Charles M. Balch

Predicting survival and recurrence in localized melanoma: A multivariate approach

Several clinical and pathologic factors appear to affect melanoma recurrence and survival. While much attention has been directed at identifying prognostic factors, few researchers have developed predictive models for survival and recurrence. Two major clinical questions are of interest in the management of melanoma: 1) what is the patients chance of surviving for a given period, e.g., 5 or 10 years, after diagnosis of melanoma; and 2) after a patient has been disease free for a period of time, e.g., 5 years, what is his or her chance of melanoma recurrence or death in the following interval, e.g., 5 years or 10 years. In this paper, a generalized multivariate prognostic model to address both of these clinical questions is presented.Tables of the estimated probabilities of melanoma recurrence and death for prognostic subgroups are shown to facilitate prediction of an individual patients outcome. The model was based on a database of 4,568 patients with localized melanoma, one of the largest melanoma databases in the world with detailed clinical and pathologic information, and long-term follow-up. Tumor thickness at diagnosis was the single most important prognostic factor for all outcomes. Tumor ulceration, Clarks level, lesion location, and sex had an impact on overall survival from diagnosis for some of the subgroups defined by tumor thickness. Tumor thickness at diagnosis was strongly indicative of melanoma recurrence and death even after a disease free interval of 2, 5, or 10 years. Lesion location and ulceration were of prognostic importance after disease free intervals up to 5 years, but their impact on melanoma recurrence and death diminished after longer disease free intervals.Prediction models for melanoma outcome at diagnosis and after a disease free period can provide useful information to clinicians in the management of melanoma patients. Utilization of the model will be valuable in identifying patients at high risk for melanoma recurrence and death.RésuméPlusieurs facteurs cliniques et anatomopathologiques semblent déterminer la récidive et la survie des mélanomes. De nombreux auteurs se sont intéressés à lidentidification des facteurs de pronostic, mais peu déquipes ont essayé délaborer un modèle permettant de prédire survie et récidive. Deux problèmes restent à résoudre dans le traitement des mélanomes: 1) quelles sont les chances de survie après le diagnostic de mélanome pour un patient donné, pendant une période donnée, par exemple 5 à 10 ans et 2) quels sont les risques de récidive ou de décès dans les 5 à 10 ans qui suivent une période donnée (par exemple 5 ans) où un patient semblait en rémission. Dans cet article, nous avons créé un modèle dévaluation pronostique multifactorielle pour tenter de répondre à ces 2 questions.Des tables montrant les probabilités de récidive et de décès par mélanome, calculées à partir de sous groupes différents, peuvent aider à déterminer le pronostic. Ce modèle repose sur une banque de données de 4568 patients atteints de mélanome non disséminé. Il sagit dune des plus grandes banques de données au monde contenant des informations cliniques, anatomopathologiques et sur lévolution à long terme. Lépaisseur de la tumeur au moment du diagnostic était le facteur pronostic le plus important pour déterminer lévolution. Le caractère ulcéré, le stade de Clark, la localisation de la lésion et le sexe avaient tous une importance pronostique, influant sur la survie globale liée à lépaisseur de la tumeur. Limportance de lépaisseur de la tumeur au moment du diagnostic était un facteur de récidive et mortalité même après un intervalle long de 2, 5 ou 10 ans. Le site de la tumeur et son caractère ulcéré étaient également des facteurs associés à un risque de récidive tumorale ou de décès après une rémission de 5 ans. Linfluence de ces facteurs diminuait en cas de rémission plus prolongée.Les modèles permettant dévaluer lévolution du mélanome malin au moment du diagnostic et apreès un intervalle de rémission sont utiles au cours du traitement du mélanome. Ils doivent permettre didentifier les patients à risque de récidive et de décès.ResumenDiversos factores clínicos y patológicos parecen afectar las tasas de recurrencia y mortalidad del melanoma. En tanto que se ha dispensado bastante atención en cuanto a identificar factores de pronóstico, pocos investigadores han desarrollado modelos de predicción de sobrevida y de recurrencia. Dos interrogantes principales son de interés en cuanto al manejo del melanoma: 1) cual es la probabilidad del paciente de sobrevivir un determinado período, por ejemplo 5 o 10 años, después del diagnóstico de melanoma; y 2) después de que el paciente se ha mantenido libre de enfermedad por un período de tiempo, por ejemplo 5 años, cual es su probabilidad de recurrencia del melanoma o de muerte en el siguiente período de tiempo, por ejemplo 5 o 10 años. En este artículo se presenta un modelo generalizado y multivariable de pronóstico para enfrentar estos interrogantes clínicos.Se presentan tablas para estimar las probabilidades de recurrencia y de muerte en divesos subgrupos de pronóstico que facilitan la predicción del destino final de un individuo. El modelo se fundamentó en una base de datos de 4568 pacientes con melanomas localizado, una de las más grandes bases de datos de melanoma existentes en el mundo, con detallada información clínica y patológica y con seguimiento a largo plazo. El espesor del tumor en el momento del diagnóstico apareció como el factor individual de pronóstico de mayor importancia. La ulceración del tumor, el nivel de Clark, la ubicación de la lesión y el sexo exhibieron importancia en cuanto a la sobrevida para algunos de los subgrupos definidos según el espesor del tumor. El espesor del tumor en el momento del diagnóstico fue un factor fuertemente indicativo de recurrencia y de muerte, aún después de un intervalo libre de enfermedad de 2, 5 o 10 años. La ubicación de la lesión y la ulceración aparecieron como de importancia en cuanto el pronóstico después de intervalos libres de enfermedad hasta de 5 años, pero tal importancia disminuyó después de intervalos libres de enfermedad de mayor duración.Los modelos de predicción del resultado final en el melanoma aplicados en el momento del diagnóstico y después de un período libre de enfermedad pueden proveer información útil para el manejo clínico de pacientes con melanomas. La utilización del modelo es de valor en la identificación de pacientes con mayor riesgo de recurrencia y muerte por melanoma.

