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Biomedical subjects

A E Chang

Publications and source records attributed to A E Chang.

At least 73 records · Page 4Linked to original sources
PubMed1995

Immediate transverse rectus abdominis musculocutaneous flap reconstruction after mastectomy.

BACKGROUND: This study examines the early and long-term outcomes of immediate transverse rectus abdominis musculocutaneous (TRAM) reconstruction of the breast after mastectomy. STUDY DESIGN: The records of all patients undergoing mastectomy and immediate TRAM breast reconstruction between December 1989 and October 1993 were reviewed retrospectively using hospital and breast care center databases. RESULTS: Fifty-three patients underwent a total of 73 immediate TRAM breast reconstructions. Reconstruction was successfully completed in all patients, using 46 pedicle flaps and 27 free tissue transfers. There were no flap losses or cardiopulmonary complications. Overall, the complication rate was 26 percent (29 percent for pedicle TRAM and 22 percent for free TRAM flaps). The median follow-up period among the 53 patients was 22.6 months (range of three to 48 months). All patients employed preoperatively resumed their occupations postoperatively. CONCLUSIONS: Our experience indicates that immediate TRAM breast reconstruction is a safe and viable option for patients seeking reconstruction at the time of mastectomy.

Adult↗
PubMed1994

Characteristics and in vivo homing of long-term T-cell lines and clones derived from tumor-draining lymph nodes.

Lymph nodes draining a progressively growing tumor contain T-cells which can be activated sequentially by anti-CD3 and IL-2 to differentiate into tumor-specific effector cells. In this study, long-term cultured T-cell lines were established from activated MCA 106 tumor-draining lymph node cells by periodic stimulation with irradiated tumor cells in the presence of low concentrations of IL-2 (< or = 60 International units/ml). Such long-term cultured cell lines maintained therapeutic effects when transferred to tumor-bearing mice. Although the initial anti-CD3/IL-2-activated T-cells displayed a broad distribution of T-cell antigen receptor beta chain variable region (V beta) usages, long-term cultured cells were dominated by T-cells expressing a few V beta elements. Of six cell lines, only three V beta phenotypes (V beta 5, 11, 13) were identified, and individual cell lines frequently expressed a single V beta gene product. Despite restricted V beta expression, each cell line mediated tumor-specific reactivity in adoptive immunotherapy. Many T-cell clones were isolated from long-term cell lines. Three V beta 13 T-cell clones demonstrated specific in vivo antitumor effects, whereas two V beta 11 and two V beta 5 clones revealed a significant degree of cross-reactivity against the antigenically distinct MCA 205 tumor. Although the initial anti-CD3/IL-2-activated cells lacked demonstrable cytotoxic reactivity, T-cell clones derived from them exhibited cytotoxic effects to the MCA 106 tumor cells. The specificity of the cytotoxicity mediated by each clone reflected its in vivo antitumor effects. Furthermore, studies of in vivo localization of cloned T-cells demonstrated tumor-specific infiltration of the 5A2 (V beta 13) clone to the MCA 106 tumor metastases, whereas clone 9H6 (V beta 5) revealed some accumulation in the MCA 205 tumor. Again, the in vivo antitumor effects of the 9H6 clone correlated with its in vivo infiltration into the specific MCA 106 and the nonspecific MCA 205 metastases. Taken together, the long-term culture of anti-CD3/IL-2-activated tumor-draining lymph node cells resulted in selective expansion of a few T-cells as evidenced by the limited T-cell receptor V beta expression. Our results also demonstrated that systemically administered antitumor T-cell clones gained access and accumulated at metastatic tumor sites, and the degree of infiltration correlated with the specificity of the in vivo antitumor effect as well as the in vitro cytotoxic activity.

Animals↗
PubMed1994

Stimulation of tumor-draining lymph node cells with superantigenic staphylococcal toxins leads to the generation of tumor-specific effector T cells.

