Connective Tissue Sarcomas Research Articles

The association between ambient air pollution exposure and connective tissue sarcoma risk: a nested case-control study using a nationwide population-based database.

A nationwide population-based database was utilized in a nested case-control study to explore the association between ambient air pollution exposure and the likelihood of developing connective tissue sarcoma. The study examined 280 cases of connective tissue sarcoma diagnosed between 2000 and 2012. A random sample of 1120 control subjects was selected from a subpopulation of claim records without a connective tissue sarcoma diagnosis in a 1:4 ratio. The control subjects were selected based on similar characteristics as the connective tissue sarcoma patients, including gender, birth year, and the year of diagnosis of the case group with medical records. Risk factors for connective tissue sarcoma were collected for analysis. Our data on exposure to air pollutants was collected from Taiwan's Air Quality Monitoring Network, which has been gathering air quality data from a growing network of sampling stations (now 76) throughout the country since 1997. It was discovered that the risk of connective tissue sarcoma was significantly increased by the Charlson comorbidity index (CCI), elevated levels of specific air pollution indices (e.g., total hydrocarbons (THC), fine particulate matter (PM2.5), and O3_8 (the annual mean of the daily maximum 8-h average concentration of O3), the High Pollutant Standards Index (hPSI) (the percentage of days in a given year in Taiwan where the PSI exceeds 100), and an insurable monthly wage over US$1100. Further investigation is needed to explore the involvement of these air pollutants in the formation of connective tissue sarcoma.

Alveolar soft-part sarcoma (ASPS) resembles a mesenchymal stromal progenitor: evidence from meta-analysis of transcriptomic data.

Alveolar soft-part sarcoma (ASPS) is an extremely rare malignancy characterized by the unbalanced translocation der(17)t(X;17)(p11;q25). This translocation generates a fusion protein, ASPL-TFE3, that drives pathogenesis through aberrant transcriptional activity. Although considerable progress has been made in identifying ASPS therapeutic vulnerabilities (e.g., MET inhibitors), basic research efforts are hampered by the lack of appropriate in vitro reagents with which to study the disease. In this report, previously unmined microarray data for the ASPS cell line, ASPS-1, was analyzed relative to the NCI sarcoma cell line panel. These data were combined with meta-analysis of pre-existing ASPS patient microarray and RNA-seq data to derive a platform-independent ASPS transcriptome. Results demonstrated that ASPS-1, in the context of the NCI sarcoma cell panel, had some similarities to normal mesenchymal cells and connective tissue sarcomas. The cell line was characterized by high relative expression of transcripts such as CRYAB, MT1G, GCSAML, and SV2B. Notably, ASPS-1 lacked mRNA expression of myogenesis-related factors MYF5, MYF6, MYOD1, MYOG, PAX3, and PAX7. Furthermore, ASPS-1 had a predicted mRNA surfaceome resembling an undifferentiated mesenchymal stromal cell through expression of GPNMB, CD9 (TSPAN29), CD26 (DPP4), CD49C (ITGA3), CD54 (ICAM1), CD63 (TSPAN30), CD68 (SCARD1), CD130 (IL6ST), CD146 (MCAM), CD147 (BSG), CD151 (SFA-1), CD166 (ALCAM), CD222 (IGF2R), CD230 (PRP), CD236 (GPC), CD243 (ABCB1), and CD325 (CDHN). Subsequent re-analysis of ASPS patient data generated a consensus expression profile with considerable overlap between studies. In common with ASPS-1, elevated expression was noted for CTSK, DPP4, GPNMB, INHBE, LOXL4, PSG9, SLC20A1, STS, SULT1C2, SV2B, and UPP1. Transcripts over-expressed only in ASPS patient samples included ABCB5, CYP17A1, HIF1A, MDK, P4HB, PRL, and PSAP. These observations are consistent with that expected for a mesenchymal progenitor cell with adipogenic, osteogenic, or chondrogenic potential. In summary, the consensus data generated in this study highlight the unique and highly conserved nature of the ASPS transcriptome. Although the ability of the ASPL-TFE3 fusion to perturb mRNA expression must be acknowledged, the prevailing ASPS transcriptome resembles that of a mesenchymal stromal progenitor.

