Does complete resection of melanoma metastatic to solid intra-abdominal organs improve survival?

BACKGROUND: Patients with distant melanoma metastases have median survivals of 4 to 8 months. Previous studies have demonstrated improved survival after complete resection of pulmonary and hollow viscus gastrointestinal metastases. We hypothesized that patients with metastatic disease to intra-abdominal solid organs might also benefit from complete surgical resection. METHODS: A prospectively acquired database identified patients treated for melanoma metastatic to the liver, pancreas, spleen, adrenal glands, or a combination of these from 1971 to 2000. The primary intervention was complete or incomplete surgical resection of intra-abdominal solid-organ metastases, and the main outcome measure was postoperative overall survival (OS). Disease-free survival (DFS) was a secondary outcome measure. RESULTS: Sixty patients underwent adrenalectomy, hepatectomy, splenectomy, or pancreatectomy. Median OS was significantly improved after complete versus incomplete resections, but median OS after complete resection was not significantly different for single-site versus synchronous multisite metastases. The 5-year survival in the group after complete resection was 24%, whereas in the incomplete resection group, there were no 5-year survivors. Median DFS after complete resection was 15 months. Of note, the 2-year DFS after complete resection was 53% for synchronous multi-site metastases versus 26% for single-site metastases. CONCLUSIONS: In highly selected patients with melanoma metastatic to intra-abdominal solid organs, aggressive attempts at complete surgical resection may improve OS. It is important that the number of metastatic sites does not seem to affect the OS after complete resection.

Surgical resection for metastatic melanoma to the liver: the John Wayne Cancer Institute and Sydney Melanoma Unit experience.

HYPOTHESIS: Metastatic melanoma to the liver is not incurable; complete surgical resection can achieve long-term survival in selected patients. BACKGROUND: Metastases to the liver are diagnosed in 10% to 20% of patients with American Joint Committee on Cancer stage IV melanoma. Surgical resection has not been generally accepted as a therapeutic option, as most patients will have other sites of disease that limit their survival to a median of only 4 to 6 months. However, there is little information on outcomes following resection in those patients with disease limited to the liver. PATIENTS AND METHODS: Review of the prospective melanoma databases at the John Wayne Cancer Institute, Santa Monica, Calif, and the Sydney Melanoma Unit, Sydney, Australia, identified 1750 patients with hepatic metastases, of whom 34 (2%) underwent exploration with intent to resect the metastases. Prognostic factors within the group of patients who underwent resection were examined by univariate and multivariate analysis, and median disease-free survival (DFS) and overall survival (OS) were calculated. RESULTS: Of 34 patients undergoing exploratory celiotomy, 24 (71%) underwent hepatic resection and 10 (29%) underwent exploration but not resection. Eighteen patients (75%) underwent complete surgical resection, while the remaining 6 underwent palliative or debulking procedures with incomplete resection. The operative resections included lobectomy (n=14), segmentectomy (4), nonanatomic resection (5), and extended lobectomy (1). The median number of resected lesions was 1, and median lesion size was 5 cm (range, 0.7-22 cm). The median disease-free interval between initial diagnosis of melanoma and development of hepatic metastases was 58 months (range, 0-264 months). Median DFS and OS estimates in the 24 patients who underwent surgical resection were 12 months (range, 0-147 months) and 28 months (range, 2-147 months), respectively. Five-year DFS and OS in this group were 12% and 29%. Macroscopically, complete resection of disease (P =.001) and histologically negative resection margins (P =.03) significantly improved DFS by univariate analysis. Patients rendered surgically free of disease also tended to have improved OS (P =.06). Median OS was 28 months for patients who underwent surgical resection compared with 4 months for patients who underwent exploration only (P<.001). CONCLUSIONS: Resection of metastatic melanoma to the liver may improve DFS and OS in selected patients, similar to resection of other metastatic sites. Therefore, patients with limited metastatic sites, including the liver, who can be rendered free of disease should be considered for complete surgical resection, as their prognosis is otherwise dismal.

Serum TA90 antigen-antibody complex as a surrogate marker for the efficacy of a polyvalent allogeneic whole-cell vaccine (CancerVax) in melanoma.

