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Biomedical subjects

Michael J Mastrangelo

Publications and source records attributed to Michael J Mastrangelo.

18 recordsLinked to original sources
PubMed2005

Chemoembolization of the hepatic artery with BCNU for metastatic uveal melanoma: results of a phase II study.

Uveal melanoma is the most common primary intraocular malignancy in adults and the liver is the most common site for systemic metastases. We conducted a phase II clinical trial for patients with hepatic metastases from uveal melanoma using chemoembolization of the hepatic artery with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) dissolved in ethiodized oil. Gelatin sponge particles were used as a transiently occlusive agent. The responses in hepatic metastases, overall survival, time to progression and side-effects related to chemoembolization were evaluated. Thirty patients were enrolled. Twenty-four patients completed at least one treatment to all targeted liver metastases and were evaluable for hepatic response. Eighteen of these 24 patients experienced regression or stabilization of hepatic metastases for at least 6 weeks (one complete response in hepatic metastases; four partial responses; 13 stable disease). One of the 13 patients with stable disease was rendered free of disease by surgical removal of metastases after chemoembolization (surgical complete response). The overall response rates (complete and partial responses) for intention-to-treat patients and for patients who were evaluable for response were 16.7 and 20.4%, respectively. The median overall survival of the entire intention-to-treat group of patients was 5.2 months (range, 0.1-27.6 months), for patients with complete or partial response in hepatic metastases 21.9 months (range, 7.4-27.6 months), for patients with stable disease 8.7 months (range, 2.9-14.4 months) and for patients with progressive disease 3.3 months (range, 1.6-5.6 months). Importantly, 13 of the 18 patients who achieved complete response, partial response or stable disease subsequently developed progression of extrahepatic metastases with control of hepatic metastases. Chemoembolization with BCNU is a useful palliative treatment for the control of hepatic metastases in uveal melanoma patients. However, progression in extrahepatic sites after stabilization of hepatic metastases requires further improvement in the therapeutic approach to this disease.

Adult↗
PubMed2003

Immunopharmacologic analysis of an autologous, hapten-modified human melanoma vaccine.

PURPOSE: We have previously reported a clinical trial of a human cancer vaccine consisting of autologous tumor cells modified with the hapten, dinitrophenyl (DNP), in patients with clinical stage III melanoma. Here we present a follow-up report expanded to 214 patients with 5-year follow-up. PATIENTS AND METHODS: Two hundred fourteen patients with clinical stage III melanoma (117 patients with stage IIIC and 97 patients with stage IIIB) who were melanoma-free after standard lymphadenectomy were treated with multiple intradermal injections of autologous, DNP-modified vaccine mixed with bacille Calmette-Guérin. Four vaccine dosage schedules were tested sequentially, all of which included low-dose cyclophosphamide. Patients were tested for delayed-type hypersensitivity (DTH) to autologous melanoma cells, both DNP-modified and unmodified, and to control materials. RESULTS: The 5-year overall survival (OS) rate of the 214 patients was 44%. DTH responses to unmodified autologous melanoma were induced in 47% of patients. The OS of this DTH-positive group was double that of DTH-negative patients (59.3% v 29.3%; P <.001). In contrast, positive DTH responses to DNP-modified autologous melanoma cells and to purified protein derivative developed in almost all patients but did not affect OS. Surprisingly, the OS after relapse was also significantly longer in patients who developed positive DTH to unmodified tumor cells (25.2% v 12.3%; P <.001). Finally, the development of DTH was dependent on the schedule of administration of the vaccine, specifically, the timing of an induction dose administered at the beginning of the treatment program. CONCLUSION: This study underscores the importance of the immunopharmacology of the autologous, DNP-modified vaccine and may be relevant to other cancer vaccine technologies.

Adjuvants, Immunologic↗
PubMed2003

Combination of monocyte-derived dendritic cells and activated T cells which express CD40 ligand: a new approach to cancer immunotherapy.

