Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide.

Previous studies have shown that melanoma patients develop an immune response to cell surface melanoma-associated antigens. The presence of this antibody response to cell surface antigens has been correlated with a better clinical outcome when melanoma patients are treated with an allogeneic melanoma cell vaccine (MCV) as an active immunotherapy protocol. It was hypothesized that the inability to consistently induce or enhance existing immune responses to melanoma-associated antigens was related to the downregulation by suppressor cells. Patients received treatments of MCV 3 times in a 4-week interval and then every fourth week. The biological response modifier cyclophosphamide (CYP) is an immunomodulator of suppressor T-cell function. In this study we set out to determine whether CYP given prior to MCV could reduce suppressor cell activity during vaccination. In a randomized trial stage II and III melanoma patients (n = 41) were given MCV alone or in conjunction with CYP at dosages of 300, 150, or 75 mg/m2. CYP was given 3 days prior to each MCV treatment. Suppressor cell activity in patients was monitored by a concanavalin A suppressor assay using peripheral blood lymphocytes from serial phlebotomies during a 12-week period of treatment. In each trial group there were patients who had major reduction in suppressor cell activity (greater than 50%). Overall, the greatest reduction in suppressor cell activity occurred in patients receiving 300 mg/m2 CYP compared to the other CYP dosages or MCV alone. For the first two treatments at all CYP dosages there was a greater number of patients showing reduced suppressor cell activity compared to later treatments. In a comparison of patients receiving MCV alone to MCV + CYP 300 mg/m2 phenotypic analysis of lymphocyte subsets showed significant (P = 0.03) reduction in the CD8+CD11B+ (suppressor) cells of the latter group. These studies suggest that CYP can be used at low dosages in conjunction with MCV to reduce suppressor cell activity.

Interleukin 4 receptor expression and growth inhibition of gastric carcinoma cells by interleukin 4.

The expression of the interleukin 4 (IL-4) receptor (IL-4R) and effects of human recombinant IL-4 on human gastric carcinoma cell lines were studied. We demonstrated that IL-4 inhibited the growth of gastric carcinoma cells in a dose dependent manner (0.1-100 units/ml) in a [3H]thymidine incorporation proliferation assay. The gastric carcinoma cells varied in sensitivity to treatment with low dose IL-4. Treatment of cells with IL-4 altered the morphology of the cells to a "flattened" morphological shape resembling differentiation. The IL-4-mediated growth inhibition was significantly abrogated by neutralization of IL-4 with specific anti-IL-4 antibody. IL-4R expression on the cell surface was determined by assessing biotin-labeled IL-4 binding to cells using flow cytometry. IL-4R expression ranged from 5 to 85% of total cell population in the gastric carcinoma cell lines assessed. There was a positive correlation between the sensitivity to IL-4-mediated growth inhibition and IL-4R expression. By Northern blot analysis, we demonstrated that mRNA of IL-4R was expressed in the gastric carcinoma cells. Using in situ hybridization, we confirmed that IL-4R mRNA was expressed in the gastric carcinoma cell at the single cell level. By using a sensitive polymerase chain reaction technique, we demonstrated that gastric carcinoma cells expressed IL-4 mRNA, suggesting a possible autocrine loop. These studies indicate that IL-4 can significantly modulate gastric carcinoma cells that possess IL-4R. IL-4R on gastric carcinoma cells may be a potential therapeutic target site for IL-4-directed therapy.

Prognostic significance of circulating microsatellite markers in the plasma of melanoma patients.

PURPOSE: Multiple genetic alterations including loss of heterozygosity (LOH) occur commonly in melanoma tumors. We demonstrated previously free-circulating DNA microsatellites with LOH in the blood of melanoma patients. These LOH markers in plasma may be useful as surrogates for subclinical disease progression. The purpose of this study was to determine whether the presence of circulating tumor microsatellite markers in the preoperative blood from patients with melanoma has prognostic utility. EXPERIMENTAL DESIGN: Plasma was analyzed for the presence of LOH at six chromosome regions, which are common for allelic loss in melanoma tumors, in 57 patients undergoing surgical resection of all of the clinically apparent disease. RESULTS: LOH was detected in 32 of 57 patients (56%). Both LOH incidence and frequency correlated with advancing American Joint Committee on Cancer stage. In patients with American Joint Committee on Cancer stage III, the presence of LOH as an independent variable in preoperative plasma was significantly associated (P = 0.05) with an increased risk of death. Furthermore, LOH at microsatellite marker D1S228 in the plasma of patients with advanced disease correlated significantly (P = 0.0009) with a poorer survival after surgical resection. LOH commonly found in melanoma tumors can be successfully identified in the plasma of a patient, providing a potentially less invasive route for following genetic changes that serve as molecular surrogates for assessing subclinical disease progression. CONCLUSIONS: This study provides evidence that blood testing for circulating tumor genetic markers may provide valuable prognostic information and guide future therapy.