INTRODUCTION: TA90 is a tumor-associated 90-kD glycoprotein antigen expressed on most melanoma cells, including those of CancerVax, a polyvalent allogeneic whole-cell vaccine. Previous studies have shown that a TA90 antigen-antibody immune complex (IC) in the serum of patients with melanoma is a marker of subclinical tumor burden and a strong prognostic factor. We hypothesized that the induction of TA90-IC during postoperative adjuvant CancerVax therapy might indicate vaccine-mediated immune destruction of subclinical melanoma cells with release of TA90, and thereby serve as a surrogate marker of vaccine efficacy. METHODS: From 1993 to 1997, 219 melanoma patients were enrolled in a prospective phase II trial of CancerVax plus bacille Calmette-Guerin (BCG) after complete tumor resection. Coded serum samples were prospectively collected and analyzed for TA90-IC before and 2, 4, 8, 12, and 16 weeks after initiation of CancerVax therapy. TA90-IC seroconverters were those patients whose negative TA90-IC values (< .410) became positive (> or = .410) after initiation of CancerVax treatment. RESULTS: Before CancerVax therapy, 51 patients had positive TA90-IC values and 168 patients had negative TA90-IC values. During CancerVax treatment, all 51 positive patients remained positive, 79 (47%) negative patients seroconverted to positive, and 89 (53%) negative patients remained negative. Seroconverters had higher 2-year rates of disease-free survival (59% vs. 32%; P < .006) and overall survival (78% vs. 63%; P < .02) than did patients whose TA90-IC values remained positive. CONCLUSIONS: CancerVax induces TA90-IC in melanoma patients with subclinical disease. TA90-IC seroconverted patients have significantly improved disease-free and overall survival compared with TA90-IC positive patients. TA90-IC is an important prognostic factor that can serve as a surrogate marker for the clinical efficacy of CancerVax.

Earlier diagnosis of second primary melanoma confirms the benefits of patient education and routine postoperative follow-up.

BACKGROUND: Rising health care costs have caused providers to question the benefit of regular follow-up after treatment for patients with early stage cutaneous melanoma. The authors hypothesized that routine reassessment and careful education of these patients would facilitate earlier diagnosis of a subsequent second primary melanoma, as reflected by reduced thickness of that lesion. METHODS: A prospective melanoma data base was used to identify patients who developed a second primary melanoma after treatment for American Joint Committee on Cancer (AJCC) Stage I or II cutaneous melanoma. After excision of the initial primary melanoma, all patients underwent routine biannual follow-up for new primary lesions. Follow-up consisted of a questionnaire and a complete skin examination by a physician. In addition, patients were regularly educated regarding the increased risk of developing a second melanoma. A paired t test was used to examine AJCC stage, thickness, and level of invasion of the initial melanoma compared with the second primary melanoma. RESULTS: Of 3310 patients with AJCC Stage I or II melanoma, 114 patients (3.4%) developed a second primary melanoma. AJCC staging of both first and second melanomas was available in 82 patients (72%). When the AJCC stages of first and second melanomas were compared, 39 of 82 patients (48%) had lower stage second primary lesions, and 41 (50%) had same-stage second primary lesions. The mean tumor thickness was 1.32 +/- 1.02 mm for the initial melanoma, decreasing to 0.63 +/- 0.52 mm for the second melanoma; in fact, tumor thickness increased in only 4 of 51 patients (8%) whose records contained data for both first and second melanomas. Similarly, the level of invasion decreased in 60% of patients, remained the same in 27% of patients, and increased in only 13% of patients. By paired t test, the differences in AJCC stage, tumor thickness, and level of invasion between first and second melanomas were each highly significant (P = 0.0001). CONCLUSIONS: In this study, the second primary melanoma in patients with a prior cutaneous melanoma was significantly thinner than the initial primary lesion. This is evidence that careful follow-up and patient education allow earlier diagnosis. All patients diagnosed with cutaneous melanoma should be counseled regarding the risks of second melanoma and should undergo lifelong follow-up at biannual intervals.

Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas?

INTRODUCTION: Postoperative radiotherapy (PR) has been recommended in patients with advanced head and neck melanomas to improve regional control. This study examined the incidence of cervical recurrence among patients who did not receive PR after surgical management of node-positive head and neck melanomas. METHODS: A computerized search of a database listing more than 10,000 patients with melanoma prospectively acquired between 1971 and 1998 identified 217 patients with pathologically positive nodes who had undergone regional lymph node dissection (RLND). Of these patients, 21 had received PR and 196 had not. RESULTS: Median follow-up after RLND was 20 months for nonsurvivors and 32 months for survivors. The overall incidence of cervical recurrence was 14% (27/196). The 5-year cervical recurrence-free survival rate was 83%. Five-year cervical recurrence-free survival rates were 69% vs. 87% for patients with vs. without extranodal disease (P = .004), 96% vs. 81% for patients with nonpalpable vs. palpable nodes (P = .0761), and 82% vs. 91% for patients with one to three positive nodes vs. more than three positive nodes (P = .256). Multivariate analysis, which included the timing of nodal disease presentation and the effect of systemic adjuvant therapy, identified extranodal disease as the only independent predictor of cervical recurrence (P = .034). Cervical recurrence was significantly related to the subsequent occurrence of distant relapse. CONCLUSIONS: The low incidence of cervical recurrence after RLND in patients with node-positive head and neck melanomas does not justify the routine use of PR. The only subset of patients who may benefit from PR are those with extranodal disease.

