study was performed to evaluate which lymphocyte subset is most markedly related to the failure of the DC system. The study included 30 patients with gastrointestinal tract cancer, 10 of whom had distant organ metastases. Immature and mature DCs were measured by FACS and monoclonal antibodies against CD123 and CD11c antigens, respectively. Low levels of immature and mature DCs were observed in 63% and 43% of patients, respectively. Patients with low levels of circulating mature DCs had significantly lower values of T lymphocytes, T helper lymphocytes and NK cells than those with normal mature DC levels. In contrast, no significant difference was seen between patients with normal or abnormally low values of immature DCs. Conversely, patients with a decreased number of T lymphocytes, T helper lymphocytes and NK cells showed significantly lower values of circulating mature DCs than those with lymphocyte subsets within the normal range, whereas no difference was seen in immature DC amounts. This study suggests that only mature DC deficiency may be associated with important lymphocyte subset alterations in cancer patients, whereas deficiency in immature DCs does not seem to be related to other immune cell disorders.
Antigens, CD↗
Effects of oncological surgery on endothelin-1 secretion in patients with operable gastric cancer.
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Adult↗
Changes in circulating dendritic cells and IL-12 in relation to the angiogenic factor VEGF during IL-2 immunotherapy of metastatic renal cell cancer.
Angiogenesis and immunosuppression are the main biological mechanisms responsible for cancer progression. Moreover, recent observations suggesting a negative influence of angiogenesis on anticancer immunity have shown that some angiogenic factors, such as VEGF, may induce immunosuppression. In addition, the evidence of abnormally high blood levels of VEGF has been proven to be associated with resistance to IL-2 immunotherapy. The present study was performed to establish a possible relation ship between the efficacy of IL-2 cancer immunotherapy and changes in circulating levels of VEGF, IL-12, mature and immature dendritic cells (DC). The study included 25 metastatic renal cell cancer patients who underwent subcutaneous low-dose IL-2 immunotherapy (6 MIU/day for 6 days/week for 4 weeks). Immature and mature DCs were identified as CD123+ and CD11c+ cells, respectively. The clinical response consisted of partial response (PR) in five, stable disease (SD) in 11 and progressive disease (PD) in the remaining nine patients. The mean IL-12 levels observed during IL-2 immunotherapy were significantly higher in patients with PR or SD than in those with PD, whereas the mean VEGF concentrations were significantly higher in patients who had PD than in those with PR or SD. Finally, a significant increase in the mean number of circulating mature DCs occurred only in patients with PR or SD, whereas no significant change was seen in patients with PD. By contrast, no significant change was observed in the mean number of immature DCs. This study shows that the efficacy of IL-2 immunotherapy is associated with a significant increase in circulating mature DCs and IL-12, without any concomitant increase in VEGF concentrations. Further studies will be required to better define the relationship between activation of anticancer immunity and control of angiogenesis-related mechanisms.
Adult↗
Changes in circulating VEGF levels in relation to clinical response during chemotherapy for metastatic cancer.
Abnormally high blood levels of vascular endothelial growth factor (VEGF) appear to be associated with a poor prognosis in advanced cancer, probably as a consequence of its angiogenic and immunosuppressive effects. The prognostic significance of changes in VEGF secretion during cancer chemotherapy is still unknown. This study aimed to investigate the relation between VEGF variations and therapeutic results during chemotherapy in advanced malignancies. The study included 90 metastatic cancer patients, 59 with non-small cell lung cancer and 31 with colorectal carcinoma. Chemotherapy consisted of cisplatin plus etoposide for NSCLC and camptothecin for colorectal cancer. Abnormally high (> 2 SD with respect to values in healthy controls) pretreatment VEGF levels were found in 38/90 (42%) patients. The percentage of non-progressive disease in response to chemotherapy was significantly higher in patients with normal levels of VEGF prior to therapy than in those with elevated pretreatment values of VEGF (10/32 vs 4/27; p < 0.05). Moreover, the percentage of VEGF level normalization during chemotherapy was significantly higher in patients with objective tumor response or stable disease than in progressing patients (10/18 vs 0/20; p < 0.001). Finally, among patients with tumor response or disease stabilization, the one-year survival rate was significantly higher in patients with chemotherapy-induced normalization of VEGF than in those with persistently high VEGF blood levels (9/10 vs 3/8; p < 0.05). These results suggest that changes in VEGF levels during chemotherapy may represent a useful biomarker to predict the effect of chemotherapy in terms of tumor response and survival in patients with metastatic solid neoplasms.
