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F Belli

Publications and source records attributed to F Belli.

At least 55 records · Page 3Linked to original sources
PubMed1997

Pharmacokinetics and effects on plasma retinol concentrations of 13-cis-retinoic acid in melanoma patients.

The pharmacokinetics of 13-cis-retinoic acid (13cisRA) and its effects on retinol plasma levels were investigated after the first and the last doses in melanoma patients, who participated in a study run to assess tolerance over a long period of a treatment schedule of 13cisRA associated with recombinant interferon alpha2a (rIFN-alpha2a). Melanoma patients with regional node metastases after radical surgery were randomized to be treated for 3 months with rIFN-alpha2a, 3 x 10(6) IU s.c. every other day, associated with oral 13cisRA at doses of 20 mg day(-1) (five patients) or 40 mg every other day (seven patients). Maximum 13cisRA blood concentrations usually occurred 4 h after drug administration, with average values of 406 and 633 ng ml(-1) (i.e. 1.3 and 2.1 microM) after the 20 and 40 mg dose respectively. The average half-life (t(1/2)) was approximately 30 h. The maximum concentration, the t(1/2) and the area under the concentration-time curves from 0 to 48 h (AUC(0-48)) of 13cisRA did not change after multiple dosing, whereas the AUC(0-48) of its major blood metabolite, 4-oxo-13-cis-retinoic acid, increased. Immediately after 13cisRA treatment, retinol plasma levels started to decline and they reached the lowest values (approximately 20% reduction) shortly after the time of maximum 13cisRA concentrations (i.e. 4-12 h after drug intake). Afterwards, values returned to baseline. The amount of retinol reduction in time was correlated with 13cisRA maximum concentrations.

Adult↗
PubMed1996

Limited antitumor T cell response in melanoma patients vaccinated with interleukin-2 gene-transduced allogeneic melanoma cells.

We have immunized advanced melanoma patients with a HLA-A2-compatible human melanoma line genetically modified to release interleukin-2 (IL-2), to elicit or increase a T cell-mediated anti-melanoma response that may affect distant lesions. Twelve stage-IV patients were injected subcutaneously at days 1, 13, 26, and 55 with IL-2 gene-transduced and irradiated melanoma cells at doses of 5 or 15 x 10(7) cells. Both local and systemic toxicities were mild, consisting of transient erythema at the vaccination site; fever occurred in a minority of patients. Three mixed responses were recorded. Seven patients were evaluable for immunological studies. Mixed tumor-lymphocyte cultures carried out with different allogeneic HLA-A2-matched melanoma lines as stimulators and targets revealed an increase in the MHC-unrestricted, but no changes in the MHC-restricted, cytotoxicity in peripheral blood lymphocytes (PBL) obtained after vaccination as compared with those obtained before vaccination. Increased recognition of the tyrosinase 368-376 peptide occurred in post-vaccination PBL of one patient, whereas a weak increase in recognition of the gp100 280-288 peptide was detectable in another patient; these 2 patients also recognized the gp100 457-466 peptide. After in vitro, stimulation with the only available autologous melanoma line, CD4+ cells with autologous tumor-specific cytotoxicity and ability to release interferon-gamma (IFN-gamma) were found in post- but not in pre-vaccination PBL. In the same patient, as well as in another patient, limiting dilution analysis showed that vaccination resulted in an increased frequency of melanoma-specific cytotoxic T lymphocyte (CTL) precursors. These results indicate that vaccination with cells releasing IL-2 locally can expand a T cell response against antigen(s) of autologous, untransduced tumor, although this response occurred in a minority of the melanoma patients studied.

Adult↗
PubMed1996

Multiple melanoma-associated epitopes recognized by HLA-A3-restricted CTLs and shared by melanomas but not melanocytes.

