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 patient's 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 patient's 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, Clark's 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.

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Resumen Diversos 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.

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Résumé Plusieurs facteurs cliniques et anatomopathologiques semblent déterminer la récidive et la survie des mélanomes. De nombreux auteurs se sont intéressés à l'identidification des facteurs de pronostic, mais peu d'équipes ont essayé d'élaborer 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 d'évaluation 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 s'agit d'une des plus grandes banques de données au monde contenant des informations cliniques, anatomopathologiques et sur l'évolution à long terme. L'épaisseur de la tumeur au moment du diagnostic était le facteur pronostic le plus important pour déterminer l'évolution. 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 l'épaisseur de la tumeur. L'importance de l'épaisseur 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. L'influence de ces facteurs diminuait en cas de rémission plus prolongée.Les modèles permettant d'évaluer l'évolution du mélanome malin au moment du diagnostic et apreès un intervalle de rémission sont utiles au cours du traitement du mélanome. Ils doivent permettre d'identifier les patients à risque de récidive et de décès.

     

A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence

The ablepharon macrostomia syndrome is an extremely rare congenital anomaly. It is characterised by bilateral absence or hypoplasia of lower eyelids, macrostomia and multiple other congenital anomalies. Three cases have been reported (McCarthy and West, 1977; Hornblass and Reifler, 1985). In addition to ablepharon and macrostomia, other anomalies common to all patients include auricular deformity, nasal alar deformity, absence of lanugo hair, dry, ichthyotic skin and ambiguous genitalia. A new feature of the syndrome is described--absence of the zygomatic arches. In addition, an expanded and revised classification of the ablepharon macrostomia syndrome and related disorders is presented. Skin graft pigmentation in this black patient has been prevented by prolonged application of sun block.     

Metabolic intervention in surgical patients. An assessment of the effect of somatostatin, ranitidine, naloxone, diclophenac, dipyridamole, or salbutamol infusion on energy and protein kinetics in surgical patients using stable and radioisotopes.

We have assessed the effect of a variety of forms of metabolic intervention on both energy and protein metabolism in 44 severely ill surgical patients. The patients were studied either in the basal state or while receiving total parenteral nutrition (TPN), and the metabolic effects were assessed using the primed-constant infusion of a combination of stable isotopes and radioisotopes. Somatostatin infusion, either in the basal state or in the TPN, did not change glucose kinetics, but there was a significant decrease in the rate of net protein catabolism (NPC). In the basal studies the rate of NPC decreased from 3.4 +/- 0.7 g/kg/d to 2.9 +/- 0.7 g/kg/d (p less than 0.002), while in the TPN patients the corresponding values were 1.48 +/- 0.61 g/kg/d and 1.10 +/- 0.50 g/kg/d, respectively (p less than 0.005). Histamine type 2 blockade with ranitidine did not significantly alter glucose kinetics, but in both the TPN patients and in the basal state ranitidine was associated with a significant decrease in the rate of NPC. In the basal state rate of NPC was 2.44 +/- 0.53 g/kg/d and during ranitidine infusion the value was 2.08 +/- 0.42 g/kg/d (p less than 0.04). Naloxone infusion did not alter glucose kinetics, but there was a significant decrease in the rate of NPC from a basal value of 2.6 +/- 0.6 g/kg/d to 2.3 +/- 0.5 g/kg/d (p less than 0.04). The infusion of the prostaglandin antagonists diclofenac or dipyridamole resulted in increases in the plasma insulin level, and as a result glucose turnover decreased in both groups. In the diclofenac group the rate of glucose turnover decreased from 14.4 +/- 1.7 mumol/kg/min to 12.6 +/- 1.3 mumol/kg/min (p less than 0.02). Neither prostaglandin antagonist resulted in any significant change in the rate of NPC. Beta-adrenergic stimulation with salbutamol resulted in a significant increase in glucose turnover from 12.1 +/- 1.1 mumol/kg/min to 13.4 +/- 0.9 mumol/kg/min (p less than 0.02), and the rates of appearance (Ra) of both alanine and free fatty acids (FFAs) also increased. Alanine Ra increased from 11.7 +/- 2.5 mumol/kg/min to 12.8 +/- 3.0 mumol/kg/min, and the corresponding values for FFA turnover were 7.6 +/- 1.1 mumol/kg/min and 10.3 +/- 2.1 mumol/kg/min (p less than 0.03), respectively. Salbutamol infusion did not result in any significant change in the rate of NPC.(ABSTRACT TRUNCATED AT 400 WORDS)     

