Rosanna Wustrack

Background: Tumor invasion and malignant transformation are spatiotemporally coordinated processes that shape clinical behavior, diagnostic classification, and treatment response. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors that can arise sporadically or in people with neurofibromatosis type 1 (NF-1), yet how distinct spatial niches underlie MPNST intratumor heterogeneity, local invasion, or malignant transformation from benign precursors is not fully understood. Methods: We integrate spatial analysis of 50,896 transcriptomes from 15 human MPNSTs with deep learning image analysis to define the interplay between genetic alterations, the immune microenvironment, and epigenetic cell fate regulation in MPNST invasion and transformation. Results: Spatial transcriptomics reveal distinct infiltrating immune cells and immunomodulatory spatial clusters in sporadic compared to NF-1–associated MPNSTs. Local invasion is marked by spatially defined immunomodulatory and dedifferentiation programs. Analysis of 2 NF-1–associated MPNSTs with contiguous morphologically defined neurofibroma and MPNST components demonstrates that NF-1–associated tumors exhibit a similar malignant transformation process associated with dynamic immune infiltration, chromosome 9p loss, and dedifferentiation concomitant with increased cell proliferation. Finally, deep learning morphology encoders were trained on spatial transcriptomic data to predict spatial transcriptomic cluster identity and chromosome 9p loss from hematoxylin and eosin–stained images although the generalizability of such encoders remains a challenge. Conclusions: Our data provide a spatial framework for peripheral nerve sheath tumor transformation although the limited sample size of the present cohort will require additional validation of the proposed model.

Background: The Compress (CPS) implant is designed to induce osseointegration at the bone–implant interface to reduce rates of aseptic loosening. Previous studies of this implant in the proximal tibia were limited by small, heterogeneous patient cohorts and minimum follow‐up.Objectives: Our primary outcome is the cumulative incidence of mechanical failure of the CPS implant when used for reconstructions of the proximal tibia for oncologic indications. Secondary aims include types and rates of all CPS failures and risk of any unplanned operation related to the implant.Methods: We conducted a multi‐institution retrospective analysis of all patients treated with resection of a primary bone tumor in the proximal tibia, reconstructed with a Compress endoprosthesis, with a minimum 2‐year follow‐up. Statistical analysis utilized the Kaplan‐Meier survival technique and Cox proportional hazard models.Results: Fifty‐three patients met the inclusion criteria. Median follow‐up was 7.5 years (range: 1.7–20.1 years). CPS survivorship at 5 and 10 years was 89.8% (95% CI 81.7, 98.7%). There were 21 unplanned reoperations with a 5‐ and 10‐year survival probability of 68.9% (95% CI 56.8%, 83.6%) and 52.5% (95% CI 37.6%, 73.2%).Conclusions: Compressive osseointegration is a durable technique to anchor large endoprostheses to bone in the proximal tibia.

Copy number and count data for tumor suppressor genes and oncogenes in primary tumors, PDXs, and PDX-derived cell lines

Copy number and count data for tumor suppressor genes and oncogenes in primary tumors, PDXs, and PDX-derived cell lines

Supplementary figures and tables

Supplementary figures and tables

Purpose: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. Experimental Design: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Results: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. Conclusions: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

Background: Although there is evidence suggesting that postoperative infection confers a survival benefit in osteosarcoma treated with resection and endoprosthetic reconstruction, there have been no prospective studies to date to support these findings. This secondary analysis of Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) study data examines the relationship between surgical site infection (SSI) and disease progression within 12 months after limb salvage surgery. Methods: The PARITY trial was an international, multicenter, prospective randomized controlled trial of 604 patients who underwent resection of a lower-extremity bone tumor and endoprosthetic reconstruction. Our primary outcome was progression-free survival (PFS) at 1 year following surgery among the patients with osteosarcoma. Subgroup analyses by disease stage at presentation and infection severity were also performed. Cox proportional hazard models were employed to examine the association between clinical and tumor characteristics, SSI, and PFS. Kaplan-Meier analysis was used to determine the effect of SSI on PFS. Results: The 274 PARITY patients with osteosarcoma were included in this secondary analysis. Thirty-two (11.7%) of the patients presented with metastasis at baseline; 53 (19.3%) of the patients developed an SSI. There was no difference in 1-year PFS between patients with and without SSI. There was no decreased risk of disease progression at 1 year in patients with localized disease at baseline who developed an SSI (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.64 to 2.28). Infection was associated with increased disease progression at 1 year in patients with baseline metastases (HR = 4.26; 95% CI = 1.11 to 16.3). Conclusions: No positive association was detected between postoperative infection and PFS at 1 year following surgery in this secondary analysis of prospective data. However, this analysis suggests infection could be a risk factor for early disease progression in patients with baseline metastases, and future investigations may better elucidate the association between disease burden and the host immune response to advance immunotherapeutic strategies for osteosarcoma. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

The treatment of parathyroid hormone-related protein (PTHrP)-mediated hypercalcemia of malignancy includes treating the malignancy, intravenous fluids, and anti-resorptive therapies such as zoledronic acid or denosumab. PTHrP-mediated hypercalcemia has been reported in benign conditions such as systemic lupus erythematous (SLE) and sarcoidosis and appears to be responsive to glucocorticoids. We report a case of PTHrP-induced hypercalcemia due to a malignancy—low grade fibromyxoid sarcoma—that responded to glucocorticoid treatment. This is the first report of glucocorticoids controlling PTHrP-mediated hypercalcemia of malignancy. Immunohistochemistry of the surgical pathology localized PTHrP staining to the vascular endothelial cells within the tumor. Further studies are needed to elucidate the mechanism of glucocorticoid action in the treatment of PTHrP-mediated hypercalcemia of malignancy.

Background: Expandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre‐Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported.Methods: We conducted a multi‐institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan–Meier survival technique and competing risk analysis.Results: Thirty‐six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7–93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty‐two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1–9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6–31.5) at 5 years. Twenty‐nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years.Conclusions: There is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery.Level of evidence: Level IV, therapeutic study.