Biomedical subjects

H F Seigler

Publications and source records attributed to H F Seigler.

At least 19 recordsLinked to original sources

PubMed2001

Generation of melanoma-specific, cytotoxic CD4(+) T helper 2 cells: requirement of both HLA-DR15 and Fas antigens on melanomas for their lysis by Th2 cells.

Recognition of melanoma antigens by HLA class-II-restricted CD4(+) T lymphocytes has been investigated. Two cytotoxic CD4(+) T cell lines were established by stimulating PBLs from a melanoma patient with either parental or IFN-gamma-transduced autologous tumor cells. These T cells secreted IL-4, but not IL-2, IFN-gamma, or TNF-beta, in response to the autologous melanoma cells, suggesting that they belong to the Th2 subtype. Their cytotoxicity was directed against the IFN-gamma-transduced melanoma cells and was HLA-DR-restricted. The autologous and two allogeneic IFN-gamma-modified melanoma cell lines shared melanoma antigen(s) presented in the context of HLA-DR15. HLA-DR15(+) nonmelanoma cells were resistant targets indicating that the shared antigen(s) is melanoma associated. Parental autologous and HLA-DR-matched allogeneic melanoma cell lines, displaying low levels of HLA-DR antigens, induced Th2 proliferation and cytokine release, but were insensitive to lysis prior to upregulation of HLA-DR and Fas antigens by IFN-gamma. Cytolysis was inhibited by anti-HLA-DR and by anti-Fas antibodies, suggesting that the cytolysis is mediated via the Fas pathway. While small amounts of HLA-DR15 molecules on melanoma cells are sufficient for Th2 proliferation and cytokine release, higher amounts of HLA-DR15 and the expression of Fas are required for CD4(+)-mediated lysis.

Antigens, Neoplasm↗

PubMed2001

Identification of higher risk thin melanomas should be based on Breslow depth not Clark level IV.

BACKGROUND: There is good prognostic correlation for the two microstaging systems, Breslow depth and Clark level, commonly used to stage melanomas. Many investigators have reported that Breslow depth is the superior microstaging method. Although Clark level has been dropped from most of the proposed American Joint Committee on Cancer (AJCC) melanoma staging system, the AJCC system still includes Clark Level IV as a criterion for upstaging thin melanomas. The authors sought to determine whether this is appropriate, based on melanoma patient data in the Duke Comprehensive Cancer Center database. METHODS: Of the 8833 patients registered between January 1, 1970 and December 31, 1995, complete data on Breslow depth and Clark level was available for 4560 patients who were without nodal or metastatic disease at presentation. Ten-year survival was measured from the date of excision of the primary tumor until death from melanoma and analyzed using Kaplan-Meier and Cox proportional hazard methodologies. RESULTS: When analyzed separately, both increased Breslow thickness and Clark level correlated with shorter survival times. During subgroup analysis, Breslow thickness remained a significant prognostic indicator of survival at Clark Levels III and IV. Conversely, at narrow levels of Breslow thickness (i.e., 0-0.75 mm, > 0.75 -1.0 mm, > 1.0-1.5 mm) survival times were indistinguishable between Clark Levels III and IV. For the broader Breslow thickness interval of 0-1.0 mm, a barely significant difference between Clark Levels III and IV could be obtained. However, for this thickness range, even greater differences in survival could be obtained by merely comparing Breslow subgroups (i.e., < or = 0.8 mm vs. > 0.8-1.0 mm, < or = 0.9 mm vs. > 0.9-1.0 mm). CONCLUSION: The authors' data suggested that, after controlling for Breslow depth, Clark level was not a good prognostic indicator for survival. If the AJCC's objective is to design a classification system that will reliably predict the higher risk melanomas, then the system should be based on tumor thickness, which is clearly a better prognostic indicator, and should not be modified because of Clark level.

Adult↗

PubMed2001

Complete response to neoadjuvant chemoradiation for rectal cancer does not influence survival.