Effects of halothane, enflurane, and isoflurane on measurements of Ca(2+) by calcium electrode and aequorin luminescence.

We assessed the possible effects of the volatile halogenated anesthetics halothane, enflurane, and isoflurane on Ca(2+) electrode measurements and on the Ca(2+) sensitivity of the bioluminescent protein aequorin. In Ca(2+)-EGTA buffers of different pCa values (7. 870, 6.726, 6.033, 4.974, 4.038, and 2.995) and in serial Ca(2+) dilutions (10(-4), 10(-3), and 10(-2) M), halothane, enflurane, and isoflurane each caused a concentration-dependent and reversible increase in the absolute value of the negative electrode potential. Isoflurane and enflurane had larger effects than halothane. Neither of these anesthetics changed aequorin luminescence at any pCa tested in the range 2-8. There was no potentiation or inactivation of aequorin luminescence over a period of up to 2 h. These results suggest that (1) halothane, enflurane, and isoflurane interfere with Ca(2+) electrode measurements, most likely by changing the physicochemical properties of the membrane; (2) these anesthetics do not inactivate or otherwise modify the characteristics of the reaction of Ca(2+) with aequorin; and (3) these anesthetics do not change the apparent affinity of EGTA for Ca(2+).

Judging the therapeutic value of lymph node dissections for melanoma.

BACKGROUND: The management of the regional lymph nodes remains controversial for early-stage melanoma and for those patients with lymph node metastases; American Joint Committee on Cancer stage III. This study examines the importance of quality of the surgical resection measured by the extent of lymph node dissection (quartile of the total number of lymph nodes removed) to determine if this factor is an important prognostic factor for survival. STUDY DESIGN: We reviewed our computer-assisted database of more than 8,700 melanoma patients prospectively collected from 1971 through the present to identify patients who underwent lymph node dissection for stage III melanoma. We included only patients who had their nodal dissections performed at our institute. Patients who underwent sentinel lymph node dissection were excluded. These patients were then analyzed as a group and by individual lymphatic basins: cervical, axillary, and inguinal basins. Univariate and multivariate analyses were used to examine the model that included tumor burden, thickness of the primary melanoma, gender, age, clinical status of the lymph nodes (palpable versus not palpable), and the primary site. The survival and recurrence rates were analyzed using the Cox proportional hazards model. RESULTS: Five hundred forty-eight patients underwent regional lymph node dissections. Of these patients, 214 underwent axillary dissections, 181 inguinal dissections, and 153 cervical dissections. The extent of the nodal dissections was based on the quartile of nodes excised, ranging from 1 to 98 (mean +/- SD = 25.8 +/- 15.8). Patients were stratified by tumor burden and quartile of number of lymph nodes removed. The overall 5-year survival of patients with four or more lymph nodes having tumor and the highest quartile of lymph nodes removed was 44% and was 23% for the lowest quartile of total lymph nodes excised (p = 0.05). By univariate analysis, tumor burden (p = 0.0001), quartile of total lymph nodes removed (p = 0.043), and primary site (p = 0.047) were statistically significant for predicting overall survival. Gender, clinical status of the nodes, primary tumor thickness, age, and dissected basin were not significant (p > 0.05). By multivariate analysis only the tumor burden (p = 0.0001) and quartile of lymph nodes resected (p = 0.044) were statistically significant. CONCLUSIONS: The extent of lymph node dissection for melanoma when analyzed by quartiles is an independent factor in overall survival. This factor appears to be more important with increasing tumor burden in the lymphatic basin. The extent of lymph node dissection should be considered as a prognostic factor in the design of clinical trials that involve stage III melanoma.

Effects of halothane and isoflurane on the intracellular Ca2+ transient in ferret cardiac muscle.

