Karen Qi

Correlation of specific immune responses with survival in melanoma patients with distant metastases receiving polyvalent melanoma cell vaccine.

PURPOSE The mechanisms that underlie the clinical efficacy of melanoma vaccines are not well understood. We hypothesized that the type and strength of the immune response generated by CancerVax (John Wayne Cancer Institute, Santa Monica, CA), a polyvalent melanoma cell vaccine (PMCV), might be correlated with its effect on overall survival (OS). PATIENTS AND METHODS Seventy-seven patients began PMCV therapy after complete surgical resection of distant metastatic melanoma. During the first two treatments, PMCV was administered with bacille Calmette-Guerin (BCG). Blood was drawn at 0, 2, 4, 8, and 12 weeks to measure serum titers of immunoglobulin G (IgG) and IgM antibodies against a tumor-associated 90-kd glycoprotein antigen (TA90) expressed on most melanoma cells, including those of PMCV. Cellular immune response to PMCV was assessed by delayed-type hypersensitivity (DTH). General immune competence was assessed by skin tests to purified protein derivative (PPD), mumps, and candida. RESULTS Median follow-up time was 31.5 months. Within the first 12 weeks of PMCV immunotherapy, there was a significant increase in the anti-TA90 IgM (P=.0001) and IgG titers (P=.0001), and in the DTH response to PMCV (P=.0001). Univariate analysis showed that high anti-TA90 IgM titer and strong PMCV-DTH were associated with improved survival (P=.051 and .0173, respectively), whereas elevated anti-TA90 IgG was correlated with decreased survival (P=.0119). Multivariate analysis considering clinical variables and PMCV immune responses identified anti-TA90 IgM, anti-TA90 IgG, and PMCV-DTH as significant independent variables influencing survival following PMCV immunotherapy (P=.0342, .0105, and .0082, respectively). These responses to PMCV were not correlated with immune responses to BCG and therefore were not a manifestation of general immune competence for responses to unrelated antigens. The median survival time and 5-year survival rate were more than 76 months and 75%, respectively, if both anti-TA90 IgM and PMCV-DTH responses were strong (> or = 800 and > or = 7 mm, respectively; n=29); 32 months and 36%, respectively, if only one response was strong (n=35); and 19 months and 8%, respectively, if neither was strong (n=13) (P < .0001). CONCLUSION PMCV induces both humoral and cell-mediated immune responses to melanoma-associated tumor antigens, the type and strength of which appear to be directly related to its therapeutic efficacy.

Biopsy method and excision volume do not affect success rate of subsequent sentinel lymph node dissection in breast cancer

Introduction: Sentinel lymph node dissection (SLND) is becoming a recognized technique for accurately staging patients with breast cancer. Its success in patients with large tumors or prior excisions has been questioned. The purpose of this study was to evaluate the effect of biopsy method, excision volume, interval from biopsy to SLND, tumor size, and tumor location on SLND success rate.Methods: Consecutive patients who underwent SLND followed by completion axillary lymph node dissection from October 1991 to December 1995 were analyzed. Included were cases performed early in the series before the technique was adequately developed. Excision volume was derived from the product of three dimensions as measured by the pathologist. Two end points were analyzed: sentinel node identification rate and accuracy of SLND in predicting axillary status. Univariate analyses using x2 or Fisher’s exact test for categorical variables and Wilcoxon rank sums for continuous variables were performed. Multivariate analysis was performed using logistic regression.Results: There were 284 SLND procedures performed on 283 patients. Median age was 55 years. The most recent biopsy method used before SLND was stereotactic core biopsy in 41 (14%), fine-needle aspiration in 62 (22%), and excision in 181 (64%) procedures. The mean excision volume was 32 ml with a range of 0.3–169 ml. The mean time from biopsy to SLND was 17 days with a range of 0–140 days. The mean tumor size was 2.0 cm (15 Tis [5%], 184 T1 [65%], 72 T2 [25%], and 13 T3 [5%]). Tumors were located in the outer quadrants in 74%, the inner quadrants in 18%, and subareolar region in 8%. The sentinel node was identified in 81%, and 39% had metastases. There were three false-negative cases early in the series. Sensitivity was 97%, and accuracy was 99%. Negative predictive value was 98% in cases in which the sentinel node was identified. On the basis of biopsy method, excisional volume, time from biopsy to SLND, tumor size, and tumor location, there was no statistically significant difference (P..05) in sentinel node identification rate or accuracy of SLND.Conclusions: SLND has a high success rate in breast cancer patients regardless of the biopsy method or the excision volume removed before SLND. In addition, the interval from biopsy to SLND, tumor size, and tumor location have no effect on the success rate of SLND, even in this series which included patients operated on before the technique was adequately defined. Patients with breast cancers located in any quadrant and diagnosed either with a needle or excisional biopsy could be evaluated for trials of SLND.