Prognostic histopathological factors in malignant melanoma

&NA; An analysis of prognostic factors in 4000 patients with cutaneous malignant melanoma at the Sydney Melanoma Unit and the University of Alabama in Birmingham has demonstrated that the histological features of the primary melanoma become less predictive of survival the more advanced the disease becomes. Thus, whilst 4 features of primary lesions were independent predictors in localized disease (tumour thickness, ulceration, level of invasion and regression), only one of the stronger ones (ulceration) remained predictive in patients with regional lymph node metastases. Once distant spread was evident, there were no parameters of the primary lesion that predicted survival. Thus, in patients with advanced disease prognosis was dictated by the extent of metastatic involvement: the number of positive lymph nodes in stage II patients and the number and location of metastatic sites in stage III patients.

CHARACTERIZATION OF HUMAN NK CELLS IDENTIFIED BY THE MONOCLONAL HNK-1 (Leu-7) ANTIBODY

Publisher Summary This chapter reviews the characterization of human natural killer (NK) cells identified by the monoclonal HNK-1 (Leu-7) antibody. The monoclonal antibody, HNK-1, was produced against the cultured cell line, HSB-2, using the hybridoma technique introduced by Kohler and Milstein. Although HSB-2 cells have been considered to be of T-cell origin, they lack T-cell-associated antigens identified by the monoclonal antibodies, OKT1, T3, T4, T5, and T8. In a study described in the chapter, when the HNK-1 antibody was tested against cultured lymphoid cell lines, it reacted with some T-cell lines (HSB-2 and MOLT-4) but not with any other T-cell line (MOLT-3), with any B-cell lines, or with cultured phagocytic cells. When human blood mononuclear cells were examined by immunofluorescence, the HNK-1 antibody reacted solely with a morphologically distinct population of granular lymphocytes with NK- and K-cell function. The results suggested that a differentiation antigen identified by the monoclonal HNK-1 antibody is exclusively expressed on human NK and K cells. The HNK-1 antibody also distinguishes the classically defined NK cell from its analogues.