BACKGROUND: Halothane and isoflurane depress myocardial contractility by decreasing transsarcolemmal Ca2+ influx and Ca2+ release from the sarcoplasmic reticulum. Decreases in Ca2+ sensitivity of the contractile proteins have been shown in skinned cardiac fibers, but the relative importance of this effect in intact living myocardium is unknown. The aims of this study were to assess whether halothane and isoflurane decrease myofibrillar Ca2+ sensitivity in intact, living cardiac fibers and to quantify the relative importance of changes in myofibrillar Ca2+ sensitivity versus changes in myoplasmic Ca2+ availability caused by these anesthetics. METHODS: The effects of halothane and isoflurane (0-1.5 times the minimum alveolar concentration (MAC) in three equal increments) on isometric and isotonic variables of contractility and on the intracellular calcium transient were assessed in isolated ferret right ventricular papillary muscle microinjected with the Ca2+-regulated photoprotein aequorin. The intracellular calcium transient was analyzed in the context of a multicompartment model of intracellular Ca2+ buffers in mammalian ventricular myocardium. RESULTS: Halothane and isoflurane decreased contractility, time-to-peak force, time to half-isometric relaxation, and intracellular Ca2+ transient in a reversible, concentration-dependent manner. Halothane, but not isoflurane, slowed the increase and the decrease of the intracellular Ca2+ transient. Increasing extracellular Ca2+ in the presence of anesthetic to produce peak force equal to control values increased intracellular Ca2+ to values higher than control values. CONCLUSIONS: Halothane decreases myoplasmic Ca2+ availability more than isoflurane; halothane and isoflurane decrease myofibrillar Ca2+ sensitivity to the same extent; in halothane at 0.5 MAC and isoflurane at 1.0 MAC, the decrease in Ca2+ sensitivity is already fully apparent; halothane decreases intracellular Ca2+ availability more than myofibrillar Ca2+ sensitivity; and isoflurane decreases myoplasmic Ca2+ availability and Ca2+ sensitivity to the same extent, except at 1.5 times the MAC, which decreases Ca2+ availability more.

Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences?

BACKGROUND: Although more than 90% of the morbidity and mortality from localized cutaneous melanoma occurs in the first decade after initial surgical treatment, melanoma can recur after a 10-year disease-free interval (DFI) with fatal consequences. We reviewed our melanoma data base of more than 8,500 prospectively acquired patients to identify clinicopathological factors that affect the type, rate of occurrence, and outcome of disease recurring 10 years or more after surgical treatment of primary cutaneous melanoma. METHODS: From 1971 to 1997, 1907 melanoma patients treated at our cancer center reached or presented with a DFI of 10 years or more after surgical treatment of clinically localized melanoma. Of these, 217 (11%) patients had recurrences (mean DFI, 182 months). The sites of recurrence were local/in-transit in 26 (12%) patients, regional lymph nodes in 101 (47%) patients, and distant sites in 90 (41%) patients. RESULTS: Univariate and multivariate analysis, using patient age and sex, type of initial treatment, and the site, Breslow thickness, and Clark level of the initial tumor, showed that the type of treatment for the primary tumor was a significant (P = .0005) prognostic factor in the development of late nodal recurrence. Of the 217 patients who had recurrences, 172 (79%) had undergone wide local excision for their primary melanoma, and 45 (21%) had undergone wide local excision plus elective lymph node dissection (ELND). The rates of nodal recurrence were 53% (92 of 172) and 20% (9 of 45), respectively, a significant (P = .0001) difference. When all patients with a DFI of 10 years or more were stratified by type of initial treatment, the ELND group demonstrated a significant improvement in disease-free survival and overall survival. CONCLUSIONS: The risk of late-recurring nodal disease increases and the chance of long-term survival decreases when wide local excision is performed without ELND. With the advent of sentinel lymphadenectomy, ELND can be selectively performed only for those nodal basins with occult tumor cells, thereby decreasing operative morbidity but allowing identification and early removal of nodal micrometastases.

Activity-induced fiber regeneration in rat soleus muscle.

In an attempt to understand why muscle recovery is limited following atrophy due to limb immobilization, satellite cell activity and muscle fiber regeneration were analyzed in rat soleus muscles. Adult rat hindlimbs were immobilized in plaster casts for a period of two to ten weeks. Soleus muscles were examined by electron microscopy for evidence of fiber degeneration or regeneration, and to quantify satellite cell nuclei. Immunocytochemical localization of embryonic myosin was used to identify regenerating myofibers. Soleus muscle wet weight to body weight ratios for the casted muscles significantly decreased over the 10-week immobilization period. The casted muscles displayed ultrastructural evidence of minor fiber damage, including myofibrillar atrophy, Z-disc disruption, and abnormal triadic junctions. No ultrastructural evidence of regeneration was seen in the casted animals. The number of satellite cells in the casted muscles significantly decreased from 6.4% to 3. 3% by eight to 10 weeks of immobilization. Approximately 1.0% of extrafusal fibers in the control soleus muscles appeared to be regenerating since they expressed embryonic myosin and were of a small diameter, while in casted muscles, only 0.1% of the fibers were embryonic myosin-positive. Following release from immobilization, a reappearance of embryonic myosin-positive fibers was noted within four days of renewed activity. In contrast to control muscles, embryonic myosin-positive fibers in the recovery muscles included both small and large diameter fibers. Subtle changes in functional activity influence muscle damage and subsequent myofiber regeneration. Reduced activity reduces muscle fiber regeneration, while increased activity, as seen by increased hindlimb weight bearing and return to normal activity following immobilization, increase regenerating fibers and also the expression of embryonic myosin in adult fibers.