BACKGROUND: Up to 30% of patients with locally advanced rectal cancer have a complete clinical or pathologic response to neoadjuvant chemoradiation. This study analyzes complete clinical and pathologic responders among a large group of rectal cancer patients treated with neoadjuvant chemoradiation. METHODS: From 1987 to 2000, 141 consecutive patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative 5-fluorouracil-based chemotherapy and radiation. Clinical restaging after treatment consisted of proctoscopic examination and often computed tomography scan. One hundred forty patients then underwent operative resection, with results tracked in a database. Standard statistical methods were used to examine the outcomes of those patients with complete clinical or pathologic responses. RESULTS: No demographic differences were detected between either clinical complete and clinical partial responders or pathologic complete and pathologic partial responders. The positive predictive value of clinical restaging was 60%, and accuracy was 82%. By use of the Kaplan-Meier life table analysis, clinical complete responders had no advantage in local recurrence, disease-free survival, or overall survival rates when compared with clinical partial responders. Pathologic complete responders also had no recurrence or survival advantage when compared with pathologic partial responders. Of the 34 pathologic T0 tumors, 4 (13%) had lymph node metastases. CONCLUSIONS: Clinical assessment of complete response to neoadjuvant chemoradiation is unreliable. Micrometastatic disease persists in a proportion of patients despite pathologic complete response. Observation or local excision for patients thought to be complete responders should be undertaken with caution.

Aged↗

PubMed2001

Primary chondroid melanoma.

BACKGROUND: Malignant melanoma is notorious for the wide range of histologic patterns it can assume, among the least frequent of which is chondroid melamona. METHODS: Two cases of primary chondroid melanoma of the distal lower extremity were studied. Tissue for light microscopy was fixed in formalin, embedded in paraffin, and processed routinely. In one case, transmission electron microscopy and immunohistochemical evaluation were performed. RESULTS: Both cases exhibited melanoma in-situ, a conventional (non-chondroid) invasive component, and areas of chondroid differentiation, as confirmed by strongly positive staining with Alcian blue at pH 2.5 and Safranin O. Immunohistochemically, one case expressed S-100 protein and vimentin, and did not express gp100 (HMB-45), tyrosinase, MART-1, the Mel-5 antigen, the NKI/C3 antigen, CD45Ro, cytokeratin, or desmin. Electron microscopy of the chondroid component revealed occasional tumor cells with rare, membrane-bound, electron-dense organelles; the extracellular compartment showed amorphous ground substance consistent with cartilaginous differentiation. CONCLUSIONS: Chondroid change in the absence of osteogenic differentiation is extremely rare in malignant melanoma. Melanoma should be considered in the differential diagnosis of primary cutaneous neoplasms exhibiting cartilaginous differentiation.

Aged↗

PubMed2001

Impact of core-needle breast biopsy on the surgical management of mammographic abnormalities.