In animal studies, lymph nodes (LN) draining progressive tumors contain immunologically sensitized but functionally deficient T cells. These preeffector cells can differentiate into mature effector cells on stimulation in vitro with anti-CD3 and IL-2. However, anti-CD3 react with all T cells and the activated cell population expressed a broad but normal distribution of V beta phenotypes. In this study, we examined the feasibility of using bacterial superantigens to stimulate tumor-draining LN cells. Because of their TCR V beta restriction, superantigen activation may afford a means to identify T cell subsets that are important in the antitumor immune response. Stimulation of draining LN cells with staphylococcal enterotoxins A (SEA) or B (SEB) followed by culture in IL-2 resulted in selective activation and expansion of V beta 3 and V beta 11 or V beta 3 and V beta 8 T cells, respectively. However, in adoptive immunotherapy, SEB- but not SEA-activated cells mediated the regression of established pulmonary metastases. To define the relative antitumor effects of V beta 3 and V beta 8 T cells, SEB-activated cells were depleted of either V beta 3 or V beta 8 T cells with mAb and magnetic beads. The antitumor effects were demonstratably diminished after V beta 8 cell depletion but enhanced after V beta 3 cell depletion. Using antigenically distinct MCA 205 and 207 sarcomas, tumor regression mediated by the activated cells was found to be immunologically specific for the tumor that stimulated the draining LN. Furthermore, the SEB-activated cells were virtually all T cells consisting of approximately equal proportions of CD4+ and CD8+ cells and the collaboration of the two T cell subsets was required for in vivo antitumor effects. However, the helper function of CD4+ cells could be facilitated by the administration of exogenous IL-2. Despite their in vivo antitumor reactivity, SEB-activated cells did not exhibit tumor cytotoxicity in the 4-h 51Cr release assay. However, they secreted IFN-gamma on specific stimulation with tumor cells. Taken together, these results provide for the first time clear evidence of the functional significance of superantigen interactions with immunologically committed T cells and suggest a preferential V beta use that might be associated with the T cell immune response to progressively growing tumors.

Animals↗
PubMed1994

Hepatoma registry of the Western world. Repeat Hepatic Resection Registry.

The western HCC registry comprised data from 322 patients who underwent hepatic resection for HCC over a 50-year period. The majority of patients had lesions > 4 cm and were symptomatic at presentation. Lesions were mostly unicentric. Cirrhosis was not a prevalent problem, unlike the East. In the most recent decade, 1980-1989, we noted a significant decrease in operative mortality from 19% to 10% overall, and 15% to 4% in the noncirrhotic group. We identified four variables that resulted in poorer postresectional outcome: cirrhosis, regional nodal disease, multicentric disease, and tumor-free resectional margin < 1 cm. Although these factors are associated with a poorer outcome after resection, whether they should serve as contraindications to surgery should be determined by individual surgeons, taking into account the patient's overall status, concomitant risk factors, and treatment objectives.

Adolescent↗
PubMed1994

Activation of T lymphocytes for the adoptive immunotherapy of cancer.

BACKGROUND: Adoptive immunotherapy of malignancy involves the passive transfer of antitumor-reactive cells into a host in order to mediate tumor regression. Based on animal models, the transfer of immune lymphoid cells can eradicate widely disseminated tumors and establish long-term systemic immunity. Critical for successful adoptive immunotherapy is the ability to isolate large numbers of immune cells. For clinical therapy, it will require the development on in vitro methods to promote the sensitization and propagation of tumor-reactive cells. However, this is a formidable task since human cancers are postulated to be poorly immunogenic because of their spontaneous origins. RESULTS: Human lymphoid cells for ex vivo activation and subsequent adoptive transfer have been derived from different sources, including peripheral blood, tumor, and lymph nodes. Peripheral blood lymphocytes can be incubated with interleukin 2 to generate lymphokine-activated killer (LAK) cells, which nonspecifically lyse autologous and allogeneic tumor cells in vitro. LAK cell therapy represented the earliest attempt to treat advanced human cancers, with encouraging results documented in patients with renal cell cancer and melanoma. From that experience, the use of more immunologically specific cellular agents with potentially greater therapeutic efficacy has been investigated. One approach uses tumor-infiltrating lymphocytes, which have been characterized experimentally to be more specific in tumor reactivity compared with LAK cells. Other techniques have involved the use of lymphoid cells derived from lymph nodes draining tumors or primed by tumor vaccines. In vitro activation of these cells with tumor antigen or anti-CD3 monoclonal antibody results in the generation of T cells that mediate the rejection of poorly immunogenic tumors in animal studies. These alternate methods are currently being evaluated in clinical studies. CONCLUSIONS: Experimentally, cellular therapy is a potent method to eradicate progressive tumors. Initial clinical studies have demonstrated that this form of therapy is technically feasible and can result in meaningful antitumor responses. Advances in this area will require improved methods to sensitize, isolate, and expand tumor-reactive T cells for adoptive transfer.