Polyvalent melanoma cell vaccine induces delayed-type hypersensitivity and in vitro cellular immune response.

Patients with melanoma metastatic to distant sites or at high risk for recurrent melanoma have been treated with a polyvalent melanoma cell vaccine (MCV) in phase II protocols. We assessed in vivo and in vitro cell-mediated responses to MCV in 163 patients who had undergone surgical resection of American Joint Committee on Cancer stage III melanoma. During the first 4 months of vaccine immunotherapy, 135 patients (83%) responded by developing a positive delayed-type hypersensitivity reaction > or = 6 mm to MCV. In a mixed lymphocyte tumor cell reaction using peripheral blood lymphocytes, 35 of 42 patients (83%) showed a recall proliferative response to one or more of the three cell lines of MCV. There was a significant correlation between delayed-type hypersensitivity reaction and mixed lymphocyte tumor cell reaction (P = 0.013). After 4 months of MCV therapy, 8 of 11 patients had an increased mixed lymphocyte tumor cell reaction to autologous melanoma cells. During the first 4 months of vaccine therapy, 16 of 33 patients developed more than a 50% increase in cytotoxic T-cell activity against one of the cell lines of MCV. Overall survival was significantly prolonged in patients with a positive delayed-type hypersensitivity reaction (P = 0.0054) and/or increased cytotoxic T-cell activity (P = 0.02). These findings suggest that MCV induces specific T-cell responses which are correlated with clinical course; the data also suggest that some of these responses are directed against autologous melanomas and may play a major role in controlling the progression of melanoma.

Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanomas of the head and neck.

PURPOSE: We developed intraoperative lymphatic mapping with selective lymphadenectomy (SLND) to identify micrometastatic spread of cutaneous melanoma to regional lymph nodes. This study was undertaken to assess the sensitivity and specificity of our technique in patients with clinical stage I (CS-I) melanoma of the head or neck. PATIENTS AND METHODS: Seventy-two CS-I melanoma patients underwent intraoperative lymphatic mapping of primary cutaneous melanomas located on the head, neck, or upper chest/back draining to the neck. Key (sentinel) cervical lymph nodes in the regional lymphatic drainage basin were identified, selectively excised during SLND, and examined for microscopic evidence of tumor cells. If these sentinel nodes were tumor-negative, the surgery was concluded; if the sentinel nodes were tumor-positive, all nodes in the drainage basin were removed during en bloc lymphadenectomy (LND). RESULTS: Intraoperative lymphatic mapping identified sentinel nodes in 90% of the regional drainage basins. Fifteen percent of these nodes were tumor-positive, indicating the need for LND. There were no false-negative sentinel nodes, and extended follow-up showed no local nodal recurrences in patients whose sentinel-node histology did not indicate the need for LND. CONCLUSION: Intraoperative lymphatic mapping and SLND is a minimally invasive and highly accurate screening technique for determining which patients with CS-I head and neck melanomas have subclinical node metastases and therefore might benefit from cervical LND.

Detection of occult melanoma cells in blood with a multiple-marker polymerase chain reaction assay.

