The prognosis and management of neuroendocrine neoplasms-related metastatic bone disease: lessons from clinical practice.

PURPOSE: To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs). METHODS: Seventy-four patients were recruited from four NEN centers in this observational multicenter study. RESULTS: Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4-395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589-14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14-463) months. CONCLUSIONS: Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes.

Putting an end to Black Wednesday: improving patient safety by achieving comprehensive trust induction and mandatory training by day 1.

The term 'Black Wednesday' has been used to describe the August national changeover day, a day when a new cohort of inexperienced doctors start work, many of whom are absent from patient care to attend organisational induction and mandatory training. In this paper, we report on the development and implementation of a novel, interactive e-learning programme for induction and mandatory training for junior doctors in a district general hospital in south-west England from August 2013. This comprehensive mandatory-training programme with summative assessment saved 19.5 hours of trust time per trainee. Since the programme's inception, the completion rate has been 100% (n = 370). Subgroup analysis of starters from August 2013 (n = 141) showed that 85.7% completed by day 1 (mean time of completion 3.0 days before day 1, standard deviation 14.2 days). Importantly, 90 minutes of induction was freed on Black Wednesday, enabling earlier, ward-based clinical orientation, thereby enhancing patient safety. We believe that this is the first programme to combine induction with fully assessed, comprehensive mandatory training in a single package. Such an approach is suitable for widespread application and is to be implemented regionally.

Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing.

Aprataxin (APTX) deficiency causes progressive cerebellar degeneration, ataxia and oculomotor apraxia in man. Cell free assays and crystal structure studies demonstrate a role for APTX in resolving 5'-adenylated nucleic acid breaks, however, APTX function in vertebrates remains unclear due to the lack of an appropriate model system. Here, we generated a murine model in which a pathogenic mutant of superoxide dismutase 1 (SOD1(G93A)) is expressed in an Aptx-/- mouse strain. We report a delayed population doubling and accelerated senescence in Aptx-/- primary mouse fibroblasts, which is not due to detectable telomere instability or cell cycle deregulation but is associated with a reduction in transcription recovery following oxidative stress. Expression of SOD1(G93A) uncovers a survival defect ex vivo in cultured cells and in vivo in tissues lacking Aptx. The surviving neurons feature numerous and deep nuclear envelope invaginations, a hallmark of cellular stress. Furthermore, they possess an elevated number of high-density nuclear regions and a concomitant increase in histone H3 K9 trimethylation, hallmarks of silenced chromatin. Finally, the accelerated cellular senescence was also observed at the organismal level as shown by down-regulation of insulin-like growth factor 1 (IGF-1), a hallmark of premature ageing. Together, this study demonstrates a protective role of Aptx in vivo and suggests that its loss results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of premature ageing, systemically.

Bring on the weekend - Improving the quality of junior doctor weekend handover.

While it is widely recognised that communication and handover are a fundamental component in providing safe clinical care for hospital patients (1,2.3). The Royal College of Physicians found that the majority of hospital doctors are dissatisfied with the standard of their handovers (4). These findings were mirrored by the junior staff at the Royal United Hospital, who felt that the weekend handover was inadequate, and detrimental to patient safety. A group of eight junior doctors at the Royal United Hospital, Bath utilised The Model For Improvement to systematically analyse and improve various aspects of the weekend handover system. Handover sheets from a subset of wards were assessed to observe direct effects of staged interventions over a nine month period, allowing small-scale testing prior to widespread implementation of a standardised intranet-based weekend handover. The effects of interventions were evaluated using a predesigned scoring system and data was collected continuously throughout the project. Over a nine month period the quality of handovers improved significantly from 76% to 93% (p <0.01): a success which was supported by a 100% improvement in formal feedback collected from hospital doctors and highlighted by the desire of senior staff and directors to implement the system throughout the trust. Using The Model For Improvement a group of junior doctors were able to introduce and develop a standardised weekend handover system that met their requirements. A structured, efficient and auditable system has been successfully produced which improves the quality and safety of patient care.

FUS immunogold labeling TEM analysis of the neuronal cytoplasmic inclusions of neuronal intermediate filament inclusion disease: a frontotemporal lobar degeneration with FUS proteinopathy.

Fused in sarcoma (FUS)-immunoreactive neuronal and glial inclusions define a novel molecular pathology called FUS proteinopathy. FUS has been shown to be a component of inclusions of familial amyotrophic lateral sclerosis with FUS mutation and three frontotemporal lobar degeneration entities, including neuronal intermediate filament inclusion disease (NIFID). The pathogenic role of FUS is unknown. In addition to FUS, many neuronal cytoplasmic inclusions (NCI) of NIFID contain aggregates of α-internexin and neurofilament proteins. Herein, we have shown that: (1) FUS becomes relatively insoluble in NIFID and there are no apparent posttranslational modifications, (2) there are no pathogenic abnormalities in the FUS gene in NIFID, and (3) immunoelectron microscopy demonstrates the fine structural localization of FUS in NIFID which has not previously been described. FUS localized to euchromatin, and strongly with paraspeckles, in nuclei, consistent with its RNA/DNA-binding functions. NCI of varying morphologies were observed. Most frequent were the "loosely aggregated cytoplasmic inclusions," 81% of which had moderate or high levels of FUS immunoreactivity. Much rarer "compact cytoplasmic inclusions" and "tangled twine ball inclusions" were FUS-immunoreactive at their granular peripheries, or heavily FUS-positive throughout, respectively. Thus, FUS may aggregate in the cytoplasm and then admix with neuronal intermediate filament accumulations.