Adult↗
Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors.
The evidence of lymphocytopenia has been demonstrated to predict a poor prognosis in terms of survival in advanced cancer patients. This finding is not surprising because of the fundamental role of lymphocytes in mediating tumor cell destruction. Despite the importance of lymphocytes in the pathogenesis of cancer, there are only few data about the profile and the function of lymphocytes during the various antitumor therapies, and in particular the relation between lymphocyte pretreatment number and response to chemotherapy remains to be established. The present study was performed to evaluate whether the evidence of lymphocytopenia before the onset of treatment may influence the efficacy of chemotherapy in metastatic cancer patients affected by the most frequent tumor types. The study included 183 patients (lung cancer: 89; colorectal cancer: 63; breast cancer: 31), 95 of whom had been previously treated with chemotherapy. The chemotherapeutic regimens consisted of oxaliplatin plus 5-fluorouracil and folates in untreated colorectal cancer, weekly irinotecan in pretreated colorectal cancer, cisplatin plus gemcitabine or etoposide in untreated lung cancer, weekly vinorelbine in pretreated lung cancer, and taxotere in breast cancer patients who had been previously treated with anthracyclines. Lymphocyte count was considered to be abnormally low for values below 1500/mm3. Lymphocytopenia was found in 79/183 (43%) patients, without any significant differences in relation to tumor histology. A complete response (CR) was achieved in 6/104 patients with a normal lymphocyte count and in none of the 79 lymphocytopenic patients. A partial response (PR) was obtained in 39 patients with a normal lymphocyte count and in only eight patients with a low lymphocyte count prior to therapy. Therefore, irrespective of the type of chemotherapy, the objective tumor response rate (CR + PR) in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (8/79 vs 45/104; p < 0.001). This study shows that the evidence of lymphocytopenia prior to chemotherapy is associated with a lower efficacy of treatment in terms of objective tumor regression rates in patients with metastatic solid tumors, and suggests that the action of chemotherapy may depend at least in part on an interaction with the antitumor immunity. Pretreatment lymphocyte count may represent a new, simple biological marker to be taken into consideration by oncologists in the chemotherapeutic treatment of metastatic cancer.
Adult↗
Increased blood concentrations of interleukin-12 are associated with a longer survival in untreatable metastatic solid tumor patients: preliminary observations.
IL-2 and IL-12 are the main antitumor cytokines in humans. Endogenous IL-2 production is generally low in metastatic cancer patients. In contrast, preliminary data suggest a possible increased secretion of IL-12 in a subgroup of metastatic cancer patients, of which the prognostic significance is still to be established. This preliminary study was performed to investigate the survival time in relation to IL-12 blood levels in patients with untreatable metastatic solid tumors. The study included 40 patients (lung cancer: 16; gastrointestinal tumors: 24). Abnormally elevated serum levels of IL-12 were observed in 15/40 (37%) patients, without any apparent relation with tumor histotype. The 1-year survival rate was significantly higher in patients with elevated IL-12 baseline values than in those with normal concentrations (8/15 vs 3/25, p < 0.01). The results of this preliminary study, which need to be confirmed in a greater number of patients by monitoring the clinical course of the neoplastic disease, seem to suggest that abnormally high baseline serum levels of the antitumor cytokine IL-12 may have a favorable prognostic significance, as they appear to be associated with a longer survival time.
Biomarkers, Tumor↗
Neopterin, soluble IL-2 receptor and IL-6 secretion during IL-2 cancer immunotherapy: prognostic significance in relation to IL-12 variations.