PURPOSE: The objective of the study was to develop a sensitive multimarker polymerase chain reaction (PCR) assay to detect circulating melanoma cells in patient blood. The rationale was that malignant melanoma is heterogeneous in regards to antigen expression. PATIENTS AND METHODS: A PCR assay that uses four melanoma-associated gene markers (tyrosinase, p97, MUC18, and MAGE-3) was developed. Sensitivity and specificity of the PCR assay for individual markers were assessed using 10 melanoma cell lines and peripheral-blood lymphocytes (PBL) from 39 normal volunteers as controls. The assay's sensitivity and specificity were improved using nested primers and Southern blot analysis. Patients (N = 119) with American Joint Committee on Cancer (AJCC) stages I to IV disease were evaluated for circulating melanoma cells using the four gene markers under optimal conditions. RESULTS: All melanoma-associated gene markers were expressed in at least 80% of the melanoma lines, whereas 37 of 39 normal PBL tested negative for all markers; the remaining two PBL were positive for MUC18. Using four markers in the PCR assay was significantly better than using tyrosinase alone. There was a significant correlation between the number of positive PCR markers, AJCC stage of disease, and progression of disease. In all AJCC stages, there were more PCR-positive patients with disease than without disease. CONCLUSION: A multimarker PCR assay is more reliable and sensitive than a single-marker assay for detection of melanoma cells in blood of patients. This assay can provide important insight into tumor progression kinetics without major surgical or conventional radiologic diagnostic procedures.

Is the survival of melanoma patients receiving polyvalent melanoma cell vaccine linked to the human leukocyte antigen phenotype of patients?

PURPOSE: An allogeneic polyvalent melanoma cell vaccine (PMCV) has been shown to be efficacious in improving overall survival of patients with malignant melanoma in a phase II clinical setting. The PMCV consists of three allogeneic melanoma cell lines. The objectives of the study were to determine (1) whether the survival of melanoma patients who received PMCV was related to the patient's human leukocyte antigen (HLA) class I phenotype matching the HLA class I phenotype of the PMCV, and (2) whether PMCV clinical efficacy was correlated to melanoma patients with a particular HLA phenotype(s). MATERIALS AND METHODS: PMCV was given to 69 melanoma patients with American Joint Committee on Cancer (AJCC) stage I to IV disease status. The PMCV and patients lymphocytes were typed for HLA-A and -B. A correlation was made between the HLA expression of PMCV lines and the HLA of patients to their survival status. A second correlation was made between the HLA of patients and survival independent of the PMCV HLA phenotype. RESULTS: Patients whose HLA phenotype (A3/11 and B7/44) matched the PMCV lines had a better overall survival (P < .029). Analysis of HLA expression of patients independent of PMCV HLA to survival showed that HLA-A25 phenotype patients had a significantly better overall survival (P = .006). HLA-B35 patients had a poorer survival outcome (P = .019). CONCLUSION: The studies indicate that overall survival following PMCV treatment in melanoma patients significantly correlates with their HLA phenotypes. These correlations may be related to the host immune response to the PMCV or due to differences in the clinical course of melanoma in patients with different HLA types.

Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma.

PURPOSE: Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen. PATIENTS AND METHODS: Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days. RESULTS: The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths. CONCLUSION: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

Testosterone-secreting adrenal adenoma containing crystalloids characteristic of Leydig cells.

A 49-year-old woman with virilization demonstrated biochemical features traditionally ascribed to virilizing ovarian tumors: marked elevation of serum testosterone level with normal urinary excretion of 17-ketosteroids and normal serum dehydroepiandrosterone level. An adrenal cortical adenoma containing neoplastic cells indistinguishable from Leydig cells, including the demonstration of characteristic crystalloids of Reinke, was shown to be the source of the elevated testosterone level. A review of the literature revealed 13 cases with a similar biochemical profile, and of these, two were reported to contain crystalloids of Reinke. Taking cognizance of the fact that these characteristic crystalloids are only found in 40 percent of Leydig cell tumors of the testis, it is concluded that Leydig cells may be present in, and may be active participants in, the pathophysiology of a number of testosterone-secreting adrenal tumors.

Cryosurgical palliation of metastatic neuroendocrine tumors resistant to conventional therapy.