Increased incidence of second primary melanoma in patients with a previous cutaneous melanoma.

BACKGROUND: Patients with cutaneous melanoma reportedly have an increased risk of developing second primary melanoma; however, this increased risk has not been well characterized with respect to age and time from first melanoma. We hypothesized that, as a result of temporal variations in environmental exposure, genetic susceptibility, and impaired immune competence, the incidence of second primary melanoma varies significantly with respect to age and time. METHODS: A review of our prospective melanoma data base, containing records for 8928 patients, was undertaken to identify patients with American Joint Committee on Cancer stage I and II cutaneous melanoma, who were treated from 1971 to 1998. RESULTS: Second primary melanoma was identified in 113 (3.4%) of 3310 patients with American Joint Committee on Cancer stage I and II cutaneous melanoma. In 11 patients (0.3%), the second melanoma was identified within 2 months of the initial tumor; the remaining 102 patients had a metachronous lesion. The incidence rate of second primary melanoma was 325 per 100,000. The standardized incidence ratio, defined as the ratio of the number of observed second melanomas to the number of expected melanoma cases, was 25.6. The 5- and 10-year risk of developing a second melanoma was 2.8% and 3.6%, respectively. Both the annual risk of developing a second melanoma and the standardized incidence ratio were elevated in younger patients (ages 15-39 years) and in older patients (ages 65-79 years). CONCLUSIONS: Patients with cutaneous melanoma are at very high risk for development of second primary melanoma. This risk approximates 0.5% per year for the first 5 years of follow-up. Patients aged 15-39 and patients aged 65-79 have a particularly high incidence of second melanoma, suggesting different causes for the development of second primaries. All patients with melanoma should undergo careful surveillance for second melanomas in addition to routine screening for recurrence.

Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma.

BACKGROUND: Lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection (LM/SL/SCLND) is an increasingly popular alternative to elective lymphadenectomy (ELND) for patients with early-stage melanoma. Although several reports have demonstrated the accuracy of the LM/SL technique, there are no data on its therapeutic value. METHODS: We performed a matched-pair statistical analysis of 534 patients with clinical stage I melanoma; one half of the patients were treated with LM/SL and the other half were treated with ELND. Patients in the two treatment groups were matched for age (54% were < or =50 years of age), gender (63% were male patients), site of the primary melanoma (49% were on the extremities, 36% on the trunk, and 15% on the head and neck), and thickness of the primary melanoma (7% were < 0.75 mm, 42% between 0.75 and 1.5 mm, 43% between 1.51 and 4.0 mm, and 8% > 4 mm). Patients in the LM/SL group underwent complete regional lymphadenectomy (SCLND) only if the LM/SL specimen contained metastatic melanoma. RESULTS: The overall incidences of nodal metastases were no different (P = .18) between LM/SL (15.7%) and ELND (12%) groups, but the incidence of occult nodal disease was significantly (P = .025) higher among patients with intermediate-thickness (1.51-4.0-mm) primary tumors who underwent LM/SL (23.7%) instead of ELND (12.2%). Survival data were compared by the log-rank score test. LM/SL/SCLND and ELND resulted in equivalent 5-year rates of disease-free survival (79 +/- 3.3% and 84 +/- 2.2%, respectively; P = .25) and overall survival (88 +/- 3.0% and 86 +/- 2.1%, respectively; P = .98). The LM/SL and ELND groups also exhibited similar incidences of same-basin recurrences (4.8% vs. 2.1%, P = .10, respectively) and in-transit metastases (2.6% vs. 3.8%, P = .48) after tumor-negative dissections. Patients who underwent ELND showed a higher incidence of distant recurrences (8.9% vs. 4.0%, P = .03), but this may be related to the longer follow-up period for these patients (median, 169 months), compared with the LM/SL-treated patients (45 months). Among patients with tumor-positive nodal dissections, the 5-year overall survival rates were higher, and approached significance (P = .077) for patients treated by LM/SL/SCLND (64 +/- 12%) compared with ELND (45 +/- 10%). CONCLUSIONS: These findings suggest that LM/SL/SCLND is therapeutically equivalent to ELND but may be more effective for identifying nodal metastases in patients with intermediate-thickness primary tumors.