The molecular characterization of melanoma-associated Ags allowed the definition of several HLA class I-presented peptides recognized by T cells. However, no HLA-A3.1-restricted melanoma epitopes have been identified to date. To gain insight into the HLA-A3.1-restricted T cell epitope repertoire of human melanoma, we analyzed the immunologic reactivity of CTLs isolated from tumor-involved or tumor-free lymph nodes in two HLA-A3.1+ melanoma patients. Three CTL lines, clonal or highly oligoclonal in their TCR composition, and two CTL clones were selected for HLA class I-restricted lysis of the autologous tumor and then tested for the recognition of HLA-A3+ and HLA-A3- normal or neoplastic cells of the melanocyte lineage. One CTL recognized a unique HLA-A3.1-restricted Ag expressed only by the autologous tumors, while all the other CTLs defined three HLA-A3.1 epitopes shared by melanomas, but not by melanocytes. Moreover, the epitopes of two CTL lines with different specificity were reconstituted by nonoverlapping fractions of HLA-A3+ melanoma-derived peptides resolved by reverse phase-HPLC, indicating that distinct naturally processed peptides were specifically recognized on melanoma cells in association with HLA-A3.1 molecules. These novel lineage-unrelated HLA-A3.1-restricted melanoma epitopes do not derive from MAGE, BAGE, or GAGE gene families, as evaluated by the COS-7 transfection assay. Our data show that CTLs may recognize HLA-A3.1-class 1 complexes presenting melanoma (but not melanocyte)-associated epitopes that are either unique to a given patient's tumor or that are shared between multiple melanomas.

Animals↗
PubMed1996

Manual dissection of adenocarcinoma of the lower third of the rectum specimens for detection of lymph node metastases smaller than 5 mm.

BACKGROUND: The question of whether manual dissection when searching for metastatic lymph nodes from rectal cancer (less than 5 mm) is a reliable method remains controversial. METHODS: We examined 50 consecutive cases of primary adenocarcinoma of the rectum treated with a sphincter-sparing total rectum resection, total mesorectum excision, and coloanal anastomosis. We used a manual method for the detection of lymph nodes. RESULTS: One thousand seven hundred ninety-three lymph nodes were found (mean, 36 per patient). One hundred seventy-four contained metastases. Seventy-nine (45.4%) of the affected lymph nodes were less than 5 mm in greatest dimension. The percentage of metastases to small lymph nodes was similar to the percentage reported by Kotanagi (50%), but lower than the report of Herrera (78%), who used a clearing technique to search for regional lymph nodes. CONCLUSIONS: A median 17 months follow-up in these patients demonstrated that metastases in small lymph nodes are important in the accurate staging of rectal tumors and that a manual method of searching for small lymph nodes is reliable.

Adenocarcinoma↗
PubMed1996

Total rectal resection, mesorectum excision, and coloendoanal anastomosis: a therapeutic option for the treatment of low rectal cancer.

BACKGROUND: There is recent and sporadic evidence indicating that patients with very low rectal cancer may be treated via a sphincter-saving procedure, obviating the need for abdominoperineal resection and definitive colostomy. This study confirms these findings. METHODS: From March 1990 to October 1994, 79 patients affected with primary low rectal cancers were submitted for total rectal resection, mesorectum excision, and coloendoanal anastomosis. All lesions were located within 8 cm of the anal verge (within 6 cm in 64 cases). RESULTS: Eight patients relapsed at the pelvic level, and one patient only at the paraanastomotic site. Postoperative morbidity attributable to the procedure was low. A perfect continence was documented in 66% of cases after colostomy closure, and many patients (63%) had one or two bowel movements a day. Sixty-two patients of this series are alive, 49 without actual evidence of disease. Follow-up ranged from 2 to 56 months (median 23). CONCLUSIONS: The clinical and pathological data derived from this study suggest that radical mesorectum excision more than a large clearance margin of resection remains the most important factor in reducing the incidence of local relapse after low rectal cancer surgery and that total rectal resection and coloendoanal anastomosis is a suitable and safe option to traditional, demolitive surgical techniques.

Adult↗
PubMed1996

Differences in frequency distribution of HLA-A2 subtypes between North American and Italian white melanoma patients: relevance for epitope specific vaccination protocols.