Interactions between dendritic cells (DCs) and activated T cells are critically important for the establishment of an effective immune response. To develop the basis for a new DC-based cancer vaccine, we investigated cell-to-cell interactions between human monocyte-derived DCs and autologous T cells that are activated to express the CD40 ligand (CD40L). Peripheral blood monocytes were cultured in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) to induce differentiation of DCs. Activated T cells (ATs) consisted of autologous peripheral blood lymphocytes that had been activated with phytohemagglutinin (PHA) and then stimulated with calcium ionophore to up-regulate expression of CD40L. Coculture of these DCs and ATs induced significant production of interleukin 12 (IL-12) and also enhanced the production of interferon gamma (IFN-gamma). The production of IL-12 was blocked by an anti-CD40L antibody or by separation of the DC and AT fractions by a permeable membrane. Furthermore, coculture of DCs and ATs induced DCs to upregulate CD83 expression and stimulated migration of DCs toward the macrophage inflammatory protein 3-beta (MIP-3beta). ATs also migrated toward the MIP-3beta. These results suggest a combination of DCs and ATs as a potentially effective therapeutic strategy.

Angiogenesis Inhibitors↗
PubMed2003

A valid method of laparoscopic simulation training and competence assessment.

BACKGROUND: The purpose of our study was to evaluate the construct validity of laparoscopic technical performance measures and the face validity of three laparoscopic simulations. MATERIALS AND METHODS: Subjects (N = 27) of varying levels of surgical experience performed three laparoscopic simulations, representing appendectomy (LA), cholecystectomy (LC), and inguinal hemiorrhaphy (LH). Five laparoscopic surgeons, blinded to the identity of the subjects, rated the subjects on procedural competence on a binary scale and in four skills categories on a 5-point scale: clinical judgment, dexterity, serial/simultaneous complexity, and spatial orientation. Using a task-specific checklist, non-clinical staff assessed the technical errors. The level of surgical experience was correlated with the ratings, the technical errors, and the time for each procedure. Subject responses to a survey regarding the utility of the inanimate models were evaluated. RESULTS: Years of experience directly correlated with the skills ratings (all P < 0.001) and with the competence ratings across the three procedures (P < 0.01). Experience inversely correlated with the time for each procedure (P < 0.01) and the technical error total across the three models (P < 0.05). Nearly all subjects agreed that the corresponding procedures were well represented by the simulations (LA 96%, LC 96%, LH 100%). CONCLUSION: The laparoscopic simulations demonstrated both face and construct validity. Regardless of the level of surgical experience, the subjects found the models to be suitable representations of actual laparoscopic procedures. Task speed improved with surgical experience. More importantly, the quality of performance increased with experience, as shown by the improvement in the skills assessments by expert laparoscopic surgeons.

Appendectomy↗
PubMed2003

Inclusion of 3-D computed tomography rendering and immersive VR in a third year medical student surgery curriculum.

Computed tomography (CT) scans are frequently used for preoperative evaluation of patients undergoing complex surgery and are therefore commonly encountered by medical students on their surgical rotations. Interpretation of these CT scan images is therefore an integral component of all medical students' surgical rotations. Additionally, advanced rendering available from modem scanners and registration of multimodal or serial scans require the student to understand how volumetric anatomy relates to cross-sectional anatomy. The utility of three-dimensional (3-D) models for conveying surgical anatomy has been demonstrated. Immersive 3-D VR overcomes many of the conceptual limitations encountered when conveying or teaching 3-D relationships via 2-D images traditionally produced by these scans. We are currently using augmented reality as a teaching tool and have incorporated 3-D immersive environments in the third year medical student Surgery rotation. Initial results suggest that this is an effective tool for teaching third year medical students. 3-D CT rendering and immersive VR provide an effective process for utilizing CT datasets to teach surgical anatomy to medical students.

Computer Simulation↗
PubMed2002

TCR rearrangement in lymphocytes infiltrating melanoma metastases after administration of autologous dinitrophenyl-modified vaccine.

