Search

Node dissection for melanoma remains the most important therapeutic decision for the optimal management of the patient with melanoma. In Australia and in some parts of the United States, the majority of patients with intermediate thickness melanoma (1.6–4.00 mm) will undergo elective lymph node dissection. In Europe, the majority of patients with similar lesions are treated with wide local excision only. The development of an agreed policy for node dissection for melanoma awaits the results of 2 current, prospective randomized trials confirming or disproving the efficacy of elective lymph node dissection. Non-randomized studies showing a benefit or not showing a benefit are readily available but the only 2 prospective randomized studies published to date showing a benefit, have been criticized on methodologic grounds. This paper summarizes the evidence and opinions on both sides of this debate. The clinician charged with responsibility for this important decision must, as yet, make the decision to dissect lymph nodes on the basis of a perspective derived from the best available evidence.

In rare instances, primary malignant melanoma thickness fails to predict the biologic course of the disease: lesions <0.8 mm thick may recur locally or metastasize, lesions >5.5 mm thick may not prove to be fatal within the expected interval of time, and melanoma recurrences may develop >10 years after first definitive melanoma treatment. The large Sydney Melanoma Unit data base of over 9,500 patients treated over a 41-year period provided a unique opportunity to study the characteristics and prognosis of these patients with unusual melanomas. In stage I patients with thin lesions, and no sign of disease elsewhere, presence of ulceration, high mitotic activity, and/or penetration into the reticular dermis predisposed these melanomas to recur and regression did not emerge as a risk factor for recurrence. This was in sharp contrast to the histology of the thin lesions in patients with concurrent regional lymph node metastases (stage II). Moderate to severe regression was present in all the latter lesions, ulceration and mitoses were absent, and none penetrated beyond the papillary dermis. No specific criteria were found that could identify those stage I or II patients with thick melanomas but at low risk for recurrence or those patients with localized disease (stage I) who required long-term follow-up beyond 10 years.

The cell-mediated cytotoxicity (CMC) of blood mononuclear cells against cultured human melanoma cells was measured in patients after surgical removal of localized melanoma, at a time when they were considered on clinical grounds to be free of melanoma. It was found that the distribution of CMC values against melanoma cells in melanoma patients was different from that in control subjects, and several sub-populations of melanoma patients were evident on the basis of these measurements. No difference in distribution of CMC values was found against non-melanoma cells, which suggested the changes were specific for melanoma. The proportion of patients with recurrence of melanoma was compared between the patient groups with low, normal or high CMC values against cultured melanoma cells after surgery. Analysis for periods extending to 2 years showed that patients with low CMC values after surgery had a significantly higher incidence of recurrence from melanoma than patients with normal or high CMC values. These results suggest there may be a sub-group of melanoma patients who have intrinsically low CMC against melanoma cells, and that this may be an important predisposing factor in the development of recurrent melanoma.

The non-subungual area of the hand is a rare anatomical site for malignant melanoma, lesions in this site comprising only 0.37% of 8,584 cutaneous melanomas in the Sydney Melanoma Unit database. This is approximately the same frequency of melanoma as is found on the subungual region of the hand, which represents a much smaller surface area. Not only is the sub-site distribution on the hand unusual but in addition the histogenetic types of melanoma found on the dorsum of the hand are not those commonly encountered on sun exposed skin. In this study, comparison is made between melanomas occurring on the non-subungual areas of the hand and those on the foot, an anatomically similar surface area. Comparison is also made between melanomas arising on the dorsal non-subungual surface of the hand and those on the face, a region with an equivalent surface area and similar sun exposure. The results of surgical treatment of 31 melanomas of the non-subungual region of the hand are reviewed.

