Excising melanomas: how wide is enough? And how to reconstruct?
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Ear Neoplasms↗
Biomedical subjects
C M Balch
Publications and source records attributed to C M Balch.
Management of local and regional recurrence after mastectomy or breast-conserving treatment.
Locoregional failures after primary treatment for breast cancer include a diverse group of lesions that represent different categories of failures with various prognoses. Although patients with chest wall recurrences and regional nodal failures after traditional radical surgery have a poor prognosis, many patients can still achieve a significant degree of palliation and even long-term survival or cure with carefully orchestrated multimodal treatment. In patients who have breast failures after breast-conservation surgery and radiation, long-term salvage and cure can be achieved for the majority with prompt detection and appropriate treatment, which, like treatment for primary breast cancer, includes a consideration not only of local control but also of the risk of subsequent systemic failure and its need for treatment.
Breast↗
Survival following locoregional recurrence after breast conservation therapy for cancer.
We postulated that locoregional recurrence after limited surgery and radiotherapy for breast cancer might be associated with an additional survival hazard, similar to that of a second primary tumor with the same extent of local and regional disease. Using this hypothesis we examined the likely resultant effect on survival. Our calculations indicated that no statistically significant survival deficit due to such recurrence would be detectable until a randomized controlled trial comparing breast conservation with mastectomy had monitored more than 10,000 patients for more than 10 years. A simple mathematical model predicted 5-year survival rates in a cohort of patients treated with breast conservation of 75%, compared to 83% in those without locoregional recurrence. From the date of locoregional recurrence, a 61% 5-year survival rate was predicted, compared to 83% if no hazard was associated with locoregional recurrence. These predictions were compared with the actuarial survival rates of 499 patients with unilateral breast cancer, 49 of whom had developed locoregional recurrence. From the date of initial treatment, the 5-year survival rate of those whose disease recurred was 79%, compared to 88% for those without locoregional recurrence (p = 0.19). The actuarial 5-year survival rate from the date of locoregional recurrence was 63%. The similarity between the patient data and the predictions of the mathematical model indicates that locoregional failure after breast conservation therapy may result in reduced survival. The lack of a significant survival deficit in our cohort or in controlled trials comparing breast conservation therapy with mastectomy is compatible to the small size of the overall effect.
Actuarial Analysis↗
Axillary lymph node dissection: differences in goals and techniques when treating melanoma and breast cancer.
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Axilla↗
Lack of comparability between binding of monoclonal antibodies to melanoma cells in vitro and localization in vivo.
The affinity and specificity of monoclonal antibodies (MAbs) to tumor-associated antigens are often determined by in vitro assays. The specific binding of two anti-human melanoma antibodies (96.5 and ZME-018) and a control antibody (ZCE-025) to three human melanoma cell lines (DX3, A375-M, and Hs294t) was examined under in vitro conditions and compared to in vivo localization of 111In-labeled antibodies to the same cells growing as solid tumors in the subcutis of nude mice. The in vitro binding of the specific MAbs to the tumor cells did not predict in vivo localization. Under in vitro conditions, MAb ZME-018 bound to all three cell lines at levels exceeding that of 96.5, yet ZME-018 did not show superior localization to subcutaneous tumors. MAb 96.5 bound to cultured DX3 cells at levels exceeding those observed with A375-M cells. Yet, 96.5 localized better to A375-M xenografts in nude mice than to DX3 or Hs294t xenografts. Antigen expression differed between in vitro and in vivo growing cells, as evidenced by alteration in binding of 96.5 to tumor cells dissociated from solid subcutaneous tumors. Collectively, the data suggest that in vitro parameters do not predict the clinically relevant localization of MAbs to tumors.
Animals↗
Involvement of both Tac and non-Tac interleukin 2-binding peptides in the interleukin 2-dependent proliferation of human tumor-infiltrating lymphocytes.