Malignant cancer and invasive placentation: A case for positive pleiotropy between endometrial and malignancy phenotypes.

Cancer metastasis is an invasive process that involves the transplantation of cells into new environments. Since human placentation is also invasive, hypotheses about a relationship between invasive placentation in eutherian mammals and metastasis have been proposed. The relationship between metastatic cancer and invasive placentation is usually presented in terms of antagonistic pleiotropy. According to this hypothesis, evolution of invasive placentation also established the mechanisms for cancer metastasis. Here, in contrast, we argue that the secondary evolution of less invasive placentation in some mammalian lineages may have resulted in positive pleiotropic effects on cancer survival by lowering malignancy rates. These positive pleiotropic effects would manifest themselves as resistance to cancer cell invasion. To provide a preliminary test of this proposal, we re-analyze data from Priester and Mantel (Occurrence of tumors in domestic animals. Data from 12 United States and Canadian colleges of veterinary medicine. J Natl Cancer Inst 1971;47:1333-44) about malignancy rates in cows, horses, cats and dogs. From our analysis we found that equines and bovines, animals with less invasive placentation, have lower rates of metastatic cancer than felines and canines in skin and glandular epithelial cancers as well as connective tissue sarcomas. We conclude that a link between type of placentation and species-specific malignancy rates is more likely related to derived mechanisms that suppress invasion rather than different degrees of fetal placental aggressiveness.

Fibrosarcoma arising in long-standing mycosis fungoides.

A patient suffering from mycosis fungoides is described, in whom a fibrosarcoma arose in the skin. No previous report of a connective tissue sarcoma occurring in a patient with mycosis fungoides has been traced.

Suicide gene therapy of sarcoma cell lines using recombinant adeno-associated virus 2 vectors

Soft-tissue sarcomas are mesenchymal tumors that respond poorly to systemic chemotherapy. Suicide gene therapy may be an alternative treatment strategy. Here we show a high susceptibility of human sarcoma cell lines for recombinant adeno-associated virus 2 (rAAV-2) suicide vectors: connective tissue sarcoma (HS-1), fibrosarcoma (HT-1080), Ewing sarcoma (RD-ES), Askin tumor (SK-N-MC), rhabdomyosarcoma (A-204) and soft-tissue sarcoma (WSKL-1). Several vectors containing the thymidine kinase (TK) gene under the control of either the cytomegalovirus promoter or the elongation-factor 1 alpha (EF1alpha) promoter were cloned and tested. Higher expression levels of the transgene were observed in the sarcoma lines when using the EF1alpha-suicide gene-containing vectors. A complete eradication of rAAV-2-EF1alpha-TK/eGFP (TK/enhanced green fluorescent protein fusion gene)-transduced tumor cells was shown following exposure to ganciclovir (2.5 microg/ml) in vitro, while at this dose level > 90% of mock-transduced tumor cells survived. Xenotransplantation tumor models (intraperitoneal, subcutaneous) for the human sarcoma cell line HS-1 were established in nonobese diabetic/severe-combined immunodeficient mice. Mice transplanted with rAAV-2-EF1alpha-TK/eGFP-transduced and ganciclovir-exposed tumor cells survived > 5 months while in the nontransduced group all mice had died approximately 1 month after inoculation. These data hold promise for further development of rAAV-2-based suicide gene therapy of sarcomas.

