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Raphael E Pollock

Publications and source records attributed to Raphael E Pollock.

At least 19 recordsLinked to original sources
PubMed2025

Blockade of interleukin-6 (IL-6) signaling in dedifferentiated liposarcoma (DDLPS) decreases mouse double minute 2 (MDM2) oncogenicity via alternative splicing.

Effective therapies for retroperitoneal (RP) dedifferentiated liposarcoma (DDLPS) remain unavailable. Loco-regional recurrence occurs in >80% of cases; 5-year disease-specific survival is only 20%. DDLPS is especially prevalent in the retroperitoneum and abdomen; evaluation of the DDLPS microenvironment in these high-fat compartments appears pertinent. Adipose is a main supplier of interleukin-6 (IL6); excessive activation of IL6 signal transducer glycoprotein 130 (GP130) underlies the development of some diseases. The role of GP130 pathway activation remains unstudied in DDLPS, so we examined the role of microenvironment fat cell activation of the IL6/GP130 signaling cascade in DDLPS. All DDLPS tumors and cell lines studied expressed elevated levels of the GP130-encoding gene IL6ST and GP130 protein compared to normal tissue and cell line controls. IL6 increased DDLPS cell growth and migration, possibly through increased signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) activation, and upregulated mouse double minute 2 (MDM2). GP130 loss conveyed opposite effects; pharmacological blockade of GP130 by SC144 produced the MDM2 splice variant MDM2-ALT1, known to inhibit full length MDM2 (MDM2-FL). Although genomic MDM2 amplification is pathognomonic for DDLPS, mechanisms driving MDM2 expression, regulation, and function beyond the MDM2:p53 negative feedback loop are poorly understood. Our findings suggest a novel preadipocyte DDLPS-promoting role due to IL6 release, via upregulation of DDLPS MDM2 expression. Pharmacological GP130 blockade reduced the IL6-induced increase in DDLPS MDM2 mRNA and protein levels, possibly through enhanced expression of MDM2-ALT1, a possibly targetable pathway with potential as future DDLPS patient therapy.

Proto-Oncogene Proteins c-mdm2↗
PubMed2024

Extracellular Vesicle- MDM2 -DNA as a Potential Liquid Biopsy Biomarker for Disease Identification in Retroperitoneal Liposarcoma.

OBJECTIVE: We aimed to assess the levels of MDM2 -DNA within extracellular vesicles (EVs) isolated from the serum of retroperitoneal liposarcoma (RLS) patients versus healthy donors, as well as within the same patients at the time of surgery versus postoperative surveillance visits. To determine whether EV- MDM2 may serve as a possible first-ever biomarker of liposarcoma recurrence. BACKGROUND: A hallmark of well-differentiated and dedifferentiated (WD/DD) retroperitoneal liposarcoma is elevated MDM2 due to genome amplification, with recurrence rates of >50% even after complete resection. Imaging technologies frequently cannot resolve recurrent WD/DD-RLS versus postoperative scarring. Early detection of recurrent lesions, for which biomarkers are lacking, would guide surveillance and treatment decisions. METHODS: WD/DD-RLS serum samples were collected both at the time of surgery and during follow-up visits from 42 patients, along with sera from healthy donors (n=14). EVs were isolated, DNA purified, and MDM2 -DNA levels determined through q-PCR analysis. Nonparametric tests were employed to compare EV- MDM2 DNA levels from patients versus the control group, as well as the time of surgery versus postsurgery conditions. RESULTS: EV -MDM2 levels were significantly higher in WD/DD-RLS than controls ( P =0.00085). Moreover, EV- MDM2 levels were remarkably decreased in WD/DD-RLS patients after resection ( P =0.00036), reaching values comparable to control group ( P =0.124). During postoperative surveillance, significant increases of EV- MDM2 were observed in some patients, correlating with computed tomography scan evidence of recurrent or persistent postresection disease. CONCLUSIONS: Serum EV- MDM2 may serve as a potential biomarker of early recurrent or postoperatively persistent WD/DD-RLS, a disease currently lacking such determinants.

Humans↗
PubMed2007

Periosteal margin in soft-tissue sarcoma.

