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Biomedical subjects

Camillo Porta

Publications and source records attributed to Camillo Porta.

At least 19 recordsLinked to original sources
PubMed2006

Cisplatin and gemcitabine with either vinorelbine or paclitaxel in the treatment of carcinomas of unknown primary site : results of an Italian multicenter, randomized, phase II study.

BACKGROUND: : To date, the standard treatment for patients who have carcinoma of unknown primary site has not been established. METHODS: : In this randomized Phase II study, 66 previously untreated patients (33 patients per arm) with carcinomas of unknown primary site received cisplatin (35 mg/m2) and gemcitabine (1000 mg/m2) with either paclitaxel (70 mg/m2) or vinorelbine (25 mg/m2), and all drugs were administered intravenously on Days 1 and 8 of a 21-day cycle. Twenty-nine patients (44%) presented with > or =2 involved sites. The pathologic diagnosis was mainly adenocarcinoma (48 patients; 72.7%) and squamous carcinoma (7 patients; 10.6%). RESULTS: : In the first arm, 16 patients (48.5%) experienced an objective response, and 9 patients (27.2%) had disease stabilization. In the vinorelbine-containing arm, 14 patients (42.3%) experienced an objective response, and 8 patients (24.2%) had disease stabilization. The median response duration and the median time to progression were similar in both treatment arms; the median overall survival was 9.6 months (95% confidence interval, 7.11-12.09 months) for patients who received the cisplatin/gemcitabine/paclitaxel regimen and 13.6 months (95% confidence interval, 6.61-20.59 months) for patients who received the vinorelbine combination. Grade 3 and 4 toxicities were more frequent in the paclitaxel-containing arm. CONCLUSIONS: : Both combinations satisfied the 2-step design, demonstrating antitumor activity without relevant differences in response rates or response duration; however, the vinorelbine-containing regimen yielded superior results both in terms of overall survival (13.6 months vs 9.6 months) and in terms of treatment tolerability. Therefore, according to a pick the winner attitude, the combination of cisplatin/gemcitabine/vinorelbine may be considered in the design of future randomized, Phase III trials for patients with carcinomas of unknown primary site.

Adult↗
PubMed2006

Maintenance biotherapy with interleukin-2 and interferon for metastatic renal cell cancer.

The term maintenance immunotherapy comprises at least two different therapeutic approaches: the continuation of immunotherapy beyond disease progression and the use of chronic immunotherapy after the achievement of an initial response (or disease stabilization) with more intensive treatment modalities, such as chemotherapy. The former therapeutic approach was proposed in renal cell carcinoma some years ago relying on several immunological considerations. Some years later, we have learned that it is feasible and endowed with a favorable therapeutic index; furthermore, its immunologic effects are well described and reproducible, and it has antitumor activity. However, due to the lack of adequate randomized Phase III studies, the actual impact of this treatment strategy on patient survival has not yet been proved. The rationale of this treatment, its immunological and clinical results, as well as its pitfalls and perspectives, will be presented and discussed in this review.

Antineoplastic Agents↗
PubMed2005

SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure.

Human malignant mesothelioma is an aggressive cancer generally associated with exposure to asbestos, although SV40 virus has been involved as a possible cofactor by a number of studies. Asbestos fibers induce cytotoxicity in human mesothelial cells (HMC), although cell survival activated by key signaling pathways may promote transformation. We and others previously reported that SV40 large T antigen induces autocrine loops in HMC and malignant mesothelioma cells, leading to activation of growth factor receptors. Now we show that SV40 induces cell survival via Akt activation in malignant mesothelioma and HMC cells exposed to asbestos. Consequently, prolonged exposure to asbestos fibers progressively induces transformation of SV40-positive HMC. As a model of SV40/asbestos cocarcinogenesis, we propose that malignant mesothelioma originates from a subpopulation of transformed stem cells and that Akt signaling is a novel therapeutic target to overcome malignant mesothelioma resistance to conventional therapies.

Apoptosis↗
PubMed2005

Raltitrexed-Oxaliplatin combination chemotherapy is inactive as second-line treatment for malignant pleural mesothelioma patients.

