PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma.

Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m2 intravenously day 1 plus palifosfamide 150 mg/m2/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.

A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma.

We performed a phase I pilot study to determine if autologous vaccine HSPPC-96 (gp96, Oncophage) could be purified from completely resected pancreas adenocarcinomas, to determine patient tolerance of vaccine and to explore immune responses and clinical outcomes of these patients. Subjects were vaccinated with 5 microg of autologous HSPPC-96 weekly for 4 doses. Serial ELISPOT assays of T cells for antitumor reactivity were performed. Subjects received neither adjuvant chemotherapy nor radiation. Ten patients received a full course of vaccinations. No dose-limiting toxicities were encountered. Immediate freezing in liquid nitrogen of the tumor specimen resulted in improved vaccine yield. Median overall survival is 2.2 years (Kaplan-Meier estimate). Autologous anti-HSPPC-96 ELISPOT reactivity increased significantly in 1 of 5 patients examined and a second had an increase of unclear significance. Three of 10 treated patients are alive without disease at 2.6, 2.7, and 5.0 years follow-up. There was no observed correlation between immune response and prognosis. This study demonstrates the feasibility of preparing HSPPC-96 from pancreatic adenocarcinomas. Examination of this novel approach using multiple dose levels is 1 approach to further investigate the immunogenicity and clinical utility of HSPPC-96 vaccination in this setting.

Antigens recognized by autologous antibodies of patients with soft tissue sarcoma.

Serological analysis of recombinant cDNA libraries (SEREX) uses high titer IgGs to identify antigens expressed by autologous cancers. In order to identify tumor antigens in soft tissue sarcoma (STS), sera from four patients with malignant fibrous histiocytoma (MFH), gastrointestinal stromal tumor (GIST), pleomorphic liposarcoma, and dedifferentiated liposarcoma were screened against cDNA libraries derived from autologous tumor. We identified 18 antigens encoded by 15 different genes, including DLG7, which is located on chromosome 14q22, a locus previously found to be altered in STS, and the proto-oncogene JUN. Ten of fourteen antigens (71%) do not react with sera from healthy donors, suggesting that antibody recognition takes place during cancer progression. Using oligonucleotide microarray technology, most genes were variably expressed across a panel of 16 benign specimens and 41 STSs of different histologies. DLG7, however, showed restricted expression in testes and cancer, similarly to known germ cell cancer-testis antigens (or germ cell antigens, GCAs). Thus, the current study identified several antigens, including molecules implicated in tumorigenesis that were recognized by high titer IgGs in STS patients. Further studies of these selected novel STS antigens are warranted to identify and characterize potential antigen targets expressed by STS.

Therapeutic cancer vaccines: using unique antigens.

A decade ago, it seemed rational that our rapidly increasing knowledge of the molecular identities of tumor antigens and a deeper understanding of basic immunology would point the way to an effective therapeutic cancer vaccine. Significant progress has been made, but we do not yet have a cancer vaccine that can reliably and consistently induce tumor destruction or improve patient survival. Random mutations in cancer cells generate unique antigens in each individual, and this may be important in terms of generating a therapeutic immune response. Autologous heat shock protein-peptide complexes produced from each patient's tumor is a logical personalized approach that may obviate the need to identify the unique antigens contained in the individual vaccine. Heat shock proteins elicit adaptive and innate immune responses and have been tested in a variety of animal models and different human cancers. Activity has been seen in several animal studies. Early-phase human studies have also suggested some activity in certain cancers. Large, randomized phase 3 studies are ongoing, and these will effectively answer the question of efficacy regarding this approach to therapeutic vaccination. There are sufficient data to support the notion that cancer vaccines can induce anti-tumor immune responses in humans with cancer. How best to translate this increase in immune responsiveness to consistently and reproducibly induce objective cancer regression or increased survival remains unclear at this time.

Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer.