BACKGROUND: Soft-tissue sarcomas frequently rest in contact with bone. The purpose of the study was to evaluate the risk of local recurrence for sarcomas adjacent to bone and to determine whether the periosteum provides an adequate margin of resection. METHODS: Fifty patients with soft-tissue sarcomas abutting bone were treated at a single institution between 1990 and 2004. All patients had high-grade, T2 (>5 cm), nonmetastatic disease in the lower extremity. Bone contact was verified by preoperative magnetic resonance imaging (MRI) and/or computed tomography (CT) scans. Forty-three of 50 patients received preoperative radiation with a mean dose of 50 Gy. In 11 cases a composite resection of bone and soft tissue was performed. In 39 cases the excision involved only soft tissue. RESULTS: True bone invasion was verified by histopathologic examination in 3 of 50 cases (6%). Local recurrence in the soft tissues developed in 8 of 50 (16%) patients. In no case did the recurrence involve destruction of cortical bone or erosion into bone. The recurrent tumor resided against the region of previous bone contact in 1 of 8 cases. There was no statistically significant difference in local recurrence between patients who had composite bone resection and patients who had soft-tissue resection only (P = .87). CONCLUSIONS: Relatively few sarcomas are able to penetrate cortical bone. Composite bone and soft-tissue resections are indicated primarily for frank bone invasion. In the absence of this, the periosteum is an adequate surgical margin for sarcomas treated with wide excision and radiation.

Adolescent↗
PubMed2007

Management of locally recurrent soft-tissue sarcoma after prior surgery and radiation therapy.

PURPOSE: The aim of this study was to evaluate outcome and treatment toxicity after wide local re-excision (WLE), with or without additional radiation therapy, for patients with isolated first local recurrence of soft-tissue sarcoma arising within a previously irradiated field. METHODS: A retrospective review was performed of 62 consecutive patients. All patients underwent prior resection and external beam radiation. For recurrent disease, 25 patients were treated with WLE alone, and 37 patients were treated with WLE and additional radiation (45- 64 Gy). In 33 patients, the radiation was delivered via an afterloaded brachytherapy, single-plane implant. RESULTS: The 5-year disease specific and distant metastasis-free survival rates were 65% and 73%, respectively. Local control (LC) at 5 years was 51%, and on multivariate analysis, a positive surgical resection margin (p< 0.001) was associated with a lower rate of LC. Reirradiation was not associated with improved LC; however complications requiring outpatient or surgical management were more common in patients who had undergone reirradiation (80% vs. 17%, p < 0.001). Amputation was also more common in the subgroup of patients who underwent extremity reirradiation (35% with radiation vs. 11% without, p = 0.05), although only one amputation was performed to resolve a treatment complication. CONCLUSION: Conservative surgery alone results in LC in a minority of patients who have failed locally after previous excision and external beam radiation. Although selection biases and small patient numbers confound the analysis, local treatment intensification with additional radiation does not clearly improve outcome after surgical excision alone, and is associated with an increase in complications.

Aged↗
PubMed2007

Surgical resection of gastrointestinal stromal tumors after treatment with imatinib.

BACKGROUND: Surgical resection of gastrointestinal stromal tumors (GISTs) has been the most effective therapy for these rare tumors. Imatinib has been introduced as systemic therapy for locally advanced and metastatic GIST. In this study, the surgical resection rates and long-term outcomes of patients treated with preoperative imatinib for locally advanced primary, recurrent, or metastatic GISTs were evaluated. METHODS: Patients were retrospectively assessed for completeness of surgical resection and for disease-free and overall survival after resection. RESULTS: Forty-six patients underwent surgery after treatment with imatinib. Eleven were treated for locally advanced primary GISTs for a median of 11.9 months, followed by complete surgical resection. All eleven were alive at a median of 19.5 months, and ten were free of disease. Thirty-five patients were treated for recurrent or metastatic GIST. Of these, eleven underwent complete resection. Six of the eleven patients had recurrent disease at a median of 15.1 months. All eleven patients were alive at a median of 30.7 months. Patients with a partial radiographic tumor response to imatinib had significantly higher complete resection rates than patients with progressive disease (91% vs. 4%; P < .001). Of the 24 patients with incomplete resection, 18 initially responded to imatinib but were unable to undergo complete resection after they progressed before surgery. CONCLUSIONS: Preoperative imatinib can decrease tumor volume and is associated with complete surgical resection in locally advanced primary GISTs. Early surgical intervention should be considered for imatinib-responsive recurrent or metastatic GIST, since complete resection is rarely achieved once tumor progression occurs.