Lymph node biopsy does not impair survival after therapeutic dissection for palpable melanoma metastases.

BACKGROUND: To determine the effects of disrupting a nodal basin in patients with American Joint Committee on Cancer stage III melanoma with clinically palpable lymph nodes, we studied patients who underwent therapeutic lymph node dissection after excisional lymph node biopsy, after fine-needle aspiration (FNA) biopsy, or without a preoperative biopsy. METHODS: We performed a retrospective review of our patients with American Joint Committee on Cancer stage III melanoma who were treated between January 1972 and June 1995, using data acquired from our 8200-patient database. The study group included 670 patients with melanoma, with known primary tumors, who underwent therapeutic lymph node dissection for palpable nodal metastases diagnosed by open biopsy (227 patients), by FNA (66 patients), or by clinical observation without biopsy (377 patients). Regional node recurrence, 5-year disease-free survival, and overall survival rates were calculated. RESULTS: The same-basin regional node recurrence rates were similar for the three groups (open biopsy, 4.6%; FNA, 3.2%; no biopsy, 4.6%; P = .14). The 5-year disease-free survival rates were 36.8% for the open-biopsy group, 29.6% for the FNA group, and 28.9% for the no-biopsy group (P = .08); corresponding 5-year overall survival rates were 40.6%, 43.9%, and 36.1%, respectively (P = .18). Multivariate analysis failed to identify preoperative biopsy as a significant risk factor. Matched-pair analysis using age, gender, primary tumor site, Breslow thickness, and tumor burden showed no differences in the 5-year disease-free survival rates (33% for the open-biopsy group vs. 27% for the FNA and no-biopsy groups, P = .42) and the 5-year overall survival rates (41% vs. 35%, P = .32). CONCLUSIONS: For patients with melanoma with palpable regional adenopathy, histological confirmation of clinical suspicion with either FNA or excisional lymph node biopsy does not adversely affect survival or recurrence rates.

Tumor-associated antigen TA-90 immune complex assay predicts subclinical metastasis and survival for patients with early stage melanoma.

BACKGROUND: TA-90 is a tumor-associated antigen first identified in the urine and sera of patients with metastatic melanoma. In the early stages of disease, TA-90 is present in circulating immune complexes (ICs) that may be detected with an antigen specific enzyme-linked immunosorbent assay (ELISA). In this study, the authors evaluated the efficacy of the TA-90 IC assay in detecting subclinical metastasis of early stage melanoma and predicting the survival of patients with this disease. METHODS: Archival sera were collected preoperatively from 114 patients who underwent wide excision with or without regional lymphadenectomy in the treatment of clinical Stage I melanoma. Sera were analyzed for TA-90 IC in a blinded fashion, and results were correlated with the patient's clinical course as determined by database and chart review. Subclinical metastases were considered present at the time of surgery if the lymphadenectomy specimen was pathologically positive and/or the patient subsequently developed recurrence. RESULTS: The TA-90 IC assay predicted subclinical metastasis in 43 of 56 patients (P < 0.0001), with 14 false-positive and 13 false-negative results. Sensitivity and specificity for the detection of occult metastasis were 77% and 76%, respectively. Positive and negative predictive values were 75% and 77%, respectively. Fifteen of 18 tumor positive regional lymph node basins (83%) and 34 of 46 recurrences (74%) were accurately predicted when considered independently (P < 0.004). Preoperative TA-90 IC status was also highly correlated with survival: 5-year overall and disease free survival rates were 63% and 46%, respectively, for the TA-90 IC positive group, compared with 88% and 82%, respectively, for the TA-90 IC negative group (P=0.0001). A multivariate analysis with standard prognostic variables identified preoperative TA-90 IC status as a strong, independent prognostic factor for both overall and disease free survival. CONCLUSIONS: To the authors' knowledge, TA-90 is the first tumor marker that accurately predicts subclinical metastatic disease and survival for patients with early stage melanoma. For this reason, the TA-90 IC assay has the potential to improve dramatically the prognostic evaluation of patients with this disease. Its role in postoperative risk stratification and early detection of recurrence is being evaluated in a prospective study.

Metastasis of primary melanoma to two separate lymph node basins: prognostic significance.