OBJECTIVE: To evaluate the accuracy of percutaneous, image-guided core-needle breast biopsy (CNBx) and to compare the surgical management of patients with breast cancer diagnosed by CNBx with patients diagnosed by surgical needle-localization biopsy (SNLBx). SUMMARY BACKGROUND DATA: Percutaneous, image-guided CNBx is a less invasive alternative to SNLBx for the diagnosis of nonpalpable mammographic abnormalities. CNBx potentially spares patients with benign lesions from unnecessary surgery, although false-negative results can occur. For patients with malignant lesions, preoperative diagnosis by CNBx allows definitive treatment decisions to be made before surgery and may affect surgical outcomes. METHODS: Between 1992 and 1999, 939 patients with 1,042 mammographically detected lesions underwent biopsy by stereotactic CNBx or ultrasound-guided CNBx. Results were categorized pathologically as benign or malignant and, further, as invasive or noninvasive malignancies. Only biopsy results confirmed by excision or 1-year-minimum mammographic follow-up were included in the analysis. Patients with breast cancer diagnosed by CNBx were compared with a matched control group of patients with breast cancer diagnosed by SNLBx. RESULTS: Benign results were obtained in 802 lesions (77%), 520 of which were in patients with adequate follow-up. Ninety-five of the 520 evaluable lesions (18%) were subsequently excised because of atypical hyperplasia, mammographic-histologic discordance, or other clinical indications. There were 17 false-negative CNBx results in this group; 15 of these lesions were correctly diagnosed by excisional biopsy within 4 months of CNBx. In two patients (0.9%), delayed diagnoses of ductal carcinoma in situ were made at 15 and 19 months after CNBx. Malignant results were obtained in 240 lesions (23%), 220 of which were surgically excised from 202 patients at our institution. Two lesions diagnosed as ductal carcinoma in situ were reclassified as atypical ductal hyperplasia and considered false-positive results (0.4%). For malignant lesions, the sensitivity and specificity of CNBx for the detection of invasion were 89% and 96%, respectively. During the first surgical procedure, 115 of 199 patients (58%) diagnosed by CNBx underwent local excision; 194 of 199 patients (97%) evaluated by SNLBx underwent local excision. For patients whose initial surgery was local excision, those diagnosed before surgery by CNBx had larger excision specimens and were more likely to have negative surgical margins than were patients initially evaluated by SNLBx. Overall, patients diagnosed by CNBx required fewer surgical procedures for definitive treatment than did patients diagnosed by SNLBx. CONCLUSIONS: Diagnosis by CNBx spares most patients with benign mammographic abnormalities from unnecessary surgery. With the selective use of SNLBx to confirm discordant results, missed diagnoses are rare. When compared with SNLBx, preoperative diagnosis of breast cancer by CNBx facilitates wider initial margins of excision, fewer positive margins, and fewer surgical procedures to accomplish definitive treatment than diagnosis by SNLBx.

Biopsy, Needle↗

PubMed2001

Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience.

OBJECTIVE: To examine clinical outcomes in patients receiving neoadjuvant chemoradiation for locally advanced rectal adenocarcinoma. SUMMARY BACKGROUND DATA: Preoperative radiation therapy, either alone or in combination with 5-fluorouracil-based chemotherapy, has proven both safe and effective in the treatment of rectal cancer. However, data are lacking regarding which subgroups of patients benefit from the therapy in terms of decreased local recurrence and increased survival rates. METHODS: A retrospective chart review was performed on 141 consecutive patients who received neoadjuvant chemoradiation (5-fluorouracil +/- cisplatin and 4,500-5,040 cGy) for biopsy-proven locally advanced adenocarcinoma of the rectum. Surgery was performed 4 to 8 weeks after completion of chemoradiation. Standard statistical methods were used to analyze recurrence and survival. RESULTS: Median follow-up was 27 months, and mean age was 59 years (range 28-81). Mean tumor distance from the anal verge was 6 cm (range 1-15). Of those staged before surgery with endorectal ultrasound or magnetic resonance imaging, 57% of stage II patients and 82% of stage III patients were downstaged. The chemotherapeutic regimens were well tolerated, and resections were performed on 140 patients. The percentage of sphincter-sparing procedures increased from 20% before 1996 to 76% after 1996. On pathologic analysis, 24% of specimens were T0. However, postoperative pathologic T stage had no effect on either recurrence or survival. Positive lymph node status predicted increased local recurrence and decreased survival. CONCLUSIONS: Neoadjuvant chemoradiation is safe, effective, and well tolerated. Postoperative lymph node status is the only independent predictor of recurrence and survival.

Adenocarcinoma↗

PubMed2001

Using a continuous transformation of the Breslow thickness for prognosis in cutaneous melanoma.

Although the Breslow thickness provides the most important histologic information for prognosis in cutaneous melanoma, controversies and uncertainty remain about how best to use thickness. It is unclear whether cut points should be used, or, if they are used, which are optimal. We studied new data collected from more than 1,000 patients followed up for a relatively long period. From Cox proportional hazards models of survival we learned that more cut points provide more prognostic information than using, for example, just 1 cut point at 1.7 mm. Nevertheless, a continuous transformation provides an effective alternative that captures the information that thickness provides, and it avoids the pitfalls of using multiple cut points. In a multivariate model, this transformation provided strong prognostic information, and the result produced a prognostic score for cutaneous melanoma. This score provides a practical way that Cox model results can be used, and we believe it consolidates the prognostic information provided by traditional histologic and clinical variables. When newer prognostic variables are introduced, we suggest that they be used with this continuous transformation of thickness rather than with cut points in thickness.