Animals↗
PubMed1994

Safety and toxicity of catheter gene delivery to the pulmonary vasculature in a patient with metastatic melanoma.

One approach to gene therapy for human cancer is transcatheter injection of DNA liposomes into tumor masses. To determine the feasibility of selective delivery of recombinant genes by a catheter to the pulmonary vasculature in humans, a patient with melanoma received two treatments of HLA-B7 plasmid DNA complexed to cationic liposomes into a right posterior basal pulmonary artery associated with a mass lesion. The treatments were well tolerated. No adverse respiratory, cardiac, immunologic, or other organ toxicities were detected. The delivery of recombinant genes by catheter may be a useful modality to treat human malignancy and other diseases.

Adenocarcinoma↗
PubMed1994

Adoptive immunotherapy of murine intracerebral tumors with anti-CD3/interleukin-2-activated tumor-draining lymph node cells.

We have recently identified a source of potent antitumor effector cells that can be generated by the sequential culture of tumor-draining lymph node (TDLN) cells with anti-CD3 monoclonal antibody (anti-CD3) and interleukin-2 (IL-2). In this study the therapeutic efficacy of these immune effector cells in the treatment of experimentally induced brain metastases was evaluated. With use of the MCA 205 sarcoma, TDLN cells were harvested from syngeneic B6 mice 9-10 days after subcutaneous inoculation with 10(6) tumor cells. These TDLN cells were activated in vitro by exposure to anti-CD3 for 2 days followed by expansion with IL-2 (10 U/ml) for 3 days. In a neutralization assay, anti-CD3/IL-2-activated cells admixed with MCA 205 tumor cells at an effector/tumor cell ratio of 10 effectively suppressed the growth of tumor cells after intracranial inoculation. In mice with 3-day established brain tumors, multiple intracranial administrations of activated TDLN cells resulted in prolonging survival for which a 50-fold increase in number of cells given intravenously did not. However, the therapeutic effectiveness of systemically (intravenously) administered activated TDLN cells in the treatment of 3-day brain tumors was achieved if tumor-bearing mice were sublethally whole-body irradiated (500 cGy). In two experiments irradiated animals that were not treated or received therapy with IL-2 alone had median survival times (MSTs) of 16 and 17 days, respectively. By contrast, in irradiated animals that received TDLN cells plus IL-2, MST was not reached beyond the observation period of 90 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of interleukin-1 alpha on the in vitro activation of tumor-draining lymph node cells for adoptive immunotherapy.

Adoptive immunotherapy using in vitro activated T-cells can mediate the destruction of metastatic tumor deposits in animal models. These antitumor effector cells can be generated from mice with subcutaneous tumor by the sequential in vitro activation of tumor-draining lymph node (TDLN) cells with monoclonal antibody to the T-cell receptor complex (anti-CD3) and expansion in low concentrations of interleukin-2 (IL-2). In this animal model, the concomitant presence of visceral tumor can suppress the sensitization of tumor-reactive TDLN cells. We investigated whether IL-1 alpha added during in vitro activation and/or expansion of TDLNs could augment their antitumor activity in adoptive therapy. Mice were inoculated subcutaneously with MCA 205 tumor. TDLN cells were harvested and activated in vitro with 1 microgram/ml anti-CD3 for 2 days (anti-CD3 phase), followed by expansion in 10 U/ml IL-2 for 3 days (IL-2 phase). Experimental cultures had IL-1 (10-10,000 U/ml) added in either or both phases. After the 5-day culture period, cells were counted to determine in vitro cellular proliferation and then adoptively transferred to mice bearing 3-day established lung metastases to assess in vivo antitumor efficacy. IL-1 added during the anti-CD3 or IL-2 phase did not alter in vitro cellular proliferation. The presence of IL-1 during the anti-CD3 phase led to the generation of cells that were significantly more therapeutically efficacious than cells generated in the absence of IL-1. The effect of IL-1 during anti-CD3 activation appeared to be dose dependent in the concentration range 10-1,000 U/ml. The addition of IL-1 during the IL-2 phase only did not enhance the antitumor reactivity of the activated cells. The beneficial effect of IL-1 during the anti-CD3 activation phase was specific for the tumor against which the TDLN had been initially sensitized; also, there was no evidence that non-tumor bearer lymphocytes developed significant antitumor reactivity when "activated" with IL-1 and anti-CD3. Furthermore, addition of IL-1 during the anti-CD3 activation phase abrogated suppression induced by the concomitant presence of lung metastases during subcutaneous tumor growth. IL-1 appears to up-regulate the in vitro activation of tumor-reactive lymphocytes derived from TDLN, in both the presence and the absence of visceral metastases.

