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M J Mastrangelo

Publications and source records attributed to M J Mastrangelo.

At least 37 records · Page 2Linked to original sources
PubMed1998

Surgical removal of solitary hepatic metastasis from choroidal melanoma.

PURPOSE: To report surgical management of solitary hepatic metastasis that occurred 25 years after an enucleation for uveal melanoma. METHODS: A 16-year-old girl, diagnosed with choroidal melanoma and treated with enucleation, was found 25 years later to have liver metastasis affecting the entire left lobe of the liver. RESULTS: She underwent partial hepatectomy with removal of the metastatic melanoma. Four years later, she was found to have a smaller circumscribed nodular melanoma in the remaining right lobe of the liver, also treated with resection. She has remained disease-free for 2 years, with no evidence of systemic disease. CONCLUSION: Surgical excision may be a useful treatment option in selected cases with solitary, circumscribed liver metastasis from uveal melanoma.

Adolescent↗
PubMed1998

Phase I study of R24 in patients with metastatic melanoma including evaluation of immunologic parameters.

R24 is a mouse IgG3 monoclonal antibody with specificity for the disialoganglioside GD3. Most human melanomas have substantial surface GD3; in addition, a significant proportion of T lymphocytes display surface GD3. In a phase I study, we have investigated the toxicity and effect on selected immunological parameters of three dose levels of R24 given intravenously daily for five days (10 mg/m2/d, 30 mg/m2/d and 50 mg/m2/d) to patients with advanced melanoma. R24 administration neither consistently diminished nor augmented expression of delayed type hypersensitivity (DTH) skin reactions to anergy panel antigens or to a contact allergen dinitrofluorobenzene. R24 was infrequently found on tumor cells, or on lymphocytes from DTH biopsies, despite measurable serum levels of R24. The 30 mg/m2/d dose of R24 produced a statistically significant drop in peripheral blood lymphocytes on treatment Day 5. Likewise, on Day 5 there was a modest but statistically significant decrement in the proportion of circulating cells which were R24+. While there was one mixed response, there were no complete or partial tumor regressions in the R24 treated patients; there was no evident clinical benefit from the R24 therapy. The toxicity of the R24 at the higher dose levels can be very substantial. One patient, on the highest dose level, died on the 4th day of R24 treatment; in the absence of a plausible alternative explanation, a relationship of the death to the administered R24 must be considered. A precipitous drop in serum albumin coincident with R24 administration was found in all cases; this effect has not been previously reported with R24.

Animals↗
PubMed1998

Superficial melanoma metastases: appearances on gray-scale and color Doppler sonography.

OBJECTIVE: The purpose of this study was to describe the sonographic appearances of melanoma metastases of the skin, subcutaneous tissues, and superficial lymph nodes. MATERIALS AND METHODS: Gray-scale sonography was performed on 31 superficial melanoma metastases in 18 patients. Discreteness of borders, contours, echogenicity, echotexture, and degree of acoustic through-transmission were evaluated for each lesion. Color Doppler sonography was also performed on 25 of the 31 lesions, by which the amount of internal color flow was qualitatively assessed. RESULTS: Twenty-eight (90%) of the 31 metastases had well-defined borders. Contours were smooth in 17 (55%), lobulated in 12 (39%), and spiculated in two (6%). Nineteen metastases (61%) were hypoechoic to muscle, 10 (32%) were isoechoic, and two (6%) were hyperechoic. Echotexture was homogeneous in six lesions (19%), mildly heterogeneous in 13 (42%), moderately heterogeneous in 11 (35%), and markedly heterogeneous in one (3%). Twenty-two lesions (71%) showed enhanced acoustic through-transmission. Of the 25 melanoma metastases for which we performed color Doppler sonography, 18 (72%) had internal arterial color flow and seven (28%) did not. The flow was characterized as mild in 13 (72%) of 18, moderate in four (22%), and marked in one (6%). CONCLUSION: On sonography, superficial melanoma metastases typically are well-defined hypoechoic lesions with smooth or lobulated contours, mild to moderate heterogeneity, and enhanced acoustic through-transmission. Internal flow revealed by color Doppler sonography is present in many, but not all, superficial melanoma metastases.