The present study was designed to examine the feasibility of in vivo administration of interleukin 2 (IL-2) to induce cytotoxic cell activity against tumours in human subjects. IL-2 was prepared from blood leukocytes stimulated with phytohaemagglutinin (PHA) and partially purified by membrane chromatography to exclude PHA. Administration of different amounts of IL-2 in vivo to 2 patients with melanoma revealed that the initial level of IL-2 in the circulation was related to the dose given and had a half-life of approximately 22.5 minutes. The initial and subsequent levels of IL-2 were lower than that expected to occur from equilibration in plasma and extracellular fluid. This was not apparently due to inactivation by serum factors because fresh human serum had little effect in vitro on the induction of mitogenic or cytotoxic activity by IL-2. Spontaneous division of lymphocytes was increased following IL-2 administration and it is suggested that clearance of IL-2 in vivo may reflect, in part, absorption by activated lymphocytes in the circulation. Side effects noted shortly after administration of the partially-purified IL-2 preparations included transient pyrexia, hypoglycaemia, increased cortisol levels, lymphocytopenia and signs of mild intravascular coagulation. No long-term effects were noted. These initial results suggest that systemic injection of purified preparations of II-2 may be a feasible approach to induce cytotoxic T cells in vivo.

Inhibitors of natural killer (NK) cell activity in cell-culture supernatants, believed to be antigens recognized by NK cells, were defined by their ability to inhibit NK cells in 51Cr-release cytotoxic assays. Supernatants from cultures of melanoma cells and Chang cells were used as the source of the antigen. Partial characterization by a number of sequential separation procedures suggested that the antigens were glycoproteins in the size range 120-140,000 daltons which had affinity for both concanavalin A and wheat germ lectin. Inhibitory activity was destroyed by trypsin digestion, but was resistant to neuraminidase and a number of physical procedures. Addition of supernatants to NK assays against a number of different target cells indicated that inhibition was restricted to certain target cells. This indicated that the inhibition of NK cells was not non-specific, and that the antigens were not expressed on all target cells. These studies provide a basis for further analysis of antigens recognized by NK cells, and allow investigation of their role in vivo in tumour-bearing hosts.

Patients with melanoma who had one or more close relatives with melanoma were studied for their natural-killer-cell (NK) activity against cultured melanoma cells and Chang cells. A high proportion of the patients and their relatives were found to have low NK activity against these target cells. In most of the patients this could not be attributed to general depression of their immune function, since B- and T-cell numbers and the mitogenic response to PHA were within normal limits. The levels of NK activity of the patients and their relatives were found to be significantly correlated, suggesting that the NK activity in these families may have been genetically (or environmentally) determined. Several genetic markers were examined in the patients and their relatives for association with the disease state and NK activity. No association with HLA antigens or ABO blood groups was detected, but there was a low incidence of the Rhesus negative phenotype in the patients (the Rh phenotype had previously been associated with high NK activity). The present results indicate that NK activity has a familial association in families with a high incidence of melanoma, and raise the question whether low NK activity may be one of the predisposing factors in the development of familial melanoma.

Studies were initiated to assess the response of patients with disseminated melanoma to recombinant alpha interferon (rIFN-alpha A) and to monitor effects of rIFN-alpha A on several tests of immune function. Twenty patients were treated with rIFN-alpha A given by i.m. injection in escalating doses from 15 to 50 X 10(6) um-2. The responses of two patients were considered unevaluable. Of the remainder there was complete remission of tumour in two and stable disease in two. Subsequent progression of tumour in one of the latter patients coincided with development of antibodies to IFN. Side effects (usually fatigue) were dose rate limiting in 11 patients. Laboratory tests on samples taken 6 hours after rIFN-alpha A indicated a marked lymphopenia and a reduction in natural killer (NK) cell activity particularly against K562 target cells. Longer term changes measured in samples taken 2 days after the previous rIFN-alpha A injections consisted of neutropenia and an increase in the T4/T8 ratio due mainly to a relative increase in OKT4 positive T cells compared to OKT8 positive T cells. NK activity against the K562 target cell increased in most patients during the first week of treatment and then returned to below or near pretreatment levels thereafter against the K562 target cell. This contrasted with NK activity against the melanoma target cell which showed a more gradual increase over the duration of the treatment in 6 patients. The latter correlated with an increase in mitogen stimulated IL 2 production from their blood lymphocytes and may indicate that the cytotoxic activity resulted from lymphokine-activated killer (LAK) cells. These results confirm the activity of rIFN-alpha A against melanoma in certain patients. They suggest that further studies are needed to select patients who may respond to rIFN-alpha A and to optimize treatment regimens. Tests of IL 2 production and LAK activity may assisted in achieving these objectives.