BACKGROUND AND METHODS: Depending on the location of the primary lesion, melanoma patients may develop metastases in more than one regional lymph node basin. To determine whether this is prognostically significant, we reviewed our experience with melanoma patients who had undergone regional lymphadenectomy (RLND) in two separate basins. RESULTS: Of 3,603 patients who underwent RLND between April 1971 and January 1993, 406 underwent procedures in two separate basins; of these, 120 (30%) had metastases in both basins and 124 (30%) had metastases in one basin. When calculated from the first positive RLND, 1-year, 3-year, and 5-year survival rates were 82%, 48%, and 33%, respectively, for patients with dual-basin involvement and 88%, 59%, and 48%, respectively, for patients with single-basin involvement (p = 0.0173). Median survival from the first positive RLND was 33.5 months for dual-basin involvement and 56.6 months for single-basin involvement. Univariate analysis demonstrated that Breslow thickness of the primary melanoma, clinical status of the regional lymph nodes, number of positive RLNDs, and tumor burden (total number of positive lymph nodes) were significant indicators of survival. The patient's age and gender, the anatomic location and Clark level of the primary melanoma, the disease-free interval before regional metastasis, and the site and timing of RLNDs were not significant by univariate analysis. Multivariate analysis demonstrated significance for Breslow thickness, number of positive RLNDs, and tumor burden. CONCLUSIONS: The survival rate of melanoma patients with regional metastases in two lymph node basins is lower than that of patients with an equal tumor burden confined to a single basin. This suggests that primary melanomas metastasizing to more than one lymph node basin may have a higher metastatic potential, or that dual-basin involvement may increase the risk of systemic spread. We advocate lymphatic mapping, sentinel node biopsy, and selective lymphadenectomy as a cost-effective technique with little morbidity to identify and manage occult metastases in patients who have two lymph basins at risk.

Surgical resection for melanoma metastatic to the gastrointestinal tract.

OBJECTIVE: To evaluate the role of surgery in the survival of patients with melanoma metastatic to the gastrointestinal (GI) tract. DESIGN: Retrospective review. SETTING: Tertiary cancer center. PATIENTS: One hundred twenty-four potential surgical candidates with metastatic melanoma in the stomach, small intestine, colon, or rectum. MAIN OUTCOME MEASURES: Operative morbidity and mortality, relief of presenting symptoms, and median and 5-year survival. RESULTS: The median disease-free interval prior to diagnosis of GI tract metastasis was 23.2 months (range, 1-154 months). Patients typically presented with crampy abdominal pain, symptomatic mass, and/or occult GI tract blood loss. Of the 124 patients, 69(55%) underwent surgical exploration of the abdomen, 46 (66%) had curative resection, and 23 (34%) had a palliative procedure. There was only 1 operative death and 1 major operative complication; 67 (97%) of 69 surgical patients experienced postoperative relief of their presenting GI tract symptoms. The median survival in patients undergoing curative resection was 48.9 months, compared with only 5.4 months and 5.7 months in those undergoing palliative procedures and nonsurgical interventions, respectively. By multivariate analysis, the 2 most important prognostic factors for long-term survival were complete resection of GI tract metastases and the GI tract as the initial site of distant metastases. CONCLUSIONS: Almost all patients with melanoma and GI tract metastases can have palliation of symptoms by surgical intervention with minimal morbidity and mortality. The high 5-year survival rate associated with complete surgical resection of GI tract metastases indicates that surgery should be strongly considered for this subgroup of patients with melanoma and distant metastatic disease.

Prognostic factors in 1,521 melanoma patients with distant metastases.

BACKGROUND: Although over 7,000 people die from malignant melanoma each year, there are limited prognostic data for patients with metastatic disease. A retrospective analysis was undertaken to identify variables that accurately predict outcome and to determine if the survival rate of patients with melanoma treated for distant metastases (American Joint Committee on Cancer [AJCC] stage IV disease) at the authors' institution changed between 1971 and 1993. STUDY DESIGN: Data for 1,521 patients with AJCC stage IV melanoma treated by the staff of the John Wayne Cancer Institute were reviewed, and a univariate and multivariate survival analysis against ten clinical and pathological variables was performed using the Cox proportional hazard regression model. RESULTS: The median survival time of the 1,521 patients was 7.5 months; the estimated five-year survival rate was 6 percent. Three independent variables predicted survival: initial site of metastases (p < 0.0001); disease-free interval before distant metastases (p = 0.0001); and stage of disease preceding distant metastases (p = 0.0001). Patients could be divided into three distinct prognostic groups based on the initial site of metastases: cutaneous, nodal, or gastrointestinal metastases (median survival of 12.5 months; estimated five-year survival rate 14 percent); pulmonary metastases (median survival of 8.3 months; estimated five-year survival rate 4 percent); and metastases to the liver, brain, or bone (median survival of 4.4 months; estimated five-year survival rate 3 percent). There was no significant change in the survival rate of patients with AJCC stage IV melanoma during the 22-year review period. CONCLUSIONS: Despite new treatment options, the survival rate of patients with metastatic melanoma has not changed significantly over the last 22 years; their prognosis remains dismal. The three prognostic variables identified in this study should be considered in the design of future clinical trials.

