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Uday Jammalamadaka,1 Karthik Tappa,1 Jeffery A Weisman,1 James Connor Nicholson,2 David K Mills1,3 1Center for Biomedical Engineering and Rehabilitation Science, 2Nanosystems Engineering, 3The School of Biological Sciences, Louisiana Tech University, Ruston, LA,USA Abstract: Halloysite nanotubes (HNTs) were investigated as a platform for tunable nanoparticle composition and enhanced opacity in poly(methyl methacrylate) (PMMA) bone cement. Halloysite has been widely used to increase the mechanical properties of various polymer matrices, in stark contrast to other fillers such as barium sulfate that provide opacity but also decrease mechanical strength. The present work describes a dry deposition method for successively fabricating barium sulfate nanoparticles onto the exterior surface of HNTs. A sintering process was used to coat the HNTs in barium sulfate. Barium sulfate-coated HNTs were then added to PMMA bone cement and the samples were tested for mechanical strength and tailored opacity correlated with the fabrication ratio and the amount of barium sulfate-coated HNTs added. The potential cytotoxic effect of barium-coated HNTs in PMMA cement was also tested on osteosarcoma cells. Barium-coated HNTs were found to be completely cytocompatible, and cell proliferation was not inhibited after exposure to the barium-coated HNTs embedded in PMMA cement. We demonstrate a simple method for the creation of barium-coated nanoparticles that imparted improved contrast and material properties to native PMMA. An easy and efficient method for coating clay nanotubes offers the potential for enhanced imaging by radiologists or orthopedic surgeons. Keywords: barium, bone cement, halloysite, imaging, PMMA, sintering

Jeffery A Weisman,1 James C Nicholson,2 Karthik Tappa,1 UdayaBhanu Jammalamadaka,1 Chester G Wilson,2 David K Mills1,3 1Center for Biomedical Engineering and Rehabilitation Science, 2Nanosystems Engineering, 3School of Biological Sciences, Louisiana Technical University, Ruston, LA, USAAbstract: Three-dimensional (3D) printing and additive manufacturing holds potential for highly personalized medicine, and its introduction into clinical medicine will have many implications for patient care. This paper demonstrates the first application of 3D printing as a method for the potential sustained delivery of antibiotic and chemotherapeutic drugs from constructs for patient treatment. Our design is focused on the on-demand production of anti-infective and chemotherapeutic filaments that can be used to create discs, beads, catheters, or any medical construct using a 3D printing system. The design parameters for this project were to create a system that could be modularly loaded with bioactive agents. All 3D-printed constructs were loaded with either gentamicin or methotrexate and were optimized for efficient and extended antibacterial and cancer growth-inhibiting cytostatic activity. Preliminary results demonstrate that combining gentamicin and methotrexate with polylactic acid forms a composite possessing a superior combination of strength, versatility, and enhanced drug delivery. Antibacterial effects and a reduction in proliferation of osteosarcoma cells were observed with all constructs, attesting to the technical and clinical viability of our composites. In this study, 3D constructs were loaded with gentamicin and methotrexate, but the method can be extended to many other drugs. This method could permit clinicians to provide customized and tailored treatment that allows patient-specific treatment of disease and has significant potential for use as a tunable drug delivery system with sustained-release capacity for an array of biomedical applications. Keywords: three-dimensional printing, polymers, antibacterial, drug delivery, medical device

Germ cell tumours (GCTs) comprise a heterogeneous group of tumours believed to arise from the totipotent primordial germ cell. While uncommon, they may present at any age from in-utero to young adulthood. Prognosis is generally good and considering them in the differential diagnosis of midline as well as gonadal masses may prevent diagnostic delay and/or escalation of potentially harmful treatment. In childhood, approximately 50% are gonadal and 50% extragonadal (20% intracranial/30% extracranial). Clinical presentation relates to mass effect at tumour site. Teratomas account for 50% of paediatric GCTs and, whilst considered benign, may recur if not completely excised. Malignant GCTs often secrete the tumour markers alpha-fetoprotein and human chorionic gonadotrophin, which may help in diagnosis and follow-up. Outcomes are generally good with >90% five-year overall survival. Management involves complete surgical resection for teratomas and non-metastatic gonadal tumours. In the UK, chemotherapy is reserved for stage 2–4 extracranial malignant GCTs. Intracranial tumours typically occur in the midline in the pineal and/or suprasellar regions. Intracranial germinomas are cured in >90% cases with radiotherapy or combined chemo-radiotherapy. About two-thirds of non-germinomatous intracranial tumours are cured with combined chemo-radiotherapy. Current issues relating to the diagnosis and management of teenagers and young adults with GCTs are highlighted.

We aimed to retrospectively assess treatments/outcomes, including the value of high-dose-chemotherapy and autologous-stem-cell-rescue (HDC + AuSCR) and re-irradiation, in a large, European patient-cohort with relapsed intracranial germ-cell-tumors (GCTs) receiving uniform first-line therapy, including radiotherapy as standard-of-care. Fifty-eight UK/German patients (48 male/10 female) with relapsed intracranial-GCTs [13 germinoma/45 non-germinomatous GCT (NGGCT)] treated 1996-2010 as per the SIOP-CNS-GCT-96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five-year overall-survival (OS) for the whole-group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard-dose-chemotherapy (SDC) and re-irradiation or HDC + AuSCR with/without re-irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non-protocol adherence, five teratoma, five palliation). Five-year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2-26%). By treatment received, 5-year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0-0%) and 14% (3-36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5-year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re-irradiation or HDC + AuSCR with/without re-irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa-based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible.

A girl with acute lymphoblastic leukemia in remission had two seizures during the maintenance phase of her treatment. Magnetic resonance imaging with angiography identified a superior sagittal sinus thrombosis as the likely explanation for her symptoms. Possible causes are considered, and previous reports of the neurotoxicity of agents used in the treatment of leukemia are reviewed.