Unique and uncommon BamHI allelic restriction fragments of the Ha-ras locus have been reported in the genomes of patients with cancer and of three affected members of a familial melanoma kindred (Krontiris et al., 1986). Analysis of the BamHI and Msp/HpaII restriction fragments of peripheral blood leucocyte DNA from the members of two families with hereditary melanoma (HM)/familial dysplastic naevus syndrome (DNS) revealed that the only Ha-ras allele common to four affected members of one kindred and two from a second kindred, was the 6.7kb allele which is found in 66% of the normal population. This allele was found equally in affected and non-affected family members, and in one affected case was inherited from an unaffected homozygous parent. It was absent in two affected sisters in a third kindred. In the first kindred the karyotype of all three melanoma sufferers was 46XX 9qh+, while six unaffected members had a normal karyotype. BamHI polymorphism of the Ha-ras gene does not identify the affected members in the HM/DNS families studied.

Biochemical characterization of serologically detected human melanoma antigens was undertaken for the development of immunodiagnostic assays in melanoma. An antiserum from a human melanoma patient, which detected melanoma antigens expressed on a large proportion of different melanoma cells, was used in leucocyte-dependent cytotoxic antibody (LDA) 51Cr-release assays to monitor the purification of melanoma antigens in urea/acetate extracts of lactoperoxidase 125I-labelled melanoma cell membranes. The separation procedures included affinity chromatography on Concanavalin A, gel filtration on porous polyacrylamide beads and preparative isoelectric focusing. The fractions were also monitored by polyacrylamide electrophoresis in sodium dodecyl sulphate and by measurement of beta 2 microglobulin and carcinoembryonic antigen content. The antigens detected by this antiserum appeared to be acidic (pI 3.5) low-mol.-wt glycoproteins of approximately 15,000 daltons which were resistant to heating at 56 degrees C and digestion with neuraminidase, but susceptible to repeated freeze-thawing and trypsin digestion. They did not appear to be related to HLA antigens, beta 2 microglobulin or known foetal antigens. The nature of the antigens detected in these studies is as yet unknown, but they appear similar to those described in the sera and urine of melanoma patients in previous reports. Thes combined results and the frequent expression of these antigens on melanoma cells from different patients suggest that assays to detect this antigen may provide a valuable immunodiagnostic aid in the management of melanoma.

Two types of zinc-base composite have been studied, one containing networks of zinc oxide and the other particles of zinc oxide dispersed within the metal matrix. The composites containing zinc-oxide networks possessed mechanical strength at above the melting point of zinc; those containing discontinuous dispersoids had no measurable strength at such temperatures. These results tend to confirm an earlier suggestion that commercial sintered aluminium powder products (SAP) contain a continuous network of alumina dispersed throughout the aluminium matrix.

CEA-like antigen has been detected on the surface of some melanoma cells using a rabbit antiserum raised against CEA antigen in 51Cr-release leucocyte-dependent cytotoxic-antibody (LDA) assays. The CEA antigen used for production of the antiserum was shown to be immunologically pure by immunoelectrophoresis procedures and reacted with a reference serum to CEA. The specificity of the CEA antiserum for CEA on the melanoma cells was further shown by removal of reactivity to melanoma cells after absorption on CEA affinity columns. LDA activity to CEA was also shown in a serum taken during pregnancy. No CEA LDA activity was found in several melanoma sera. These findings suggest that CEA may have biological significance in tumour rejection, and that CEA assays may be of value in monitoring disease activity in melanoma patients.