Follow-Up Studies↗

PubMed2000

Positron emission tomography scanning in malignant melanoma.

BACKGROUND: Several recent studies have demonstrated the low yield of anatomically based computed tomography scans in evaluating Stage III (American Joint Committee on Cancer) patients with malignant melanoma. The purpose of this study was to investigate the efficacy and clinical utility of functionally based positron emission tomography (PET) scans in the same patient population. METHODS: A prospective evaluation of 106 whole body PET scans obtained after injection of 2-fluorine-18, 2-fluoro-2-deoxy-D-glucose (FDG) was performed in 95 patients with clinically evident Stage III lymph node and/or in-transit melanoma. Areas of abnormality on FDG PET scanning were identified visually as foci of increased metabolic activity compared with background, and all positive foci were assessed pathologically. RESULTS: In this patient population, there were 234 areas that were evaluated pathologically of which 165 were confirmed histologically to be melanoma. PET scanning identified 144 of the 165 areas of melanoma for a sensitivity of 87.3%. The 21 areas of melanoma that were missed included 10 microscopic foci, 9 foci less than 1 cm, and 2 foci greater than 1 cm. There were 39 areas of increased PET activity that were not associated with malignancy for a 78.6% predictive value of a positive test. Of the 39 false-positive areas (false-positive rate of 56.5%), 13 could be attributed to recent surgery, 3 to arthritis, 3 to infection, 2 to superficial phlebitis, 1 to a benign skin nevus, and 1 to a colonic polyp. Pathologic evaluation of the remaining false-positive areas failed to reveal a definitive etiology for their increased activity on PET scan. With the application of pertinent clinical information, the predictive value of a positive PET scan could be improved to 90. 6%. The specificity of PET scanning in this study was only 43.5% because very few prophylactic lymph node dissections were performed. Thirty-six of the total 183 abnormal areas (19.7%) on PET scanning proved to be unsuspected areas of metastatic disease. These findings led to a change in the planned clinical management in patients after 16 of the 106 PET scans (15.1%). CONCLUSIONS: FDG PET scanning can be helpful in managing patients with Stage III melanoma in whom further surgery is contemplated. Although false-positive areas are not uncommon, PET scans did change the management of patients 15% of the time. PET's inability to identify microscopic disease suggests that it is of limited use in evaluating patients with Stage I-II disease.

Fluorodeoxyglucose F18↗

PubMed2000

Dendritic cells infected with a vaccinia vector carrying the human gp100 gene simultaneously present multiple specificities and elicit high-affinity T cells reactive to multiple epitopes and restricted by HLA-A2 and -A3.

To investigate the ability of human dendritic cells (DC) to process and present multiple epitopes from the gp100 melanoma tumor-associated Ags (TAA), DC from melanoma patients expressing HLA-A2 and HLA-A3 were pulsed with gp100-derived peptides G9154, G9209, or G9280 or were infected with a vaccinia vector (Vac-Pmel/gp100) containing the gene for gp100 and used to elicit CTL from autologous PBL. CTL were also generated after stimulation of PBL with autologous tumor. CTL induced with autologous tumor stimulation demonstrated HLA-A2-restricted, gp100-specific lysis of autologous and allogeneic tumors and no lysis of HLA-A3-expressing, gp100+ target cells. CTL generated by G9154, G9209, or G9280 peptide-pulsed, DC-lysed, HLA-A2-matched EBV transformed B cells pulsed with the corresponding peptide. CTL generated by Vac-Pmel/gp100-infected DC (DC/Pmel) lysed HLA-A2- or HLA-A3-matched B cell lines pulsed with the HLA-A2-restricted G9154, G9209, or G9280 or with the HLA-A3-restricted G917 peptide derived from gp100. Furthermore, these DC/Pmel-induced CTL demonstrated potent cytotoxicity against allogeneic HLA-A2- or HLA-A3-matched gp100+ melanoma cells and autologous tumor. We conclude that DC-expressing TAA present multiple gp100 epitopes in the context of multiple HLA class I-restricting alleles and elicit CTL that recognize multiple gp100-derived peptides in the context of multiple HLA class I alleles. The data suggest that for tumor immunotherapy, genetically modified DC that express an entire TAA may present the full array of possible CTL epitopes in the context of all possible HLA alleles and may be superior to DC pulsed with limited numbers of defined peptides.