A human B cell differentiation antigen selectively expressed on mature B cells identified by a monoclonal antibody (HB-2)

A monoclonal IgM antibody (HB-2), produced against a membrane antigen on the Raji, B cell line, reacted by indirect immunofluorescence with 2 to 40% of lymphoblasts from the B cell lines, Raji, Daudi, SN-1036, and SB but not with other types of cell lines, including pre-B, myeloid, melanoma, or T cells. HB-2 antibody reacted with 10 +/- 3% of normal blood mononuclear cells, and was unreactive with monocytes, granulocytes, platelets, or erythrocytes. Two-color immunofluorescence revealed that HB-2 antigen expression was confined to cells bearing surface Ig. An interesting finding was the fact that 25% of plasmablasts induced by pokeweed mitogen also expressed the HB-2 antigen. However, pre-B and plasma cells from normal bone marrow did not express the HB-2 antigen either on their membrane surface or in their cytoplasm. Analysis of 85 leukemias revealed that the HB-2 antigen was expressed on acute and chronic B cell leukemias and Burkitts lymphomas, but not on malignancies of pre-B, T, myelocytic, or plasma cells. The results suggest that expression of the HB-2 antigen is confined to mature B cells.

Immunogenetics of Melanoma

Human melanoma of the skin is a disease that has received a great deal of attention from basic scientists and clinicians over the last several years. One reason for this increased interest is that the incidence of the disease is rapidly increasing in the United States as well as in other countries (Crombie, 1979; Cutler and Young, 1975; Elwood and Lee, 1974; Magnus, 1977; Ohsumi and Seiji, 1977). In attempting to understand the etiology of melanoma, one must consider two major factors: the genetic makeup of the host and environmental insults (Clark et al., 1977; Klepp and Magnus, 1979; McGovern, 1977). Ultimately, one would like to be able to identify highly susceptible individuals in the population early in life and provide measures to minimize or prevent insult by environmental agents. With this in mind, we will attempt to review the current state of knowledge with regard to the immunogenetics of melanoma in order to establish whether this goal is in sight. The authors have taken the liberty of selecting data by others that illustrate the current level of understanding in this area rather than attempting an all-encompassing review. Since the highest melanoma mortality rate in the United States is found in Alabama (Mason and McKay, 1974), we will review the immunogenetic data collected from patients mainly residing in the state of Alabama treated at the Melanoma Clinic of the University of Alabama in Birmingham. The clinical and pathological characteristics of this patient group have previously been published (Balch et al., 1978, 1979a,b, 1980, 1981; Balch, 1980).

893 MORPHOLOGY, DEVELOPMENT AND DISTRIBUTION OF HUMAN NK CELLS IDENTIFIED BY A MONOCLONAL ANTIBODY (HNK-1)

A monoclonal IgM antibody (HNK-1) has been shown to react with a subset of human lymphocytes that can function as natural killer (NK) and antibody dependent killer (K) cells. HNK-1 antigen is present on 60% of Tγ cells (Fcγ receptor+, E-rosette+) and 56% of “null” cells (FcγR+ER−sIg-) but not on sIg-bearing B cells and monocytes. In the present studies we have used immunofluorescent and cell sorter techniques to examine the development, distribution, morphology and function of cells expressing HNK-1. Fewer than 1% of cells in thymus and newborn blood samples were HNK-1+. The number of circulating HNK-1+ cells increased as a function of age: <5% of blood mononuclear cells in children under 15, 5-35% in adults 15 to 40 and 25-45% in adults >40 years of age. HNK-1+ cells comprised a mean of 12% of spleen cells but <1% of lymph node cells. The level of NK and K cell functions was closely related with the numbers of HNK-1+ cells in all tissues examined. Morphologically, HNK-1+ cells were defined as a homogeneous population of lymphocytes with abundant cytoplasm containing azurophilic granules. A significant proportion of HNK-1+ cells coexpressed antigens previously defined by monoclonal antibodies on T cells and monocytes. Our studies define a morphologically distinct subpopulation of lymphocytes of unknown origin with NK and K activities, the HNK-1+ cells were shown to expand as a function of age and exhibit selective migration. NIH CA 16673 and CA 27197.

