P2X receptors within the CNS mediate excitatory synaptic transmission and also act presynaptically to modulate neurotransmitter release. We have studied the targeting and trafficking of P2X4 and P2X2 ...receptors heterologously expressed in cultured olfactory bulb neurons. Homomeric P2X4 receptors had a punctate distribution, and many of the puncta colocalized with early endosomes. In contrast, P2X2 receptors were primarily localized at the plasma membrane. By antibody-labeling of surface receptors in living neurons, we showed that P2X4 receptors undergo rapid constitutive internalization and subsequent reinsertion into the plasma membrane, whereas P2X2 receptors were not regulated in such a way. The internalization of P2X4 receptors was dynamin-dependent, and the binding of ATP enhanced the basal rate of retrieval in a Ca2+-independent manner. The presence of the P2X4 subunit in a P2X4/6 heteromer governed the trafficking properties of the receptor. P2X receptors acted presynaptically to enhance the release of glutamate, suggesting that the regulated cycling of P2X4-containing receptors might provide a mechanism for modulation of synaptic transmission.
Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor, most commonly located in the pharyngeal recess and endemic to parts of Asia. It is often detected at a late stage which is associated ...with poor prognosis (5-year survival rate of 63%). Treatment for this malignancy relies predominantly on radiotherapy and/or systemic chemotherapy, which can be associated with significant morbidity and impaired quality of life. In endemic regions NPC is associated with infection by Epstein-Barr virus (EBV) which was shown to upregulate the somatostatin receptor 2 (SSTR2) cell surface receptor. With recent advances in molecular techniques allowing for an improved understanding of the molecular aetiology of this disease and its relation to SSTR2 expression, we provide a comprehensive and up-to-date overview of this disease and highlight the emergence of SSTR2 as a key tumor biomarker and promising target for imaging and therapy.
Summary
In the Medical Research Council (MRC) Myeloma IX trial (ISRCTN684564111) patients were randomised to sodium clodronate or zoledronic acid and induction treatment: cyclophosphamide, ...vincristine, doxorubicin and dexamethasone (CVAD) or cyclophosphamide, thalidomide and dexamethasone (CTD) followed by autologous stem cell transplant (ASCT) in the intensive pathway; attenuated CTD or melphalan and prednisolone (MP) in the non‐intensive pathway. Subsequent randomisation allocated patients to either thalidomide or observation. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QoL) questionnaires, QLQ‐C30 and QLQ‐MY24, were administered at baseline, 3, 6 and 12 months and annually thereafter, enabling the effect of sequential treatment on patient‐reported health‐related QoL (HR‐QoL) to be investigated. The protocol specified four subscales of interest: Pain, Fatigue, Global Health Status/Quality of Life and Physical Functioning at 3, 6 and 12 months that were compared using linear models. The intensive pathway showed significant differences in favour of CTD for Fatigue at 3 months and Physical Functioning at 12 months. The non‐intensive pathway and maintenance phase reported significant differences at 3 months; Pain (improved with attenuated CTD) and Global Health status/Quality of Life (improved with observation). The improved outcomes in MRC Myeloma IX were accompanied by some beneficial and few detrimental effects on HR‐QoL.
Objective To describe the outcomes of clinical evaluation, skin testing, and vaccine challenge in adolescent schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus ...vaccine introduced in Australian schools in 2007.Design Retrospective cohort study.Setting Two tertiary paediatric allergy centres in Victoria and South Australia, Australia.Participants 35 schoolgirls aged 12 to 18.9 years with suspected hypersensitivity reactions to the quadrivalent human papillomavirus vaccine.Main outcome measures Clinical review and skin prick and intradermal testing with the quadrivalent vaccine and subsequent challenge with the vaccine.Results 35 schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus vaccine were notified to the specialised immunisation services in 2007, after more than 380 000 doses had been administered in schools. Of these 35 schoolgirls, 25 agreed to further evaluation. Twenty three (92%) experienced reactions after the first dose. Thirteen (52%) experienced urticaria or angio-oedema, and of these, two experienced anaphylaxis. Thirteen had generalised rash, one with angio-oedema. The median time to reaction was 90 minutes. Nineteen (76%) underwent skin testing with the quadrivalent vaccine: all were skin prick test negative and one was intradermal test positive. Eighteen (72%) were subsequently challenged with the quadrivalent vaccine and three (12%) elected to receive the bivalent vaccine. Seventeen tolerated the challenge and one reported limited urticaria four hours after the vaccine had been administered. Only three of the 25 schoolgirls were found to have probable hypersensitivity to the quadrivalent vaccine.Conclusion True hypersensitivity to the quadrivalent human papillomavirus vaccine in Australian schoolgirls was uncommon and most tolerated subsequent doses.
To determine safety of short in-hospital delays before appendicectomy.
Short organizational delays before appendicectomy may safely improve provision of acute surgical services.
The primary endpoint ...was the rate of complex appendicitis (perforation, gangrene, and/or abscess). The main explanatory variable was timing of surgery, using less than 12 hours from admission as the reference. The first part of this study analyzed primary data from a multicentre study on appendicectomy from 95 centers. The second part combined this data with a systematic review and meta-analysis of published data.