Within a single-institution phase II trial, we investigated the antitumor activity of the Raltitrexed-Oxaliplatin combination as second-line therapy for malignant pleural mesothelioma (MPM). Fourteen patients were enrolled and all were assessable for response. The trial was then closed because chemotherapy, though well tolerated, yielded no objective responses. The best response observed was disease stabilization in 4 patients only (28.57%), while the other 10 patients (71.42%) progressed despite treatment. Median time to progression (TTP) was 8 weeks (average: 9.85, range: 7-20), while median overall survival was just 14 weeks (average: 21.69, range: 9-66+).

Adult↗
PubMed2005

New agents in the management of advanced mesothelioma.

Malignant pleural mesothelioma (MPM) is a seemingly uncommon tumor whose incidence has in fact increased steadily and progressively over the last 30 years. Indeed, an actual "epidemic" is expected in Europe over the next 20 years. Despite unquestionable improvement in the diagnostic methods at our disposal and the availability of new treatment strategies, the prognosis of MPM patients remains dramatically poor (12 to 18 months' median survival from diagnosis), although exceptional cases of long-survivors are reported in all literature series. The current review will cover the dramatic improvements in the treatment of this rare disease that have been recently achieved, as well as the promise that new, molecular-targeted therapies, such as bortezomid, mTOR ( m ammalian t arget o f r apamycin) inhibitors, and Met inhibitors, seem to offer for the next few years. With pemetrexed we now have a drug that is able to impact patient survival. Together with the newer drugs, rapidly emerging from the laboratory to be applied in the clinic, we have the hope of making further advances in the struggle against this disease.

Animals↗
PubMed2005

Autoimmunity in thrombotic thrombocytopenic purpura.

In the last few years, an autoimmune hypothesis for the pathogenesis of thrombotic thrombocytopenic purpura (TTP) has been proposed often, with variable success because of inconsistent supporting data. We are now aware that at least one subgroup of TTP patients does present with pathogenic autoantibodies (i.e, anti-ADAMTS13); this group consequently is a putative candidate for a curative treatment including plasma exchange (still the cornerstone of TTP treatment), together with corticosteroids or other immunosuppressants. Furthermore, for patients not responding to or relapsing following plasma exchange, the use of stronger immunosuppression (e.g., with the use of the anti-CD20 monoclonal antibody rituximab) should be considered as appropriate. Conversely, few data are actually available regarding the complex relationship between TTP and the antiphospholipid (aPL) syndrome, as well as other autoimmune diseases. Indeed, a correct differential diagnosis should be done on the basis of both different clinical presentations and autoantibody profile. At present, the presence of aPL antibodies should give evidence against a diagnosis of TTP, even though we cannot exclude that aPL antibodies may, in a minority of patients, be associated with a primary endothelial damage ultimately resulting in overt TTP.

ADAM Proteins↗
PubMed2005

Pro-neoangiogenic cytokines (VEGF and bFGF) and anemia in solid tumor patients.

Using a commercial ELISA assay, we evaluated circulating VEGF and bFGF levels in 203 consecutive patients with solid tumors, and sought a correlation between them and with the grade of anemia. Serum VEGF values were within the normal range in 128 patients (63.05%), with a mean value of 675.04 pg/ml (median, 571.00; range, 0-2796.54). The analysis of VEGF values per tumor group did not provide any statistically significant difference. Regarding bFGF, 143 patients (70.44%) had measurable, and thus abnormal, bFGF values. Overall, mean bFGF serum value was 57.14 pg/ml (median, 8.30; range, 0-4334.71), with the highest bFGF levels found in breast carcinoma patients. As expected, a large number of our patients was fairly anemic, mean hemoglobin level being 11.47 g/dl (median, 11.30; range, 7.1-19.20), the lowest titers being observed in prostate carcinoma patients. No statistically significant correlation was found between serum VEGF and hemoglobin values (r=0.004) but a significant negative correlation was seen between serum bFGF and hemoglobin (r=-0.22, p<0.05). Considering the different tumor groups, a statistically significant negative correlation between bFGF and hemoglobin becomes even more apparent in the subgroup of renal carcinoma patients (r=-0.55, p<0.05). In conclusion, our results demonstrate that there is a statistically significant correlation between systemic hypoxia (evaluated in terms of hemoglobin levels) and circulating bFGF values, but not VEGF; this correlation may lead to therapeutic interventions.

