A Short-Lived but Highly Cytotoxic Vanadium(V) Complex as a Potential Drug Lead for Brain Cancer Treatment by Intratumoral Injections.

The chemistry and short lifetimes of metal-based anti-cancer drugs can be turned into an advantage for direct injections into tumors, which then allow the use of highly cytotoxic drugs. The release of their less toxic decomposition products into the blood will lead to decreased toxicity and can even have beneficial effects. We present a ternary VV complex, 1 ([VOL1 L2 ], where L1 is N-(salicylideneaminato)-N'-(2-hydroxyethyl)ethane-1,2-diamine and L2 is 3,5-di-tert-butylcatechol), which enters cells intact to induce high cytotoxicity in a range of human cancer cells, including T98g (glioma multiforme), while its decomposition products in cell culture medium were ≈8-fold less toxic. 1 was 12-fold more toxic than cisplatin in T98g cells and 6-fold more toxic in T98g cells than in a non-cancer human cell line, HFF-1. Its high toxicity in T98g cells was retained in the presence of physiological concentrations of the two main metal-binding serum proteins, albumin and transferrin. These properties favor further development of 1 for brain cancer treatment by intratumoral injections.

PEG site metastasis in oropharyngeal squamous cell carcinoma managed with cetuximab and radiotherapy: A case report.

Percutaneous endoscopic gastrostomy (PEG) tube insertion is commonplace in head and neck cancer (HNC) patients. A rare but serious complication of PEG insertion in HNC is PEG site metastasis (PSM), which may precipitate rapid deterioration. We present the first case of PSM in a HNC patient managed without chemoradiotherapy and/or surgery, but rather with concurrent radiotherapy and cetuximab, followed by second-line pembrolizumab. Following histopathologic diagnosis of PSM, positron emission tomography confirmed primary site recurrence and multiple metastases in the axilla, abdomen and pelvis, managed palliatively with focal abdominal wall radiotherapy, pembrolizumab and carboplatin. The patient deteriorated and passed away 20 months after initial HNC diagnosis, 5 months after confirmation of PSM. Patients and clinicians should be aware of PSM in HNC. Though a proven prevention strategy is yet to be confirmed, prompt PSM diagnosis spares the patient unnecessary antibiotics for presumed infection and suggests the possibility of intra-abdominal metastases.

Chronic osteomyelitis caused by Achromobacter xylosoxidans following orthopaedic trauma: A case report and review of the literature.

BACKGROUND: Achromobacter xylosoxidans is an opportunistic environmental aerobe. In cases where A. xylosoxidans infects humans, it most commonly manifests as bacteraemia in the immunosuppressed. A. xylosoxidans causing chronic osteomyelitis is rare, particularly in the immunocompetent and young. CASE: We present the case of a 23-year-old man with chronic osteomyelitis of the right femur caused by co-infection of A. xylosoxidans and Staphylococcus aureus. Five years earlier, he had sustained a right femur fracture and was treated with intramedullary fixation at a peripheral hospital in a developing nation. Past medical history was otherwise unremarkable. Management comprised of surgical debridement and culture-directed antibiotic therapy, resulting in clinical cure. CONCLUSION: In the context of local trauma and previous surgery, osteomyelitis caused by atypical pathogens must be considered. A multidisciplinary approach commensurate with duration and severity of infection and tailored to the causative organism is paramount.

Volumetric Response of Limited Brain Metastatic Disease to Focal Hypofractionated Radiation Therapy.

Background: This is a retrospective study aimed at assessing the volumetric response, morbidity and failure rates of hypofractionated radiation therapy (HFRT) for definitive focal management of limited brain metastasis. Methods: Patients managed with HFRT for unresected limited metastatic (≤10 lesions) brain disease were entered into an ethics-approved database. Included patients had been deemed unsuitable for surgical resection, and lesions managed with prior radiation therapy were excluded. HFRT was delivered using IMRT or VMAT with 25 Gy or 30 Gy in five fractions. Individual lesions had volumetric assessment performed at three timepoints. The primary endpoint was the change of volume from baseline (GTV0) to one month post-HFRT (GTV1) and to seven months post-HFRT (GTV7). Secondary endpoints were local failure, survival and rates of radiation necrosis. Results: One hundred and twenty-four patients with 233 lesions were managed with HFRT. Median follow-up was 23.5 months with 32 (25.8%) patients alive at censure. Median overall survival was 7.3 months with 36.3% survival at 12 months. Superior survival was predicted by smaller GTV0 (p = 0.003) and increased percentage of volumetric response (p < 0.001). Systemic therapy was delivered to 81.5% of patients. At one month post-HFRT, 206 metastases (88.4%) were available for assessment and at seven months post-HFRT, 118 metastases (50.6%) were available. Median metastasis volume at GTV0 was 1.6 cm3 (range: 0.1-19.1). At GTV1 and GTV7, this reduced to 0.7 cm3 (p < 0.001) and 0.3 cm3 (p < 0.001), respectively, correlating to percentage reductions of 54.9% and 83.3%. No significant predictors of volumetric response following HFRT were identified. Local failure was identified in 4.3% of lesions and radiation necrosis in 3.9%. Conclusion: HFRT is an effective therapy for limited metastatic disease in the brain to maximise initial volumetric response whilst minimising toxicity.