The cohort study included 2510 patients with acute appendicitis, of whom 812 (32.4%) had complex findings. Adjusted multivariable binary regression modelling showed that timing of operation was not related to risk of complex appendicitis 12-24 hours odds ratio (OR) 0.98 (P = 0.869); 24-48 hours OR 0.88 (P = 0.329); 48+ hours OR 0.82 (P = 0.317). However, after 48 hours, the risk of surgical site infection and 30-day adverse events both increased adjusted ORs 2.24 (P = 0.039) and 1.71 (P = 0.024), respectively. Meta-analysis of 11 nonrandomized studies (8858 patients) revealed that delay of 12 to 24 hours after admission did not increase the risk of complex appendicitis (OR 0.97, P = 0.750).
Short delays of less than 24 hours before appendicectomy were not associated with increased rates of complex pathology in selected patients. These organizational delays may aid service provision, but planned delay beyond this should be avoided. However, where optimal surgical systems allow for expeditious surgery, prompt appendicectomy will still aid fastest resolution of pain for the individual patient.
Introduction:
Multiple myeloma (MM) is molecularly heterogeneous but so too are the patients it affects. This heterogeneity becomes more significant in older, less fit patients in whom factors ...affecting their ability to withstand treatment may be more important than disease biology. Treatment tolerability does not deteriorate linearly with age and is better defined as ‘frailty’. Patient-reported activities of daily living and comorbidities have been combined with age to derive the IMWG Frailty Score (Palumbo A et al, Blood 2015), which can predict outcome. This requires completion of 3 patient questionnaires and may be open to bias.
Several biochemical markers of frailty have been associated with adverse outcomes including inflammatory markers such as CRP, renal dysfunction and the ratio of lymphocytes to total white cells (L:W). Using biochemical surrogates to measure patient frailty is objective and avoids the need for potentially burdensome questionnaires. Here we describe a novel prognostic score (Leeds Risk Profile; LRP) that combines readily available laboratory measures of patient frailty with age and WHO performance status (PS) to predict outcomes in transplant non-eligible (TNE) MM patients.
Methods:
1852 TNE patients recruited to the NCRI Myeloma XI (MyXI) trial were used as a training set and 520 TNE patients recruited to the MRC Myeloma IX (MyIX) trial used as a validation set. MyXI compared IMiD-containing triplet combinations: cyclophosphamide and dexamethasone with thalidomide (CTD) or lenalidomide (CRD). Patients with a suboptimal response (<VGPR) were eligible for further induction with a PI-based triplet (cyclophosphamide, bortezomib and dexamethasone). There was a maintenance randomisation between lenalidomide and observation. MyIX compared induction with melphalan and prednisolone to CTD and maintenance thalidomide to observation.
Baseline variables considered included PS, LDH, CRP, international staging score (ISS), age and L:W. The primary objective was overall survival (OS). Missing data in the training set (MyXI) for the variables was imputed via multiple imputation by chained equations. The model was built using a Cox model with LASSO penalty within each imputed dataset. The final model was derived by combining the coefficients and standard errors by Rubin's rules. The model was internally validated by bootstrap sampling and externally validated in the test set using the prognostic separation D-statistic.
Results:
Univariate Cox-regression analysis demonstrated a significant effect of PS, CRP, ISS, Age and L:W (all p<0.001) but not LDH (p=0.333) on OS within the training set.
The final multivariable model (LRP) included PS, Age, ISS and CRP. The discrimination and calibration of the model were good, with calibration better closer to trial entry. The model was successfully internally validated by bootstrap re-sampling according to pre-defined criteria. The combined prognostic index was divided into tertiles to define 3 groups: Fit, Intermediate-fitness, Frail. All variables increased in severity across the three groups. The groups predicted outcomes as shown in Figure 1a (median OS: Fit 60 months 95%CI 55-NR, Intermediate-fitness 44 39-48 and Frail 25 22-30 (Log-rank p<0.0001)).
External validation was successfully carried out using patients from MyIX. The test data was split into three separate risk groups using the same cut-offs derived and implemented within the training data. Significant differences in OS were again predicted (Figure 1b) (median OS: Fit 43 months 35-NR, Intermediate-fitness 34 27-38 and Frail 20 14-25 (Log-rank p<0.0001)).
In exploratory analyses the risk groups derived for overall survival were applied to progression-free survival, early mortality and treatment delivery modifications and predicted outcome as expected. Predictive ability was maintained in those patients who were exposed to both IMiD and PI therapy.
Conclusion:
We have defined a novel score predictive of outcome in TNE MM patients (LRP). This score uses only factors already collected at baseline for MM patients using objective laboratory bloods tests combined with age and a simple WHO PS assessment. As such it would be easy and quick to use in the clinic and apply within clinical trials. The LRP will be prospectively validated, including a comparison to the IMWG Frailty Score, within the UK-MRA Myeloma XIV trial (FITNESS).
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Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetcs: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pawlyn:Takeda: Honoraria, Other: Travel support; Janssen: Other: Travel support; Celgene: Honoraria, Other: Travel support. Gregory:Janssen: Honoraria; Celgene: Consultancy, Honoraria. Davies:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Morgan:Takeda: Consultancy, Honoraria; Bristol Myers: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Jackson:Chugai: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; J&J: Honoraria.
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