Solid tumours undergo considerable alterations in their metabolism of nutrients in order to generate sufficient energy and biomass for sustained growth and proliferation. During growth, the tumour ...microenvironment exerts a number of influences (e.g. hypoxia and acidity) that affect cellular biology and the flux or utilisation of fuels including glucose. The tumour spheroid model was used to characterise the utilisation of glucose and describe alterations to the activity and expression of key glycolytic enzymes during the tissue growth curve. Glucose was avidly consumed and associated with the production of lactate and an acidified medium, confirming the reliance on glycolytic pathways and a diminution of oxidative phosphorylation. The expression levels and activities of hexokinase, phosphofructokinase-1, pyruvate kinase and lactate dehydrogenase in the glycolytic pathway were measured to assess glycolytic capacity. Similar measurements were made for glucose-6-phosphate dehydrogenase, the entry point and regulatory step of the pentose-phosphate pathway (PPP) and for cytosolic malate dehydrogenase, a key link to TCA cycle intermediates. The parameters for these key enzymes were shown to undergo considerable variation during the growth curve of tumour spheroids. In addition, they revealed that the dynamic alterations were influenced by both transcriptional and posttranslational mechanisms.
Oral food challenges (OFCs) are routinely used to confirm ongoing food allergy. Serum-specific IgE (sIgE) and skin prick testing (SPT) are imperfect predictors of which patients will pass OFCs.
The ...objective of this study was to describe the design and implementation of a Standardized Clinical Assessment and Management Plan (SCAMP) to study and iteratively improve sIgE and SPT thresholds to determine when and where to conduct OFCs for patients.
Allergists consulted recommended sIgE and SPT thresholds when ordering challenges although diversions were permitted. Criteria were iteratively improved after periodic analyses of challenge outcome and diversions.
Over 3 years, allergists ordered 2368 food challenges for 1580 patients with histories of IgE-mediated reactions to food: 1386 in an outpatient clinic and 945 in a higher resource infusion center. Reactions to challenge were observed in 13% of clinic and 23% of infusion center challenges. Six patients challenged in clinic required treatment with epinephrine compared with 22 in the infusion center. The need for epinephrine was more common in patients with asthma-5% of asthmatic patients required epinephrine compared with 1% of nonasthmatic patients (P < .01). Recommended sIgE and SPT thresholds were incrementally changed and, using the control chart methodology, a significant decrease was noted in the proportion of challenges ordered in the higher resource location.
By setting and continually refining sIgE and SPT recommendations using the SCAMP method, allergists can better determine the risk of severe reaction and triage patients to the appropriate setting for an OFC.
Purpose
Neutropenic sepsis (NS) is a medical emergency in which urgent treatment with antibiotics is known to improve outcomes, yet there are minimal data about what happens to patients with NS ...before they reach hospital. We aimed to examine the pre-hospital experiences of patients with NS, identifying its early presenting features and exploring the factors potentially delaying patients’ arrival at hospital.
Methods
We conducted in-depth, qualitative interviews with 22 cancer patients admitted to hospital for treatment of NS and 10 patient carers. The setting was a tertiary referral centre in Southern England.
Results
Thirty seven percent of patients took over 12 h to present to hospital after symptom onset. The mean delay in presentation was 11 h (range 0–68 h).
Thematic analysis of the interviews, using grounded theory, revealed wide-ranging, potentially modifiable factors delaying patients’ presentation to hospital. For example, information provided to patients about NS from different sources was inconsistent, with ‘mixed messages’ about urgency triggering delays. All patients self-monitored their temperature and understood the implication of a fever but few appreciated the potential significance of feeling unwell in the absence of fever. Attempts to obtain treatment were sometimes thwarted by nonspecialists’ failure to recognise possible neutropenia in a patient with apparently mild signs, and several patients with NS were discharged without treatment. Some patients denied their symptoms to themselves and others to avoid hospital admission; palliative patients seemed particularly prone to these attitudes, while their carers were keen to seek medical attention.
Conclusions
This investigation of patients’ and carers’ experiences of NS identifies numerous strategies for improving patient education, support and pre-hospital management, all of which may reduce pre-hospital delays and consequently decrease morbidity and mortality from NS.
Conclusions By setting and continually refining ssIgE and skin prick test recommendations using the SCAMP method, allergists can better determine the risk of severe reactions and triage patients to ...the appropriate resource setting for an OFC.
▪
Introduction: The national Venous Thromboembolism (VTE) Prevention Programme in England was launched in 2010 and incorporates standardised guidance on risk assessment (RA) and thromboprophylaxis ...(TP) with a requirement for root cause analysis of all episodes of hospital associated thrombosis (HAT), defined as any VTE occurring whilst an inpatient or within 90 days of discharge. We previously reported findings of root cause analysis for HAT over 2010 - 2012, demonstrating that achieving a 90% risk assessment rate resulted in a significant reduction in the incidence of HAT. We update our findings on the impact of implementation of the national programme on the incidence of HAT, proportion of potentially preventable HAT episodes, and mortality from hospital-associated pulmonary embolism (PE). As appropriate TP only reduces the risk of VTE by two-thirds, we also looked at risk factors for TP failure.
