Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients

Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m−2, followed by a fixed dose of 5.0 g m−2 treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m−2 gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m−2 gemcitabine combined with 5.0 g m−2 treosulfan

D1-Strings in Large RR 3-Form Flux, Quantum Nambu Geometry and M5-Branes in C-Field

We consider D1-branes in a RR flux background and show that there is a low energy - large flux double scaling limit where the D1-branes action is dominated by a Chern-Simons-Myers coupling term. As a classical solution to the matrix model, we find a novel quantized geometry characterized by a quantum Nambu 3-bracket. Infinite dimensional representations of the quantum Nambu geometry are constructed which demonstrate that the quantum Nambu geometry is intrinsically different from the ordinary Lie algebra type noncommutative geometry. Matrix models for the IIB string, IIA string and M-theory in the corresponding backgrounds are constructed. A classical solution of a quantum Nambu geometry in the IIA Matrix string theory gives rise to an expansion of the fundamental strings into a system of multiple D4-branes and the fluctuation is found to describe an action for a non-abelian 3-form field strength which is a natural non-abelian generalization of the PST action for a single D4-brane. In view of the recent proposals of the M5-branes theory in terms of the D4-branes, we suggest a natural way to include all the KK modes and propose an action for the the multiple M5-branes in a constant C-field. The worldvolume of the M5-branes in a C-field is found to be described by a quantum Nambu geometry with self-dual parameters. It is intriguing that our action is naturally formulated in terms of a 1-form gauge field living on a six dimensional quantum Nambu geometry.Comment: 34 pages. LaTe

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Supplementary Material for: Low Back Pain in Pregnancy: Investigations, Management, and Role of Neuraxial Analgesia and Anaesthesia: A Systematic Review

<p><b><i>Background:</i></b> Low back pain (LBP) is commonly experienced during pregnancy and is often poorly managed. There is much ambiguity in diagnostic work-up, appropriate management and decision-making regarding the use of neuraxial analgesia and anaesthesia during labour and delivery in these patients. This systematic review summarises the evidence regarding investigations, management strategies and considerations around performing neuraxial blocks for pregnant women with LBP. <b><i>Methods:</i></b> We searched 3 databases and reviewed literature concerning LBP in pregnancy with regards to diagnostic modalities, management strategies and use of neuraxial techniques for facilitating labour and delivery.<b><i> Results:</i></b> In all, we included 78 studies in this review, with 32 studies concerning diagnostic investigations, 56 studies involving management strategies, and 4 studies regarding the use of neuraxial techniques for labour and delivery. <b><i>Summary:</i></b> MRI is the safest investigative modality for LBP in pregnancy. Antenatal educational programmes, exercise and steroid injections into the epidural space or sacroiliac joints may help with pain management. Worsening neurological deficits, vertebral fractures and tumours may need surgical management. There is limited evidence on challenges of performing neuraxial blocks in the peripartum period for analgesia and anaesthesia, but there is a potential for increased risk of neurological complications in parturients with pre-existing neurological deficits.</p