The Occurrence of Melanoma and Its Relationship with Host, Lifestyle and Environmental Factors

Human melanoma of the skin is a malignancy whose incidence is rapidly increasing in the United States as well as in other countries [1–7]. The highest melanoma mortality rate in the U.S. is found in Alabama [8]. In order to understand the reasons for this increased incidence, one must consider three major interacting factors, the constitutional makeup of the host, the lifestyle of the host and environmental exposure [9–11]. This review will look at the studies of each of these factors in an effort to better understand the etiology of melanoma. We have tried to consider the majority of reports which bear on this subject. However, some selection of data has obviously occurred, and we have relied heavily on the reviews of others to make certain points. Reference when appropriate is also made to our own data collected from patients, greater than 95% of whom reside in the State of Alabama, treated at the Melanoma Clinic of the University of Alabama in Birmingham (UAB). Finally, we will propose a model based on our review which, taking into account both host specific, environmental factors and their interactions, could explain the incidence of melanoma in most Caucasian populations. Provided the relative contributions of these three factors to the etiology of melanoma can be discerned, one should be able to identify highly susceptible individuals in the population and therefore suggest measures to alter lifestyle to minimize exposure to environmental agents.

Subpopulations of Human Lymphocytes and their Alterations in Immunodeficiency Diseases

The two major lines of immunocompetent cells, T and B cells, are thought to derive from a common lymphoid precursor or more directly from the multipotent hemopoietic stem cell. For both T and B cells, it is clear that special inductive microenvironments play important roles in the initiation of their separate differentiation pathways. The epithelial thymus serves both as a generation site for T cells and as a source of hormones that can modulate proliferation and function of T cells even after they enter the circulation to migrate through peripheral lymphoid tissues. The inductive micro-environments for the B cell pathway in mammals are not as sharply delineated, and these change during development. The fetal liver is an early site of B cell generation, and bone marrow assumes this function later. Much has been learned about the details of the development and differentiation of functionally diverse subpopulations of T and B cells in recent years, and practical markers are now available for the study of these processes in humans.

Indomethacin, Prostaglandin, and Immune Regulation in Melanoma

Melanoma patients exhibit decreased immunocompetence as measured by a variety of in vitro and in vivo immunological responses (Golub et al.,1974; Eilber et al.,1975; Zembala et al.,1977). It has been assumed that this decreased immunocompetence is due to a deficiency of effector-cell function (e.g., antibody-forming B lymphocytes, cytotoxic T lymphocytes). Such a concept led to a strategy of immunotherapy; manipulations with the goal of stimulating the immune system to correct the deficit. However, information obtained in recent years has demonstrated that the tempo, intensity, and even the choice of effector cells may be regulated in part by suppressor cells and by helper cells (also called amplifying cells, accessory cells, or inducer cells). Thus, the observation that melanoma patients exhibit decreased immunocompetence should be examined in the context of helper and suppressor lymphocytes or macrophages or both, for the immunosuppressed state in some patients might be due to too little “help” or too much suppression. Furthermore, this concept may partially explain the failure of immunotherapy to improve survival rates, since there is some experimental evidence that immunotherapy agents may have a dual effect by stimulating both effector cells and suppressor cells with the result that there is no net change in immune balance.

A randomized evaluation of adjunctive chemoimmunotherapy versus immunotherapy in patients with resected metastatic melanoma

Until the mid-1970s, there was a lack of systematic clinica! effort in studying single agent activity in gynecologic malignancies; therefore, the Gynecologic Oncology Group (GOG), encouraged by the Division of Cancer Treatment, National Cancer Institute (NCI), established a master protocol system (GOG f26) for Phase II clinical studies in treating advanced recurrent pelvic malignancies. The protocols section A gives patients eligibility requirements, exclusion, evaluation, response, and study duration. Subsequent sections deal with information for each selected drug, including background and rationale, toxicity, drug formulation, treatment plan and modification, study parameters, and serial observations. Each drug is planned for studies in each major tumor type, including squamous cell cervix, ovarian, endometrial, and other gynecologic malignancies. Accrual of 25 patients is planned for each tumor type, to detect an active drug (> 90% confidence to detect 20% response rate).