Animals↗
PubMed1994

Enhancement of immune reactivity in the lymph nodes draining a murine melanoma engineered to elaborate interleukin-4.

The adoptive transfer of immune T cells has been demonstrated to mediate regression of established tumors in animals, with encouraging results in human clinical trials. In animal studies, lymph nodes (LN) draining a progressively growing immunogenic tumor contain tumor-sensitized but functionally deficient T cells. These "preeffector" cells can be activated in vitro by sequential stimulation with anti-CD3 and interleukin (IL)-2 to differentiate into mature effector cells capable of mediating the regression of disseminated tumor. However, the preeffector cell response is weak during the growth of poorly immunogenic tumors such as the B16-BL6 melanoma. In this study, a clone of B16-BL6, A9, was transfected with the cDNA encoding for murine IL-4, in an attempt to enhance tumor immunogenicity. IL-4 secreting clones grew significantly slower than controls after intradermal (i.d.) inoculation, but all animals eventually succumbed to the progressive tumor. The ability of IL-4-secreting tumor cells to stimulate a preeffector cell response was then investigated. LN draining the IL-4-secreting tumors for 10 days were activated by the anti-CD3/IL-2 method. The resulting lymphocytes were adoptively transferred into animals bearing 3-day established parental pulmonary metastases. The transfer of cells derived from sensitization with the IL-4-secreting tumors was capable of significantly reducing the numbers of pulmonary metastases more effectively than cells sensitized to the parental tumor. Thus, genetic modification of tumor cells to secrete IL-4 can stimulate an increase in the preeffector cell response in the tumor-draining LN, suggesting an enhancement in T-cell-mediated immune function against the parental tumor.

Animals↗
PubMed1994

Detection of breast cancer in women after augmentation mammoplasty using fluorine-18-fluorodeoxyglucose-PET.

UNLABELLED: The purpose of this study was to determine the feasibility of FDG-PET imaging in women with silicone implant augmentation mammoplasties where mammographic detection of breast cancers is challenging due to the implants' radiodensity, which can obscure tumor visualization. METHODS: FDG-PET imaging was performed in two women with augmentation mammoplasties and small palpable breast abnormalities. Mammograms with and without breast displacement were also performed. RESULTS: PET clearly demonstrated focal FDG accumulation in the suspicious breasts, corresponding to tumors of less than 1.5 cm in diameter. There was no degradation of image quality by the implants and no need for breast displacement views. By contrast, implant displacement mammograms were necessary to fully delineate the tumors. CONCLUSION: While mammograms with displacement views represent the initial choice for imaging the augmented breast, FDG-PET can image tumors in the augmented breast without implant displacement and without obvious degradation of image quality by the implant. FDG-PET warrants additional evaluation as an adjunctive study in the augmented breast, particularly when displacement mammographic views are not adequate or are impossible to perform due to peri-implant capsule formation.

Adult↗
PubMed1993

Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans.