Adult↗
PubMed2006

Retroperitoneal soft tissue sarcoma: an analysis of radiation and surgical treatment.

PURPOSE: To evaluate the clinical outcomes of patients with localized retroperitoneal soft tissue sarcoma (STS) treated with complete surgical resection and radiation. METHODS AND MATERIALS: The medical records of 83 patients were reviewed retrospectively. Sixty patients presented with primary disease and the remaining 23 had recurrence after previous surgical resection. RESULTS: With a median follow-up of 47 months, the actuarial overall disease-specific survival (DSS), distant metastasis-free survival, and local control (LC) rates were 44%, 67%, and 40%, respectively. Of the 38 patients dying of disease, local disease progression was the sole site of recurrence for 16 patients and was a component of progression for another 11 patients. Multivariate analysis indicated that histologic grade was associated with the 5-year rates of DSS (low-grade, 92%; intermediate-grade, 51%; and high-grade, 41%, p = 0.006). Multivariate analysis also indicated an inferior 5-year LC rate for patients presenting with recurrent disease, positive or uncertain resection margins, and age greater than 65 years. The data did not suggest an improved local control with higher doses of external-beam radiation (EBRT) or with the specific use of intraoperative radiotherapy (IORT). Radiation-related complications (10% at 5 years) developed in 5 patients; all had received their EBRT postoperatively. CONCLUSIONS: Although preoperative radiation therapy and aggressive surgical resection is well tolerated in patients, local disease progression continues to be a significant component of disease death. In this small cohort of patients, the use of higher doses of EBRT or IORT did not result in clinically apparent improvements in outcomes.

Adult↗
PubMed2006

Wild-type p53 inhibits nuclear factor-kappaB-induced matrix metalloproteinase-9 promoter activation: implications for soft tissue sarcoma growth and metastasis.

Human soft tissue sarcoma (STS) is a highly lethal malignancy in which control of metastasis determines survival. Little is known about the molecular determinants of STS dissemination. Here, we show that human STS express high levels of matrix metalloproteinase-9 (MMP-9) and that MMP-9 expression levels correlate with sequence analysis-defined p53 mutational status. Reintroduction of wild-type p53 (wtp53) into mutant p53 STS cell lines decreased MMP-9 mRNA and protein levels, decreased zymography-assessed MMP-9 proteolytic activity, and decreased tumor cell invasiveness. Reintroduction of wtp53 into STS xenografts decreased tumor growth and MMP-9 protein expression. Luciferase reporter studies showed that reintroduction of wtp53 into mutant p53 STS cells decreased MMP-9 promoter activity. Deletion constructs of the MMP-9 promoter identified a region containing a p53-responsive element that lacked a p53 consensus binding site but did contain a nuclear factor-kappaB (NF-kappaB) site. Mutating this NF-kappaB binding site eliminated the wtp53-repressive effect. Electrophoretic mobility shift assays confirmed decreased NF-kappaB binding in STS cells in the presence of wtp53. Our findings suggest a role for MMP-9 in STS progression and expand the role of p53 in molecular control of STS growth and metastasis. Therapeutic interventions in human STS targeting MMP-9 activity directly or via reintroduction of wtp53 merit further investigation.

Cell Line, Tumor↗
PubMed2006

The effect of preoperative radiotherapy and reconstructive surgery on wound complications after resection of extremity soft-tissue sarcomas.