Female↗
PubMed1998

Color Doppler sonographic detection of tumor flow in superficial melanoma metastases: histologic correlation.

Color Doppler sonographic detection of tumor flow within superficial melanoma metastases was investigated to determine if tumor size, vessel size, or vessel number influences signal detection. Color Doppler imaging of 32 pathologically proved melanoma metastases was performed at 6 MHz with color Doppler imaging parameters optimized for each lesion scanned. All lesions were measured in three dimensions and the presence or absence of internal flow was documented. Seven surgically excised metastases underwent immunohistochemical staining for endothelial markers. Internal flow was detected in 21 of 32 masses and was completely absent in 11. In comparison to all masses without flow, the masses with flow had significantly greater anteroposterior dimensions (P < 0.00036) and volumes (P < 0.01). Histologically, mean vessel diameter in masses with flow was significantly greater (P < 0.05) than in those without flow, but mean vessel number was not significantly different. In conclusion, detectability of tumor blood flow in superficial melanoma metastasis may be related more to tumor size and vessel size than vessel number. Failure to detect color signal within a superficial melanoma mass does not indicate a lack of internal vascularity.

Adult↗
PubMed1998

Autologous, hapten-modified vaccine as a treatment for human cancers.

We have devised a novel approach to active immunotherapy based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). The treatment program consists of multiple intradermal injections of DNP-modified autologous tumor cells mixed with BCG. Administration of DNP-vaccine to patients with metastatic melanoma induces a unique reaction- the development of inflammation in metastatic masses. Histologically, this consists of infiltration of T lymphocytes, most of which are CD8+. These T cells usually produce interferon-gamma in situ. Moreover, they represent expansion of T-cell clones with novel T-cell receptor (TCR) structures. Occasionally, administration of DNP-vaccine results in regression of measurable metastases. The most common site of regression has been small lung metastases. Administration of DNP-vaccine to patients in the postsurgical adjuvant setting produces a more striking clinical effect. Of 62 patients with clinically evident stage III melanoma who had undergone lymphadenectomy, the 5-year relapse-free survival rate was 45% and the overall survival rate was 58%. These results appear to be better than those obtained with high-dose interferon, although a randomized phase III trial is required to prove that point. A recent phase I study suggests that this therapeutic approach is also applicable to stage III ovarian cancer. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.

Animals↗
PubMed1997

Dinitrophenyl-modified autologous melanoma vaccine induces a T cell response to hapten-modified, melanoma peptides.

Active specific immunotherapy with dinitrophenyl (DNP)-modified autologous melanoma vaccine elicits inflammatory responses in metastatic tumor sites. Postsurgical adjuvant immunotherapy with this vaccine prolongs survival in stage III melanoma patients. We have reported that, after administration of DNP-modified melanoma vaccine, T cell responses to DNP-modified autologous tumor cells are demonstrable in vivo and in vitro. These responses are hapten specific and MHC restricted. To elucidate this phenomenon, we investigated the immune response to DNP-modified peptides eluted from autologous cells. Short peptides were extracted from DNP-modified and unmodified autologous melanoma cells by an acid elution technique and HPLC fractionation. Peptides were also extracted from DNP-modified and unmodified, EB virus-transformed, autologous B lymphoblasts. These various peptide fractions were loaded onto autologous B lymphoblasts and tested for ability to elicit a response by a DNP-specific T cell line as measured by IFN-gamma production. Unexpectedly, stimulatory activity of peptides from DNP-modified melanoma cells was confined to a single HPLC fraction. Spectrometric analysis of this fraction confirmed modification of peptides with DNP. A weaker T cell response was observed to a single HPLC fraction of DNP-modified peptides from the patient's B lymphoblasts. No T cell response was elicited by corresponding fractions of peptides eluted from unmodified melanoma cells or B lymphoblasts. These findings demonstrate the human T cell response to DNP-modified autologous melanoma cells is mediated by hapten-modified, MHC-associated peptides. Further investigation of these peptides could lead to a new strategy for peptide-based cancer immunotherapy.

Antigens, Neoplasm↗
PubMed1997

Autologous hapten-modified melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases.