Aged↗
PubMed2005

Flow cytometric analysis of circulating dendritic cell subsets and intracellular cytokine production in advanced breast cancer patients.

Patients with advanced cancer are known to have dysfunctions of the immune system. Dendritic cells (DCs) are potent antigen-presenting cells that play a crucial role in antitumor immune response. At least two peripheral blood DC subsets have been described: myeloid-derived CD11c+CD123- DCs (DC1) and lymphoid-derived CD11c-CD123+ DCs (DC2). Upon interaction with T cells, DC2 seemed to support the generation of a Th2 response, while DC1 predominantly prime a Th1 response. Our study was aimed at investigating the number of circulating DCs, and their subsets and functions in 32 patients with advanced breast cancer that achieved an objective response after a standard-dose sequential chemotherapy (CT), compared to 40 healthy controls. Circulating DC subsets and intracellular cytokine production in CD4+ and CD8+ subsets were analyzed using a tri-color flow cytometry assay. DC subsets were identified in peripheral blood, calculating their percentage gated as lin- HLA-DR+ and using BDCA-1, BDCA-2 and BDCA-3 specific markers, as DC1 and DC2 according to expression of CD11c and CD123, respectively. Intracellular cytokines were evaluated in CD4+(Th1 and Th2) and CD8+ (Tc1 and Tc2) T lymphocytes. The mean percentage of BDCA-1+BDCA-2+BDCA-3 was similar to that of DC1+DC2 (p=ns). The mean percentage of DCs and DC1/DC2 ratio were slightly decreased before CT in cancer patients compared with healthy controls (p=ns). After CT, the percent-age of DC1 further decreased (p=0.02). The production of IFN-gamma (Th1 and Tc1) significantly decreased (p<0.03) while that of IL-4 (Th2 and Tc2) increased (p=0.04), thus confirming a shift toward a Th2 CD4 and Tc2 CD8 phenotype and the predominance of type 2 DCs. Our results could help clarify the mechanisms of the immune response or immune status of patients with advanced breast cancer that undergo cytotoxic CT and contribute to improve the selection of potential candidates for active immunotherapy trials.

Adult↗
PubMed2004

Gemcitabine and oxaliplatin in the treatment of patients with immunotherapy-resistant advanced renal cell carcinoma: final results of a single-institution Phase II study.

BACKGROUND: Currently, there is no standard treatment for patients with advanced renal cell carcinoma (RCC) who do not experience a response to first-line immunotherapy. In the current Phase II study, the authors explored the antitumor activity of a combination of gemcitabine and oxaliplatin (L-OHP) in this setting. METHODS: Forty-two patients with RCC who had progressive disease following immunotherapy received gemcitabine (1000 mg/m2 intravenously on Days 1 and 8 every 21 days) and L-OHP (90 mg/m2 intravenously on Day 1 every 21 days) for a minimum of 2 cycles before responses were evaluated. Responses to treatment and toxicity were recorded according to the Response Evaluation Criteria in Solid Tumors and the National Cancer Institute Common Toxicity Criteria, respectively. RESULTS: No complete responses were recorded; however, 6 patients experienced a partial response (14.28%; 95% confidence interval, 5.43-28.5%), 11 patients (26.19%) had temporary stable disease as a best response, and the remaining 25 patients (59.52%) experienced progression despite receiving treatment. The median time to disease progression was 2.5 months (mean, 3.86 months; range, 1.5-11.0 months), whereas the median overall survival was 9.5 months (mean, 10.46 months; range, 4.0-22.5 months). With regard to toxicity, treatment generally was well tolerated, with only one episode of Grade 4 toxicity and expected episodes of Grade 3 toxicity, including myelosuppression and neuropathy. CONCLUSIONS: The current results suggest that the combination of gemcitabine and L-OHP possesses a certain level of activity and an acceptable toxicity profile in patients with immunotherapy-resistant advanced RCC.

Adenocarcinoma, Clear Cell↗
PubMed2004

Docetaxel, carboplatin and concomitant radiotherapy for unresectable squamous cell carcinoma of the head and neck: pharmacokinetic and clinical data of a phase I-II study.