BACKGROUND: Major wound complications (MWCs) are frequent after preoperative radiotherapy (RT) for extremity soft-tissue sarcoma (STS). We examined the rate of MWCs at a single institution with readily available reconstructive surgery. METHODS: The medical records of consecutively treated extremity STS patients treated with preoperative external-beam RT and surgical resection from June 1996 through February 2003 were reviewed. Patients underwent RT (median 50 Gy), followed by resection 4-8 weeks later. Patients believed to be at higher risk for MWC underwent wound closure by the reconstructive surgery service (RSS). MWCs included secondary operation, invasive procedure, hospital readmission, or persistent deep packing or dressing changes. RESULTS: A total of 173 patients underwent preoperative RT. Median age was 54 years; 51% were female; 80% had lower extremity STS. Wound closure was performed by the primary surgeon in 91 cases (53%). The RSS performed wound closure in the remaining 82 patients (47%). One or more MWCs occurred in 55 patients (32%). Wound complications were more likely in patients with lower extremity (49/138, 36%) than upper extremity (6/35, 17%) STS (P = 0.03). Among patients with lower-risk wounds closed by the primary surgical team, 29 (32%) experienced MWC, whereas in the higher-risk patients closed by the RSS, MWC occurred in 26 (32%). CONCLUSIONS: MWCs are frequent after preoperative RT and occur more commonly in patients with lower extremity tumors. The MWC rate observed in a single-institution setting was comparable to that observed in the preoperative therapy arm of a multicenter Canadian trial. Patients believed to be at higher risk for MWCs undergoing RSS closure have MWC rates comparable to those with lower-risk wounds closed by the primary team.

Adolescent↗
PubMed2006

Vascular endothelial growth factor overexpression by soft tissue sarcoma cells: implications for tumor growth, metastasis, and chemoresistance.

To better elucidate the role of vascular endothelial growth factor (VEGF)(165) in soft tissue sarcoma (STS) growth, metastasis, and chemoresistance, we generated stably transfected human STS cell lines with VEGF(165) to study the effect of VEGF(165) on STS cells in vitro and the effect of culture medium from these cells on human umbilical vascular endothelial cells. Severe combined immunodeficient mice bearing xenografts of transfected cell lines were used to assess the effect of VEGF overexpression and the effect of VEGF receptor (VEGFR) 2 inhibition on STS growth, metastasis, and response to doxorubicin. VEGF(165)-transfected xenografts formed highly vascular tumors with shorter latency, accelerated growth, enhanced chemoresistance, and increased incidence of pulmonary metastases. Blockade of VEGFR2 signaling using DC101 anti-VEGFR2 monoclonal antibody enhanced doxorubicin chemoresponse; this combined biochemotherapy inhibited tumor growth and decreased pulmonary metastases without overt toxicity. Combined therapy reduced microvessel counts while increasing vessel maturation index. VEGF overexpression did not affect on the sarcoma cells per se; however, conditioned medium from VEGF transfectants caused increased endothelial cell proliferation, migration, and chemoresistance. Addition of DC101 induced endothelial cell sensitivity to doxorubicin and suppressed the activity of matrix metalloproteinases secreted by endothelial cells. We therefore conclude that VEGF is a critical determinant of STS growth and metastasis and that STS chemoresistance, in our model, is a process induced by the interplay between STS cells and tumor-associated endothelial cells. STS growth and metastasis can be interrupted by combined low-dose doxorubicin and anti-VEGFR2, a strategy that attacks STS-associated endothelial cells. In the future, such therapeutic approaches may be useful in treating STS before the development of clinically apparent metastases.

Animals↗
PubMed2006

Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma.

BACKGROUND: The reported data on surgery plus radiotherapy for retroperitoneal soft tissue sarcomas (RPS) have been mostly from retrospective studies. We evaluated the long-term outcome of patients with operable RPS who were treated with protocol-based preoperative radiotherapy followed by complete surgical resection. METHODS: Data from two prospective trials that included preoperative radiotherapy and surgery for patients with radiographically resectable RPS were combined to define long-term relapse rates and survival. RESULTS: Seventy-two patients with intermediate- or high-grade RPS were treated with preoperative radiotherapy (median dose, 45 Gy; range, 18.0-50.4 Gy). Fifty-four patients (75%) had primary RPS, whereas 18 (25%) had recurrent disease. The median tumor size was 15.5 cm. Sixty-four patients completed the planned preoperative radiotherapy; 57 (89%) underwent laparotomy with curative intent, and 54 (95%) had a macroscopically complete (R0 or R1) resection. With a median follow-up of 40.3 months, 28 patients (52%) who received preoperative radiotherapy and underwent a macroscopically complete resection had recurrences. For the 54 patients who underwent R0 or R1 resection after preoperative radiotherapy, the 5-year local recurrence-free, disease-free, and overall survival rates were 60%, 46%, and 61%, respectively. The median overall survival has not been reached (>60 months). CONCLUSIONS: Patients with intermediate- or high-grade RPS treated with preoperative radiotherapy plus complete resection had a median survival >60 months. This compares favorably to historical data for similar patients treated with surgery alone.