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Adjuvants, Immunologic↗
Vascular endothelial growth factor (VEGF) serum levels during cancer immunotherapy with IL-2: preliminary considerations.
Neoangiogenesis has been proven to play a fundamental role in promoting cancer spread, and vascular endothelial growth factor (VEGF) is known to represent one of the most important angiogenic factors. The present study was planned to investigate changes in VEGF secretion in cancer patients undergoing immunotherapy with IL-2, with the aim of establishing whether VEGF variations play a role in mediating the IL-2-induced control of neoplastic diseases. The study involved 14 metastatic renal cell cancer patients treated with IL-2 immunotherapy (6 million IU/day subcutaneously for 6 days/week for 4 weeks). The clinical response consisted of partial response (PR) in 3, stable disease (SD) in 6 and progressive disease (PD) in the remaining 5 patients. VEGF serum levels were measured by an enzyme immunoassay designed to determine both bound and unbound VEGF. No significant changes in VEGF mean levels occurred during IL-2 therapy. Moreover, neither in patients with PR or SD nor in those with PD did the mean serum levels of VEGF change significantly in response to IL-2. This preliminary study seems to exclude that changes in the angiogenic factor VEGF may play a role in mediating the therapeutic efficacy of IL-2 cancer immunotherapy. However, since the method of measurement used in our study was designed to detect the total amount of VEGF, it cannot be excluded that changes in the free fraction of the molecule may occur during IL-2 cancer immunotherapy.
Adult↗
IL-2 immunotherapy-induced increase in IL-12 blood concentrations may depend on an increase in circulating dendritic cell number.
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Aged↗
Pre-operative IL-2 immunoprophylaxis of cancer recurrence: long-term clinical results of a phase II study in radically operable colorectal cancer.
This study evaluates retrospectively the outcome of 20 colorectal cancer patients radically operated (M/F 13/7; primary/recurrent 15/5; Dukes B=11; C=6; D=3) who received pre-operative IL-2 (18,000, 000 IU/daily s.c. for 3 days) and the outcome of 40 colorectal cancer (primary/recurrent 40/0) patients age, sex and stage-matched radically operated, as control group. After a median follow-up of 72 months, in the IL-2 pre-operative group we observed 6/20 recurrences (30%) vs. 19/40 (47.5%) in controls. Mean and median disease-free period in patients who relapsed were respectively 21 months and 20.5 months (range 6-36) in IL-2 group vs. 14.1 and 12 months in the control group (range 3-34). After a 5-year follow-up, 4/20 (20%) IL-2 treated patients were dead vs. 19/40 control patients (47.5%) (log-rank chi2=3.7, p=0.05). Pre-operative IL-2 administration is safe, active in preventing post-operative lymphocytopenia and seems to improve the clinical outcome in radically operated colorectal cancer patients.
Adult↗
Changes in lymphocyte number during cancer chemotherapy and their relation to clinical response.
Since hematologic examination during cancer chemotherapy is generally limited to the evaluation of neutrophil and platelet numbers, at present there are no clear data about the possible prognostic significance of changes in lymphocyte number in relation to the clinical efficacy of chemotherapy itself. To obtain some preliminary data about this issue, we have evaluated changes in lymphocyte number and percentage in a group of 50 advanced non-small cell lung cancer patients treated with three cycles of cisplatin (20 mg/m2/day) plus etoposide (100 mg/m2/day) i.v. for three days every 21 days. The clinical response consisted of partial response (PR) in nine (18%), stable disease (SD) in 18 (36%) and progressive disease (PD) in the remaining 23 (46%) patients. The lymphocyte percentage increased during chemotherapy, without, however, a significant difference with respect to the pretreatment values. In contrast, the mean number of lymphocytes observed after the first chemotherapeutic cycle significantly decreased in patients with PD, whereas it increased in patients with PR or SD, even though the difference did not reach statistical significance. These preliminary data, which have to be confirmed in a large number of patients and in patients treated with other chemotherapeutic schedules for different tumor types, seem to suggest that a chemotherapy-induced decline in lymphocyte number may be associated with a lack of efficacy of chemotherapy itself.
Adult↗