PURPOSE: To determine whether treatment with an autologous whole-cell vaccine modified with the hapten dinitrophenyl (DNP vaccine) is an effective postsurgical adjuvant treatment for melanoma patients with clinically evident nodal metastases. PATIENTS AND METHODS: Eligible patients had regional nodal metastases that were large enough (> or = 3 cm diameter) to prepare vaccine. Following standard lymphadenectomy, patients were treated with DNP vaccine on a monthly or weekly schedule. RESULTS: Of 62 patients with metastasis in a single lymph node bed (stage III), 36 are alive after a median follow-up time of 55 months (range, 29 to 76); the projected 5-year relapse-free and overall survival rates are 45% and 58%, respectively. Of 15 patients with metastases in two nodal sites, five are alive with a median follow-up time of 73 months. An unexpected finding was the significantly better survival of older patients; the projected 5-year survival of patients greater than 50 versus < or = 50 years was 71% and 47%, respectively (P = .011, log-rank test). The development of a positive delayed-type hypersensitivity (DTH) response to unmodified autologous melanoma cells was associated with significantly longer 5-year survival (71% v 49%; P = .031). Finally, the median survival time from date of first recurrence was significantly longer for patients whose subcutaneous recurrence exhibited an inflammatory response (> 19.4 v 5.9 months; P < .001). CONCLUSION: Postsurgical adjuvant therapy with autologous DNP-modified vaccine appears to produce survival rates that are markedly higher than have been reported with surgery alone. Moreover, this approach has some intriguing immunobiologic features that might provide insights into the human tumor-host relationship.

Adult↗
PubMed1997

Time to systemic metastases in patients with posterior uveal melanoma.

A total of 116 patients, all of whom had systemic metastases from posterior uveal melanoma, were evaluated to identify potential indicators for time to systemic metastasis. In the multivariate Cox proportional hazards model with clinically available variables, the age at initial treatment for uveal melanoma, gender and diameter of the primary tumor were revealed to be independent predictive factors for time to systemic metastasis. Age older than 60 years, male gender, and diameter of the primary uveal melanoma more than 10 mm were proved to be independent unfavorable factors. The estimated median time to systemic metastasis for the most unfavorable group (age > 60, male, diameter > 10 mm) was 20.2 months in contrast with 76.1 months for the most favorable group (age < or = 60, female, diameter < or = 10 mm). Although the results of this study cannot be applied to all patients with posterior uveal melanoma, predictive factors for time to systemic metastasis in those patients who have recurred supplement the information obtained from prognostic factors for the likelihood of metastasis or survival. They contribute not only to our understanding of the biology of metastasizing posterior uveal melanoma, but also in developing appropriate strategies for follow-up and treatment.

Analysis of Variance↗
PubMed1997

BOLD+interferon in the treatment of metastatic uveal melanoma: first report of active systemic therapy.

We conducted a phase II trial of bleomycin+vincristine+lomustine+dacarbazine (BOLD) with intercycle alpha interferon-2b in previously untreated patients with metastatic uveal melanoma. Objective tumor response and toxicity were assessed. Twenty-three patients with histologically verified metastatic uveal melanoma were enrolled into this study between November 1992 and August 1995. Chemotherapy was administered in the following fashion: dacarbazine (DTIC), 200 mg/m2 intravenously on days 1-5; vincristine, 1 mg/m2 (not to exceed 2 mg) intravenously on days 1 and 4; bleomycin, 15 mg intravenously on days 2 and 5; lomustine (CCNU), 80 mg orally on day 1; and alpha interferon-2b, 3 x 10(6) IU subcutaneously on days 8, 10, 12, 15, 17, 19. A cycle was 28 days, and patients were reevaluated after every 2 cycles. Among twenty evaluable patients, four objective responses were observed (RR = 20%). Hematologic toxicity was modest by comparison to some other combination chemotherapy regimens in common use. Neurotoxicity was frequently observed, but it was seldom severe. An unexpected and unpredictable severe pulmonary toxicity was observed in 3 patients, the etiology of which remains unclear. The regimen of BOLD+interferon is active in the treatment of metastatic uveal melanoma. The precise role of the regimen has to be defined in light of its toxicity, particularly the unpredictable pulmonary toxicity. The pattern of occurrence of these pulmonary events is most consistent with either an acquired hypersensitivity reaction or a cumulative toxic effect of 2 or more of the agents. Patients considered for treatment with this regimen must be judiciously selected. Those with no clear contraindications may benefit from a trial of this regimen, but they must be monitored closely.