Adult↗
PubMed2006

Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver.

HYPOTHESIS: A subset of patients with sarcoma liver metastasis may benefit from hepatic resection and/or ablation. DESIGN: Retrospective review of prospectively collected cancer center database records. PATIENTS AND METHODS: Sixty-six patients who underwent hepatic resection and/or open radiofrequency ablation of metastatic sarcoma between July 1, 1996, and April 30, 2005, were identified from the database. Clinicopathologic, operative, recurrence, and long-term survival data were analyzed. RESULTS: The primary sarcoma site was the abdomen or retroperitoneum (n = 22), stomach (n = 18), small or large bowel (n = 17), pelvis (n = 4), uterus (n = 3), or other (n = 2). Tumor pathologic types included gastrointestinal stromal tumor (n = 36), leiomyosarcoma (n = 18), and sarcoma not otherwise classified (n = 12). Thirty-five patients underwent resection, 18 underwent resection plus radiofrequency ablation, and 13 underwent radiofrequency ablation only. With a median follow-up of 35.8 months, 44 patients (66.7%) had recurrence (intrahepatic only, n = 16; extrahepatic only, n = 11; both, n = 17). Treatment with radiofrequency ablation (either alone or combined with resection) (P = .002) and lack of adjuvant chemotherapy (P = .01) predicted shorter disease-free survival. The 1-, 3-, and 5-year overall survival rates were 91.2%, 65.4%, and 27.1%, respectively. Patients with gastrointestinal stromal tumor who were treated with adjuvant imatinib mesylate had the longest median survival (not reached) (P = .003). CONCLUSIONS: Long-term survival can be achieved following surgical treatment of sarcoma liver metastasis, especially in patients with gastrointestinal stromal tumor. Patients with sarcoma liver metastasis should be evaluated by a multidisciplinary team, as recurrence is common and adjuvant therapy may prolong survival.

Adult↗
PubMed2006

Unsupervised analysis uncovers changes in histopathologic diagnosis in supervised genomic studies.

Human gastrointestinal stromal tumors (GIST) have recently emerged as a distinct mesenchymal tumor type that has a unique phenotype characterized by a gain of function mutations in c-kit. In contrast, leiomyosarcomas (LMS) of the gastrointestinal tract or retroperitoneum, which were previously classified together with GISTs as gastrointestinal sarcomas, have much less frequent mutations of c-kit. We performed microarray analyses to gain a comprehensive understanding of the difference between the two types of soft-tissue sarcomas at the level of gene expression. Microarray experiments were performed on 30 GISTs and 30 LMSs that were collected at the time of surgical resection. These tumors were categorized based on the histopathologic diagnosis recorded in our institutional database. Prior to our search for genes that are differentially expressed between these two types of cancers, we first carried out an unsupervised analysis using multidimensional scaling (MDS) to determine whether the two groups have marked overall differences in gene expression. Initially, the MDS did not reveal a good separation between the two groups. We then re-reviewed the histopathology of these tumors and realized that some of the cases included in our study were acquired 10 years ago when the diagnosis of gastrointestinal sarcoma was made according to histopathologic criteria alone without immunohistochemistry for c-kit. An experienced pathologist reviewed all of the specimens and this revealed that a number of the GIST cases were classified as LMS in the clinical database. Correction of the histopathologic diagnosis and relabeling of the samples resulted in a much more pronounced separation of GIST and LMS in the MDS analysis. This study underscores the need to re-review histopathology as reclassification occurs. While updating the clinical database may be desired, this is usually impractical. For molecular studies that use archival samples, it is critical to have the archival samples re-reviewed by a pathologist. Further, unsupervised analysis often proves to be a critical quality control step in identifying structural problems that may exist. Finally, MDS analysis further supports that GIST is a distinct type of sarcoma.

Biomarkers, Tumor↗
PubMed2006

Molecular diagnosis of sarcomas: chromosomal translocations in sarcomas.