PURPOSE: Heat shock proteins (HSP) from tumor cells contain the gp96 polypeptide associated with cancer-specific antigenic peptides. Mice that are immunized with HSP/peptide-complex (HSPPC) derived from cancer tissue reject tumor from which HSPs are purified. We tested in humans whether vaccination with HSPPC-gp96 (Oncophage) from autologous liver metastases of colorectal carcinoma induces cancer-specific T-cell responses in patients rendered disease free by surgery. EXPERIMENTAL DESIGN: Twenty-nine consecutive patients underwent radical resection of liver metastases [Memorial Sloan-Kettering Cancer Center (MSKCC) score 1-3 (good prognosis), 18 patients; score 4-5 (bad prognosis), 11 patients] and received autologous tumor-derived HSPPC-96. Two vaccine cycles were administered (four weekly injections followed by four biweekly injections after 8 weeks). Class-I HLA-restricted, anti-colon cancer lines T-cell response was measured by ELISPOT assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Feasibility, safety, and possible clinical benefits were also evaluated. RESULTS: Either a de novo induced or a significant increase of preexisting class I HLA-restricted T-cell-mediated anti-colon cancer response was observed in 15 (52%) of 29 patients. Frequency of CD3+, CD45RA+, and CCR7- T lymphocytes increased in immune responders. No relevant toxicity was observed. As expected, patients with good prognosis had a significantly better clinical outcome than those with poor prognosis [2-year overall survival (OS), 89 versus 64%, P = 0.001; disease-free survival (DFS), 46 versus 18%, P = 0.001]. Patients with immune response had a statistically significant clinical advantage over nonresponding subjects (2-year OS, 100% versus 50%, P = 0.001; DFS, 51% versus 8%, P = 0.0001). Occurrence of immune response led to better tumor-free survival, whatever the predicted prognosis was (hazard ratio, 0.11-0.12 with/without stratification; P = 0.0012-0.0003). CONCLUSIONS: HSPPC-96 vaccination after resection of colorectal liver metastases is safe and elicits a significant increase in CD8+ T-cell response against colon cancer. In this limited number of patients, two-year OS and DFS were significantly improved in subjects with postvaccination antitumor immune response, independently from other clinical prognostic factors.

Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells.

Heat shock proteins (hsp) 96 play an essential role in protein metabolism and exert stimulatory activities on innate and adaptive immunity. Vaccination with tumor-derived hsp96 induces CD8(+) T cell-mediated tumor regressions in different animal models. In this study, we show that hsp96 purified from human melanoma or colon carcinoma activate tumor- and Ag-specific T cells in vitro and expand them in vivo. HLA-A*0201-restricted CD8(+) T cells recognizing Ags expressed in human melanoma (melanoma Ag recognized by T cell-1 (MART-1)/melanoma Ag A (Melan-A)) or colon carcinoma (carcinoembryonic Ag (CEA)/epithelial cell adhesion molecule (EpCAM)) were triggered to release IFN-gamma and to mediate cytotoxic activity by HLA-A*0201-matched APCs pulsed with hsp96 purified from tumor cells expressing the relevant Ag. Such activation occurred in class I HLA-restricted fashion and appeared to be significantly higher than that achieved by direct peptide loading. Immunization with autologous tumor-derived hsp96 induced a significant increase in the recognition of MART-1/Melan-A(27-35) in three of five HLA-A*0201 melanoma patients, and of CEA(571-579) and EpCAM(263-271) in two of five HLA-A*0201 colon carcinoma patients, respectively, as detected by ELISPOT and HLA/tetramer staining. These increments in Ag-specific T cell responses were associated with a favorable disease course after hsp96 vaccination. Altogether, these data provide evidence that hsp96 derived from human tumors can present antigenic peptides to CD8(+) T cells and activate them both in vitro and in vivo, thus representing an important tool for vaccination in cancer patients.

Classification and subtype prediction of adult soft tissue sarcoma by functional genomics.

Adult soft tissue sarcomas are a heterogeneous group of tumors, including well-described subtypes by histological and genotypic criteria, and pleomorphic tumors typically characterized by non-recurrent genetic aberrations and karyotypic heterogeneity. The latter pose a diagnostic challenge, even to experienced pathologists. We proposed that gene expression profiling in soft tissue sarcoma would identify a genomic-based classification scheme that is useful in diagnosis. RNA samples from 51 pathologically confirmed cases, representing nine different histological subtypes of adult soft tissue sarcoma, were examined using the Affymetrix U95A GeneChip. Statistical tests were performed on experimental groups identified by cluster analysis, to find discriminating genes that could subsequently be applied in a support vector machine algorithm. Synovial sarcomas, round-cell/myxoid liposarcomas, clear-cell sarcomas and gastrointestinal stromal tumors displayed remarkably distinct and homogenous gene expression profiles. Pleomorphic tumors were heterogeneous. Notably, a subset of malignant fibrous histiocytomas, a controversialhistological subtype, was identified as a distinct genomic group. The support vector machine algorithm supported a genomic basis for diagnosis, with both high sensitivity and specificity. In conclusion, we showed gene expression profiling to be useful in classification and diagnosis, providing insights into pathogenesis and pointing to potential new therapeutic targets of soft tissue sarcoma.