Interleukin 2 (IL-2) receptor expression was examined on recombinant IL-2 (rIL-2)-propagated tumor-infiltrating lymphocytes (TIL) from eight metastatic melanoma and three sarcoma samples. All 11 TIL expanded with similar growth rates. rIL-2 propagated TIL from five of eight metastatic melanoma specimens contained no Tac antigen-positive lymphocytes as determined by immunofluorescence and flow cytometry performed multiple times during the 4 to 8 week culture period. However, "Tac-negative" TIL did express the non-Tac IL-2-binding peptide, p70-75 as determined by [125I]IL-2 cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. IL-2-binding assays revealed that these "Tac-negative" TIL expressed only an intermediate affinity IL-2 receptor. In contrast, TIL from the other three of eight melanoma and all three sarcoma contained one-third Tac-positive cells as assessed by flow cytometry analysis, and expressed surface non-Tac (p70-75) and Tac (p55) peptides by [125I]IL-2 cross-linking. These "Tac-positive" TIL displayed both the high and intermediate affinity IL-2 receptors. However, rIL-2-dependent growth of both "Tac-negative" and "Tac-positive" TIL was significantly inhibited by anti-Tac mAb, suggesting a transient Tac expression on the "Tac-negative" TIL. Additionally, due to the limits of our methodology, we cannot rule out the possibility of a constitutive expression of a low level of Tac, with an indicible expression of higher levels. Addition of culture supernatants from phytohemagglutinin- and phorbol myristate acetate-stimulated peripheral blood mononuclear cells to the "Tac-negative" TIL-induced detectable Tac expression within 48 h. These results indicate that both non-Tac and Tac IL-2 receptors play important roles during IL-2-dependent proliferation of TIL.
Antibodies, Monoclonal↗
The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer.
We compared the prognostic value of surgical lymph node staging after preoperative chemotherapy relative to other patient and tumor variables in 136 patients with locally advanced breast cancer (T3-4 and/or N2-3) who received preoperative chemotherapy followed by mastectomy and axillary dissection as part of a prospective protocol. Univariate analysis revealed that the number of metastatic lymph nodes, clinical tumor stage at presentation, clinical and pathologic response, and menopause status were significant variables associated with survival and disease-free survival, but clinical node stage at presentation and estrogen receptor status were not. The number of metastatic lymph nodes had more prognostic value than the other factors, and when evaluated by multivariate regression, surgical node staging added significantly more information to the remaining variables. Surgical staging is an important component of treatment for patients with breast cancer undergoing preoperative chemotherapy because it can provide an accurate and quantitative method for subgrouping patients with different survival rates and it can be used to compare results between preoperative chemotherapy trials.
Adult↗
Patterns of relapse in 1001 consecutive patients with melanoma nodal metastases.
The impact of nodal tumor burden on patterns of relapse and survival was retrospectively analyzed in 1001 patients with stage III melanoma. The incidence of tumor recurrence within the node dissection field was lower in patients with 1 nodal metastasis (9%) or with no extranodal invasion (15%) than in patients with multiple involved nodes (15% to 33%) or connective tissue invasion (28%). Patients with 1 "positive" node (a node in which cancer was detected) had a 45% 5-year and 39% 10-year survival rate compared with patients who had 2 to 4 positive nodes (37% and 28%), 5 to 10 nodes (20% and 17%), more than 10 nodes (5% and 3%), or extranodal invasion (14% and 11%). The occurrence of in-transit metastases in 10% of patients after nodal dissection was not influenced by the extent of nodal tumor burden.
Adolescent↗
Monocyte-dependent, serum-borne suppressor of induction of lymphokine-activated killer cells in lymphocytes from melanoma patients.
Both phytohemagglutinin-induced cytotoxicity and recombinant-interleukin-2 (rIL-2)-induced lymphokine-activated killer (LAK) activity against noncultured melanoma cells were significantly reduced when peripheral blood mononuclear cells (PBMC) from patients with metastatic melanoma were incubated in RPMI medium 1640 and 10% autologous human serum instead of 10% fetal calf serum, while serum from either healthy donors or patients with primary melanoma did not affect the level of cytotoxicity. The serum-mediated suppression was not restricted by major histocompatibility complex and was time-dependent. Addition of 10% human serum from the patients with metastatic melanoma [HS-Pt(m)] to the culture of PBMC with rIL-2 at the same time or 1 day after incubation significantly inhibited LAK activity. However, addition of 10% HS-Pt(m) 2 or 3 days after incubation did not inhibit LAK activity. Incubation of PBMC for 2 h with a high dose (10(4) U/ml) of rIL-2 in the presence of 10% HS-Pt(m), followed by incubation in the absence of either rIL-2 or HS-Pt(m), did not affect LAK cell activity. These results suggest that HS-Pt(m) inhibits the early stage of LAK cell differentiation, rather than the binding of rIL-2 to PBMC or a later stage in the differentiation. In contrast to PBMC, monocyte-depleted peripheral blood lymphocytes exhibited comparable levels of LAK activity when cultured with rIL-2 either in 10% fetal calf serum, 10% human serum from healthy donors or 10% HS-Pt(m). Addition of purified autologous monocytes to the culture of monocyte-depleted peripheral blood lymphocytes with rIL-2 suppressed LAK cell induction when 10% HS-Pt(m) was present. Thus serum-mediated suppression of LAK cell induction is largely dependent on the presence of monocytes, which may produce a secondary inhibitor that acts on lymphocytes. Addition of indomethacin to the culture did not reverse this monocyte-dependent serum-mediated suppression in a majority of cases, suggesting that prostaglandin E2 does not have a major role in the suppression.