Resection and adjuvant immunotherapy for melanoma metastatic to the lung and thorax.

Although melanoma that metastasizes to distant sites is generally associated with a median survival of only 6 to 8 months, certain metastatic sites including the lung may carry a better prognosis than others. Surgical therapy for pulmonary metastases remains controversial because of the variable survival rates reported for previous small series. To determine the prognosis and optimal management of patients with melanoma with pulmonary metastases, we reviewed our 22-year melanoma database of over 6100 patients. Of 984 patients with metastatic melanoma involving the lung or thorax, 106 underwent resection by posterior lateral thoracotomy or median sternotomy. There were no operative deaths, and the median follow-up period for surgical patients was 55 months. The remaining 878 patients were treated without operation with immunotherapy, chemotherapy, radiation therapy, or a combination. In both treatment groups the male/female ratio was approximately 2:1. The primary lesion's Clark level of invasion and Breslow thickness and the patient's age at diagnosis of metastatic disease were not significantly different between the two groups. The 1-year, 3-year, and 5-year survival rates for surgical patients were 77%, 37%, and 27%, respectively, compared with 32%, 7%, and 3% for nonsurgical patients; these differences were highly significant (p = 0.0001). The highest 5-year survival rate (39%) occurred in those patients with a single metastatic lesion. Sixty-three percent of the surgical patients received some form of immunotherapy, compared with 34% of the nonsurgical patients. Multivariate analysis showed that resection and immunotherapy with a melanoma cell vaccine were both independent predictors of survival (p < 0.0001). These results indicate that the prognosis associated with metastatic melanoma may be less dismal than previously thought when distant metastases involve thoracic sites. We believe that surgical resection is the treatment of choice for patients with melanoma with pulmonary metastases; when combined with immunotherapy, this regimen offers the best chance for long-term survival.

Presence of embryonic myosin in normal postural muscles of the adult rat.

Indirect immunofluorescence was used to localize embryonic myosin heavy chains in soleus, adductor longus, tibialis anterior, plantaris, and extensor digitorum longus muscles of 6-month-old rats. A monoclonal antibody (2B6), specifically recognizing rat embryonic myosin, was applied to unfixed, transverse, frozen sections. The number of embryonic myosin-positive (EMP) extrafusal fibers was expressed as a percentage of the total number of fibers. EMP extrafusal fibers were only seen in the soleus and adductor longus muscles, both postural muscles. Approximately 1% of the soleus muscle fibers appeared positively stained for embryonic myosin. The majority of such fibers had a small diameter (< 500 mu2), appeared intensely fluorescent, and typically contained central nuclei. Re-expression of embryonic myosin due to spontaneous fiber denervation is not a likely factor in this study, since alpha-bungarotoxin and N-CAM localization were restricted to the motor end-plate region of EMP fibers. Since embryonic myosin was shown to disappear in all normal-sized myofibers by 2 to 3 months of age, the results suggest that the EMP extrafusal fibers seen in postural muscles of 6 to 12-month-old animals are regenerating myofibers. We speculate that a small number of muscle fibers may be regenerating in normal, adult postural muscles, in response to fiber damage possibly caused by excessive recruitment or overloading.

Application of multistage Markov modeling to malignant melanoma progression.

BACKGROUND: A fundamental research goal in clinical melanoma studies is to understand the natural history of melanoma and its relationship with prognostic factors. The current understanding of melanoma progression and the relationship of risk factors is based on two-stage modeling. METHODS: The authors propose a multistage Markov model for melanoma progression. This model is applied to a data set consisting of approximately 3900 follow-up staging visits of patients with melanoma. The approach takes into account the heavy censoring encountered in this data set and all chronic, subclinically progressive disease. The Markov transition parameters are expressed as Cox regression functions of the relevant prognostic variables. Parameter estimation is achieved by using a missing-data approach. RESULTS: Tumor thickness, level, and site and patient gender and age at diagnosis are independent risk factors in the transition from local to nodal disease. Tumor thickness and level of invasion and patient age are factors in the transition from local disease to dissemination (without intervening involvement of the nodes). Tumor thickness, patient age, primary site, and the number of involved lymph nodes are factors in the transition from nodal disease to dissemination. Transition from dissemination to death is affected by primary thickness, patient gender, number of nodes involved, and site of metastases. CONCLUSION: This multistage analysis contributes to a more accurate understanding of the progress of melanoma and is likely to be applicable to the study of other progressive diseases. Graphic goodness-of-fit results suggest satisfactory predictability of the model to other data sets.