Concomitant chemoradiotherapy is the most effective treatment of unresectable head and neck cancer. Docetaxel and carboplatin are two active drugs that potentiate radiotherapy. Thirty patients (median age = 56 years; median Eastern Cooperative Oncology Group performance status = 1) received radiotherapy (70 Gy, 2 Gy/d, 5 d/wk) concurrent with carboplatin AUC 0.3 to 0.5 on day 1-5, weeks 1, 3, 5, 7, and docetaxel 15 to 25 mg/m2 on day 4 of weeks 2, 4, and 6. Site of unresectable squamous cell carcinoma was as follows: oropharynx, 41%; hypopharynx, 27%; oral cavity, 16%; and larynx, 16%. Stage was III in 13% and IV in 87%. In 11 patients, pharmacokinetic parameters were evaluated. Acute G4 toxicity was as follows: neutropenia, 20%; mucositis, 33%. We had the following acute G3 toxicities: mucositis, 40%; neutropenia, 37%; dermatitis, 23%; and anemia, 13%. The maximum tolerated dosage was area under the curve 0.5 for carboplatin and 20 mg/m2 for docetaxel. Median radiotherapy dose was 69 Gy, and 175 out of 210 courses (83%) were administered. At the end of the treatment, we had 20 complete responses (CR) (67%), 9 partial responses (30%), and 1 no change (3%). After radial neck dissection, 2 patients achieved a CR (overall CR = 73%). After a median follow-up of 2.5 years, we had a 3-year local progression-free survival of 85%, failure-free survival of 69%, and overall survival of 60%. A significant increase of Cmax of carboplatin concentration was noted at the beginning of weeks 3, 5, and 7. Total plasma platinum raises during each course of 5 days of carboplatin without reaching a steady state. Carboplatin, docetaxel, and concomitant conventional radiotherapy is a feasible and effective treatment of unresectable head and neck cancer. The concurrent administration of two drugs does not alter pharmacokinetic drug behavior compared with single-agent data.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Low doses of subcutaneous interleukin-2 plus interferon-alpha do not induce thyroid function alterations in advanced renal cell carcinoma patients.

The incidence of thyroid function changes among renal cell carcinoma (RCC) patients treated with high-dose IL-2 plus IFN-alpha ranges from 9 to 59%, independently of the administration route (i.v. or s.c.) of IL-2. Although several studies demonstrated a correlation between high-dose IL-2/IFN-alpha regimens and autoimmune thyroid disease, only very limited data are available when low doses of IL-2 plus IFN-alpha are used. We prospectively studied thyroid function in 52 patients with metastatic RCC undergoing immunotherapy with low-dose IL-2 + IFN-alpha. All patients received treatment cycles consisting of both s.c. IL-2 and i.m. IFN-alpha for 4 consecutive weeks; cycles were repeated at 4-month intervals in all patients, irrespectively of their response. Thyroid stimulating hormone (TSH), 3,3',5-triiodo-L-thyronine (T3), thyroxine (T4), human anti-thyroglobulin antibodies (hTg-Ab) and human anti-thyroid peroxidase antibodies (hTPO-Ab) were assayed in all patients before and after each of the first 3 cycles. None of the patients showed clinical signs of dysthyroidism, nor required replacement or suppressive treatment on thyroid function; specifically, no statistically significant differences were found when the median pre- and post-treatment TSH, T3, T4, hTg-Ab and hTPO-Ab levels of each cycle were compared. The median TSH values after the 3 cycles were, respectively, 1.06 [Inter Quartile Range (IQR) 0.58-1.51], 1.21 (IQR 0.58-1.51) and 1.05 micro U/ml (IQR 0.67-1.73). As for thyroid hormones, median values after each of the 3 cycles were: 1.38 (IQR 1.19-1.50), 1.46 (IQR 1.17-1.66) and 1.36 (IQR 1.16-1.46) ng/ml for T3, and 8.74 (IQR 7.26-9.45), 8.67 (IQR 7.12-9.18) and 8.40 (IQR 7.12-9.33) micro g/dl for T4. These data show that a regimen of low-dose IL-2 plus IFN-alpha does not seem to affect thyroid function, neither inducing signs or symptoms of dysthyroidism, nor by causing major biochemical changes in TSH and thyroid hormone levels, or an increase in thyroid-specific auto-antibodies.

