An Unusual Case of BIA-ALCL Associated with Prolonged/Complicated Biocell-Textured Expander, followed by Smooth Round Breast Implant Exposure, and Concurrent Use of Adalimumab.

SUMMARY: Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a malignancy associated with textured breast implants. BIA-ALCL is typically restricted to the periprosthetic capsule, presenting as a unilateral recurrent seroma years after placement of a textured breast implant. Current estimates suggest an incidence of one in 3300 for patients with Allergan Biocell textured implants. As of February 6, 2019, U.S. Medical Device Reporting associated with BIA-ALCL showed 457 unique cases of BIA-ALCL, with 24 "unverified and potentially inaccurate" cases associated with a nontextured implant. As of February of 2019, there were 688 reported cases to date worldwide. To date, there are no published case reports of BIA-ALCL associated exclusively with smooth implants or with smooth implants after textured expanders, and there has been no reported smooth-only case in any registry, database, or journal worldwide. The authors present a case of BIA-ALCL associated with smooth round implants and textured tissue expanders. A 56-year-old woman was treated for left stage IIA invasive ductal carcinoma with bilateral mastectomies and immediate reconstruction with bilateral subpectoral textured tissue expanders. She underwent exchange to Mentor smooth-round implants, and completed adjuvant chemotherapy. Magnetic resonance imaging and examination 4.5 years after implant placement showed no abnormal findings. The patient had left breast trauma 5 years following implant placement while taking adalimumab, and developed an open wound requiring explantation. A recurrent seroma developed, and tested positive for BIA-ALCL on cytology. Surgical pathologic examination after total capsulectomy demonstrated stage IA BIA-ALCL. To the authors' knowledge, this is the first case report of BIA-ALCL in a patient with textured expanders followed by prolonged exposure to smooth round implants.

Micrometastatic Drug Screening Platform Shows Heterogeneous Response to MAP Chemotherapy in Osteosarcoma Cell Lines.

BACKGROUND: Approximately 80% of patients with osteosarcoma harbor subclinical pulmonary micrometastases at diagnosis. Conventional chemotherapy includes methotrexate, doxorubicin, and cisplatin (MAP); however, this regimen and thus overall survival (60%-70%) have remained largely unchanged for 30 years. It therefore is necessary to identify novel therapeutics targeting the metastatic progression of osteosarcoma. QUESTIONS/PURPOSES: This laboratory study explored application of osteosarcoma spheroids (sarcospheres) for drug screening with the following purposes: (1) to characterize sarcosphere size; (2) to establish accurate measurement of sarcosphere growth; (3) to confirm sarcosphere uniformity; and (4) to apply the platform to evaluate MAP chemotherapy. METHODS: Sarcospheres were first characterized to establish accurate measurement of sarcosphere growth and uniform production. The refined platform then was applied to evaluate MAP chemotherapy to validate its use in drug screening. Sarcospheres were generated from highly metastatic human cell lines (143B, MG-63.3, and LM7) by centrifugation to form three-dimensional aggregates modeling micrometastases. Sarcospheres were matured for 24 hours and then incubated with or without drug from Days 0 to 2. Size was assessed by diameter and volume using brightfield microscopy. Growth was measured by volume and resazurin reduction in viable cells. Sarcosphere uniformity was assessed by diameter and resazurin reduction at Day 0 and the Z' factor, a measure of assay suitability for high-throughput screening, was calculated at Day 2. Sarcospheres were treated with individual MAP agents (0 to 1000 µmol/L) to determine concentrations at which 50% of growth from Days 0 to 2 was inhibited (GIC50). Cell lines resistant to MAP in sarcospheres were treated in monolayer for comparison. RESULTS: Sarcosphere diameter and growth from Days 0 to 2 were quantitatively dependent on the number of cells seeded and the cell line used. Accurate measurement of growth occurred after resazurin incubation for 6 hours, without EDTA-mediated permeabilization, and was correlated with the number of cells seeded and sarcosphere volume for 143B (Spearman's r: 0.98; p < 0.001), MG-63.3 (0.99; p < 0.001), and LM7 (0.98; p < 0.001). Sarcospheres met established criteria for screening applications as mean Z' factors were greater than 0.5 for all cell lines. Response to MAP therapy was cell line-dependent, because MG-63.3 and LM7 sarcospheres exhibited greater than 2000-fold resistance to methotrexate (GIC50 = 88 ± 36 µmol/L and 174 ± 16 µmol/L, respectively) compared with the 143B cell line (GIC50 = 0.04 ± 0.01 µmol/L; p < 0.001 for MG-63.3 and LM7). MG-63.3 monolayers were more sensitive to methotrexate (GIC50 = 0.01 ± 0.01 µmol/L; p < 0.001) than MG-63.3 sarcospheres, whereas LM7 monolayers remained chemoresistent (GIC50 not reached). CONCLUSIONS: This study developed and validated a drug screening platform for progression of osteosarcoma micrometastases. It also highlights heterogeneity among osteosarcoma cell lines. These findings appear to reflect known patient-to-patient heterogeneity and underscore the importance of evaluating multiple tumor models when testing drugs for the treatment of osteosarcoma. CLINICAL RELEVANCE: The described approach is a promising starting point for drug screening in osteosarcoma because it is tailored to evaluate micrometastatic disease. A reliable and rapid method to identify novel therapeutics is critical to improve stagnant outcomes for patients with osteosarcoma.