Cytotoxicity, Immunologic↗
Altered biodistribution of indium-111-labeled monoclonal antibody 96.5 to tumors and normal tissues of nude mice bearing human melanoma xenografts in visceral organs.
Human melanoma xenografts were produced in the subcutis, kidney, cecum and liver of different nude mice. An 111In-labeled anti-(human melanoma) monoclonal antibody (96.5) or an 111In-labeled nonspecific control monoclonal antibody (ZCE-025) was injected intravenously in separate groups of mice. Radioactive antibody accumulation was measured in tumor, blood, viscera, and carcasses. mAb 96.5 targeted specifically to tumor tissue regardless of site of growth. Tumors in the liver exhibited significantly (P less than 0.05) higher tumor-to-blood ratios (45 +/- 6, mean +/- SEM) than xenografts at other visceral organs, the lowest value being found for subcutaneous melanoma (2.6 +/- 0.5). The differences in tumor-to-blood ratio were due to significant alterations of antibody biodistribution, since the actual antibody concentration in the different tumor sites was similar. The percentage of recovered anti-melanoma antibody per milliliter of blood in mice with visceral lesions (4.6 +/- 1.1% ml) was significantly lower than that found in mice with subcutaneous tumors (9.5 +/- 1.4%/ml, P less than 0.05). Moreover, significantly higher levels (18.2 +/- 3.2%/g, 31.0 +/- 5.1%/g, respectively) of the melanoma mAb 96.5 were found in normal liver and spleen tissue recovered from mice with visceral tumors as compared to tissue from mice with subcutaneous tumors (9.2 +/- 0.9%/g, 13.5 +/- 1.9%/g, respectively; P less than 0.05). These results demonstrate that the presence of visceral tumor can significantly affect tumor-to-blood ratios, blood levels, and biodistribution of 111In-labeled mAb 96.5.
Animals↗
Gastric cancer.
The overall cure rate for gastric cancer has changed relatively little in the United States over the past 30 years, largely because patients continue to present for treatment in advanced stages. The paucity of symptoms in early gastric cancer, the low incidence in the general United States population, and the lack of cost-effective screening methods suggest that improvements in early detection are unlikely. Hope for improved survival in late stage cases lies mostly in a better understanding of the pathophysiology and patterns of spread, in evolving techniques for more accurate perioperative staging, and in the gradually improving results of multimodality therapy for local-regional and systemic disease. A proposal is made for a new staging system integrating newer approaches to staging and for controlled trials of multimodality therapy in patients unlikely to be cured by surgery alone.
Algorithms↗
The NIH clinician-investigator award: how to write a training grant application.
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Budgets↗
Interleukin-2 alone and in combination with other cytokines in melanoma: the investigational approach at the University of Texas M.D. Anderson Cancer Center.
The clinical data that have been accumulated so far suggests a significant influence of IL-2 dose and schedule on the immunobiological effects and clinical toxicities observed with this cytokine. Consequently, the series of Phase I and Phase II clinical trials conducted at the University of Texas M. D. Anderson Cancer Center in patients with advanced malignant melanoma investigating the use of IL-2 in combination with other cytokines, monoclonal antibodies, or ex vivo activated effector cells have used a common dose and schedule of IL-2 administration for which abundant immunobiological information already exists. This approach allows cross-trial comparison of experience with toxicities, immunobiological observations and clinical activity by a group of investigators within a single institution, and more rapid and valid evolution towards combination biological therapy, which preclinical data suggest will have greater activity than single agent therapy.