Cytotoxic T lymphocytes (CTL) associated in vivo with tumor regression recognize the product of nonmutated genes expressed by most melanoma cells as peptides bound to human leukocyte antigen (HLA) molecules. Multiple HLA-A*0201 restricted peptides derived from melanoma associated antigens (MAA) have been described, and peptide-based vaccination protocols against melanoma are being developed worldwide for the treatment of HLA-A2 melanoma patients based on the assumption that most serologically typed HLA-A2+ individuals will be suitable for such vaccinations. Serologic typing of HLA-A2, however, encompasses a family of at least 17 related alleles recognized by molecular typing techniques and differing at one or more functional residues of the HLA class I molecule. We have recently shown that naturally occurring single-residue variants of HLA-A*0201 are responsible for significant differences in CTL response to MAA-peptide stimulation. Existing data for HLA-A*02 subtype frequencies among whites (who are most affected by melanoma) derive from analyses of Northern European and North American populations that are of similar heritage and predict an exceedingly rare (< 5%) frequency of non-HLA-A*0201 alleles. Melanoma however, affects other white populations in which the prevalence of HLA-A*02 alleles could be more variable. This study was done to identify HLA-A*02 subtypes and their prevalence in two ancestrally different white melanoma populations. HLA-A*02 subtype frequencies were compared by polymerase chain reaction between serologically HLA-A2+ melanoma patients referred for treatment to the Istituto Nazionale Tumori of Milan (n = 93), Italy or the National Cancer Institute, Bethesda, MD, U.S.A. (n = 100). This analysis demonstrated differences in subtype specificity and distribution between the two populations, with a significantly higher percentage of non HLA-A*0201 subtypes in the Italian population. Only 2% of serologically HLA-A2+ Northern American white melanoma patients did not express HLA-A*0201. In contrast, 15% of HLA-A2+ Italian patients were not HLA-A*0201 (p2 value = 0.001). As allele-specific/peptide-based vaccination protocols are presently pursued at several institutions, a proportion of patients might be inappropriately enrolled basing their eligibility on serologically defined HLA-typing.

Amino Acid Sequence↗
PubMed1996

Biological activity and clinical efficacy of intravenous high-dose thymopentin in metastatic melanoma patients.

Eight patients with cutaneous metastatic melanoma were submitted to high-dose intravenous thymopentin (TP5) treatment for 5 weeks: three patients received 1 g three times a week, three received 1 g daily and two received 2 g daily. Four out of eight patients presented a partial response of cutaneous lesions lasting for 1-7 months, and six remain alive with evidence of disease after a follow-up of 2-7 months. A remarkable histologic observation is the presence of tumour necrosis, which was seen as both single cells and large confluent areas. The majority of lymphoid cells present in the tumour are CD45RO+ and CD4+. The CD4+ cells might play an important role in the anti-tumour immune local response by secreting cytokines and inducing apoptotic and necrotic cell death. This hypothesis seems to be confirmed by the presence of a high number of CD4+ cells around intratumoral vessels, while the presence of endovascular micro-thrombosis provides indirect evidence of cytokine activity. Cellular lysis may be produced by the activity of both CD8+ and CD4+ lymphoid cells. The role of TP5 may be an activation of CD4+ and CD8+ lymphoid cells. Clinical and pathological data indicate that TP5 is able to produce consistent clinical and immunological effects in melanoma patients with cutaneous metastases.

Adjuvants, Immunologic↗
PubMed1996

Cytokine-based gene therapy of human tumors. An overview.

This review first summarizes the different strategies of gene therapy of cancer and then focuses on the immunological approach. Several studies in animal models with cytokine gene-transduced tumor cells indicate that local cytokine release usually results in tumor growth inhibition. Moreover, in a number of cases vaccination with such cells can reduce growth of established tumors or even cure the tumor-bearing animals. Translation of such a principle in human clinical setting is reported. We have transduced human melanoma cells with genes coding for interleukin (IL)-2, IL-4 or B7-1 and characterized such lines. The phenotype did not change after gene insertion but the functional, immunostimulatory activity of IL-2 or B7-1 gene-transduced melanoma cells was significantly increased compared to that of parental lines. These-lines were then used to vaccinate melanoma patients. Preliminary results of trials with IL-2 gene-transduced cells are presented which indicate a weak clinical response and the activation of a melanoma-specific cytotoxic T lymphocyte response in a low percentage of patients.