Adult↗
PubMed1996

Malignant melanoma: impact of superficial US on management.

PURPOSE: To evaluate the impact of superficial ultrasonography (US) on clinical management of melanoma. MATERIALS AND METHODS: Superficial US in areas at high risk for local recurrence or nodal metastases was performed in 33 patients with cutaneous melanoma. Impact categories were assigned to each US study (n = 55): category 3, US added information that altered clinical management; category 2, US added information that did not change management; category 1, no added information and management unchanged; category 0, not helpful or was misleading. RESULTS: Twenty-two US studies (40%) were category 3: detection of nonpalpable metastases altered surgical therapy (n = 2), demonstration of pharmacodynamic response to chemotherapy (n = 5), and determination of benignancy or malignancy (n = 15). Nine (16%) were category 2: identification of nonpalpable metastases did not alter management. Twenty-two (40%) were category 1: supported clinical impression of no metastases (n = 18) or helped confirm cutaneous, subcutaneous, or nodal metastases (n = 4). Two (4%) were category 0: missed proved metastases. CONCLUSION: Superficial US affected management of melanoma by allowing detection and characterization of masses, guidance of biopsy, and assessment of pharmacodynamic response.

Female↗
PubMed1996

Gene therapy for human cancer: an essay for clinicians.

In the last decade our understanding of the processes that govern growth and differentiation has become quite sophisticated. A variety of tumor suppressor genes and more than 100 oncogenes have been identified. The roles of developmental genes in shaping the expression of neoplasia and of defective housekeeping genes in allowing mutations to persist and be transcribed have been appreciated. These advances have revolutionized our ability to diagnose and to formulate prognoses for patients with cancer. However, successful gene therapy for cancer has been elusive. This review highlights the current approaches to gene therapy for cancer and their scientific bases. The requirement that the therapy repair or destroy every cancer cell seems an insurmountable hurdle. Environmental manipulation through systemic administration of exogenous antisense may circumvent this problem in cases where it is appropriate. The more practical application of the technology of genetic engineering to facilitate cancer chemotherapy and immunotherapy is also reviewed. Particularly encouraging are the preclinical and clinical results of in vivo, in situ gene transfer. It remains to be determined if this local approach impacts favorably on survival.

Gene Transfer Techniques↗
PubMed1996

In situ cytokine gene transfection using vaccinia virus vectors.

Studies by a number of investigators have focused on inducing tumor-specific immunity as a therapeutic approach to cancer. Successful immunotherapeutic strategies have involved localized treatment with immune-active adjuvants, systemic administration using cytokines such as interleukin-2, and the use of whole tumor cells or tumor cell fragments as vaccines. With an increasing understanding of the requirements for the development of an immune response, immunotherapeutic strategies have focused on providing mechanistic requirements, such as tumor or accessory antigen expression and cytokine-based "immune help." Recent preclinical studies have shown that ex vivo cytokine gene transfection of tumor cells and their use as vaccines result in the enhanced development of antitumor immunity and in some cases can be used to successfully treat pre-existing tumors. Studies from our laboratory have explored the use of vaccinia virus recombinants to directly transfect tumor cells in situ with cytokine genes as a strategy for enhancing the development of antitumor immunity. We have demonstrated that vaccinia virus recombinants are highly efficient in transfecting a wide range of murine and human tumors in vitro and can be used with similar effects in in vivo murine models. In addition, we have found that vaccinia virus productively infects human melanoma cells following intratumoral injection in patients with accessible lesions. In situ transfection is highly efficient, and therapy with increasing doses of virus is safe with only minor side effects. The results of our studies support the use of cytokine-encoding recombinant vaccinia virus vectors for in situ transfection in patients with cancer.

Animals↗
PubMed1996

Active specific immunization in the treatment of patients with melanoma.