Acute septic arthritis in infancy and childhood

Despite intensive study of acute septic arthritis in infancy and childhood, poor outcomes continue to occur. Failures are often due to delayed diagnosis and inadequate therapy, but can be due to factors beyond physicians' control such as associated osteomyelitis and occurrence during infancy. Recent advances in the understanding and management of septic arthritis include: (1) demonstration of beneficial effects of continuous passive motion in rabbits; (2) identification of inflammatory mediators of cartilage destruction and their respective sources; (3) recognition of changing patterns of pathologic organisms; (4) evolution of new antibiotics and standards for oral and home intravenous therapy; (5) development of arthroscopic debridement of septic knees; and (6) further refinement of indications for aspiration-irrigation versus open surgical drainage of septic joints. Permanent sequelae from septic arthritis can only be prevented by early diagnosis and aggressive treatment.     

Buserelin in premenstrual syndrome.

Buserelin, a luteinizing hormone releasing hormone agonist was administered nasally in doses of 900 micrograms daily to inhibit the ovarian cycle. Of 16 patients recruited, ten completed the treatment. Daily symptoms were measured on the Visual Analogue Scale and Trigg's trend analysis utilized for the analysis. The peak severity of symptoms (ESAmax) and the maximum global scores (Gmax) reduced on buserelin treatment. The minimum global scores (Gmin) and the minimum score for each symptom (ESAmin) increased, suggesting worsening of underlying symptoms. The difference between ESAmax and ESAmin (ESAdelta) and Gmax and Gmin (Gdelta) were calculated to determine the degree of symptom change. The delta scores for symptoms of depression, bloatedness and breast symptoms, and Gdelta were significantly reduced (p less than 0.05) on buserelin, whilst the latter significantly worsened in the follow-up months. Side-effects may limit the place of buserelin in the long-term treatment of premenstrual syndrome, although combination of additional hormonal treatment may facilitate long-term treatment.     

Distinct p53/56lyn and p59fyn domains associate with nonphosphorylated and phosphorylated Ig-alpha.

Among the earliest detectable events in B-cell antigen receptor-mediated signal transduction are the activation of receptor-associated Src-family tyrosine kinases and the tyrosine phosphorylation of Ig-alpha and Ig-beta receptor subunits. These kinases appear to interact with resting B-cell antigen receptor complexes primarily through the Ig-alpha chain antigen receptor homology 1 (ARH1) motif. Recent studies showed a dramatic increase in the amount of Src-family kinase p59fyn bound to Ig-alpha when ARH1 motif tyrosines were phosphorylated. To explore the submolecular basis of these interactions, we conducted mutational analysis to localize sites in p53/56lyn and p59fyn that bind nonphosphorylated and phosphorylated Ig-alpha. Here we report that distinct regions within these kinases bind nonphosphorylated and phosphorylated Ig-alpha ARH1 motifs. The N-terminal 10 residues mediate binding to the nonphosphorylated Ig-alpha ARH1 motif. Association with the phosphorylated Ig-alpha ARH1 motif is mediated by Src homology 2 domains. These findings suggest a mechanism whereby ligand-induced Ig-alpha tyrosine phosphorylation initiates a change in the orientation of an associated kinase that may alter its activity and/or access to substrates and other effectors.