Animals↗
PubMed1995

Isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine-activated killer cells in the treatment of in-transit metastases from limb cutaneous melanoma.

BACKGROUND: Therapies of advanced melanoma patients with interleukin-2 (IL-2) and cytotoxic lymphocytes have produced interesting results, but a larger diffusion of these treatments is limited by the severe side effects due to IL-2 systemic infusion. A strictly regional administration of IL-2 and cells by an isolation perfusion (IP) in extracorporeal circulation (ECC) for the treatment of regional melanoma metastases could improve tolerability and efficacy of this specific modality of immunotherapy. METHODS: Ten patients were submitted to adoptive immunotherapy with IL-2 and lymphokine-activated killer (LAK) cells by IP in ECC. The schedule of treatment included the first course of a 5-day systemic administration of IL-2 (Proleukin, EuroCetus 9-12 x 10(6) IU/m2/day continuous infusion); autologous LAK cells were obtained via leukapheresis and after in vitro activation were given (range 8-28 x 10(9)) along with IL-2 (120-2,400 IU/ml of perfusion priming) to the affected limb by IP; IL-2 (9-12 x 10(6) IU/m2/day) was also administered by systemic continuous infusion for 5 days starting on the day after IP. RESULTS: All patients concluded the treatment without any major local or systemic toxicities. Clinical responses included one complete and six partial remissions; three patients had stable disease. All patients are alive. Follow-up after IP ranged from 12 to 35 months (median: 22). The analysis of circulating lymphocytes revealed the rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. CONCLUSIONS: IP with IL-2 and LAK cells is a new approach for the treatment of in-transit metastases due to cutaneous melanoma. The treatment appears to be feasible and reliable. Further biological and immunological studies should permit amelioration of the present modality of treatment.

Adult↗
PubMed1994

Frequency of cytotoxic T lymphocyte precursors (CTLp) interacting with autologous tumor via the T-cell receptor: limiting dilution analysis of specific CTLp in peripheral blood and tumor-invaded lymph nodes of melanoma patients.

The frequencies of cytotoxic T-lymphocyte precursors (CTLp) that lyse autologous tumor by a T-cell receptor (TCR)-dependent mechanism (specific CTLp) were evaluated by limiting dilution analysis (LDA) using lymphocytes from peripheral blood (PBL) and from surgically resected, tumor-invaded lymph nodes (LNL) in 9 melanoma patients. The frequency of specific CTLp was determined in PBLs and/or LNIs of all patients by a modified LDA assay, enabling us to measure lytic activity on the autologous tumor that could be significantly inhibited by an anti-CD3 monoclonal antibody (MAb). This assay allowed us to detect frequencies of specific CTLp ranging from 1/720 to 1/32,037 in peripheral blood and from 1/328 to 1/22,061 in tumor-invaded lymph nodes. These frequencies indicated that lymphoid populations from PBLs or LNLs of melanoma patients may contain as low as 30 to as much as 3,000 specific CTLp/10(6) lymphocytes. In addition, comparison of wells containing specific CTLp with those showing no inhibition by anti-CD3 MAb indicated that specific CTLp represent between 3 and 88% of all precursors with lytic activity on the tumor. In 6 of 9 patients, no marked differences between PBLs and LNIs in specific CTLp frequencies were found. A 10-fold increase of specific CTLp, in comparison to PBL and LNL, was found only in lymphocytes isolated from a subcutaneous metastasis of one patient. Our results indicate that CTLp interacting with autologous tumor by a TCR-dependent mechanism exist in PBL and LNL of most melanoma patients, although a wide variation in their absolute number is evident among different patients.

Adult↗
PubMed1994

Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan.