Previous studies, using plasmapheresis to remove blocking factors of cell-mediated cytotoxicity to melanoma cells from the circulation of melanoma patients, suggested that leucocyte-dependent antibody to melanoma cells may also be blocked by factors in their sera. The present study confirms these findings, by showing that most patients with disseminated melanoma had melanoma LDA activity in the IgG fraction when this was separated from their sera. This also applied to a high percentage of patients with primary melanoma. Evidence that the blocking factors may be immune complexes was shown by experiments in which LDA activity to melanoma cells was revealed after acidification of melanoma sera to dissociate immune complexes, followed by ultrafiltration through membranes retaining molecules of size greater than 100,000 daltons. Blocking of LDA activity in the retentate recurred when the retentate was recombined with the filtrate. Further studies indicated that the blocking activity showed affinity for the target cell and not the effector cell. Preliminary analysis of the specificity of the blocking suggests that this was similar to that of melanoma antisera. These results appear to show that blocking of LDA activity to melanoma cells is common in melanoma patients and that the assay system may provide a quantitative method for their analysis that may yield information of biological importance in the management of melanoma patients.

In rare instances, primary malignant melanoma thickness fails to predict the biologic course of the disease: lesions <0.8 mm thick may recur locally or metastasize, lesions >5.5 mm thick may not prove to be fatal within the expected interval of time, and melanoma recurrences may develop >10 years after first definitive melanoma treatment. The large Sydney Melanoma Unit data base of over 9,500 patients treated over a 41-year period provided a unique opportunity to study the characteristics and prognosis of these patients with unusual melanomas. In stage I patients with thin lesions, and no sign of disease elsewhere, presence of ulceration, high mitotic activity, and/or penetration into the reticular dermis predisposed these melanomas to recur and regression did not emerge as a risk factor for recurrence. This was in sharp contrast to the histology of the thin lesions in patients with concurrent regional lymph node metastases (stage II). Moderate to severe regression was present in all the latter lesions, ulceration and mitoses were absent, and none penetrated beyond the papillary dermis. No specific criteria were found that could identify those stage I or II patients with thick melanomas but at low risk for recurrence or those patients with localized disease (stage I) who required long-term follow-up beyond 10 years. These results indicate that guidelines for follow-up of melanoma patients after first definitive treatment may not be appropriate for a small proportion of patients. Since recurrences are mainly loco-regional and most patients who develop a recurrence detect the recurrence themselves, education of the patient in self-examination, and also self-referral may be the best pragmatic approaches to facilitate early diagnosis of recurrences without imposing too heavy a burden on health services. L'épaisseur du mélanome malin primitif n'est parfois pas un bon élément prédictif de l'évolution de la maladie. Des lésions dont l'épaisseur est < à 0.8 mm peuvent récidiver ou donner des métastases. Au contraire, des lésions > 5.5 mm d'épaisseur n'ont pas toujours le taux de mortalité classique dans les délais habituellement décrits et il existe des cas où