Antigen Presentation↗

PubMed2000

Analysis of prognosis and disease progression after local recurrence of melanoma.

BACKGROUND: Local recurrence of melanoma is associated with a grave prognosis. However, the characteristics and the mode of disease progression for patients with local recurrence have not been adequately addressed in the literature. METHODS: A retrospective analysis of patients treated at a single institution revealed a subset of patients (n = 648) with local recurrence of melanoma as a first event. Patient characteristics, histologic determinants, and disease free interval were variables used to identify prognostic factors. RESULTS: In this group of patients, male gender (P = 0. 0163), increasing age (P = 0.0001), head and neck primaries (P = 0. 0001), thicker Breslow depths (P = 0.0022), deeper Clark levels (P = 0.0010), and ulceration of the primary tumor (P = 0.0348) suggested a shorter time until local recurrence. Breslow depth (P = 0.0004), Clark level (P = 0.0043), and ulceration (P = 0.0001) still factored into the survival prognosis after recurrence. Truncal primaries (P = 0.0005) and shorter disease free intervals (P = 0.0098) were also associated with poorer outcomes after recurrence. Of the 648 patients, 124 showed no progression, 196 developed another local recurrence, 178 developed in-transit/lymph node metastases, and 150 had systemic recurrences. Survival was only 33.6% for patients with further metastases, compared with 77.4% for patients with no progression of disease after a median follow-up of 38.9 months. CONCLUSIONS: There was a 48.5% mortality rate at 5 years of follow-up after local recurrence. Long term survival (> 10 years) was estimated to be 34.9%. The patterns of failure after local recurrence suggest that patients may benefit from aggressive locoregional therapy.

Aged↗

PubMed2000

Gastrointestinal carcinoids: characterization by site of origin and hormone production.

OBJECTIVE: To describe a large series of patients with carcinoid tumors in terms of presenting symptoms, hormonal data, stage at diagnosis, pathologic features, and survival. SUMMARY BACKGROUND DATA: Published series have described significant prognostic features of carcinoid tumors as site of origin, age, sex, stage at diagnosis, presence of high hormone levels, and increased T stage. Of these, stage at diagnosis and T stage seem to emerge most often as independent predictors of survival in multivariate analyses. Of carcinoid tumors, those arising from a midgut location have higher levels of serotonin and serotonin breakdown products, as well as more frequent metastatic disease at presentation, than those arising from either foregut or hindgut locations. METHODS: A prospective database of carcinoid patients seen at Duke University Medical Center was kept from 1970 to the present. Retrospective medical record review was performed on this database to record presenting symptoms, hormonal data, pathologic features, and survival. Statistical methods included analysis of variance, Kaplan-Meier analysis, and Mantel-Cox proportional hazard survival analysis, with P <.05 considered significant for all tests. RESULTS: Carcinoids arising in different locations had different presentations: rectal carcinoids presented significantly more often with gastrointestinal bleeding, and midgut carcinoids presented significantly more often with flushing, diarrhea, and the carcinoid syndrome. Patients with midgut tumors had significantly higher levels of serotonin and serotonin breakdown products, corresponding to higher metastatic tumor burdens. Although age, stage, region of origin, and urinary level of 5-hydroxyindoleacetic acid predicted survival by univariate analysis, only the latter three were independent predictors of survival by multivariate analysis. Of the patients with metastatic disease at diagnosis, those with midgut tumors had better survival than those with foregut or hindgut tumors. CONCLUSIONS: Although region of origin is certainly an important factor in determination of prognosis, stage of disease at presentation is more predictive of survival. Pancreatic and midgut carcinoids are metastatic at diagnosis more often than those arising in other locations, leading to a worse overall prognosis. Among patients with distant metastases, patients with midgut primary tumors have improved survival despite increased hormone production compared with patients with tumors arising in other primary sites.