Detection of metastases in sentinel lymph nodes of breast cancer patients by multiple‐marker RT‐PCR

This study was undertaken to assess a multiple‐marker RT‐PCR and Southern blot assay for detection of metastases in frozen sections of sentinel lymph nodes from breast cancer patients. Sentinel lymphadenectomy was performed in 41 AJCC (American Joint Committee on Cancer) stage I‐IIIA breast cancer patients and 57 sentinel nodes (SNs) were excised. The SN, which is the first node in the lymphatic basin to receive metastases from the primary tumor, was identified using isosulfan blue dye. Hematoxylin and eosin (H&E), immuno‐histochemistry (IHC) and RT‐PCR were performed on adjacent sections of the SN. Six consecutive 12‐μm frozen sections of each SN were obtained for the RT‐PCR assay to determine expression of mRNA tumor markers C‐Met, β1 → 4GalNAc‐T and P97. Metastatic breast cancer was detected by H&E in 10 of 57 (18%) SNs and by IHC in an additional 7 (12%). Only 1 of 17 (6%) SNs with metastases did not express any of the 3 tumor mRNA markers. C‐Met, β1 → 4GalNAc‐T and P97 tumor mRNA markers were expressed in 31 (78%), 21 (53%) and 25 (63%) of 40 SNs without metastases, respectively. At least 2 mRNA tumor markers were expressed in 25/40 (63%) histo‐pathologically tumor‐free SNs, whereas all 3 mRNA tumor markers were expressed in 17/40 (43%) SNs. Expression of all 3 mRNA tumor markers in a SN was significantly higher in patients with a family history of breast cancer (p= 0.05), prior history of breast cancer (p< 0.05), infiltrating lobular carcinoma (p = 0.06), estrogen receptor‐negative (p= 0.04) tumor or a higher Bloom Richardson score (p= 0.04). The multiple‐marker RT‐PCR and Southern blot assay improves the detection of occult metastases in the SN when compared to conventional H&E and IHC analysis. Expression of all 3 tumor mRNA markers in the SN correlated with poor prognostic clinico‐pathologic factors compared to expression of 0 to 2 markers. Int. J. Cancer (Pred. Oncol.) 79:645–651, 1998.

Immune response to polyvalent melanoma cell vaccine in AJCC stage III melanoma: An immunologic survival model

AbstractBackground: Our polyvalent, allogeneic melanoma cell vaccine (MCV) induces immunoglobulin M (IgM) and immunoglobulin G (IgG) class antibodies to a 90-kDa glycoprotein melanoma-associated antigen (MAA). Additionally, MCV induces delayed-type hypersensitivity (DTH) responses that we previously correlated with survival. We hypothesized that early DTH responses to MCV and early humoral responses to the 90-kDa MAA expressed on MCV cells may be predictive of overall survival. We tested this hypothesis by monitoring immunologic profiles in 59 patients with melanoma who were receiving MCV after surgical resection of regional lymph node or soft-tissue metastases. Methods: Blood was drawn before vaccine administration, biweekly for 6 weeks, and then monthly. DTH to MCV was recorded at 0, 2, 4, and 8 weeks of MCV therapy. Mean antibody titers during the first 6-week interval were calculated. Changes in DTH were calculated as the difference between peak and prevaccine values (ΔDTH). Results: At a median follow-up of 75.6 months (range 5–138), univariate analysis assigned prognostic significance to gender (p=0.046), lymph node involvement (p=0.024), ΔDTH (p=0.044), mean anti-90-kDa MAA IgG (p=0.0009), and mean anti-90-kDa MAA IgM (p=0.0014). In multifactorial analysis, only the three immunologic variables significantly impacted survival (p=0.046, 0.0005, and 0.0053, respectively). A mathematical model based on ΔDTH and mean anti-90-kDa MAA IgG and IgM titers closely approximated the observed individual and overall survival rates. Conclusions: The correlation between overall survival and initial humoral/cellular immune responses to MCV immunotherapy may be useful in selecting patients most likely to benefit from prolonged adjuvant immunotherapy.

Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma

BackgroundAlthough the presence of tumor cells in the blood of patients with metastatic melanoma suggests widely disseminated disease many of these patients enjoy prolonged survival or cure after surgical resection. Our previous study of adjuvant vaccine therapy after complete resection of metastatic melanoma revealed a strong correlation between postoperative survival and elevated antibody titers to a 90-kDa tumor-associated antigen (TA90) expressed by melanoma cells of the vaccine. We hypothesized a similar correlation between postoperative survival and endogenous anti-TA90 antibody titers induced by the patient’s melanoma in the absence of postoperative adjuvant immunotherapy.MethodsFrom 1970 to 1996, 64 patients underwent complete resection of distant melanoma metastases and did not receive postoperative adjuvant immunotherapy. Serum collected within 4 months after surgery was tested in a coded and blinded fashion for anti-TA90 IgG and IgM by enzyme-linked immunosorbent assay, and for total IgG and IgM (controls) by radial immunodiffusion.ResultsMedian follow-up for the study population was 19 months (range, 3–147 months). There was no significant correlation between anti-TA90 IgG titer and total IgG level (P=.4785), or between anti-TA90 IgM and total IgM (P=.0989). Univariate analysis showed that postoperative anti-TA90 IgM titer as a continuous variable was significantly associated with overall survival (OS); i.e, the higher the anti-TA90 IgM titer, the longer the OS. Using an established cutoff titer of 800, median OS was 42 months for patients with high anti-TA90 IgM titer (n=28) vs. 9 months for patients with low titers (n=36) (P=.0001). There was no significant correlation between total IgG/IgM and survival (P=.4107 and .4044, respectively). Multivariate, analysis identified anti-TA90 IgM as the most significant independent variable influencing OS after complete resection of distant melanoma metastases (P-.0001).ConclusionsWe conclude that the endogenous immune response to metastatic melanoma determines the outcome after surgical therapy. Enhancement of this specific immune response may prolong the survival of patients with distant melanoma metastases.