344. Recombinant Adeno-Associated Virus 2 Suicide Vectors for the Treatment of Human Sarcomas and Mesotheliomas

Top of pageAbstract Although great efforts have been made to improve conventional therapy for sarcoma and malignant mesothelioma, the median survival time of these entities after appearance of clinical symptoms stays poor. Effective locoregional therapy using viral vectors that contain a suicide gene may be an alternative treatment strategy. For sarcoma, we previously reported the highest susceptibility for recombinant adeno-associated virus 2 (rAAV-2) vectors in human connective tissue sarcoma cells (HS-1). Now we confirm our findings in five further human sarcoma cell lines: fibrosarcoma (HT-1080), Ewing's sarcoma (RD-ES), Askin's tumor (SK-N-MC), rhabdomyosarcoma (A-204) and soft tissue sarcoma (WSKL-1). Furthermore, we found that rAAV-2 also achieved both high transduction rates and GFP expression levels in human mesothelioma (H-Messo-1, MSTO-211H and NCI-H-28). Among rAAV-2-constructs containing different promotors, after transduction, the vector with the elongation factor 1-alpha (EF1a) promotor showed the highest expression rates in both the sarcoma and mesothelioma cell lines. To ensure the use of constant vector particles number, all stocks were titrated using both the functional and our real-time PCR-based titration assay. Several new thymidine kinase (TK) gene-containing vectors under control of either the Cytomegalovirus or the elongation-factor 1 alpha (EF1a) promoter were cloned and tested. A higher expression level of the transgene was observed in the sarcoma and mesothelioma lines when using the EF1a-suicide gene-containing vectors. For the sarcomas, we were able to show a complete eradication of all rAAV-EF1a-TK/eGFP (contains a thymidine kinase/enhanced green fluorescent protein fusion protein) transduced tumor cells following exposure to ganciclovir (2.5 μg/ml) in vitro, while at this dose level >90% of mock-transduced tumor cells survived. Using mesotheliomas, a nearly complete eradication (>2 log) of transduced and GCV-treated cells could be obtained using this vector. Xenotransplantation tumor models (i.p., s.c., i.v.) for both the human sarcoma and mesothlioma cell lines were established in nonobese diabetic (NOD)/LtSz-severe-combined immunodeficient (scid)/scid (NOD/SCID) mice. In proof-of-principle experiments, mice transplanted with rAAV-TK/eGFP-transduced and ganciclovir-exposed sarcoma or mesothelioma tumor cells survived >5 months while in the non-transduced group all mice had died 1 month after inoculation. Currently, further animal experiments using this suicide system are ongoing. The data shown here hold promise for further development of AAV-2-based suicide gene therapy of both soft tissue sarcoma and mesothelioma towards a future clinical application.

Superior gene transfer into solid tumour cells than into human mobilised peripheral blood progenitor cells using helpervirus-free adeno-associated viral vector stocks

Autologous peripheral blood progenitor cell (PBPC) grafts can be contaminated with tumour cells that potentially give rise to relapse following myeloablative therapy and PBPC transplantation. Adeno-associated virus (AAV)-based vectors produced by a new adenovirus-free technique are a gene delivery system which may be applicable for tumour cell purging. To test for the host range of these vectors, solid tumours of clinical relevance and normal CD34 + PBPC were selected as target cells for an AAV-vector, encoding the green-fluorescent protein (GFP) as the indicator gene. At a multiplicity of infection (MOI) of 100: 79.94%±14.36% (mean±SEM) of the connective tissue sarcoma cell line (HS-1) and 64.84%±6.91% of the cervical carcinoma cell line cells (HeLa-RC) expressed GFP while the other cell lines tested (1 ovarian tumour, 1 germ cell tumour, 1 osteosarcoma, 2 small cell lung cancer) ranged between 2.82% and 11.94%. Optimising the transduction protocol by use of higher MOIs of up to 500 and by pretreatment with the tyrosine kinase inhibitor, genistein, resulted in up to 95.97% and 94.10% green-fluorescent HS-1 and HeLa-RC cells, respectively. In contrast, only 1.39%±0.51% of the normal haematopoietic CD34 + progenitor cells expressed GFP at a MOI of 100. The differential infectivity between HS-1 and CD34 + cells was maintained after tumour cell spiking in leucapheresis products. Our observations suggest that AAV-based vectors may prove useful for purging of autologous PBPC grafts from solid tumour cells.