BACKGROUND: Hepatic cryosurgery is a well-recognized modality for hepatic colon metastases. We examined its potential use for refractory neuroendocrine tumors causing progressive symptoms. METHODS: Between July 1992 and February 1997, 19 patients (with islet cell, 7; carcinoid, 8; vasoactive intestinal peptide, 1; gastrinoma, 3) underwent cryosurgery with ultrasonography. The number of lesions frozen ranged from 1 to 16 (median, 8), and their diameters ranged from 2 to 15 cm with an average of 4 cm. Patients underwent resection of the primary tumor either before (37%) or concurrent with (32%) cryosurgery, and half underwent excision of metastases with cryosurgery. Before cryosurgery, patients received chemotherapy (63%), somatostatin (47%), interferon (10%), hepatic artery ligation (5%), radiation (10%), and/or omeprazole (16%). RESULTS: The reduction in tumor markers reached 90% (5-hydroxyindoleacetic acid), 80% (vasoactive intestinal peptide), 90% (gastrin), 90% (pancreatic polypeptide), and 80% (serotonin). At a median follow-up of 17 months, the metastases had progressed in 11 patients (two underwent a second cryosurgical procedure that eliminated symptoms) and five had died. Subsequently an additional five patients received chemotherapy and three somatostatin. Median symptom-free and overall survival were 10 months and more than 49 months, respectively. CONCLUSIONS: Cryosurgery dramatically relieved symptoms with significant reduction in tumor markers. The reduced tumor burden may explain the subsequent response to systemic therapy. Cryosurgery is a useful adjuvant in symptomatic patients with refractory hepatic neuroendocrine metastases.

The role of surgery in the treatment of nonregionally recurrent melanoma.

BACKGROUND: Between 1971 and 1989, 144 patients underwent 183 surgical procedures for resection of nonregional metastatic melanoma. METHODS: Thirty-six patients with subcutaneous or nodal metastases, 46 patients with pulmonary metastases, 17 patients with brain metastases, 19 with gastrointestinal metastases, and 26 patients with miscellaneous sites of metastatic involvement underwent resection. RESULTS: The overall 5- and 10-year actuarial survival rates were 20% and 14%, respectively. A single postoperative death occurred in a patient operated on for palliative treatment of gastrointestinal metastases. CONCLUSIONS: Cox regression analysis suggests that patients with a solitary metastasis confined to the subcutaneous, nonregional lymph nodes or lung are most likely to benefit from aggressive surgical intervention. Surgical intervention represents a potentially important modality in the management of selected patients with nonregional metastatic melanoma.

Standardized probe-directed sentinel node dissection in melanoma.

BACKGROUND: Radiopharmaceutical agents appear to improve the accuracy of sentinel node (SN) identification in patients with early-stage melanoma, but the optimal radiopharmaceutical agent and its timing from injection to surgery remain controversial. We undertook this investigation to examine the utility of 3 methods of intraoperative lymphatic mapping with radiopharmaceutical-directed sentinel lymphadenectomy (LM/SL). We suspected that concurrent injection of radiopharmaceutical and blue-dye would lead to the greatest success of SN identification. METHODS: The study was composed of 247 consecutive patients who had American Joint Committee on Cancer stage I or II melanoma. Before LM/SL, all patients underwent cutaneous lymphoscintigraphy by 1 of 3 techniques: technetium 99m (Tc 99m) human serum albumin (HSA) injected at least 24 hours before LM/SL (124 patients), Tc 99m filtered sulfur colloid (SC) injected no more than 4 hours before LM/SL (same-day SC, 95 patients), or Tc 99m SC injected at least 18 hours before LM/SL (prior-day SC, 28 patients). At the time of LM/SL, isosulfan blue dye was injected alone (SC groups) or with a second dose of HSA (HSA group). A hand-held gamma probe was used to determine the radioactive (hot) counts of blue-stained and nonstained nodes, and the in vivo and ex vivo node-to-background count ratios of the nodes were compared. RESULTS: Preoperative LS identified 299 drainage basins; LM/SL identified at least 1 SN in 119 (98%) of 121 basins using same-day SC, 142 (97%) of 146 basins using HSA, and 32 (100%) of 32 basins using prior-day SC. There was no difference (P = .62) in the accuracy rate between the 3 techniques. The total number of SNs was 463. Same-day SC yielded higher intraoperative node-to-background count ratios than did either of the other techniques (P < .0001). Same-day SC also had the greatest relative change in radioactivity between the blue sentinel node and the post-excision basin (P < .0001), and the highest rate of SNs that were both blue and hot (in vivo or ex vivo ratio > or = 2, P = .05). CONCLUSIONS: LS and LM/SL performed on the same day with a single injection of filtered Tc 99m SC serves as the most useful method for probe-directed LM/SL. This technique demonstrated the highest in vivo and ex vivo count ratios, fall-off of radioactivity between the excised nodes and post-excision basin, and concordance between blue dye and hot nodes. It should be recommended as the method of choice for probe-directed LM/SL.