Adjuvants, Immunologic↗
PubMed2003

Lack of dendritic cell mobilization into the peripheral blood of cancer patients following standard- or high-dose chemotherapy plus granulocyte-colony stimulating factor.

BACKGROUND: Dendritic cells (DC), the most specialized antigen-presenting cells, can be detected in the peripheral blood (PB) and divided into two subsets of populations, DC1 and DC2, endowed with different functions. The aim of this study was to evaluate the effect on DC release and on their subsets of three regimens utilized to mobilize CD34+ cells into the PB in cancer patients and in normal CD34+ cell donors. PATIENTS AND METHODS: The mobilizing sequences were: standard-dose epirubicin+taxol+granulocyte-colony-stimulating factor (G-CSF; 15 patients with advanced breast cancer), high-dose cyclophosphamide (CTX)+G-CSF (10 patients with breast cancer patients and 7 with non-Hodgkin's lymphoma, NHL), and G-CSF alone (5 normal donors of CD34+ cells for allogeneic transplantation). Comparative data were obtained from the steady-state PB of 20 healthy volunteers. For flow cytometric analysis, DC were gated as negative for specific lineage markers (CD3, CD11b, CD14, CD16, CD56, CD19, CD20, CD34) and positive for HLA-DR. The DC1 and DC2 subsets were defined as CD11c and CDw123 positive, respectively. RESULTS: The percentages of DC at baseline and the time of CD34+ cell peak were: 0.48 and 0.51 for standard-dose chemotherapy (CT); 0.55 and 0.63 for breast cancer after high-dose CTX+G-CSF; 0.53 and 0.71 for NHL after high-dose CTX+G-CSF; and 0.51 and 0.54 for normal donors of CD34+ cells after G-CSF alone (all p=n.s.). Mean DC1/DC2 ratios in each study group at the time of CD34+ cell peak were 0.10, 0.12, and 0.18, respectively. Finally, in the group of healthy volunteers, the percentage of circulating DC was 0.95 and the mean DC1/DC2 ratio was 1.28. CONCLUSION: To our knowledge, this is the first report that demonstrates that both standard-dose or high-dose CT, when utilized together with G-CSF, do not induce DC mobilization into the PB, whereas a reversed DC1/DC2 ratio is observed. Furthermore, a lack of significant DC mobilization after G-CSF alone was also seen, in contrast to what was previously observed by others. These data should be taken in account when evaluating clinical correlations between DC number and CPC engraftment in both the transplantation setting, when monitoring the effects on the immune system of combinations of new drugs and/or cytokines, and when high numbers of DC are required for both experimental and clinical applications.

Adult↗
PubMed2003

Transforming growth factor-beta released by PPD-presenting malignant mesothelioma cells inhibits interferon-gamma synthesis by an anti-PPD CD4+ T-cell clone.

Besides acting complexly on both normal and tumor cells, transforming growth factor-beta (TGF-beta) can determine the nature of the response to the antigen, strongly inhibiting the differentiation of naive CD4+ T-cells toward a T helper-1 (Th-1) phenotype; in a number of experimental models, TGF-beta also appeared to be a potent immunosuppressant factor. TGF-beta was shown to be released by some human malignant mesothelioma (MMe) cells, which affects the immune response to this tumor. Thus, for a better understanding of the role of TGF-beta in the immune response to MMe cells, we evaluated the production of a Th-1 cytokine (IFN-gamma) and of a Th-2 cytokine (IL-4), following Purified Protein Derivative (PPD) recall antigen presentation by human MMe cells to a class-II major histocompatibility complex (MHC-II)-matched PPD clone (PPD clone). Our data confirm that human MMe cells possess the unusual capability of presenting a common recall antigen to CD4+ lymphocytes but also show that these tumor cells can abrogate Th-1 immune response, as evidenced by a shift in favor of the production of IL-4 over that of IFN-gamma, through a TGF-beta-mediated pathway; only the simultaneous block of TGF-beta1 and beta2 effects can significantly restore a typical Th-1 pattern of cytokine production by PPD clone in response to PPD presentation by MMe. Even though the role of TGF-beta in the promotion of MMe growth should be further and better defined, this effect should be considered when designing new therapeutical approaches aimed at improving the immune response to MMe.