Methods: We examined HAT data collected from the root cause analysis programme at King's College Hospital from April 2011 to March 2015. Further data were gathered through retrospective review of patient notes. VTE risk factors for HAT attributed to TP failure were compared to a "non-HAT" group, (patients who received appropriate TP and did not develop HAT) drawn from VTE prevention audit data from 2013-2014. Episodes of HAT that developed following inadequate prescription or administration of either anticoagulant or mechanical TP were deemed as "potentially preventable" episodes.
Results: Across the four-year study period there were 725 episodes of HAT, giving an incidence of 3.28 episodes per 1000 hospital admissions. There was no significant change in incidence from 2011-2015. The median age of the cohort was 64 years (IQR = 27 years). 56.7% (n = 411) of the HAT episodes were deep vein thromboses, of which 54.7% (n = 225) involved the proximal vasculature. PE accounted for 41.7% (n = 302) episodes, of which 10.9% (n = 33) were fatal events. HAT developed following medical, surgical or obstetric admission in 43.3% (n = 314), 54.6% (n = 396) and 2.1% (n = 15) respectively. VTE risk factors were present in 97.9% (n = 710) of patients with HAT with concomitant bleeding risk factors in 37.1% (n = 269). Consistently, the most common outcome of root cause analysis was TP failure (47.6% overall, n = 345) with no significant trend across the study period; 19.7% (n = 143) of episodes were attributed to inadequate anticoagulant TP, 26.1% (n = 189) to contraindication to anticoagulant TP, 4.4% (n = 32) to contraindication to all forms of TP, and 2.2% (n = 16) episodes were unexpected (HAT occurring in a patient without identifiable VTE risk factors). There has been a significant reduction in the proportion of potentially preventable HAT episodes from 38.2% (n = 66) in 2011-2012 to 20.3% (n = 39) in 2014-2015 (p < 0.001). Furthermore, the proportion of fatal PE reduced over the study period from 16.0% (n = 12) of HAT in 2011-2012 to 6.3% (n = 5) of HAT in 2014-2015 (p = 0.049). The audit of VTE prevention practice over 2013/14 included 515 patients, of which 423 (82.1%) received appropriate TP and did not develop HAT. Compared to this group, patients with HAT attributed to TP failure had more risk factors (3.1 vs. 2.7, p < 0.002), were more likely to be over 60 years of age (59.4% vs. 42.3%, p = 0.01), or to have had orthopaedic surgery(6.7% vs. 1.8%, p = 0.001).
Discussion: Implementation of a comprehensive VTE prevention programme incorporating root cause analysis of HAT has led to a significant fall in the proportion of HAT that were potentially preventable with a corresponding reduction in mortality attributed to PE. However, there has been no change in the overall incidence of HAT with a rise in cases associated with TP failure. Further research is required to optimise TP in high VTE risk groups.
Arya:Bayer plc: Research Funding.
We report the case of a patient with severe systemic symptoms (weight loss, malaise, and anorexia), eosinophilic oesophagitis, and raised inflammatory markers coinciding with the use of lisinopril. ...The onset of symptoms occurred after the administration of lisinopril and resolved shortly after cessation of the medication. Despite thorough investigation, no other cause of the systemic inflammation and anaemia of chronic disease was found. “Drug rash with eosinophilia and systemic symptoms” (DRESSs) syndrome describes a potentially serious multiorgan inflammatory response to certain classes of drugs; this includes the use of ACE inhibitors. Although this patient did not meet strict criteria for DRESSs, the subacute inflammatory syndrome with eosinophilic organ infiltration bears similar features. ACE inhibitors should be considered in the differential diagnosis in patients with nonspecific systemic inflammation and anaemia of chronic disease where no other cause is found.
Ataxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). ...RP-3500 is highly potent with IC
values of 1.0 and 0.33 nmol/L in biochemical and cell-based assays, respectively. RP-3500 is highly selective for ATR with 30-fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000-fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kα) kinases.
, RP-3500 treatment results in potent single-agent efficacy and/or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg/kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (IC
= 18.6 nmol/L) and induction of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). RP-3500 exposure at MED indicates that circulating free plasma levels above the
tumor IC
for 10 to 12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on/4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with RP-3500 and demonstrating superior efficacy compared with sequential treatment. These results provide a strong preclinical rationale to support ongoing clinical investigation of the novel ATR inhibitor, RP-3500, on an intermittent schedule as a monotherapy and in combination with PARP inhibitors as a potential means of maximizing clinical benefit.
PDF