A single heteroclitic epitope determines cancer immunity after xenogeneic DNA immunization against a tumor differentiation antigen.

Successful active immunization against cancer requires induction of immunity against self or mutated self Ags. However, immunization against self Ags is difficult. Xenogeneic immunization with orthologous Ags induces cancer immunity. The present study evaluated the basis for immunity induced by active immunization against a melanoma differentiation Ag, gp100. Tumor rejection of melanoma was assessed after immunization with human gp100 (hgp100) DNA compared with mouse gp100 (mgp100). C57BL/6 mice immunized with xenogeneic full-length hgp100 DNA were protected against syngeneic melanoma challenge. In contrast, mice immunized with hgp100 DNA and given i.p. tolerizing doses of the hgp100 D(b)-restricted peptide, hgp100(25-33), were incapable of rejecting tumors. Furthermore, mice immunized with DNA constructs of hgp100 in which the hgp100(25-27) epitope was substituted with the weaker D(b)-binding epitope from mgp100 (mgp100(25-27)) or a mutated epitope unable to bind D(b) did not reject B16 melanoma. Mice immunized with a minigene construct of hgp100(25-33) rejected B16 melanoma, whereas mice immunized with the mgp100(25-33) minigene did not develop protective tumor immunity. In this model of xenogeneic DNA immunization, the presence of an hgp100 heteroclitic epitope with a higher affinity for MHC created by three amino acid (25 to 27) substitutions at predicted minor anchor residues was necessary and sufficient to induce protective tumor immunity in H-2(b) mice with melanoma.

Histopathologic type: an independent prognostic factor in primary soft tissue sarcoma of the extremity?

BACKGROUND: We attempted to define the effect of tumor histotype on local recurrence, distant metastasis, and disease-specific survival in patients with surgically treated primary extremity sarcoma. METHODS: A total of 951 patients with primary, localized soft tissue extremity sarcoma were followed up prospectively. Patient- and tumor-related variables, including histopathologic type, were used to identify independent prognostic factors for the study end points of local recurrence, distant recurrence, and disease-specific survival. RESULTS: There were 137 local recurrences, and significant adverse prognostic factors for local recurrence were patient age >50 years, microscopically positive margins, and malignant peripheral nerve tumor. Adverse prognostic factors for distant recurrence (200 patients) were tumor size >5 cm, tumors beneath the investing fascia, high tumor grade, and leiomyosarcoma. Of the 199 patients who died of disease-related causes, patient age >50 years, tumors beneath the investing fascia, high tumor grade, microscopically positive margin, tumor size >5 cm, leiomyosarcoma, and malignant peripheral nerve tumor were adverse prognostic factors. CONCLUSIONS: These data suggest that differences in biological behavior may exist between sarcoma histotypes and deserve further study.

The role of lipopolysaccharide in T-cell responses following DNA vaccination.

Bacterial products, including lipopolysaccharide (LPS), are potential impurities in plasmid DNA vaccines. LPS has immunostimulatory properties even at exceedingly low concentrations through activation of Toll-like receptor 4 (TLR4). The potency of T-cell responses after vaccination was tested with DNA containing high LPS or depleted of LPS in TLR4-competent and TLR4-deficient mice. CD8(+) T-cell responses were readily induced in TLR4-deficient mice immunized with DNA depleted of LPS. LPS in DNA vaccines is not required for CD8(+) T-cell responses.

Primary adult soft tissue sarcoma: time-dependent influence of prognostic variables.

PURPOSE: To define prognostic factors for postrelapse survival and their time-dependent influence for adult soft tissue sarcoma (STS). PATIENTS AND METHODS: We analyzed 2,123 patients with completely resected localized primary STS treated from 1982 to 1999. Variables studied included tumor site, size, depth, grade, and resection margin but not treatment other than resection. Landmark time frames were used to assess the influence of disease-free interval (DFI) on disease-specific survival (DSS). DSS was estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed using log-rank test and the Cox proportional hazards regression model. Time-dependent stepwise regression analysis evaluated the time-dependent influence of each variable. RESULTS: Two thirds of recurrences developed within 2 years of initial resection. Tumor size (P <.001), grade (P <.001), and microscopic resection margin (P <.001) independently predicted DSS for all STS. Size and grade independently predicted early (DFI 3 years) DSS. Risk of tumor-related death was the same across all sites 3 years postresection and decreased significantly for extremity/trunk STS when DFI exceeded 3 years (P <.001). Influence of initial high-risk factors for tumor-related mortality in extremity/trunk STS decreased by 40% 3 years postresection, but their influence over DSS for non-extremity/trunk sites remained constant over time. Likelihood of complete resection after recurrence (all sites) increased with DFI (9% and 33% for DFI < 6 and > 36 months, respectively). CONCLUSION: Tumor size, grade, and resection margin predict outcome for completely resected STS, and their influence for DSS is time- and site-dependent. The influence of prognostic factors changes over the natural history of extremity/trunk STS. Time to recurrence exerts significant influence over complete resection rates for recurrent disease.