Direct gene transfer offers the potential to introduce DNA encoding therapeutic proteins to treat human disease. Previously, gene transfer in humans has been achieved by a cell-mediated ex vivo approach in which cells from the blood or tissue of patients are genetically modified in the laboratory and subsequently returned to the patient. To determine the feasibility and safety of directly transferring genes into humans, a clinical study was performed. The gene encoding a foreign major histocompatibility complex protein, HLA-B7, was introduced into HLA-B7-negative patients with advanced melanoma by injection of DNA-liposome complexes in an effort to demonstrate gene transfer, document recombinant gene expression, and determine the safety and potential toxicity of this therapy. Six courses of treatment were completed without complications in five HLA-B7-negative patients with stage IV melanoma. Plasmid DNA was detected within biopsies of treated tumor nodules 3-7 days after injection but was not found in the serum at any time by using the polymerase chain reaction. Recombinant HLA-B7 protein was demonstrated in tumor biopsy tissue in all five patients by immunochemistry, and immune responses to HLA-B7 and autologous tumors could be detected. No antibodies to DNA were detected in any patient. One patient demonstrated regression of injected nodules on two independent treatments, which was accompanied by regression at distant sites. These studies demonstrate the feasibility, safety, and therapeutic potential of direct gene transfer in humans.

Aged↗
PubMed1993

Cross-reactivity of anti-CD3/IL-2 activated effector cells derived from lymph nodes draining heterologous clones of a murine tumor.

Cells from lymph nodes (LN) draining progressively growing tumors can differentiate into immune effector cells upon in vitro stimulation with anti-CD3 monoclonal antibodies followed by interleukin-2. The adoptive transfer of these activated LN cells to tumor-bearing mice mediates potent tumor-specific therapeutic effects. In this study, we sought to further characterize the antitumor efficacy and specificity mediated by the anti-CD3/IL-2 activated tumor-draining LN cells against heterologous clones derived from the murine MCA 106 sarcoma. Ten clones of divergent characteristics with regard to morphology, in vivo growth rate, ability to establish pulmonary metastases, MHC class I (H-2) antigen expression, susceptibility to lysis by allogeneic cytotoxic T-lymphocytes, as well as sensitivity to doxorubicin were selected and analyzed. In adoptive immunotherapy experiments, pulmonary metastases derived from each clone were found to be sensitive to the therapeutic effects of activated cells derived from LN draining the parental MCA 106 tumor. The antigenic cross-reactivity was evident from the observation that activated cells from LN draining each of the individual tumor clones were capable of mediating the regression of parental tumor metastases. The specificity of the antitumor reactivities mediated by LN cells draining MCA 106 clones was demonstrated by a lack of in vivo efficacy against metastases derived from the antigenically distinct MCA 205 sarcoma. Additionally, selected clones were tested for their ability to stimulate draining LN against other cloned tumors or used as targets for therapy with activated LN cells draining different clones. In all 29 adoptive immunotherapy experiments, there was complete cross-reactivity between different MCA 106 tumor clones. These findings suggest that the MCA 106 tumor-specific antigen(s) that stimulates draining LN in vivo and recognized by the anti-CD3/IL-2 activated cells is present on most if not all tumor cells. However, in the absence of a demonstrably resistant tumor clone, a very highly polymorphic antigen with many cross-reactive, but distinct epitopes might be operative and attributable to these observations.

Animals↗
PubMed1993

Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer.

BACKGROUND: Treatment using interleukin-2 (IL-2) alone or in conjunction with lymphokine-activated killer (LAK) cells has been shown to mediate disease regression in selected patients with advanced cancer. PURPOSE: This prospective randomized trial was designed to determine whether the administration of LAK cells in conjunction with high-dose IL-2 alters response and survival rates, compared with those for IL-2 alone, in patients with advanced cancer. METHODS: The 181 patients who had metastatic cancer that had failed to respond to standard therapy or who had disease for which no effective therapy existed received treatment with high-dose IL-2 alone or with LAK cells plus IL-2. Both treatment groups were to receive the same dose of IL-2 administered according to the same schedule. IL-2 doses were omitted depending on the tolerance of the patient. Of the 181 patients, 97 had renal cell cancer and 54 had melanoma. RESULTS: Median potential follow-up was 63.2 months. There were 10 complete responses among the 85 assessable patients who received IL-2 plus LAK cells, compared with four among the 79 who received IL-2 alone. There were 14 and 12 partial responses, respectively. Complete response continues in seven patients at 50-66 months. The 36-month actuarial survival with IL-2 plus LAK cells was 31%, compared with 17% with IL-2 alone (two-sided P value [P2] = .089). A trend toward improved survival was seen for patients with melanoma who received IL-2 plus LAK cells, compared with those who received IL-2 alone (24-month survival: 32% versus 15%; 48-month survival: 18% versus 4%; P2 = .064 [corrected]). None of 26 patients with melanoma who received IL-2 alone are alive; five of 28 who received IL-2 plus LAK cells are alive, and three continue in complete response. No difference in survival was seen in patients with renal cell cancer in the two treatment groups. There were six treatment-related deaths (3.3%); three were due to myocardial infarction. Other toxic effects resolved by discontinuation of IL-2. Many toxic effects were related to increased vascular permeability induced by IL-2. CONCLUSIONS: Some patients with metastatic cancer have prolonged remission when they are treated with high-dose IL-2 alone or in conjunction with LAK cells. Our results suggest a trend toward increased survival when IL-2 is given with LAK cells in patients with melanoma, but no trend was observed for patients with renal cell cancer. IMPLICATIONS: As these studies continue, efforts are underway to develop improved immunotherapies using tumor-infiltrating lymphocytes (TIL) and gene-modified TIL.