CONTEXT: Sarcomas are rare, numerous in type, and often difficult to definitively classify. Work in the last 2 decades has revealed that a significant subset of sarcomas are associated with specific chromosomal translocations producing chimeric (fusion) genes that play a role in the sarcomas' biology and are helpful in their differential diagnosis. OBJECTIVE: To briefly review the sarcomas associated with specific translocations presenting Ewing sarcoma and synovial sarcoma as archetypes and to further explain how cytogenetic and molecular biologic approaches are being used in the diagnosis of sarcomas. DATA SOURCES: This work is based on a selected review of the relevant medical and scientific literature and our extensive experience with molecular testing in sarcomas. CONCLUSIONS: In addition to, and complementing, the traditional diagnostic methods of examination of hematoxylin-eosin stained slides, immunohistochemistry, and sound clinical-pathologic correlation, additional cytogenetic and molecular biologic methods are being increasingly utilized and relied on in sarcoma pathology. These methods include chromosomal karyotyping, fluorescence in-situ hybridization, spectral karyotyping, and polymerase chain reaction- based methods for demonstrating specific chromosomal translocations and fusion genes. Understanding the basis of these methods and their application is critical to better provide accurate and validated specific diagnoses of sarcomas.

Bone Neoplasms↗
PubMed2005

Angiosarcoma of the breast.

BACKGROUND: Angiosarcoma of the breast is a rare entity. The objectives of this study were to evaluate prognostic factors and determine outcomes in a large contemporary series of patients. METHODS: Clinical and pathologic factors were analyzed in all patients with angiosarcoma of the breast treated between 1990 and 2003. Overall survival (OS) and disease-free survival (DFS) were estimated using the methods of Kaplan and Meier. Multivariate analyses were performed to evaluate prognostic factors. RESULTS: Fifty-five women with angiosarcoma of the breast were identified. The median age was 49.1 years, and the median follow-up time was 3.7 years. The median OS and DFS were 2.96 years and 2.26 years, respectively. For the 32 patients with primary angiosarcoma of the breast 5-year OS was 59%. Twenty-three (42%) patients had received prior radiation therapy for the treatment of breast cancer. These patients with radiation therapy-associated angiosarcoma were on average 30 years older and less likely to present with distant metastatic disease than patients presenting with radiation-naive angiosarcoma of the breast. Although radiation-naive patients appeared to have had better early DFS and OS, the Kaplan-Meier curves were not statistically different between patients with radiation therapy-associated disease and radiation therapy-naive patients. On multivariate analysis, tumor recurrence (P = 0.006) was the only significant adverse prognostic factor noted for OS. CONCLUSIONS: In this series of 55 patients with angiosarcoma of the breast, radiation therapy-naive angiosarcomas occurred in younger patients, but they behaved similarly to radiation therapy-associated angiosarcomas.

Adult↗
PubMed2005

Activation of the ALT pathway for telomere maintenance can affect other sequences in the human genome.

Immortal human cells maintain telomere length by the expression of telomerase or through the alternative lengthening of telomeres (ALT). The ALT mechanism involves a recombination-like process that allows the rapid elongation of shortened telomeres. However, it is not known whether activation of the ALT pathway affects other sequences in the genome. To address this we have investigated, in ALT-expressing cell lines and tumours, the stability of tandem repeat sequences known to mutate via homologous recombination in the human germline. We have shown extraordinary somatic instability in the human minisatellite MS32 (D1S8) in ALT-expressing (ALT+) but not in normal or telomerase-expressing cell lines. The MS32 mutation frequency varied across 15 ALT+ cell lines and was on average 55-fold greater than in ALT- cell lines. The MS32 minisatellite was also highly unstable in three of eight ALT+ soft tissue sarcomas, indicating that somatic destabilization occurs in vivo. The MS32 mutation rates estimated for two ALT+ cell lines were similar to that seen in the germline. However, the internal structures of ALT and germline mutant alleles are very different, indicating differences in the underlying mutation mechanisms. Five other hypervariable minisatellites did not show elevated instability in ALT-expressing cell lines, indicating that minisatellite destabilization is not universal. The elevation of MS32 instability upon activation of the ALT pathway and telomere length maintenance suggests there is overlap between the underlying processes that may be tractable through analysis of the D1S8 locus.

Cell Line, Tumor↗
PubMed2005

Expression of receptor tyrosine kinases epidermal growth factor receptor and HER-2/neu in synovial sarcoma.