Biological Factors↗
Surgical aspects of lymphoma.
Improvements in histologic classification, staging and multimodality therapy have dramatically changed the natural history of patients with lymphoma. Systematic staging accurately defines the extent of disease and minimizes the toxic effects of excessive treatment. Surgical diagnosis and staging with laparotomy provide the basis for choosing methods of definitive radiotherapy and chemotherapy for selected patients. Patients with extranodal disease in early stages may be treated effectively by surgical excision.
Hodgkin Disease↗
Autologous tumor-specific cytotoxic T lymphocytes in the infiltrate of human metastatic melanomas. Activation by interleukin 2 and autologous tumor cells, and involvement of the T cell receptor.
TIL from metastatic melanoma proliferated by greater than 1,000-fold (840-3,675, mean 1,543) after 6 wk in culture of mixtures of TIL and tumor cells with rIL-2 alone. Cytolysis was restricted to autologous tumor cells. CD8+ T cells were the predominant population of TIL before and after expansion, and were primarily responsible for autologous tumor-specific CTL activity. No other rIL-2-activated lymphocytes from peripheral blood, lymph nodes with melanoma metastasis, or TIL from sarcoma or renal cell carcinoma had autologous tumor-specific CTL activity. There were few or no CD16+ NK cells in TIL from metastatic melanoma before or after incubation with rIL-2, respectively. However, TIL from sarcoma or renal cell carcinoma contained a substantial proportion of CD3-CD16+ NK cells, which increased in number in culture with rIL-2. Purified CD16+ NK cells as well as CD3+CD16- T cells from rIL-2-activated TIL of renal cell carcinoma displayed MHC-nonrestricted cytotoxicity. At the clonal level as determined by limiting dilution, 8 of 10 clones from melanoma TIL displayed cytotoxicity restricted to autologous tumor cells, while all 13 clones from renal cancer TIL equally lysed autologous and allogeneic tumor cells. Anti-T cell receptor (TCR)-alpha/beta(WT31) mAb as well as anti-CD3 mAb inhibited autologous melanoma cell-specific CTL activity mediated by rIL-2-activated TIL at the effector phase. These two mAbs also inhibited rIL-2-dependent proliferation of these TIL when added to the culture. Pretreatment of fresh melanoma cells with mAb to MHC antigens followed by washing inhibited specific CTL activity. These results suggest that both TCR-alpha/beta on effector TIL and MHC antigens on fresh tumor cells are involved in the specific immune-recognition. After reaching maximum propagation, TIL from metastatic melanoma responded poorly to rIL-2 alone. However, stimulation with fresh autologous melanoma cells restored both CTL activity and proliferation in response to rIL-2. The latter is associated with IL-2 receptor (Tac antigen) expression on the surface. These results indicate that TIL from metastatic melanomas may have unique characteristics different from lymphocytes obtained from the other sources, and may contain precursor CTL sensitized in vivo to autologous tumor cells, and thus can be propagated in larger numbers with rIL-2 alone while retaining autologous tumor-specific CTL activity.
Antibodies, Monoclonal↗
Adjuvant therapy for node-negative breast cancer patients. Who benefits?
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Breast Neoplasms↗
Monocyte-independent interleukin-2 production and proliferation of human T cells in response to murine hybridomas expressing the OKT3 monoclonal antibody: interleukin-1 is not required for T-cell proliferation.