Survival in borderline resectable and locally advanced pancreatic cancer is determined by the duration and response of neoadjuvant therapy.

BACKGROUND: Pancreatic cancer is the 8th commonest cancer and the 5th commonest cause of cancer-related death in Australia, with a 9% average 5-year survival. This study aims to investigate the effects of neoadjuvant treatment on overall survival (OS) and recurrence-free survival (RFS) in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic adenocarcinoma followed by curative resection. MATERIALS AND METHODS: Prospectively-collected demographic, medical, surgical and pathological data of patients with BRPC and LAPC treated with both neoadjuvant therapy (NAT) and surgery at a single tertiary referral centre in Australia were reviewed and analysed. RESULTS: Between 2012 and 2018, 60 patients, 34 with BRPC and 26 with LAPC, were treated with NAT followed by curative resection. The commonest neoadjuvant chemotherapy regimens were Gemcitabine + Abraxane (51.7%) and FOLFIRINOX (35.0%), with 48.3% of patients additionally receiving neoadjuvant radiotherapy. Median RFS was 30 months and median OS was 35 months. On multivariable analysis, inferior OS was predicted by enlarged loco-regional lymph nodes on initial computed tomography (p = 0.032), larger tumour size post-NAT (p = 0.006) and Common Terminology Criteria for Adverse Events post-NAT toxicity greater than grade 2 (p = 0.015). LAPC patients received more neoadjuvant chemotherapy (p = 0.008) and radiotherapy (p = 0.021) than BRPC and achieved a superior pathological response (p = 0.010). CONCLUSION: Patients who respond to NAT likely have a favourable disease biology and will progress well following resection. It is these patients who should be selected for more aggressive upfront management, and those with resistant disease should be spared from high-risk surgery.

The utility of cross-sectional imaging in the management of suspected scaphoid fractures.

INTRODUCTION: Scaphoid fractures are the commonest carpal bone fracture. If untreated they pose significant risk to patients, thus if a scaphoid fracture is suspected, patients are managed with immobilisation. Although scaphoid fractures may be difficult to diagnose on plain radiography, sometimes for months after injury, ongoing radiographic surveillance is preferred due to its low upfront cost. Patients in immobilising casts for long periods experience significant personal and social ramifications such as difficulty working and self-caring. This study examines whether cross-sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) is quicker than serial X-ray surveillance at allowing a scaphoid fracture to be either excluded or confirmed. METHODS: A retrospective record review was performed of the 1709 patients who presented to Royal North Shore Hospital in 2015 with wrist injuries, finding 104 patients clinically suspicious for a fractured scaphoid. RESULTS: All patients were examined by X-ray during their initial hospital presentation, providing 33.7% of final diagnoses in 0.6 ± 1.7 days. However, if initial X-ray proved inconclusive, subsequent serial X-ray surveillance made a final diagnosis after a mean of 24.1 ± 17.2 days, with some being immobilised for up to 67 days before diagnosis. Cross-sectional imaging significantly reduced diagnosis time to 9.8 ± 5.8 days (P = 0.0016), with a maximum immobilisation time of 24 days. CONCLUSION: Cross-sectional imaging allows for faster scaphoid fracture diagnosis than X-ray. We propose a protocol for scaphoid fracture diagnosis wherein patients undergo two episodes of X-ray separated by 7 days, followed by a single MRI if clinical suspicion remains, minimising unnecessary immobilisation.

Hydrophobicity may enhance membrane affinity and anti-cancer effects of Schiff base vanadium(v) catecholate complexes.

Anti-cancer activities of vanadium compounds have generated recent interest because of a combination of desirable properties for chemotherapy, i.e., strong cytotoxicities, anti-metastatic activities and relatively low systemic toxicities. Certain hydrophobic vanadium(v) Schiff base/catecholate compounds, which as shown herein, have increased stability in aqueous media and affinity for membrane interfaces. Depending on their hydrophobicity, they may be able to enter cells intact. In this manuscript, two hydrophobic V(v) catecholate substituted analogues, [VO(Hshed)(cat)] and [VO(Hshed)(dtb)], (Hshed = N-(salicylideneaminato)-N'-(2-hydroxyethyl)-1,2-ethanediamine, cat = pyrocatechol, and dtb = 3,5-di(tert-butyl)catechol and the vanadium(v) precursor [V(O)2(Hshed)]) were synthesized for their ability to interact with membranes and their anti-cancer effects. Using 51V and 1H NMR spectroscopy, the presence and location of the free ligand, H2shed, and the three V(v) complexes were examined in a model membrane microemulsion system. The stability of the three complexes was measured in aqueous solution, cell media and an inhomogeneous microemulsion system. Our results demonstrated that free ligand H2shed and the intact V(v) complexes associated with the interface but that the V-complexes hydrolyzed to some extent because oxovanadates were observed by 51V NMR spectroscopy and decreasing complex by absorption spectroscopy in cell media. When determining the effects of V(v) catecholate complexes on bone cancer cells, the strongest effects were observed with the more stable hydrophobic complex [VO(Hshed)(dtb)] that was able to best associate and penetrate the model membrane system intact. These studies are consistent with the membrane permeability studies being a good predictor for in vitro cytotoxicity assays because [VO(Hshed)(dtb)] can pass through the cellular membrane intact, which may enhance its anti-cancer activities.