Conventional hemangiopericytoma: modern analysis of outcome.

BACKGROUND: Hemangiopericytoma (HPC) is a rare vascular tumor, and pathologic distinction from synovial sarcoma and solitary fibrous tumor is a significant problem due to shared histologic features. In the current report the authors defined the clinical behavior and prognosis for patients with HPC. METHODS: Between July 1982 and February 1998, 62 patients with a diagnosis of primary, recurrent, or metastatic HPC were identified from a prospectively maintained database. The pathology of all cases for which material was available (57 cases) was re-reviewed for histologic confirmation of the HPC diagnosis. Using strict pathologic criteria, including immunohistochemistry and electron microscopy, tumors from 25 of 57 patients qualified for the diagnosis of conventional hemangiopericytoma; those tumors formed the basis of the current report. Survival was determined by the Kaplan-Meier method. RESULTS: At the time of initial presentation, 19 patients had primary tumors, 3 had locally recurrent disease, and 3 had metastatic disease. The most frequent anatomic sites for HPC were the extremities, the pelvis, and the head and neck, accounting for 80% of the total cases. The median followup (n = 25) was 49 months (range, 1 to 160 months). The two and five year overall survival rates (n = 25) were 93% and 86% respectively. The disease-specific survival was 86% at last followup. Patients undergoing complete resection (n = 16) showed a 100% median survival at 60 months. CONCLUSIONS: At present, complete tumor resection for patients with conventional HPC is recommended. However, considering the favorable outcome in this disease, the authors caution against performing operations that may potentially cause loss of function or are limb threatening.

Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings.

PURPOSE: To determine the immunogenicity and antitumor activity of a vaccine consisting of autologous, tumor-derived heat shock protein gp96-peptide complexes (HSPPC-96, Oncophage; Antigenics, Inc, Woburn, MA) in metastatic (American Joint Committee on Cancer stage IV) melanoma patients. PATIENTS AND METHODS: Sixty-four patients had surgical resection of metastatic tissue required for vaccine production, 42 patients were able to receive the vaccine, and 39 were assessable after one cycle of vaccination (four weekly injections). In 21 patients, a second cycle (four biweekly injections) was given because no progression occurred. Antigen-specific antimelanoma T-cell response was assessed by enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Immunohistochemical analyses of tumor tissues were also performed. RESULTS: No treatment-related toxicity was observed. Of 28 patients with measurable disease, two had a complete response (CR) and three had stable disease (SD) at the end of follow-up. Duration of CR was 559+ and 703+ days, whereas SD lasted for 153, 191, and 272 days, respectively. ELISPOT assay with PBMCs of 23 subjects showed a significantly increased number of postvaccination melanoma-specific T-cell spots in 11 patients, with clinical responders displaying a high frequency of increased T-cell activity. Immunohistochemical staining of melanoma tissues from which vaccine was produced revealed high expression of both HLA class I and melanoma antigens in seven of eight clinical responders (two with CR, three with SD, and the three with long-term disease-free survival) and in four of 12 nonresponders. CONCLUSION: Vaccination of metastatic melanoma patients with autologous HSPPC-96 is feasible and devoid of significant toxicity. This vaccine induced clinical and tumor-specific T-cell responses in a significant minority of patients.

Soft tissue sarcoma brain metastases. Prevalence in a cohort of 3829 patients.