BACKGROUND: Utilization of alpha-tumor necrosis factor (alpha-TNF) in clinical practice is limited by severe general side effects. Very promising results with low toxicity were reported with administration of alpha-TNF by isolation perfusion in extracorporeal circulation. METHODS: From December 1991 to November 1992, 14 patients underwent perfusion with alpha-TNF (2-4 mg, total dose), gamma-interferon (1.5 x 10(6) IU), and melphalan (10 mg/l/perfused limb). Twelve patients presented in-transit metastases of the limbs, one patient, a clear cell sarcoma of the hand, and one patient, a wide spindle cell carcinoma of the thigh. Perfusion lasted 90 minutes and was conducted in mild hyperthermia (38-40.5 degrees C, muscle temperature). RESULTS: Nine complete regressions and four stable diseases were recorded. In one case, a reliable evaluation of response was not possible for diffused tissue necrosis. Five patients relapsed or progressed locally from 3 to 4 months after surgery, five presented distant localizations from 2 to 7 months after surgery, and one died of disease 6 months after perfusion. Twelve patients are alive, seven without evidence of disease. A septic-like shock syndrome was observed in all patients and required administration of dopamine, dobutamine, or noradrenaline. One patient died 30 days after perfusion from a multiorgan-failure syndrome, likely due to alpha-TNF. The follow-up time ranges from 4 to 15 months (median, 6). CONCLUSIONS: The preliminary, impressive results reported in other series were not completely confirmed in this study adopting the same treatment scheme. Further clinical experience and biologic data are needed to state the real efficacy of the approach and to reduce the severe general toxicity consistently associated with this type of treatment.

Adult↗
PubMed1994

Total rectal resection and colo-anal anastomosis with colonic reservoir for low rectal cancer.

From March 1990 to December 1992, 47 patients with primary or recurrent low rectal cancer underwent total rectal resection and a coloendoanal anastomosis. Rectal resection was extended downward to the ano-rectal junction. The restorative technique included a colo-endoanal anastomosis between the dentate line and a J-shaped colic reservoir. All lesions were located within 7 cm of the anal verge (within 6 cm in 33 primary cases). Macroscopic and histological radicality was documented in all cases. Pelvic recurrence occurred in six patients and was para-anastomotic in one case. Post-operative morbidity was low. Perfect continence was documented in 36 patients and 72 of the cases had one or two bowel movements a day. All but four patients are alive at a follow-up ranging from 6 to 40 months (median 20 months). This approach is a safe option to conventional total rectal excision with permanent colostomy for lower third rectal carcinoma.

Adenocarcinoma↗
PubMed1994

New perspective in the treatment of low rectal cancer: total rectal resection and coloendoanal anastomosis.

PURPOSE: Presently abdominoperineal resection still remains the most diffuse modality of treatment of low rectal cancer. However, a new surgical approach is now available to avoid such a demolitive surgery and a definitive colostomy. METHODS: From March 1990 to March 1993, 58 total rectal resections were performed in 55 patients affected with primary or recurring cancers of the low rectum. As a restorative procedure, a colic J-shaped pouch and a handsewn pouch-endoanal anastomosis was adopted. All of the primary lesions were within 7 cm of the anal verge; in 74 percent the distal tumor margin was located less than 6 cm from the cutaneous edge. RESULTS: Histologic clearance of the rectum cut edge was documented in all cases. Seven patients relapsed locally from 7 to 14 months after surgery and in 3 more cases distant metastases were documented. Postoperative morbidity is low. After colostomy closure in 78 percent of patients, perfect continence was achieved and in 74 percent less than two bowel movements a day were recorded. Fifty patients are presently alive, 46 without evidence of disease. The follow-up ranged from 2 to 37 (median, 13) months. CONCLUSION: This experience, along with data obtained from last year's literature, indicates that a conservative surgical procedure, such as total rectal resection and coloendoanal anastomosis, can be considered a feasible and radical option for treatment of low rectal cancer.

Adult↗
PubMed1994

Total rectal resection and colo-anal anastomosis for low rectal tumours: comparative results in a group of young and old patients.

Rectal cancer incidence is increasing among the elderly who are more often considered for palliation rather than for surgical cure. Moreover, sphincter-sparing surgery is often avoided when treating the elderly. We report our experience on a consecutive series of 38 subjects, suffering from a lower third rectal tumour with a median distance of 5.6 cm from the anal verge (7 Dukes' A, 6 Dukes' B, 17 Dukes' C, 3 Dukes' D, 3 anastomotic recurrences and 2 large villous adenomas). All subjects were prospectively collected in a 2-year period and treated with total resection and colo-anal hand-sewn anastomosis on a J colic reservoir. 20 patients younger than 65 years and 18 over 65 years were matched for surgical complications, late morbidity, oncological and functional results but no statistical difference was found. Our hope is that a conservative approach in treating the low rectal tumours will progressively be accepted for elderly patients.