Enhancement of complement-dependent cytotoxicity by polyvalent melanoma cell vaccine (CancerVax): Correlation with survival

AbstractBackground: Case control studies have demonstrated that administration of CancerVax, a polyvalent melanoma cell vaccine (PMCV), after complete resection of melanoma metastases produces a significant improvement in disease-free survival (DFS). Because PMCV has no direct cytotoxic effect on melanoma cells, the authors hypothesized that it prolongs survival by enhancing antibody-mediated antimelanoma cytotoxicity. Methods: One hundred melanoma patients participating in a trial of PMCV adjuvant therapy following complete resection of regional node metastases were randomly selected for study. Serum samples obtained immediately before (T0) and 4, 8, 12, and 16 weeks after initiation of PMCV adjuvant therapy were adsorbed with L-14 lymphoblastoid cells and then tested for in vitro complement-dependent cytotoxicity (CDC) against M-14 cells, a melanoma cell line not used in PMCV. CDC was expressed as percentage of total cells (n=10,000) killed. Survival curves were estimated by the Kaplan-Meier method. Statistical analysis was performed by the signed rank sum test, Spearman test, log-rank test, and Cox proportional hazard regression. Results: Median CDC at T0 was 4.5% (range, 0% to 40%). Within 16 weeks after initiation of PMCV therapy, CDC had increased in 82 (82%) patients. The median increase of 7.5% (range, −9% to 39%) represented a highly significant change (signed rank sum test;P=.0001). At a median follow-up of 29 months (range, 6 to 92 months), the maximum increase in CDC (ΔCDC) as a continuous variable was significantly correlated with DFS (P=.0001). Median survival and 5-year DFS were more than 54 months and less than 54%, respectively, for patients with ΔCDC≥10% (n=44) but only 7 months and 14%, respectively, for those with ΔCDC<10% (n=56;P=.0001). Multivariate analysis confirmed ΔCDC as the most significant independent variable associated with DFS following initiation of PMCV therapy (P=.0001). Conclusion: PMCV therapy greatly enhances serum CDC against melanoma cells. This enhancement is directly correlated with DFS following initiation of vaccine therapy.

Survival of patients with melanoma of the lower extremity decreases with distance from the trunk

Early stage melanoma of the lower extremity is generally associated with a favorable prognosis. However, several retrospective studies have suggested that melanoma on the foot portends poor survival. The authors hypothesized that the region of the lower extremity has prognostic importance.

Positron emission tomography plus serum TA90 immune complex assay for detection of occult metastatic melanoma

BACKGROUND Whole-body positron emission tomography (PET) using 18F-fluorodeoxyglucose is very sensitive for detection of metastatic melanoma. We previously reported the accuracy of a serum TA90 enzyme-linked immunosorbent assay (ELISA) in predicting the recurrence of early-stage melanoma. This serum ELISA measures a circulating immune complex composed of TA90 a tumor-associated 90-kD glycoprotein antigen, and its IgG antibody. We hypothesized that using PET examination in conjunction with our serum TA90 ELISA would increase the detection of occult melanoma lesions. STUDY DESIGN From November 1, 1993 to December 31, 1995, 87 patients underwent PET examination followed within 6 weeks by serum TA90 ELISA. All patients had undergone complete resection of local, regional, or distant metastatic melanoma and had no clinical evidence of disease at the time of PET examination. Each patient had complete followup for 12 months after PET examination. The clinical course was determined by chart review of clinical and radiographic findings. RESULTS Of the 25 patients who experienced recurrence of disease within 6 months of followup, 22 (88%) had a positive result on one or both tests. Of the 52 patients with a negative result on both tests, 49 (94%) remained disease-free at 6 months of followup. Of the 14 patients who developed distant metastases within 6 months after PET examination, 13 (93%) had a positive PET examination and/or a positive TA90 ELISA. CONCLUSIONS The TA90 ELISA correlated well with PET examination for detection of metastatic melanoma. The high sensitivity of PET examination plus TA90 ELISA suggests that this combination may have a role in the surveillance of patients at high risk of developing metastatic melanoma.