Prospective evaluation of the use of antigen-specific immune complexes in predicting the development of recurrent melanoma.

We previously demonstrated that the antigen-specific immune complexes captured by the monoclonal antibody MAb JSI in a sandwich enzyme-linked immunosorbent assay were associated with recurrent melanoma. To determine the potential use of antigen-specific immune complex analysis in predicting the development of recurrent melanoma, we prospectively analyzed serum obtained from patients with melanoma following surgical treatment. Two hundred fifty-three patients have been followed up for a median of 25 months (range, 17 to 29 months). Seventy-seven patients (30%) have developed recurrent melanoma. Antigen-specific immune complexes correlated with the stage of disease at time of entry into the study. The absence of antigen-specific immune complexes in postoperative serum samples is predictive of a disease-free status. Long-term follow-up will define the false-positive rate of antigen-specific immune complex analysis. Continued refinement of this approach should lead to clinically useful methodology to monitor human melanoma.

Clarifying the role of fine-needle aspiration cytologic evaluation and frozen section examination in the operative management of thyroid cancer.

The final histologic diagnoses of 486 patients who underwent thyroidectomy at UCLA Medical Center from March 1975 to August 1988 were reviewed. There were 146 patients with a diagnosis of thyroid malignant neoplasm. All patients who had preoperative fine-needle aspiration cytologic evaluation, intraoperative frozen section analysis, or both were included in the present study. Carcinoma was diagnosed by frozen section in 87 (69%) of 126 cases. Frozen section analysis was incorrect in 39 (31%) of 126 cases. Fine-needle aspiration was performed in 62 patients. A malignant neoplasm was identified by fine-needle preoperative fine-needle aspiration and intraoperative frozen section analysis, and carcinoma was detected by both methods in 32 (57%) of 56 cases. Fine-needle aspiration cytologic evaluation is extremely valuable in the diagnosis of thyroid cancer and is at least as accurate as frozen section analysis with less morbidity and expense. When fine-needle aspiration demonstrates malignant neoplasm, thyroid resection may be planned with confidence.

Technical details of intraoperative lymphatic mapping for early stage melanoma.

The initial route of metastases in most patients with melanoma is via the lymphatics to the regional nodes. However, routine lymphadenectomy for patients with clinical stage I melanoma remains controversial because most of these patients do not have nodal metastases, are unlikely to benefit from the operation, and may suffer troublesome postoperative edema of the limbs. A new procedure was developed using vital dyes that permits intraoperative identification of the sentinel lymph node, the lymph node nearest the site of the primary melanoma, on the direct drainage pathway. The most likely site of early metastases, the sentinel node can be removed for immediate intraoperative study to identify clinically occult melanoma cells. We successfully identified the sentinel node(s) in 194 of 237 lymphatic basins and detected metastases in 40 specimens (21%) on examination of routine hematoxylin-eosin-stained slides (12%) or exclusively in immunohistochemically stained preparations (9%). Metastases were present in 47 (18%) of 259 sentinel nodes, while nonsentinel nodes were the sole site of metastasis in only two of 3079 nodes from 194 lymphadenectomy specimens that had an identifiable sentinel node, a false-negative rate of less than 1%. Thus, this technique identifies, with a high degree of accuracy, patients with early stage melanoma who have nodal metastases and are likely to benefit from radical lymphadenectomy.

Comparison of blue dye and probe-assisted intraoperative lymphatic mapping in melanoma to identify sentinel nodes in 100 lymphatic basins.