Adult↗
PubMed1994

Interleukin-2 gene-transduced human melanoma cells efficiently stimulate MHC-unrestricted and MHC-restricted autologous lymphocytes.

Two human melanoma lines were transduced by a retroviral vector with the gene of the human interleukin-2 (IL-2) and characterized for their immunological properties in comparison with the parental lines. Transduction resulted in the production of biologically active IL-2 in the average amounts of 2,282 and 2,336 pg/ml per 10(5) cells per 24 hr over 3 and 2 months by the Me14932/IL-2 and the Me1B6/IL-2 lines, respectively. Melanoma-transduced cells lost their tumorigenicity in nude mice. No major changes in the phenotype were observed in IL-2 gene-transduced lines. In fact, more than 90% of cells expressed class I and II(DR) HLA, adhesion molecules, integrins, and melanoma-associated antigens. Irradiation with 100-400 Gy, while inhibiting tumor cell growth in vitro, allowed the release of IL-2 by the transduced cells for at least 5 weeks. The two melanoma lines also maintained susceptibility to lysis by lymphokine-activated killer (LAK) cells and by a HLA-A2-restricted melanoma-specific cytotoxic T lymphocyte (CTL) clone recognizing the melanoma antigen (Melan-A). In a limiting dilution assay, transduced, but not parental melanoma lines unless added with an amount of IL-2 comparable to that released by the transduced cells, were able to expand both nonspecific and melanoma-specific CTL precursors from autologous peripheral blood lymphocytes (PBL). In mixed lymphocytes-tumor cultures, IL-2 gene-transduced melanoma cells stimulated the expansion of major histocompatibility complex (MHC)-unrestricted effectors from autologous PBL, and of CD3+ CD8+ MHC-restricted CTL from tumor-invaded lymph nodes. These results indicate that IL-2 gene transduction does not alter significantly the expression of the immunologically relevant molecules of human melanoma lines while increasing their ability to stimulate both specific and nonspecific lymphocyte responses. These lines will be of value in the vaccination of melanoma patients.

Animals↗
PubMed1994

Treatment of in-transit metastases from cutaneous melanoma by isolation perfusion with tumour necrosis factor-alpha (TNF-alpha), melphalan and interferon-gamma (IFN-gamma). Dose-finding experience at the National Cancer Institute of Milan.

From December 1991 to July 1993, 22 consecutive patients with grade IIIA-IIIAB melanoma underwent isolation perfusion with TNF-alpha (0.5-4 mg), melphalan (10 mg/l perfused limb) and, in the first 12 cases, IFN-gamma (1.5 x 10(6) U). The first series of 12 patients received a total dosage TNF-alpha of 2-4 mg, and the second series of 10 cases received an escalating dosage of TNF-alpha (1.5-1.0-0.5 mg) and no IFN-gamma before or during surgery. The perfusion lasted 90 min and was conducted in mild hyperthermia (39-39.5 degree C muscle temperature). The results of the first series included seven patients in complete remission, four with stable disease and one case not evaluable for local toxicity. Fifty per cent of cases developed a regional relapse from 3 to 4 months after surgery. Presently with a median follow up of 10 months, five patients of this group have no evidence of disease, four are alive with disease, two died from melanoma and one died of complications likely due to treatment (multi-organ failure syndrome). In the second series, the immediate responses included seven patients in complete remission and three in partial remission; with a median follow up of 3 months, two patients developed a regional relapse, respectively, 3 and 5 months after surgery. So far our experience of perfusion with TNF-alpha has not reproduced the data reported by other investigators. Further clinical and biological findings and a longer follow-up period are needed to draw any conclusion, and a decreasing TNF-alpha dose should be carefully evaluated.

Adult↗