Systems for local, sustained release of zoledronic acid as a potential treatment for metastatic bone disease.

Bone pain is the leading cause of morbidity in patients with metastatic cancer. Systemic administration of zoledronic acid (ZA) decreases skeletally-related events in bone cancer patients but is associated with major side effects. This project investigated two biomaterials, poly(methyl methacrylate) (PMMA) bone cement and poly(lactic-co-glycolic acid) (PLGA), for local ZA delivery. Compressive properties of PMMA samples were tested with increased drug loading, and in vitro ZA release profiles from PMMA cylinders and PLGA films were measured over 8 weeks. The activity of ZA eluted from both materials was evaluated on the RAW 264.7 macrophage cell line. PMMA samples released up to only 17% of incorporated drug, whereas PLGA films released over 95%. A burst profile was observed for PMMA, while ZA release from PLGA exhibited a typical triphasic profile. Drug bioactivity remained above 50% for both materials. Local ZA delivery from these materials may be useful in the treatment of metastatic bone cancer.

Superficial Soft-Tissue Sarcomas Rarely Require Advanced Soft-Tissue Reconstruction following Resection.

OBJECTIVE: Soft-tissue sarcomas are most frequently located deep within myofascial compartments. Superficial soft-tissue sarcomas (S-STS) are relatively less common and may be managed differently than deep sarcomas because generous resection margins are often possible without sacrificing critical structures. We sought to investigate the frequency and types of soft-tissue reconstructive procedures that are required following excision of S-STS. METHODS: We reviewed 457 consecutively treated patients with S-STS with a minimum 2-year follow-up from our prospectively maintained database between 1989 and 2009. RESULTS: Mean follow-up was 10.5 years (range, 2-23). Four hundred twenty-one tumors (91%) were excised with negative margins, 38 (8.3%) had microscopically positive margins, and three (0.7%) had grossly positive margins. One patient required an amputation. In 271 (58%) patients, the wounds were closed primarily. In comparison, 93 patients (20%) required a rotation flap, 70 (15%) required a split-thickness skin graft, and 23 (5%) underwent a free tissue transfer (ie, advanced reconstructive procedure). The overall complication rate was 12%, although 43% of patients undergoing free tissue transfer developed complications (P = 0.04). An unplanned excision before referral to our center was a risk factor for local recurrence (P = 0.03) when residual tumor was recovered in the reexcision specimen pathologically. CONCLUSIONS: Although concern about the morbidity associated with a free tissue transfer (ie, advanced reconstructive procedure) may potentially limit the adequacy of resection in some patients with S-STS, the results of this study showed that the majority of patients had complete excisions with negative margins and primary closure. Obtaining a negative margin when excising a known or suspected S-STS rarely requires an advanced reconstructive procedure and almost never results in loss of limb.

The effect of the setting of a positive surgical margin in soft tissue sarcoma.

BACKGROUND: The objectives of this study were to evaluate the risk of local recurrence and survival after soft tissue sarcoma (STS) resection with positive margins and to evaluate the safety of sparing adjacent critical structures. METHODS: One hundred sixty-nine patients with localized STS who had positive resection margins were identified from a prospective database. Patients who had positive margins were stratified into 3 groups, each representing a specific clinical scenario: critical structure positive margin (eg major nerve, vessel, or bone), tumor bed resection positive margin, and unexpected positive margin. The rates of local recurrence-free survival (LRFS) and cause-specific survival (CSS) were calculated and compared with relevant control patients who had negative margins after STS resection. RESULTS: After planned close dissection to preserve critical structures, the 5-year LRFS and CSS rates both depended on the quality of the surgical margins (97% and 80.3%, respectively, for those with negative margins vs 85.4% and 59.4%, respectively, for those with positive margins; P = .015 and P = .05, respectively). Negative margins achieved through resection of critical structures because of tumor invasion or encasement only slightly improved the 5-year rates of LRFS (91.2%) and CSS (63.6%; P = .8 and P = .9, respectively). The lowest 5-year LRFS and CSS rates were 63.4% and 59.2%, respectively, after an unexpected positive margin during primary surgery. CONCLUSIONS: After patients undergo resection of STS with positive margins, oncologic outcomes can be predicted based on the clinical context. Sparing adjacent critical structures in this setting is safe and contributes to improved functional outcomes.

Chemotherapy influences the pseudocapsule composition in soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas are a heterogeneous group of malignant tumors. Standard treatment for soft tissue sarcoma of the extremity is surgical excision and adjuvant therapy; however, the role of neoadjuvant chemotherapy is controversial. QUESTIONS/PURPOSES: We sought to (1) define the histologic characteristics of the pseudocapsule in soft tissue sarcomas; (2) compare the appearance of this structure in chemotherapy-treated versus untreated soft tissue sarcomas; and (3) evaluate the effect of chemotherapy on the presence and viability of tumor cells at the host-sarcoma interface. METHODS: Twenty-eight patients with biopsy-proven, deep, high-grade extremity soft tissue sarcomas greater than 5 cm (AJCC stage III) treated with chemotherapy and surgical excision were compared histologically with 47 matched control subjects treated with surgery alone. RESULTS: A pseudocapsule was identifiable in the majority of tumors and consisted of two identifiable layers, each with specific histological characteristics suggesting the biologic processes occurring in these layers are different. The pseudocapsule was more frequently observed in the group treated with chemotherapy and it was more frequently continuous, thicker, and better developed in this group. Chemotherapy decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CONCLUSIONS: Neoadjuvant chemotherapy contributed to the development of a pseudocapsule and decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CLINICAL RELEVANCE: These findings may provide a histological explanation for the clinical effect of chemotherapy in soft tissue sarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Early follow-up of a custom non-fluted diaphyseal press-fit tumour prosthesis.