Carcinoid Tumor↗

PubMed2000

A model for pretest probability of lymph node metastasis from cutaneous Melanoma.

Although many statistical models have been developed to predict survival in cutaneous melanoma, few predict the end point of regional lymph node metastasis shortly after the diagnosis of melanoma. We used routine clinical and histologic data from 573 patients referred to the Duke University Melanoma Clinic, Durham, NC, during the 1980s and 1990s who underwent lymph node resections during the first year after the diagnosis of primary cutaneous melanoma. The outcome we modeled (using the logistic regression model) was the probability of lymph node metastasis. We found that tumor thickness was the variable most significantly associated with the probability of nodal metastasis, and the presence of ulceration and tumor location also were significant, but age, sex, and mitotic rate were not. When the resulting logistic model predicted that the probability of nodal metastasis was more than .6, 93 of 115 patients had nodal metastasis. When the model predicted that the probability was less than .3, just 32 of 88 patients had positive nodes. Furthermore, after the result of the node sampling was known, Cox model analysis demonstrated that the pretest probability added significant information about subsequent survival.

Biopsy↗

PubMed2000

Subungual melanoma. A review of 93 cases with identification of prognostic variables.

From 1970 to 1996, 93 patients received diagnoses of subungual melanoma. Followup data were complete on all patients and reviewed with a median duration of followup of 5.2 years. This study identifies significant clinicopathologic variables that affect survival and provides the orthopaedic surgeon assistance in the early diagnosis and treatment of this lesion. Eight-three percent of patients presented with Stage I disease, whereas 17% had nodal or distant disease. Fifty-three percent had locally advanced disease at presentation. Twelve percent of the patients were African-American. Fifty-five percent of the lesions arose on the hands with thumb involvement predominating in more than half of these cases. Operative therapy consisted of amputation. Elective lymph node dissection was performed in 34 patients (37%) for Stage I tumors of intermediate thickness. Therapeutic node dissection was required in 16 patients (17%) for positive nodes. Five-year survival was 74% for patients with Stage I disease and 40% for patients with Stage II disease. Statistical analysis identified stage at diagnosis, Clark and Wihm's level, the patient's race, and the presence of ulceration as prognostic variables affecting survival. The diagnosis of subungual melanoma carries a grave prognosis and often is misdiagnosed in the early stages. The treatment of choice is amputation at the appropriate level.

Adolescent↗

PubMed1999

Murine dendritic cells transfected with human GP100 elicit both antigen-specific CD8(+) and CD4(+) T-cell responses and are more effective than DNA vaccines at generating anti-tumor immunity.