CD4-Positive T-Lymphocytes↗
PubMed2002

Determination of free and total (free plus protein-bound) melatonin in plasma and cerebrospinal fluid by high-performance liquid chromatography with fluorescence detection.

A simple, sensitive and accurate method for the estimation of free and total (free plus protein-bound) melatonin (MLT) in human plasma and cerebrospinal fluid (CSF) is described. Via Chem-Elut cartridges, free and total MLT (the latter obtained after a deproteinization step) were quantified in dichloromethane-extracted samples and analyzed in one chromatographic run by high-performance liquid chromatography (HPLC) with fluorimetric detection. The column used was an Extrasil ODS-2 (3 microm, 150 x 4.6 mm I.D.), while the mobile phase consisted of 75 mM sodium acetate-acetonitrile (72:28, v/v) (pH 5.0). Repeatability and reproducibility of the method were 3.24 and 9.4%, respectively. The recovery of melatonin from plasma and CSF was 99.9+/-4.0% for non-deproteinized samples and 93.2+/-4.8% for deproteinized samples. The detection limit of the assay was 0.5 pg/ml. In human plasma, the mean+/-SD concentrations in the darkness period were 23.18+/-7.44 pg/ml for free melatonin and 82.5+/-36.48 pg/ml for total melatonin, while the lowest concentrations detected during daytime were 2.23+/-2.22 and 7.40+/-5.68 pg/ml, respectively. Detection of MLT in CSF was 5.01+/-2.31 and 28.55+/-6.95 pg/ml for the free and total fraction, respectively.

Chromatography, High Pressure Liquid↗
PubMed2002

Intrapleural interleukin-2 induces nitric oxide production in pleural effusions from malignant mesothelioma: a possible mechanism of interleukin-2-mediated cytotoxicity?

Due to the frequent use of intrapleural interleukin-2 (IL-2) to treat pleural effusions from malignant mesothelioma (MMe), we measured nitric oxide (NO) end product nitrite (NO(2)(-)) in pleural effusions of 12 MMe patients with chronic or chronic-relapsing pleurisy. Through high performance liquid chromatography analysis, NO(2)(-) was found in the initial pleural fluid sample of all patients (156.25 pmol ml(-1)), and increased significantly following IL-2 intrapleural instillation, both at 24 (589.91 pmol ml(-1), P < or = 0.0005) and 48 h (756 pmol ml(-1), P< or = 0.0005). Even though it is difficult to argue if the large amounts of NO end product NO(2)(-) we observed is produced by IL-2-stimulated and recruited immune cells, by MMe cells themselves, or by both, it is possible that NO could contribute to the complex antitumor activity of IL-2.

Aged↗
PubMed2002

The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular endothelial growth factor.

The aim of this study was to evaluate whether the presence of simian virus-40 (SV40) is associated with increased release of vascular endothelial growth factor (VEGF) in human malignant mesothelioma (MM) cells. We studied nine cell lines derived from pleural effusion (PE) of patients with MM, and three different cultures of normal human mesothelial cells (NHMC) derived from pleural fluid of patients with congestive heart failure. NHMC were transfected with full length SV40 (NHMC-FL) or large T antigen (NHMC Tag) DNAs. High levels of VEGF were detected in conditioned media of each of two MM cells that tested positive for SV40 by PCR amplification and Southern blot hybridization and for Tag transcript by reverse transcription- polymerase chain reaction (RT-PCR) and immunoprecipitation. We also found that NHMC-FL released high amounts of VEGF. Conditioned media from SV40-positive MM cells and from FL-NHMC increased proliferation of human umbilical vein cells (HUVEC) and this effect was partially abrogated by adding specific blocking antibodies against VEGF. These results offer the first evidence that SV40 can cause VEGF release in SV40-positive MM cells and that entire viral genome is required for this effect.

Antigens, Polyomavirus Transforming↗