We report a new, monocyte-independent system for the induction of activation and proliferation of human T cells in response to murine hybridomas expressing the OKT3 monoclonal antibody (OKT3 hybridomas). Incubation of nylon-wool-nonadherent (NA) lymphocytes or purified T cells with OKT3 hybridomas resulted in interleukin-2 (IL-2) production, expression of IL-2 receptor, modulation of the CD3 antigen, and proliferation. In contrast, murine hybridomas (OKT4, OKT8, anti-HLA-DR, and others) expressing monoclonal antibodies (mAb) other than OKT3 did not induce T-cell activation and proliferation. T cells did not respond to OKT3 mAb alone. OKT3 hybridomas alone did not produce interleukin-1 (IL-1) or other soluble factors that might be involved in the induction of IL-2 production by T cells, and they did not contain membrane-bound IL-1. In addition, IL-1 activity was not detected in cultures of NA-lymphocytes and OKT3 hybridomas, clearly demonstrating that IL-1 was not required, at least in this system, for T-cell activation and proliferation. Direct cell-cell contact between T cells and OKT3 hybridomas was required for IL-2 production. Thirty to fifty percent of T cells formed conjugates with the OKT3 hybridomas but not with the OKT4 or OKT8 hybridomas. Both conjugate formation and IL-2 production were significantly inhibited by the OKT3 mAb and by the anti-LFA-1 mAb. The cells responsible for IL-2 production were found to be of the T3+ T4+ T8- Leu 7- Leu 11- phenotype. IL-2 activity produced by NA-lymphocytes in response to OKT3 hybridomas became detectable as early as 1 hr and reached a maximum by 8 hr, preceding IL-2 receptor expression, modulation of the CD3 antigen, and [3H]thymidine incorporation of T cells. T cells produced higher concentrations of IL-2 in response to OKT3 hybridomas than in response to equal numbers of monocytes and OKT3 mAb. Addition of monocytes to cultures of T cells and OKT3 hybridomas resulted in suppression of IL-2 production in a concentration-dependent manner, suggesting that monocytes regulate the levels of IL-2 production. This monocyte-independent system may be useful for further dissection of T-cell activation and proliferation and its regulation by monocytes.
Adult↗
CD8+ T cells lyse autologous monocytes in the presence of anti-CD3 monoclonal antibody: association with interleukin-1 production.
Human peripheral blood T cells lysed autologous or allogeneic monocytes, but not polymorphonuclear cells (PMN) or lymphocytes, in the presence of anti-CD3 (OKT3 (IgG2a) or anti-Leu 4 (IgG1)) monoclonal antibody (mAb). Other mAbs such as OKT4 (IgG2b), OKT8 (IgG2a), OKT11 (IgG2a), and OKM1 (IgG2a) did not mediate lysis of monocytes. Lysis of monocytes also did not occur in the presence of F(ab')2 fragments of OKT3 mAb. OKT3 mAb and control murine IgG2a mAb, but not F(ab')2 fragments of OKT3 mAb, were bound to the monocyte cell surface. Purified human IgG1 and IgG3 myeloma proteins, polyclonal human IgG, or Con A inhibited anti-CD3-dependent T-cell cytotoxicity against monocytes when added to the 4-hr 51Cr-release assay. Pretreatment of monocytes with an irrelevant murine IgG2a mAb also inhibited OKT3 mAb (IgG2a)-dependent lysis of these cells, but did not affect anti-Leu 4 mAb (IgG1)-dependent lysis, suggesting that two different Fc receptors were involved. These results strongly suggest that Fc IgG receptors on monocytes are a critical structure for anti-CD3-dependent cytotoxicity. Lysis of monocytes was accompanied by interleukin-1 (IL-1) production, which was detected in supernatants from 4-hr cultures of T cells and monocytes in the presence of the OKT3 mAb. Both anti-CD3-dependent lysis of monocytes and IL-1 production were severely decreased after treatment of T cells with either OKT3 or OKT8 mAb plus complement, but were not affected significantly by treatment with the OKT4 mAb plus complement. Purified CD8+ cells, prepared using the cell sorter, exhibited significant levels of anti-CD3-dependent monocyte lysis (greater than 10%). In contrast, purified CD4+ cells did not exhibit significant levels of anti-CD3-dependent cytotoxicity (less than 10%). Production of high concentrations of IL-1 was observed in cultures of purified CD8+ cells and monocytes in the presence of anti-CD3 mAb. Only low concentrations of IL-1 were detected in cultures of purified CD4+ cells, monocytes, and OKT3 mAb. These results suggest that CD8+ cells are primarily responsible for lysis of monocytes, which is associated with IL-1 production. It appears that anti-CD3 mAb brings CD8+ T cells and monocytes into close proximity by binding to the CD3 antigen on T cells and to the Fc IgG receptor on monocytes. This interaction results in lysis of monocytes primarily by CD8+ cells, after bypassing any antigen recognition requirements that may be otherwise needed. Lysis of monocytes appears to be associated with IL-1 release.
Adult↗