Naturally Arising Tumors of the Inbred WAB/Not Rat Strain. I. Classification, Age and Sex Distribution, and Transplantation Behavior23

During a 3-year period, 97 naturally arising tumors were collected from an inbred colony of WAB/Not rats. These tumors were largely confined to the breeding groups of approximately 5,300 female and 2,700 male rats retained up to 2 years of age. The tumors included 39 nephroblastomas and 41 mammary tumors (24 of which were histologically benign); the remaining tumors were mainly connective tissue sarcomas and skin tumors with 1 lymphoma and 2 gastrointestinal lesions. With the exception of the incidence of mammary tumors, males and females had similar tumor incidence, although nephroblastomas in female rats had a marked preference for growth in the left kidney. Most tumors occurred in the first year of life, especially the histologically malignant mammary tumors and the nephroblastomas. Of the tumors investigated, 31 were transplantable. Poor correlation between histologic malignancy and transplantation was seen with the mammary tumors. Only 50% of the nephroblastomas were transplantable. Although most transplanted tumors retained histologic characteristics of the primary tumor, 1 mammary tumor, 1 gastrointestinal tumor, and 1 nephroblastoma deviated from this general finding. In the case of this nephroblastoma, separate transplant lines from opposite poles of the primary tumor also showed differences in histology.

Prognosis after surgical excision of canine fibrous connective tissue sarcomas.

One hundred eighty seven dogs from which fibrous connective tissue sarcomas had been excised were studied until death or for at least 3 years after surgery. Dogs with a skin fibrosarcoma had a median survival time of 80 weeks, compared with 140 weeks for animals with haemangiopericytoma in similar sites, this difference being statistically significant. However, the difference in survival time between the two histologic types disappeared when tumours with a similar mitotic index were compared. Dogs with a tumour of mitotic index 9 or more had a median survival time of 49 weeks, compared with 118 weeks for those with a tumour of mitotic index less than 9, regardless of tumour morphology. Tumour recurrence rates of 62% and 25% respectively for the two groups were also significantly different.

Radiotherapy of spontaneous fibrous connective-tissue sarcomas in animals.

The clinical records and follow-up data obtained over 13 years on the results of radiotherapy of spontaneous fibrous connective-tissue sarcomas in dogs, cats, and horses were reviewed. The results obtained from the treatment of fibrosarcomas and sarcoids of horses indicated that radiation administered with 60Co is important in the medical and surgical management of these tumors. Fibrous connective-tissue sarcomas in horses were radioresponsive. When radiotherapy was applied postoperatively, the probability of a 2-year cure approached 50% for all prescribed radiation doses of less than 2,000 to greater than 4,000 rads. If radiation doses of 4,500-6,000 rads were used, a 2-year cure rate may approach or exceed 60%.

Treatment of connective tissue sarcomas by local excision followed by radioactive implant

Thirty-two cases of connective tissue sarcoma were treated by local excision immediately followed by a radioactive implant, sometimes supplemented by external radiation. The method is effective in preventing local recurrence, and is particularly valuable for patients in whom persistent local recurrences following simple excision have occurred. The patient experiences little extra discomfort, and complications are unusual; hazard to staff is low. Long-term survival appears to be just as good in our series as in others in which radical surgery was used, the radical surgery has the disadvantages of greater operative morbidity and mortality, causes greater disfiguration, and may in any case be impossible for tumours in certain anatomical sites.

Histocompatibility Antigens and Solid Malignant Neoplasms

To evaluate the relation between histocompatibility antigen phenotypes and solid malignant neoplasms, HL-A type was determined in 633 cancer patients and compared with those of 489 normal controls. HL-A8 was elevated in patients with squamous cancer, melanoma, and adenocarcinoma. The highest incidence occurred in patients with salivary gland adenocarcinoma (67% vs only 17% in normal controls). A threefold increase in HL-A5 was detected in patients with connective tissue sarcomas (28% incidence vs 9% in normal controls). Antigen frequencies did not vary when analyzed by time of diagnosis or interval after treatment. The finding that certain malignant neoplasms have associations with increased frequency of individual HL-A antigens may give clues to cause and genesis for these tumors.