les récidives se développent plus de 10 ans après le traitement initial du mélanome. La banque de données de Sydney sur le mélanome, qui comprend plus de 9500 patients traités pendant 41 ans, est une situation unique pour étudier les caractéristiques et le pronostic des patients ayant un mélanome atypique. Chez le patient ayant une lésion mince stade I et sans signe d'extension, la présence d'ulcération, d'une activité mitotique élevée et/ou de signes d'envahissement de la couche réticulaire du derme sont des facteurs prédisposants à la récidive. Ceci contraste avec les lésions minces s'associant à des métastases lymphatiques (stade II). Dans ces cas, on est en présence de lésions modérément régressives avec absence de mitose et d'ulcération et aucune lésion ne dépassait le derme papillaire. Il n'existe aucun critère spécifique qui permette d'identifier les patients avec des lésions de stade I ou II dont l'épaisseur est > 5.5 mm mais avec un risque de récidive peu élevé ou chez lesquels une survie de plus de 10 ans est possible. Ces résultats indiquent qu'une conduite à tenir standardisée peut être inappropriée pour certains patients. Puisque les récidives sont essentiellement locorégionales et que la plupart des patients qui développent des métastases les détectent eux-mêmes, l'éducation du patient, l'apprentissage d'un examen attentif par le patient lui-même et l'indication de signes qui doivent l'amener à consulter sont les meilleurs éléments pour faciliter un diagnostic précoce de récidives sans imposer aux services de santé une tâche trop lourde. En algunos casos aislados el espesor del melanoma primario falla en cuanto a la predicción de la evolución biológica de la enfermedad: lesiones <0.8 mm pueden hacer recurrencia local o metástasis, lesiones >5.5 mm pueden no ser fatales en el curso del esperado período de tiempo y recurrencia del melanoma puede aparecer >10 años después del tratamiento primario definitivo. La gran base de datos de la Unidad de Melanoma de Sydney de más de 9500 pacientes tratados en el curso de un período de 41 años provee una oportunidad única para estudiar las caracteristicas y el pronóstico de estos pacientes con melanomas inusuales. En pacientes con lesiones delgadas en estado I y libres de evidencia de enfermedad en otros lugares, la presencia de ulceración, elevada actividad mitósica y/o penetración de la dermis reticular, predispone a la recurrencia y la regresión no aparece como factor de riesgo de recurrencia, en fuerte contraste con la histología de las lesiones delgadas en pacientes con metástasis ganglionares regionales concurrentes (estado II): regresión moderada a severa fue observada en todas las lesiones de este último tipo, con ulceración y mitosis ausentes, y ninguna penetró más allá de la dermis papilar. No se hallaron criterios específicos que pudieran identificar aquellos pacientes en estados I o II con melanomas gruesos pero con bajo riesgo de recurrencia o aquellos con enfermedad localizada (estado I) que requirieron seguimiento prolongado por más de 10 años. Estos resultados indican que las directrices para el seguimiento de pacientes con melanoma después del tratamiento primario definitivo pueden no ser apropiadas para una pequeña proporción de los casos. Puesto que las recurrencias son principalmente loco-regionales y que la mayoría de los pacientes que desarrollan recurrencia detectan ellos mismos la recurrencia, la instrucción en el autoexamen y en el auto-referencia pueden ser los mejores aproches pragmáticos para facilitar el diagnóstico precoz de la recurrencia sin crear una carga excesiva sobre los servicios de salud.