BACKGROUND: Brain metastases from soft tissue sarcoma (STS) are uncommon. To the authors' knowledge limited information is available regarding the influence of the initial STS site, the significance of parenchymal versus leptomeningeal metastases, and the role of surgical resection. METHODS: STS patients evaluated between July 1982 and March 1999 who presented with or developed brain metastases were identified from a prospective database. Association between factors was determined using the Fisher exact test. Survival was estimated using the Kaplan-Meier method. The influence of factors on the endpoint (disease specific survival [DSS]) was analyzed using the log-rank test. Significance was defined at P < or = 0.05. RESULTS: A total of 3829 STS patients were evaluated during the study interval; 21 patients presented with and 19 patients subsequently developed brain metastases, accounting for < 1% (40 of 3829 patients) of the total patient group. The STS presentation status for this group of patients (n = 40) included 15 patients with primary STS, 1 patient with local recurrence, and 24 patients with metastatic disease. The most frequent types of STS metastasizing to the brain were leiomyosarcoma (eight patients), liposarcoma (five patients), rhabdomyosarcoma (four patients), and malignant fibrous histiocytoma (MFH) (four patients). Fourteen other sarcoma types were determined in the remaining 19 patients. Of the 19 patients who developed subsequent brain metastases, 18 had lung metastases as the immediate prior site of disease. The median overall follow-up for the 40 patients was 14 months (range, 1-128 months); for survivors (n = 5), the median overall follow-up was 18 months. During follow-up, 34 patients died of disease and 1 patient died of other causes. Brain metastasectomy was performed in 27 of the 40 patients and was highly associated with the initial site of STS; 20 of the 27 patients who underwent resection versus 2 of the 13 patients who did not undergo resection initially had extremity or trunk STS (P < 0.001). No association was observed between parenchymal versus leptomeningeal site of metastases and any outcome factor. The 1-year and 2-year overall DSS for the 40 patients was 55% and 25%, respectively, with a median survival of 15 months. The 1-year and 2-year postmetastasis survival rates were 34% and 20%, respectively, with a median survival of 7 months. Metastasectomy (n = 27) was associated with an improved median postmetastasis survival (9.6 months vs. 2.7 months for unresected patients; P < 0.01). The 2-year postmetastasis survival was 27% for those patients who underwent resection and 0% for the unresected patients. CONCLUSIONS: Although brain metastases from STS are rare, vigilance is warranted. Symptomatic patients should be examined neurologically and investigated thoroughly for metastases. Surgical resection may be an appropriate treatment for selected patients; however, survival is dismal.

T-cell responses against tyrosinase 368-376(370D) peptide in HLA*A0201+ melanoma patients: randomized trial comparing incomplete Freund's adjuvant, granulocyte macrophage colony-stimulating factor, and QS-21 as immunological adjuvants.

We conducted a randomized trial in HLA*A0201+ patientswith American Joint Committee on Cancer stage III or IV melanoma immunized with tyrosinase 368-376(370D) peptide and gp100 209-217(210M) peptide to compare the potency of three different adjuvants. Patients received 3 monthly immunizations with 500 microg of each peptide either with incomplete Freund's adjuvant (IFA), QS-21, or granulocyte macrophage colony-stimulating factor (GM-CSF). The primary end point was induction of IFN-gamma release by CD8+ T cells against tyrosinase and gp100 peptides measured by enzyme-linked immunospot assays without in vitro prestimulation measured pretreatment, 2 and 8 weeks after the third vaccination. Four of 9 and 4 of 8 patients immunized using QS-21 and GM-CSF, respectively, developed increased frequencies of CD8+ T cells against tyrosinase 370D peptide compared with 0 of 9 patients immunized using IFA (P = 0.045). T-cell responses against a gp100-related peptide showed similar results, but their relevance to T-cell reactivity against native gp100 209-217 is uncertain. These results show that: (a) QS-21 and GM-CSF are superior to IFA as immunological adjuvants for vaccination against tyrosinase 370D peptide; and (b) with appropriate adjuvants, increased frequencies of peptide-specific T cells after vaccination can be detected by enzyme-linked immunospot without prolonged prestimulation in vitro.

Analysis of the prognostic significance of microscopic margins in 2,084 localized primary adult soft tissue sarcomas.