A G2 population of cells in autogenous rodent sarcoma

Continuous infusion of 3H-TdR was carried out in rats with autogenous methylcholanthrene-induced connective tissue sarcomas, for forty hours, which is the duration of the generation time of the tumor cells. Forty-five % of the cells were labeled. Twenty-seven % of the mitoses were unlabeled. They were derived from cells which had completed DNA synthesis and had spent at least 40 h in G2. The presence of this large cohort of G2 cells may account for some of the variations in the growth patterns of tumors.

A TECHNIC FOR LARGE-DOSE IRRADIATION OF CONNECTIVE-TISSUE SARCOMA OF AN EXTREMITY.

When radiation is administered to a connective-tissue sarcoma of an extremity with curative intent, large tumor doses ranging from 6,500 to 9,000 rads may be necessary. Doses of this magnitude, delivered through two to four cross-firing portals, commonly produce constricting fibrosis with blockage of blood and lymph flow. When the entire cross section of an extremity has been so treated, the resultant ederna distal to the constriction becomes very severe and may even necessitate amputation. To avoid this complication, one portion of an extremity should be spared when feasible. The author describes a technic designed for this purpose. Case Report T. A., a 57-year-old white woman, had a low grade myxosarcoma arising from the fascia of the biceps muscle of the right arm. On April 19, 1961, a group of three coalesced encapsulated tumors were excised, the largest one measuring 3 × 2 × 1 cm. One year later, a superficial recurrence in the form of two adjacent nodules was excised on May 3, 1962. Radiation therapy was started June 14, 1962. A sheet of Lucite was bent to form a hemicylinder and snugly applied to the lateral (remote) aspect of the arm (Fig. 1). During each x-ray treatment force was applied to the lateral aspect of the prosthesis to compress the underlying tissues. At the same time, this force displaced the tumor-containing tissues of the medial half of the arm away from the bone. Supervoltage (2 Mv) x radiation was directed at the medial half of the arm through two cross-firing portals, each measuring 8 × 20 cm. The total tissue dose throughout the tumor ranged from 8,600 rads (maximum) to 7,800 rads (minimum) in forty-three days. This produced a mild second-degree epidermitis which healed eight days after the last treatment. Two months after irradiation, dense fibrosis appeared in the biceps and brachialis muscles. The resultant contracture grew progressively worse. One year after treatment extension of the elbow joint lacked 40 degrees. This improved to 20 degrees after physical therapy. To date there have been no interference with circulation and no edema in the distal forearm and hand because of the integrity of all the soft tissues in the posterior half of the arm at the level of irradiation (Fig. 2). Conclusion When massive doses of radiation are given an extremity, a portion of its cross section should be protected against postradiation constriction fibrosis, thereby avoiding crippling edema or possible amputation. A technic for this purpose has been described.

BEHAVIOR AND MANAGEMENT OF SOFT CONNECTIVE TISSUE SARCOMAS.

BEHAVIOR AND MANAGEMENT OF SOFT CONNECTIVE TISSUE SARCOMAS.

Stromal sarcomas of the breast. A unified approach to connective tissue sarcomas other than cystosarcoma phyllodes.

Stromal sarcomas of the breast. A unified approach to connective tissue sarcomas other than cystosarcoma phyllodes.

Irradiation of Hemangiopericytoma of Stout

The place of irradiation in the management of connective-tissue sarcoma is not well defined, chiefly because the radio-resistance of most sarcomas has discouraged attempts at aggressive therapy. Some of these tumors, however, are moderately radiosensitive and irradiation should play a more important role in their treatment. This report of 5 cases of hemangiopericytoma of Stout is designed to supplement the meager information concerning radiation dosage and the response of this tumor. Pathology Hemangiopericytoma of Stout is a rare tumor, occurring in bone or connective tissues anywhere in the body, showing a certain consistency in morphology and histogenesis but a varied clinical picture. It was first described by Stout and Murray (1) as a neoplasm arising from the peri-capillary cells or pericytes of Zimmermann (2). The age range is from two months to ninety years; the modal age group is forty to sixty years. The microscopic appearance of this blood-vessel tumor is illustrated in Figures 1–3. The feature...