Node dissection for melanoma remains the most important therapeutic decision for the optimal management of the patient with melanoma. In Australia and in some parts of the United States, the majority of patients with intermediate thickness melanoma (1.6–4.00 mm) will undergo elective lymph node dissection. In Europe, the majority of patients with similar lesions are treated with wide local excision only. The development of an agreed policy for node dissection for melanoma awaits the results of 2 current, prospective randomized trials confirming or disproving the efficacy of elective lymph node dissection. Non-randomized studies showing a benefit or not showing a benefit are readily available but the only 2 prospective randomized studies published to date showing a benefit, have been criticized on methodologic grounds. This paper summarizes the evidence and opinions on both sides of this debate. The clinician charged with responsibility for this important decision must, as yet, make the decision to dissect lymph nodes on the basis of a perspective derived from the best available evidence. La lymphadénectomie reste la décision thérapeutique la plus importante dans le traitement optimal d'un patient avec mélanome. En Australie et dans certaines régions des Etats Unis la majorité des patients ayant un mélanome d'épaisseur moyenne (1.6 à 4.0 mm) auront une lymphadénectomie élective. En Europe, la majorité des patients avec le même type de lésions aura seulement une excision locale élargie. L'attitude thérapeutique à adopter dépendra certainement des résultats de deux essais thérapeutiques randomisés et prospectifs pour confirmer ou infirmer la valeur de la lymphadénectomie élective. Il existe à l'heure actuelle beaucoup d'études non randomisées qui ne permettent pas de trancher, et seulement deux études randomisées en faveur de la lymphadénectomie mais qui restent criticables du point de vue méthodologique. Cet article résume les preuves et les opinions qui sont à la base de ce débat. Le clinicien qui a la responsabilité de cette décision thérapeutique importante se doit de la pendre en connaissance des résultats les plus scientifiquement étayés. El papel de la disección ganglionar electiva (DGE) en el manejo del melanoma sigue siendo motivo de controversia; a pesar de múltiples trabajos relacionados con este tópico no se ha logrado un consenso a nivel mundial. Sin embaro, la decisión sobre remoción de los ganglios de drenaje linfático en un paciente con melanoma primario puede significar la vida o la muerte del paciente. En Australia y en algunas partes de los Estados Unidos la mayoría de los pacientes con melanomas de espesor intermedio (1.6–4.0 mm) es sometida a DGE; en Europa la mayoría de los pacientes con lesiones similares es tratada con resección local solamente. El desarrollo de una política unificada sobre disección ganglionar está a la espera de los resultados de dos estudios prospectivos y randomizados que corren en la actualidad para confirmar o negar la eficacia de la DGE. Estudios no randomizados que muestran un beneficio o que niegan tal beneficio están disponibles, pero los dos únicos estudios prospectivos y randomizados publicados hasta la fecha han sido motivo de crítica sobre bases metodológicas. El presente artículo resume la evidencia y las opiniones correspondientes a los dos aspectos del debate. El médíco responsable de tan importante decisión está sometido, todavía, a emprender o no la DGE con base en una perspectiva que se deriva de la mejor evidencia disponible y teniendo en cuenta las siguientes conclusiones: la DGE no logra mejores resultados que una disección ganglionar pospuesta hasta la aparición de metástasis ganglionares, especialmente en el caso de melanomas de la extremidades; existe correlación evidente entre la incidencia de metástasis ganglionares y el espesor del melanoma, y pacientes con melanomas >2.0 mm de espesor deben ser sometido a vigilancia especial por su alta propensión a las metástasis ganglionares; en los melanomas del tronco persiste la controversia sobre si la disección ganglionar debe hacer parte del tratamiento primario en lo relativo a pacientes masculinos, en quienes se recomienda que aquellos con estado I y melanomas >1.5 mm sean ingresados a estudios randomizados, por cuanto parece existir una pequeña ventaja con la DGE. En resumen, el manejo óptimo de los pacientes con melanoma en estado I debe ser la resección del tumor primario, controles clínicos cada 3 meses por 5 años con especial atención a los ganglios regionales y disección ganglionar en el momento de aparición de ganglios clínicamente afectados; las dos excepciones son los hombres con melanomas de espesor >1.5 mm, que deben ser ingresados a estudios randomizados, y los pacientes con melanomas de espesor >2.0 mm que no puedan ser sometidos a cuidadoso seguimiento, por su alto riesgo de desarrollar metástasis ganglionares inoperables.

Background: Lymphocoele formation can be a troublesome surgical complication after lymph node dissection and mobilization of large skin flaps. Occasionally, lymphocoeles persist for prolonged periods despite repeated aspiration. Treatment by sclerotherapy has been recommended, but this requires a prolonged treatment time and often causes intense pain.

A NUMBER of zinc-based alloys containing equiaxed particles of various stable and insoluble hard second phases were prepared as part of an investigation into the high-temperature compression creep characteristics of dispersion-hardened materials1. It was found that the dispersed particles produced a substantial strengthening effect at temperatures above 0.60 of the absolute melting temperature of zinc. Room-temperature tensile tests were made in order to measure the expected loss in ductility of zinc caused by the hard particles. It was surprising to find, therefore, that most of the dispersed particles reduced the strength and increased the ductility of zinc. These results are briefly reviewed here.