PURPOSE: The objective of this study was to evaluate the early results of a custom non-fluted diaphyseal press-fit stem for use with the global modular replacement system (GMRS) tumour prosthesis and the early complications associated with this implant. METHODS: A total of 53 patients (54 implants) were identified from a prospective database where a custom non-fluted diaphyseal press-fit stem was used as part of the reconstruction of the limb. All patients had a minimum of 22 months of follow-up. RESULTS: The rates of stem revision for any reason were calculated. The median follow-up was 36 months (range 22-85 months). Aseptic loosening was not observed in any patient. CONCLUSIONS: At early term follow-up, an uncemented non-fluted stem used with the GMRS tumour endoprosthesis provides a stable bone-prosthesis interface with no evidence of aseptic loosening.

Can Experienced Observers Differentiate between Lipoma and Well-Differentiated Liposarcoma Using Only MRI?

Well-differentiated liposarcoma represents a radiographic diagnostic dilemma. To determine the accuracy, interrater reliability, and relationship of stranding, nodularity, and size in the MRI differentiation of lipoma and well-differentiated liposarcoma, MRI scans of 60 patients with large (>5 cm), deep, pathologically proven lipomas or well-differentiated liposarcomas were examined by 10 observers with subspecialty training blinded to diagnosis. Observers indicated whether the amount of stranding, nodularity, and size of each tumor suggested a benign or malignant diagnosis and rendered a diagnosis of lipoma or well-differentiated liposarcoma. The accuracy, reliability, and relationship of stranding, nodularity, and size to diagnosis were calculated for all samples. 69% of reader MRI diagnoses agreed with final pathology diagnosis (95% CI 65-73%). Readers tended to err choosing a diagnosis of liposarcoma, correctly identifying lipomas in 63% of cases (95% CI 58-69%) and liposarcomas in 75% of cases (95% CI 69-80%). Assessment of the relationship of stranding, nodularity, and size to correct diagnosis showed that the presence of each was associated with a decreased likelihood of a lipoma pathological diagnosis (P < 0.01). While the radiographic diagnosis of lipoma or well-differentiated liposarcoma cannot be made with 100% certainty, experienced observers have a 69% chance of rendering a correct diagnosis.

Cutting edge: induction of the antigen-processing enzyme IFN-gamma-inducible lysosomal thiol reductase in melanoma cells Is STAT1-dependent but CIITA-independent.

Presentation and CD4(+) T cell responses to Ag in the context of MHC class II molecules require processing of native proteins into short peptide fragments. Within this pathway, IFN-gamma-inducible lysosomal thiol reductase (GILT) functions to catalyze thiol bond reduction, thus unfolding native protein Ag and facilitating further processing via cellular proteases. In contrast with professional APCs such as B cells, class II-positive human melanomas expressed relatively little to no GILT protein or mRNA. Tumor cell GILT expression was partially restored with IFN-gamma treatment but unlike other genes required for class II Ag presentation, GILT was not regulated by CIITA. Rather, studies revealed STAT1 plays a direct role in IFN-gamma-inducible GILT expression. These results define a molecular mechanism for the uncoupled regulation of MHC class II genes and the processing enzyme GILT in human melanomas.

Inhibition of glycolipid shedding rescues recognition of a CD1+ T cell lymphoma by natural killer T (NKT) cells.

Neoplastic transformation of cells is accompanied by an aberration of cell surface glycolipid composition. These tumor-associated, altered glycosphingolipids are often shed into the tumor cell microenvironment and mediate immunosuppressive activity. The nature and form of glycolipids shed by a variety of tumor cell lines and the mechanism(s) of shedding have been well characterized. The murine T cell lymphoma line, L5178Y-R, is known to shed a tumor-associated glycolipid, gangliotriaosylceramide, into the culture medium. We analyzed the effect of glycolipids from L5178Y-R on antigen presentation by murine CD1d1 molecules. CD1d1 molecules present glycolipid antigens to a specialized class of T cells called natural killer T (NKT) cells that mainly express a T cell receptor alpha chain (Valpha14Jalpha281) associated with Vbeta chains of limited diversity. In the current report, we found that L5178Y-R cells express CD1 on their cell surface yet are unable to stimulate CD1d1-specific NKT cells. We hypothesized that the glycolipid(s) shed by L5178Y-R inhibited antigen presentation by CD1d1. Pretreatment of CD1d1(+) cells with conditioned medium from L5178Y-R inhibited CD1-specific stimulation of canonical (Valpha14(+)) but not noncanonical (Valpha5(+)) NKT cells. Exogenous addition of lipids extracted from L5178Y-R cells as well as purified gangliotriaosylceramide mimicked this effect. Inhibition of glycolipid shedding in L5178Y-R cells with d-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol resulted in the rescue of CD1d1 recognition by canonical (but not noncanonical) NKT cells. These results suggest that one means by which certain tumor cells can evade the host's innate antitumor immune response is by shedding glycolipids that inhibit CD1-mediated antigen presentation to NKT cells.