Preclinical testing of a targeted TRAIL therapeutic for bone sarcoma

PhD ThesisBackground: TNF-related apoptosis-inducing ligand (TRAIL) can induce cell death in cancer cells after binding to its TRAIL receptors [TRAILR, Death Receptor 4 (DR4) and Death Receptor 5 (DR5)] while sparing non-malignant cells. The application of TRAIL provides an approach that can potentially overcome drug resistance and toxicity associated with high doses of conventional therapies. It could be administered alone or in combination with conventional therapies and, therefore, may offer a promising new approach to bone sarcoma treatment. Enhancing the cytotoxic effect of TRAIL involves targeting a tumour associated antigen (TAA). Here, the aim was to characterise bone sarcoma cells for TRAILR expression and to assess the effectiveness, both in vitro and in vivo of a novel TRAIL construct, neural/glial antigen 2 (NG2) targeted TRAIL (ScFvNG2-Fc-scTRAIL). Methods: Bone sarcoma cell lines were characterised for TRAILR and NG2 expression on RNA and protein level. Together with non-malignant cell lines, they were exposed to the novel TRAIL therapeutic (ScFvNG2-Fc-scTRAIL) in vitro and then tested in vivo in a newly developed xenograft model of dedifferentiated chondrosarcoma. Results: Surface DR5 was expressed in all cell lines examined (very high: HT1080, MG63; moderate: SW153, U2OS, TC71). NG2 was also expressed (very high: SW1353, MG63; moderate: U2OS, HT1080). ScFvNG2-Fc-scTRAIL demonstrated enhanced cytotoxicity in DR5- and NG2-expressing cell lines (MG63>HT1080>U2OS), which increased with doxorubicin and was also found in vivo when engrafting a luciferase expressing HT1080 cell line in a dedifferentiated chondrosarcoma mouse model. Conclusion: I demonstrate that a novel targeted TRAIL therapeutic, ScFvNG2-FcscTRAIL, has a selective and significant cytotoxic effect on cell lines expressing both cell surface DR5 and NG2, and these cytotoxic effects can be enhanced further with doxorubicin. Such combinations could minimise the risk of treatment failure due to drug resistance, a common problem of single agent approaches. Furthermore, these findings provide a framework for the clinical development of ScFvNG2-Fc-scTRAIL and could potentially be used in the neoadjuvant setting, which would be a shift from the usual convention of prioritising excision of the sarcoma

Inflammatory fibroid polyp (Vanek's tumour), an unusual large polyp of the jejunum: a case report

We report the case of a 46-year-old man who presented with recurrent episodes of severe upper abdominal pain over a period of three months. A computerized tomography scan of his abdomen demonstrated a large non-obstructing jejunal mass. He underwent laparotomy and resection of a 13.5 cm tumour from the distal jejunum. Histopathological examination confirmed a large inflammatory fibroid polyp of the jejunum. The clinical presentation and microscopic features are discussed

Cowden syndrome. Managing multiple skeletal metastases of different origin: a case report

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Posterior reversible encephalopathy syndrome in a child with cyclical vomiting and hypertension: a case report

<p>Abstract</p> <p>Introduction</p> <p>Posterior reversible encephalopathy syndrome is characterized by headache, nausea and vomiting, seizures and visual disturbances. It has certain characteristic radiological features, which allow diagnosis in the appropriate clinical setting and enable appropriate clinical therapy to be instituted.</p> <p>Case presentation</p> <p>A 10-year-old Caucasian girl who was hospitalized due to recurrent vomiting was diagnosed as having posterior reversible encephalopathy syndrome after an initial diagnosis of cyclical vomiting and hypertension was made.</p> <p>Conclusion</p> <p>Posterior reversible encephalopathy syndrome is a rare disorder in children. Early recognition of characteristic radiological features is key to the diagnosis as clinical symptoms may be non-specific or mimic other neurological illnesses. To the best of our knowledge this is the first case to report an association between posterior reversible encephalopathy syndrome, cyclical vomiting and hypertension. Furthermore, in this case, the resolution of the abnormalities found on magnetic resonance imaging over time did not appear to equate with clinical recovery.</p

Lower respiratory tract infection and rapid expansion of an abdominal aortic aneurysm: a case report

<p>Abstract</p> <p>Introduction</p> <p>The rate of abdominal aortic aneurysm expansion is related to multiple factors. There is some evidence that inflammation can accelerate aneurysm expansion. However, the association between pulmonary sepsis and rapid abdominal aortic aneurysm expansion is rarely reported.</p> <p>Case presentation</p> <p>Here we present a case of a rapidly expanding abdominal aortic aneurysm in a 68-year-old Caucasian man with a concomitant lower respiratory tract infection and systemic sepsis requiring intensive monitoring and urgent endovascular intervention. Our patient had an uncomplicated post-operative recovery and a follow-up computed tomography scan at one month demonstrated no evidence of an endoleak.</p> <p>Conclusion</p> <p>This case highlights the potential association between pulmonary sepsis and rapid abdominal aortic aneurysm expansion. In such cases, a policy of frequent monitoring should be adopted to identify those patients requiring definitive management.</p

Collared versus collarless hydroxyapatite-coated stems for primary cementless total hip arthroplasty; a systematic review of comparative studies. Is there any difference in survival, functional, and radiographic outcomes?

Introduction: This systematic review aims to critically assess the literature comparative studies investigating collared and collarless Corail stem in primary total hip arthroplasty (THA) to find differences in revision rates, radiographic and clinical outcomes, and postoperative complications between these two types of the same stem. Methods: Eligible studies were found by searching PubMed, Science Direct/Scopus, and the Cochrane Database of Systematic Reviews from conception till May 2023. The PRISMA guidelines were followed. The investigation encompassed randomized controlled trials, case series, comparative, cohort, and observational studies that assessed at least one comparative outcome or complication between collared and collarless Corail stems. Results: Twelve comparative studies with 90,626 patients undergoing primary THA were included. There were 40,441 collared and 58,543 collarless stems. The follow-up ranged from 12 to 360 months. Our study demonstrated no significant difference in stem revision relative risk (RR = 0.68; 95% confidence interval (CI), 0.23, 2.02; p = 0.49), number of radiolucent lines (RR = 0.3; 95% CI, 0.06, 2.28; p = 0.29) and overall complication risk (RR = 0.62; 95% CI, 0.22, 1.76; p = 0.37) between collared and collarless stems. The collared stems demonstrated significantly lesser subsidence (mean difference: 1.01 mm; 95% CI, −1.77, −0.25; p = 0.009) and risk of periprosthetic fractures (RR = 0.52; 95% CI, 0.29, 0.92; p = 0.03). Conclusion: The comparative studies between collared and collarless stem groups showed similar survival and overall complication rates and functional outcomes. The similar revision rates between groups make the impact of higher subsidence for collarless stems uncertain. The lower risk of periprosthetic fractures in the collared stems group must be clarified further but could be related to increased rotational stability