Adolescent↗
PubMed1993

Clinical observations on adoptive immunotherapy with vaccine-primed T-lymphocytes secondarily sensitized to tumor in vitro.

The adoptive immunotherapy of human malignancy requires reliable methods to sensitize and expand patients' T-cells reactive to autologous tumors. In animal studies, we have generated therapeutic effector cells against a poorly immunogenic tumor by a two-step procedure: vaccination of the host followed by the secondary stimulation of vaccine-primed lymph node (LN) cells by in vitro sensitization (IVS) with tumor in the presence of interleukin 2 (IL-2). Based on these observations, we performed a clinical trial in patients with advanced cancer to evaluate the antitumor efficacy of vaccine-primed LN cells which were similarly activated in vitro. Patients were vaccinated with irradiated autologous tumor admixed with Bacillus Calmette-Guérin and had draining LN excised 10 days later for IVS culture. During IVS culture, LN cells expanded up to 14-fold (average of 8.4-fold). A mean of 6.7 x 10(9) cells was infused in ten patients (seven melanoma, three renal cell cancer) along with the concomitant i.v. administration of IL-2 (180,000 IU/kg every 8 h for 5 days). Phenotype analysis of IVS-LN cells revealed 78 +/- 4% CD3+ T-cells which were predominantly CD4+ (67 +/- 5%) with expression of HLA-DR and IL-2 receptor. IVS-LN cells displayed relative specificity of autologous tumor lysis in four of ten cases compared to zero of seven IVS-peripheral blood lymphocytes derived from the same patients as measured by the 51Cr release assay. One mo after therapy, seven of nine patients treated with IVS-LN cells and IL-2 developed delayed-type hypersensitivity reactivity to autologous tumor compared to zero of nine patients treated with tumor vaccination and IL-2 only (P < 0.002). These observations suggest that antitumor reactivity was passively transferred with the IVS-LN cells. Major toxic side effects including fever, hepatic dysfunction, and weight gain associated with the capillary leak syndrome were associated with exogenous IL-2 administration. Tumor vaccination and cell transfer were well tolerated without significant complications. Of the ten patients treated with IVS-LN cells and IL-2, there were one partial and one minor response, and one patient has had stable disease for 27+ mo. There was no evidence of tumor response in ten patients treated with tumor vaccination and IL-2 only. Further clinical studies evaluating the antitumor reactivity of vaccine-primed LN cells are warranted.

Adult↗
PubMed1993

Adoptive cellular therapy of malignancy.

The realization that human cancers can be responsive to the manipulation of the immune system has only recently been documented. The immune approaches to the treatment of malignancy can be broadly classified into either active or passive immunotherapies. With active immunotherapy, treatment relies on the in vivo stimulation of the endogenous host immune system to react against tumors with the administration of biological response-modifying agents (ie, bacterial adjuvants, cytokines, tumor vaccines). With passive immunotherapy, treatment involves the delivery of biologic reagents with established tumor-immune reactivity (ie, antibodies or cells) that can directly or indirectly mediate antitumor effects and does not necessarily depend on an intact host immune system. Cellular therapy of malignancy has become more feasible with increased understanding of the interactions between immune cells and tumors. This article will review our current understanding of the principles underlying these interactions.

Adjuvants, Immunologic↗