Dendritic cells (DCs) are potent inducers of cytotoxic T lymphocytes (CTLs) when pulsed with an antigenic peptide or tumor lysate. In this report, we have used liposome-mediated gene transfer to examine the ability of plasmid DNA encoding the human melanoma-associated antigen gp100 to elicit CD8(+) and CD4(+) T-cell responses. We also compared the efficacy between gp100 gene-modified DCs and naked DNA (pCDNA3/gp100)-based vaccines at inducing anti-tumor immunity. DCs were generated from murine bone marrow and transfected in vitro with plasmid DNA containing the gp100 gene. These gp100-modified DCs (DC/gps) were used to stimulate syngeneic naive spleen T cells in vitro or to immunize mice in vivo. Antigen-specific, MHC-restricted CTLs were generated when DC/gps were used to prime T cells both in vitro and in vivo. Thus, these CTLs were cytolytic for gp100-transfected syngeneic (H-2(b)) tumor MCA106 (MCA/gp) and vaccinia-pMel17/gp100-infected syngeneic B16 and MCA106, but not parental tumor MCA106 and B16, or gp100-transfected allogeneic tumor P815 (H-2(d)). Immunization with DC/gp protected mice from subsequent challenge with MCA/gp but not parental MCA106. Antibody-mediated T-cell subset depletion experiments demonstrate that induction of CTLs in vivo is dependent on both CD4(+) and CD8(+) T cells. Furthermore, DC/gp immunization elicits an antigen-specific CD4(+) T-cell response, suggesting that DC/gps present MHC class II epitopes to CD4(+) T cells. In addition, our data show that gene-modified, DC-based vaccines are more effective than the naked DNA-based vaccines at eliciting anti-tumor immunity in both prophylactic and therapeutic models. These results suggest that the use of DCs transfected with plasmid DNA containing a gene for TAA may be superior to peptide-pulsed DCs and naked DNA-based vaccines for immunotherapy and could provide an alternative strategy for tumor vaccine design.

Animals↗

PubMed1999

Melanoma of the gallbladder: a review of cases seen at Duke University Medical Center.

BACKGROUND: Both primary and metastatic melanoma of the gallbladder are rare. In cases involving isolated tumors of the gallbladder, there continues to be controversy regarding the establishment of primary status. Despite appropriate therapy, the diagnosis of either condition portends a poor prognosis, with few patients surviving more than 2 years. METHODS: A review of all patients seen at Duke University Medical Center since 1970 generated 1 case of primary and 19 cases of secondary melanoma of the gallbladder. These were analyzed with respect to presentation, clinical and pathologic diagnosis, treatment, and prognosis. RESULTS: The sole patient with a primary lesion presented with acute cholecystitis. Ultrasound demonstrated a mass in the lumen of the gallbladder. Cholecystectomy revealed melanoma, and the patient eventually died of disseminated disease 13.5 months later. Survival was poor for patients who presented with metastases to the gallbladder in the setting of widespread disease, with 0% survival at 1 year (n=11). Those with isolated, resectable lesions fared better overall, with 100% survival (n=6) at 1 year. One patient remains alive and free of disease 13.8 years later, which, to our knowledge, represents the longest documented survival for a patient with melanoma that has metastasized to the gallbladder. CONCLUSIONS: Surgery remains the mainstay of therapy for patients with gallbladder melanoma and appears to improve patient outcome in the setting of resectable disease. Hopefully, further investigations will lead to standardized protocols for the treatment of these lesions.

Adult↗

PubMed1999

MCA106 fibrosarcoma cells transduced with granulocyte/macrophage colony-stimulating factor are not superior to the wild-type cells in suppressing the growth of hepatic metastases.

BACKGROUND AND OBJECTIVES: Vaccination with cytokine gene-modified tumor cells augments the immune response against established tumors and protects against tumor challenges. In this study, we investigated the vaccine potential of GM-CSF-transduced MCA106 fibrosarcoma (MCA-GMCSF) cells in the C57BL/6 (B6) murine hepatic metastasis model. METHODS: Experimental mice received one to three weekly vaccines (subcutaneous/intramuscular, s.c./i.m.) of irradiated, parental, or GM-CSF-transduced MCA106 tumor cells. One week after the last immunization, hepatic metastases were established through the intrasplenic injection of live MCA106 parental (MCA106P) tumor cells. The animals were then sacrificed 3-4 weeks after surgery for evaluation of hepatic tumor burden. RESULTS: Based on in vivo experiments, both GM-CSF-modified and parental MCA106 tumor cell vaccines induced strong protection against hepatic tumor growth with grossly visible tumors rarely identified. This protection was evident even at a single vaccine dose of as low as 1x10(5) irradiated cells. Unimmunized control mice, on the other hand, consistently developed substantial hepatic tumors. Cytotoxicity assays on splenocytes (cultured in vitro for 4-5 days) showed that both groups of vaccinated mice developed strong tumor-specific cytotoxic T-lymphocyte (CTL) responses. Immunohistochemical analysis of injection sites showed infiltration of dendritic cells (DCs) and macrophages into subcutaneously injected MCA-GMCSF cells. Mostly macrophages, however, were seen at the injection site of MCA106P cells. Furthermore, the MCA106P cells expressed high levels of MHC class I antigens and the level of expression was not significantly altered by transduction with the GM-CSF gene. The high expression of MHC class I antigens probably contributed to the strong immunogenicity of the MCA106P cell vaccine. CONCLUSIONS: This study demonstrates that MCA106 parental cells are as effective as the GM-CSF-transduced cells in suppressing the growth of hepatic metastases. The cellular immune responses induced by these two vaccines, however, are probably mediated by different subsets of host effector cells. These results have important implications for the use of GM-CSF-transduced cell vaccines in the immunotherapy of tumors that have the propensity to metastasize through the lymphatic channels and the circulatory system.