OBJECTIVE: To determine whether combining isosulfan blue dye with a radiopharmaceutical agent will increase intraoperative detection of sentinel nodes (SNs) in patients with early-stage melanoma. PATIENTS AND DESIGN: Clinical trial with a consecutive sample. Eighty-seven patients with clinical stage I melanoma underwent preoperative lymphoscintigraphy with 1 of 3 radiopharmaceutical agents to identify the lymphatic basin and the site of the SN. All patients subsequently underwent intraoperative lymphatic mapping and selective lymph node dissection (SLND) with isosulfan blue dye and a radiopharmaceutical agent. A handheld gamma probe determined the radioactive counts over the draining lymph node basins and individual blue-stained lymph nodes before (in vivo) and after (ex vivo) their removal. An irrelevant body site was used as the denominator of a count ratio by which absolute counts were standardized for comparison. Completion lymphadenectomy was undertaken in patients whose SLND specimen had histopathologic evidence of tumor cells. SETTING: Tertiary care cancer center. INTERVENTION: Lymph node sampling. MAIN OUTCOME MEASURE: Accuracy of SN detection by blue dye and radiopharmaceutical techniques. RESULTS: Preoperative lymphoscintigraphic images identified 100 lymph node basins and 135 lymph nodes in 87 patients. All 3 radiopharmaceutical agents were equally effective in imaging the SN before surgery. During SLND, we identified and removed 136 blue-stained and radioactive (hot) SNs and 8 additional non-blue-stained hot nodes from 98 basins (98.0%). Of the 144 excised lymph nodes, 132 nodes (91.7%) from 83 basins had either an in vivo- or an ex vivo-background count ratio of 2:1 or more and 125 nodes (86.8%) from 77 basins had a count ratio of 3:1 or more. Twelve blue-stained SNs had count ratios of less than 2:1. Seventeen SNs (11.8%) from 15 basins contained metastases: 16 were identified with blue dye and probe and 1 was identified with blue dye alone. Four (1.1%) of 377 non-SNs excised during completion lymphadenectomy contained metastases. There have been no lymph node recurrences during mean follow-up of 16.3 months (range, 7-42 months). CONCLUSIONS: The blue dye technique remains the criterion standard for SLND in melanoma. The addition of a radiopharmaceutical tracer serves as a useful adjunct to the visualization of blue-stained SNs.

Systemic irinotecan or regional floxuridine chemotherapy prolongs survival after hepatic cryosurgery in patients with metastatic colon cancer refractory to 5-fluorouracil.

Most colorectal cancers metastatic to the liver are resistant to chemotherapy and are not amenable to surgical resection. This study evaluated our 6-year experience (July 1992-July 1998) in treating patients with unresectable hepatic colorectal metastases refractory to systemic 5-fluorouracil (5-FU). One hundred fifty-three patients underwent cryosurgical ablation (CSA) of 5-FU-resistant hepatic metastases. The patients then received either hepatic arterial floxuridine (FUDR), systemic CPT-11, or no postoperative adjuvant chemotherapy. Number, size, and location of hepatic metastases, carcinoembryonic antigen (CEA) levels, and type of postoperative treatment were analyzed. One to 15 lesions were frozen (median number, 3; median size, 6 cm), for a total of 73 synchronous and 80 metachronous lesions. Overall median survival was 28.4 months from the date of diagnosis of liver metastases and 16.1 months from the time of CSA. After cryosurgery alone, median survival was 13 months, which was significantly shorter than the post-CSA survival of 23.6 months with adjuvant CPT-11 and 21.2 months with hepatic FUDR (P = 0.007). Predictors of survival included preoperative CEA, postoperative reduction in CEA, and adjuvant chemotherapy (P < 0.05). Neither size, number of lesions, nor tumor location impacted survival. At a median follow-up of 13 months, 67% of patients have recurred (35% hepatic, 16% extrahepatic, and 49% both). Twenty percent of the recurrences were in the lobe of the CSA site. The 25 patients who underwent a second CSA had a median survival of 28.4 months from CSA and 40 months from the date of diagnosis of liver metastases. These data indicate that CSA offers an effective alternative for unresectable patients resistant to 5-FU. Systemic CPT-11 or regional FUDR may further prolong survival after CSA.

Lymphatic mapping and sentinel lymphadenectomy after wide local excision of primary melanoma.