BACKGROUND: Synovial sarcomas are high-grade soft tissue neoplasms often characterized by a biphasic spindle and epithelioid cell morphology. The majority of synovial sarcomas harbor a specific chromosomal translocation in which the proximal portion of the SYT gene at chromosome 18q11 is fused to the distal portion of one of several duplicated SSX genes (most notably SSX1 and SSX2) at chromosome Xp11. SYT/SSX1 translocations are seen in nearly three times as many synovial sarcomas as SYT/SSX2 translocations. Although the SYT/SSX2 fusion is usually associated with the monophasic disease pattern, the SYT/SSX1 fusion is present in tumors with biphasic or monophasic patterns. The SYT/SSX1 fusion gene is associated with more aggressive tumor growth and poor outcome. Despite advances in the therapy of local disease, distant metastasis remains the predominant cause of death. Accordingly, there is a need for alternate therapies, such as those recently developed against the receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and HER-2/neu. METHODS: Archival specimens of synovial sarcoma (n=38) representing 30 patients were assessed for EGFR and HER-2/neu protein expression by standard immunohistochemical techniques. To validate the immunohistochemistry results, quantitative real-time polymerase chain reaction (Q-PCR) assays using either fresh and/or archival material was performed. The presence of gene amplification was determined by chromogenic in-situ hybridization. RESULTS: EGFR and HER-2/neu protein were detected by immunohistochemistry in 21 of 38 (55.3%) and 20 of 38 (52.6%) synovial specimens, respectively. EGFR immunoreactivity showed a granular and membranous pattern, whereas HER-2/neu immunoreactivity demonstrated only a membrane pattern. Coexpression was observed in 13 of 38 specimens (34.2%). HER-2/neu expression by immunohistochemistry in synovial sarcomas was restricted to tumors with the SYT/SSX1 translocations. Of 6 specimens with SSX2 translocation, none (0%) showed HER-2/neu immunoreactivity and 1 (17%) demonstrated EGFR expression. Q-PCR demonstrated the presence of mRNA for EGFR and HER-2/neu in 19 of 30 specimens (63.3%) and 22 of 30 specimens (73.3%), respectively. EGFR and HER-2/neu were expressed at low concentrations compared with the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). No evidence of gene amplification was observed. CONCLUSIONS: EGFR and HER-2/neu are expressed in the majority of patients with SYT/SSX1 synovial sarcomas, albeit at low levels. Treatment with tyrosine kinase inhibitors may represent appropriate alternate therapy for these patients.

Adolescent↗
PubMed2005

A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas.

PURPOSE AND EXPERIMENTAL DESIGN: Telomeres of tumor cells may be maintained by telomerase or by alternative lengthening of telomeres (ALT). The standard ALT assay requires Southern analysis of high molecular weight genomic DNA. We aimed to establish and validate an ALT assay suitable for archived paraffin-embedded tumors and to use it to examine the prevalence and clinical significance of ALT in various types of tumors that are often telomerase negative. RESULTS: To assay for ALT, we detected ALT-associated promyelocytic leukemia (PML) bodies (APBs) by combined PML immunofluorescence and telomere fluorescence in situ hybridization. APBs are PML nuclear domains containing telomeric DNA and are a known hallmark of ALT in cell lines. The APB assay concurred with the standard ALT assay in 62 of 62 tumors and showed that 35% of 101 soft tissue sarcomas (STS), 47% of 58 osteosarcomas (especially younger patients), 34% of 50 astrocytomas, and 0% of 17 papillary thyroid carcinomas were ALT positive (ALT+). The prevalence of ALT varied greatly among different STS subtypes: malignant fibrous histiocytomas, 77%; leiomyosarcomas, 62%; liposarcomas, 33%; synovial sarcomas, 9%; and rhabdomyosarcomas, 6%. ALT correlated with survival in glioblastoma multiforme and occurred more often in lower-grade astrocytomas, but ALT+ and ALT- sarcomas were equally aggressive in terms of grade and clinical outcome. CONCLUSION: The APB assay for ALT is suitable for paraffin-embedded tumors. It showed that a substantial proportion of STS, osteosarcomas, and astrocytomas, but not papillary thyroid carcinomas use ALT. APB positivity correlated strongly with survival of patients with astrocytomas.

Adult↗