Administration of a vaccine consisting of autologous melanoma cells modified with a hapten, dinitrophenyl (DNP), induces T cell infiltration of metastatic sites. We have reported an analysis of these infiltrating T cells, indicating that certain TCR-Vbeta gene segments are greatly overexpressed. In this study, we investigate the rearrangement of the TCR-Vbeta as well as the junctional diversity in T cells infiltrating melanoma metastases following treatment with DNP vaccine. In 19 of 26 control specimens, V-D-J length analysis showed the expected polyclonal patterns. In contrast, postvaccine tumors from 9 of 10 patients showed dominant peaks of V-D-J junction size in one or more Vbeta families. Dominant peaks were seen most frequently in six Vbeta families (Vbeta7, 12, 13, 14, 16, and 23) and were never seen in seven others. Further analysis of the oligoclonal Vbeta products showed dominant peaks in the J region as well. Of particular interest was the finding that Vbeta and Jbeta peaks were similar in inflamed metastases obtained at different times or from different sites from the same patient. Although 6 of 10 patients expressed HLA-A1, there was no common pattern of TCR rearrangements among them. Finally, the amplified PCR products from seven of these specimens were cloned and sequenced and the amino acid sequence of the complementarity-determining region 3 was deduced. In six of seven specimens, the same complementarity-determining region 3 sequence was repeated in at least two clones and in five of seven in at least three clones. Our study indicates that DNP vaccine induces the expansion of particular T cell clones that may be agents of its antitumor effects.

Cancer Vaccines↗
PubMed2002

Effect of the dose and composition of an autologous hapten-modified melanoma vaccine on the development of delayed-type hypersensitivity responses.

We have reported that treatment of melanoma patients with a vaccine consisting of autologous tumor cells modified with the hapten, dinitrophenyl (DNP) and preceded by low-dose cyclophosphamide induces delayed-type hypersensitivity (DTH) to autologous, unmodified tumor cells and that this response is a significant predictor of survival. We analyzed the vaccines prepared for 284 patients who were treated following resection of regional or distant metastases to find out whether the dose and composition determined the immunological response. A positive DTH response (> or =5 mm induration) to unmodified autologous tumor cells was induced in 57% of the patients (median: 5 mm; range: 0-22 mm). Regression analysis showed no significant association between the magnitude of DTH and the number of live (trypan blue exclusion) melanoma cells per dose over a dosage range of 0.5-25.0 x 10(6). Surprisingly, there was a small but significant positive relationship between the mean number of dead cells in the vaccines of a given patient and that patient's maximum DTH to unmodified melanoma cells. Only 37% of patients whose vaccines contained >50% live cells developed DTH, as compared with 69% and 65% of patients whose vaccines contained 26% to 50% or < or =25% live cells, respectively. Thus, it appears that dead tumor cells contribute to the immunogenicity of the DNP vaccine, but other factors such as the administration schedule may be more important determinants of immunological and clinical outcome.

Adjuvants, Immunologic↗
PubMed2002

Virotherapy clinical trials for regional disease: in situ immune modulation using recombinant poxvirus vectors.

The ability of viruses to readily infect tumor cells both in vitro and in vivo has resulted in their study as antitumor agents through a variety of strategies. Replicating and conditionally replicating viruses and recombinant viruses encoding genes for toxins and/or prodrugs have been studied for their direct antitumor activity with promising results. However, to date, the lack of a targettable construct able to localize to all tumors following systemic administration has proven to be a major limitation in their use for metastatic disease. The ability of a variety of well-characterized viruses to serve as vectors for expression of tumor antigens and/or cytokines has also resulted in their study as immunotherapeutic agents. In this review, we discuss preclinical and clinical data that support the use of recombinant poxviruses as vectors for in situ tumor transfection with immune-enhancing cytokines and immune costimulatory antigens. We hypothesize that such an approach will ultimately lead to enhanced immune recognition of tumor and the development of an effective systemic antitumor immune response capable of eradicating primary and metastatic tumor foci.

Clinical Trials as Topic↗
PubMed2002

Advancements in immersive VR as a tool for preoperative planning for laparoscopic surgery.

The utility of three-dimensional (3D) models for planning laparoscopic surgery and surgical training has been demonstrated. (1) Computed tomography (CT) scans with oral and intravenous contrast medium are frequently used for preoperative evaluation of patients undergoing complex laparoscopic surgery. Immersive 3D VR overcomes many of the conceptual limitations encountered when conveying or teaching 3D relationships via 2D images traditionally produced by these scans. Over the past year we have made advancements in several areas. First, we have improved the quality of our datasets by utilizing higher resolution multi-detector scans and altering the protocols used. Second, we now register multiple isosurface views with standard axial views and volume textured views to provide additional information and perspective. Third, we now routinely use auto-segmentation techniques to visualize individual structures.

Computer Simulation↗