BACKGROUND: Lymphatic mapping and sentinel lymphadenectomy (LM/SL) are generally avoided in patients who have already undergone wide local excision (WLE) of a primary melanoma, because of concern that disruption of the cutaneous lymphatics might alter lymphatic flow to the sentinel node. We reviewed carefully chosen patients who had undergone LM/SL after WLE to identify circumstances that might make this approach otherwise safe and clinically accurate. STUDY DESIGN: From our melanoma database of 8,300 patients, of whom 1,015 had undergone LM/SL, we retrospectively identified 47 patients who had previously undergone WLE. Patient and tumor characteristics were collected and compared with followup data from clinic files. RESULTS: Median WLE surgical margins before LM/SL were 2.0 cm and most patients had extremity lesions. Eleven of the 47 patients (23%) had tumor-involved sentinel nodes, and 8 of these patients (73%) had a solitary nodal metastasis. With a median followup period of 36 months, 3 sentinel node-negative patients developed nodal recurrences. Two of these patients had positive sentinel nodes on pathology re-review and were not considered failures of the lymphatic mapping surgical procedure. The third patient developed in-transit metastases and delayed nodal recurrence. An additional patient, who had a primary tumor on the trunk, developed a nodal recurrence in the basin opposite that identified by lymphoscintigraphy. The overall error rate of the technique was 4 in 36 (11%). This included 2 pathology misdiagnoses (5.6%), 1 nodal recurrence associated with in-transit regional metastases (2.8%), and 1 lymphatic mapping error (2.8%). CONCLUSIONS: LM/SL can be cautiously performed in patients who have undergone previous WLE if the primary resection margin was no greater than 2.0 cm and the primary was not in a region of ambiguous drainage. Lymphatic mapping may be inaccurate when melanomas have been resected with large margins, especially if the wound was closed with rotation flaps, and when melanomas are on the head and neck or trunk regions.

Radiofrequency ablation: a novel primary and adjunctive ablative technique for hepatic malignancies.

The majority of primary and metastatic tumors of the liver are not amenable to surgical resection at presentation. Radiofrequency ablation (RFA) is a new modality for local tumor destruction with minimal local and systemic complications. We prospectively reviewed the experience with RFA at a single institute as a primary or adjunctive ablative technique in the treatment of hepatic malignancies. Between November 1997 and December 1998, 30 patients with primary or metastatic hepatic lesions were treated with RFA at the John Wayne Cancer Institute and the Cancer Center at Century City Hospital. Pathology of the treated lesions included colorectal metastases (29 in 14 patients), neuroendocrine metastases (29 in 4 patients), noncolorectal metastases (29 in 9 patients), and hepatocellular carcinoma (6 in 3 patients). Twelve patients underwent RFA laparoscopically, 12 at celiotomy, and the remaining 6 patients had percutaneous ablation. RFA was the only procedure in 17 patients, whereas the remainder underwent a combination of RFA and other procedures including resection, cryosurgical ablation, and hepatic artery infusion pump placement. Median length of stay for all patients was 6 days (2 days for laparoscopic patients). A single complication of a delayed intrahepatic abscess was noted in this series (3%). There have been no deaths associated with RFA. At a median follow-up of 5 months, 16 patients remain disease free, and 10 are alive with disease. RFA is a safe and effective method of tumor ablation for hepatic malignancies. This technique can be performed laparoscopically, at celiotomy, or percutaneously and can be used as a primary technique or in conjunction with other interventional procedures.

Focused examination of sentinel lymph nodes upstages early colorectal carcinoma.

Approximately 30 per cent of patients with early colorectal carcinoma (CRC) develop systemic disease. A subgroup of these patients may harbor occult micrometastatic disease and might benefit from adjuvant chemotherapy. We investigated sentinel lymph node (SLN) mapping and focused pathologic examination of the SLN as a means of detecting nodal micrometastases. Between 1996 and 2000 SLN mapping was performed in 50 consecutive patients undergoing colectomy for CRC. All lymph nodes in the resection specimen were examined via routine hematoxylin and eosin (H&E) staining. In addition multiple sections of each SLN were examined via both H&E and cytokeratin immunohistochemistry. At least one SLN was identified in 47 patients (94%). In seven patients (14%) SLN mapping identified aberrant drainage that altered the planned resection. The SLN(s) correctly predicted nodal basin status in 44 of 47 (94%) cases; there were three falsely negative SLNs. Sixteen cases had positive SLNs by conventional H&E staining. An additional 10 (20%) cases were upstaged by a focused examination of the SLNs. Micrometastases were identified in three cases by H&E staining of multiple sections of the SLN and in seven only by cytokeratin immunohistochemistry. In nine cases the SLN was the only node containing tumor cells. In this study, SLN mapping demonstrated aberrant nodal drainage patterns that altered the surgical resection in patients with CRC. Focused examination of SLNs may detect micrometastases missed by conventional techniques and thereby identify patients who might benefit from adjuvant therapy.