OBJECTIVE: To define the significance of positive microscopic resection margins in a large cohort treated for soft tissue sarcoma. METHODS: The authors analyzed 2,084 patients with localized primary soft tissue sarcoma (all anatomic sites) treated from 1982 to 2000. Clinicopathologic variables studied included tumor site, size, depth, histologic type, grade, and resection margin status. Treatment other than resection was not analyzed. Study endpoints included local and distant recurrence-free and disease-specific survival rates, estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the log-rank test and the Cox proportional hazards model. RESULTS: Median follow-up was 50 months. After primary resection, 1,624 (78%) patients had negative and 460 (22%) had positive resection margins. Having positive margins nearly doubled the risk of local recurrence and increased the risk of distant recurrence and disease-related death. Seventy-two percent of patients with positive margins had no recurrence. Resection margin did not predict local control for retroperitoneal sarcomas or fibrosarcomas. Resection margin remained significantly associated with distant recurrence-free survival and disease-specific survival across all subsets after adjusting for other prognostic variables. The overall 5-year disease-specific survival rates for negative and positive margins were 83% and 75%. CONCLUSIONS: Positive microscopic resection margins significantly decrease the local recurrence-free survival rate for other-than-primary fibrosarcoma and retroperitoneal sarcomas, and independently predict distant recurrence-free survival rates and disease-specific survival rates for all patient subsets. Adjuvant therapy should be considered in the management of soft tissue sarcoma to increase local control. Because 72% of positive margins did not equate with inevitable local recurrence, considerable clinical judgment is required in considering additional treatment. Microscopic resection margins should be considered for inclusion in staging systems and treatment algorithms that address local recurrence.

Clinicopathologic correlates of solitary fibrous tumors.

BACKGROUND: Solitary fibrous tumors (SFTs) are rare fibrous neoplasms. Since their initial description as arising from the pleura, SFTs have been reported at a wide range of anatomic sites. To the authors's knowledge, there are no large series reporting both thoracic and extrathoracic SFTs nor are there any large series that analyze clinicopathologic correlates of tumor behavior. METHODS: Institutional soft tissue tumor and pathology databases were reviewed to identify patients. Pathologic material was reviewed by an experienced soft tissue pathologist and scored for the presence of a histologically malignant component. Clinical information was obtained from medical records and phone calls to patients. Statistical analysis was performed using the Student t test, Pearson chi-square test, and log-rank test. RESULTS: Seventy-nine patients with SFTs treated at a single institution over an 18-year period were identified. These tumors arose in a wide range of anatomic sites. Thoracic and extrathoracic SFTs had similar clinical and pathologic features, although extrathoracic tumors were more likely to be symptomatic on diagnosis. Seventy-five patients underwent surgical excision of a SFT at our institution. Overall, SFTs had a low rate of local recurrence and metastasis after surgical treatment. Extrathoracic SFTs had an increased risk of local recurrence that was small but statistically significant. There was no difference in metastasis-free survival between thoracic and extrathoracic SFTs. Positive surgical margins and the presence of a histologically malignant component were factors predicting worse local recurrence-free survival. Positive surgical margins, tumor size greater than 10 cm, and the presence of a malignant component predicted worse metastasis-free survival. CONCLUSIONS: Solitary fibrous tumors are rare tumors that occur at all anatomic sites. Most SFT patients fare well after surgical treatment. Closer surveillance is warranted for those tumors that are larger than 10 cm or with the presence of a histologically malignant component.

Xenogeneic DNA immunization in melanoma models for minimal residual disease.

INTRODUCTION: DNA immunization with xenogeneic genes encoding homologous antigens protects mice against tumor challenge with syngeneic melanoma in a lung metastasis model. The effect of xenogeneic human TRP-2 (hTRP2) DNA immunization on disease confined to an orthotopic site, the skin, and in a model of minimal residual disease that is relevant to a setting of adjuvant therapy for micrometastatic cancer is reported. METHODS: Immunization and tumor challenge with B16F10LM3 melanoma were performed in C57BL/6 mice and in mice genetically deficient in MHC class I or II molecules. A melanoma variant of B16 with a predilection for lung metastasis was selected and used to challenge C57BL/6 mice. Tumor challenge in the footpad with the B16 variant was followed by local tumor growth and lung metastasis. The tumor-bearing distal extremities were surgically resected and mice were randomized to receive hTRP2 DNA immunization or no treatment. Approximately 3-5 weeks after surgical resection, lungs were harvested and metastases counted. RESULTS: Xenogeneic DNA immunization with hTRP2 prevented tumor growth in the skin by a mechanism requiring CD4(+) and CD8(+) T cells but did not inhibit the growth of established tumors. Adjuvant immunization with hTRP2 DNA after resection significantly reduced lung metastases and decreased local recurrence rates after surgical resection. CONCLUSIONS: Xenogeneic DNA immunization with hTRP2 was effective in protecting mice from intradermal tumor challenge. Immunization prevented local recurrence and the development of metastases in a mouse model of minimal residual disease, supporting a role for DNA immunization against melanosomal antigens as an adjuvant to surgery in high-risk primary melanomas.