Animals↗

PubMed1999

Tumor cells cotransduced with B7.1 and gamma-IFN induce effective rejection of established parental tumor.

Genetic modification of tumor cells with the gene for the B7.1 or with the genes for cytokines results in increased tumor cell immunogenicity. In the work reported here, immunization of naive animals with either B7.1 or gamma-IFN gene-modified MCA106 tumor cells effectively protects the host from subsequent challenge with parental tumor. The same treatment fails to induce regression of established tumors, although tumor-specific CTL are generated in the tumor-bearing animals. In contrast, a large tumor burden of the MCA106 fibrosarcoma can be successfully eliminated by treatment with MCA106 tumor cells cotransduced with the B7.1 and gamma-IFN genes. Antitumor immunity induced by the cotransductants is primarily dependent on CD8+ T cells and partly on CD4+ T cells and NK cells, and the enhanced therapeutic effect may be attributed to the in vivo increase of CTL precursors following treatment. The gamma-IFN and B7.1 genes must be expressed on the same tumor cell for optimal therapeutic effect. Our results suggest that tumor vaccines with a potent immunoprotective effect do not necessarily have therapeutic potential and that weakly immunogenic tumors may be rendered highly immunogenic by cotransfection with the genes for B7.1 and gamma-IFN.

Animals↗

PubMed1999

Timing of sentinel lymph node mapping after lymphoscintigraphy.

BACKGROUND: Sentinel lymph node (SLN) mapping is an effective technique for staging patients with melanoma. In an attempt to avoid reinjection of radiolabeled colloid and facilitate SLN mapping at the time of surgery, we examined whether residual radioactivity from preoperative lymphoscintigraphy could be used to accurately identify SLNs during surgery 18 to 24 hours later. METHODS: Forty-six patients with newly diagnosed melanoma underwent injection of 0.22-micron filtered technetium 99m-labeled sulfur colloid followed by lymphoscintigraphy. Patients returned the next day for SLN biopsy with Isosulfan blue dye and the hand-held gamma-probe to identify SLNs. Thirty of 46 patients underwent repeat imaging before operation. No patient had reinjection of radiocolloid. RESULTS: Ninety-five SLNs were identified on initial lymphoscintigraphy, and repeat imaging on the day of surgery confirmed all SLNs previously identified. A total of 122 SLNs (2.65 per patient) were resected from 58 basins. Eighty-four (69%) of 122 SLNs stained blue, and 118 (97%) of 122 SLNs had in vivo gamma-counts greater than 4 times background. Microscopic metastases were present in 13 (10.7%) of 122 SLNs in 12 (26.1%) of 46 patients. There have been no recurrences over a mean follow-up time of 320 days. CONCLUSIONS: Intraoperative gamma-probe detection combined with blue dye injection is highly effective in identifying SLNs 18 to 24 hours after injection of 0.22-micron filtered 99mTc-sulfur colloid. Reinjection of radiocolloid is not required. This technique avoids radiopharmaceutical administration in the operating room, minimizes radiation exposure, and increases scheduling flexibility.

Adult↗