The bonafide albeit infrequent examples of tumor regression observed with whole tumor cell vaccines give evidence for the hypothesis that active specific immunization can induce a therapeutically effective immune response in melanoma patients. A dinitrophenyl-conjugated autologous whole tumor cell plus bacille Calmette-Guérin (BCG) vaccine administered in conjunction with low dose cyclophosphamide has produced clinically significant prolongation of disease free survival when used as a postsurgical adjuvant in patients with stage III melanoma. However, tumor cell-based vaccines are cumbersome and consequently of limited applicability. Improvements in our understanding of the antimelanoma immune response and technological advances have allowed investigators to explore better defined immunogens and antigenic targets; these include anti-idiotypic antibodies, gangliosides, and tumor associated/specific proteins and derived peptides. The rationale for, promise of, and progress to date with these materials are reviewed.

Adjuvants, Immunologic↗
PubMed1996

Interleukin 10 production by human melanoma.

Interleukin 10 (IL-10) has the physiological role of down-regulating cell-mediated immunity. We have recently reported that mRNA for IL-10 was present in most metastatic melanoma tissues. The purpose of this investigation was to determine whether melanoma metastases produce IL-10 protein. Single-cell suspensions were prepared by enzymatic dissociation of 28 lymph node metastases and 7 s.c. metastases and cryopreserved. Of these 35 samples, 30 produced IL-10 after a 24-h incubation (median, 125.1 pg/ml). IL-10 production was slightly diminished after 25 Gy irradiation but almost completely abrogated after modification with the hapten dinitrophenyl. After 7 or 14 days in tissue culture, melanoma cells continued to produce IL-10 but only at about 10% of the levels of freshly dissociated tissues. Moreover, of eight melanoma cell lines established from these cultures, only one produced IL-10 protein. To determine whether IL-10 was produced by melanoma cells or tumor-associated leukocytes, single-cell suspensions were fractionated with anti-CD45 antibody-conjugated magnetic beads. In four of five samples, IL-10 production was increased by depletion of leukocytes, suggesting that the primary source was the melanoma cells themselves. This was confirmed by immunohistochemical staining of cytospin preparations and frozen tissue sections. Finally, 10 of 55 patients with clinically evident metastases showed elevations of circulating IL-10; three patients who had been melanoma-free developed high serum IL-10 levels, concurrent with the appearance of distant metastases. These data indicate that production of IL-10 is characteristic of metastatic melanomas and raise the possibility that this cytokine allows tumors to avoid or to modulate immunological attack.

Cryopreservation↗
PubMed1995

Human immune response to DNP-modified autologous cells after treatment with a DNP-conjugated melanoma vaccine.

Immunizing patients with metastatic melanoma by injection of autologous tumor cells modified by DNP induces inflammatory responses in metastatic masses, which is sometimes associated with tumor regression. To elucidate this phenomenon, we studied the immune response to DNP-modified cells in these patients. All developed DTH to DNP-modified autologous lymphocytes (mean +/- SE: 13.3 +/- 1.3 mm), but not to TNP-modified lymphocytes. Larger responses (21.9 +/- 3.6 mm) were elicited by DNP-modified autologous melanoma cells. In 8/11 patients tested, PBL proliferated in vitro when stimulated by autologous DNP-modified lymphocytes, and in 5 patients the stimulation resulted in production of interferon-gamma. DNP-modified autologous melanoma cells elicited lymphocyte responses as well. PBL from 1 patient were expanded by culture in IL2 and repeated restimulation with DNP-modified B lymphoblastoid cells. This T cell line proliferated and produced interferon-gamma but not IL4, when stimulated by autologous DNP-modified lymphocytes or melanoma cells. Both CD4+ and CD8+ subpopulations responded as determined by panning experiments and by testing of phenotypically homogeneous cultures obtained by limiting dilution. Studies of a stable CD8+ subline of the expanded T cells indicated that the response to DNP-modified cells was MHC-restricted, since it was blocked by antibody to class I determinants. Moreover, these T cells were able to respond to allogeneic DNP-modified stimulators that were matched at one or both HLA-A loci, but not to stimulators that were HLA-A mismatched. Finally, the CD8+ subline killed DNP-modified autologous melanoma cells, but not an HLA-A mismatched allogeneic melanoma, in a 6-hr 51Cr-release assay. These results may have significant implications for understanding the pathogenesis of drug-induced autoimmunity and for the development of new approaches to cancer immunotherapy.

Antibody Formation↗