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Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results.
No full textINTRODUCTION
This prospective, single-arm, phase 2 study assessed the efficacy and safety of lanreotide autogel (LAN) administered at a reduced dosing interval in patients with progressive neuroendocrine tumours (NETs) after LAN standard regimen.
METHODS
Patients had metastatic or locally advanced, grade 1 or 2 midgut NETs or pancreatic NETs (panNETs) and centrally assessed disease progression on LAN 120 mg every 28 days. They were treated with LAN 120 mg every 14 days for up to 96 weeks (midgut cohort) or 48 weeks (panNET cohort). The primary end-point was centrally assessed progression-free survival (PFS). PFS by Ki-67 categories was analysed post hoc. Secondary end-points included quality of life (QoL) and safety.
RESULTS
Ninety-nine patients were enrolled (midgut, N = 51; panNET, N = 48). Median (95% CI) PFS was 8.3 (5.6-11.1) and 5.6 (5.5-8.3) months, respectively. In patients with Ki-67 ≤ 10%, median (95% CI) PFS was 8.6 (5.6-13.8) and 8.0 (5.6-8.3) months in the midgut and panNET cohorts, respectively. Patients' QoL did not deteriorate during the study. There were no treatment-related serious adverse events and only two withdrawals for treatment-related adverse events (both in the panNET cohort).
CONCLUSIONS
In patients with progressive NETs following standard-regimen LAN, reducing the dosing interval to every 14 days provided encouraging PFS, particularly in patients with a Ki-67 ≤ 10% (post hoc); no safety concerns and no deterioration in QoL were observed. Increasing LAN dosing frequency could therefore be considered before escalation to less well-tolerated therapies
NKp30 Receptor Upregulation in Salivary Glands of Sjögren's Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment.
No full textPrimary Sjögren's syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. /NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the /NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 () and its ligand B7/H6 () in pSS salivary gland tissues. Levels of /NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between /NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, /NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory , while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of /NKp30 within the glands
Brain injury after cardiac arrest.
No full textAs more people are surviving cardiac arrest, focus needs to shift towards improving neurological outcomes and quality of life in survivors. Brain injury after resuscitation, a common sequela following cardiac arrest, ranges in severity from mild impairment to devastating brain injury and brainstem death. Effective strategies to minimise brain injury after resuscitation include early intervention with cardiopulmonary resuscitation and defibrillation, restoration of normal physiology, and targeted temperature management. It is important to identify people who might have a poor outcome, to enable informed choices about continuation or withdrawal of life-sustaining treatments. Multimodal prediction guidelines seek to avoid premature withdrawal in those who might survive with a good neurological outcome, or prolonging treatment that might result in survival with severe disability. Approximately one in three admitted to intensive care will survive, many of whom will need intensive, tailored rehabilitation after discharge to have the best outcomes
The negative impact of the COVID-19 pandemic on UK haematology registrars' well-being and training: Results of a UK nationwide survey.
No full textThe COVID-19 pandemic has disturbed medical training. Haematology registrars were surveyed using SurveyMonkey. Eighty-nine out of 269 (24.9%) responded. Reported stressors included concerns about transmitting the infection, disruption of leave, inferior patient outcomes, survivors' guilt and interruption of career progression. Only 31.2% felt ready to progress to the next training stage. Reported causes of lack of training were disruption of clinics and training days and utilisation of telephone consultations. Several stressors negatively impacted haematology registrars' well-being, training and progression. More emphasis on psychological support, outpatient clinic work and e-learning is needed
Role of early transjugular intrahepatic portosystemic stent-shunt in acute variceal bleeding: An update of the evidence and future directions.
No full textVariceal bleeding is a serious complication of cirrhosis and portal hypertension. Despite the improvement in management of acute variceal bleed (AVB), it still carries significant mortality. Portal pressure is the main driver of variceal bleeding and also a main predictor of decompensation. Reduction in portal pressure has been the mainstay of management of variceal bleeding. Transjugular intrahepatic porto-systemic stent shunt (TIPSS) is a very effective modality in reducing the portal hypertension and thereby, controlling portal hypertensive bleeding. However, its use in refractory bleeding (rescue/salvage TIPSS) is still associated with high mortality. "Early" use of TIPSS as a "pre-emptive strategy" in patients with AVB at high risk of failure of treatment has shown to be superior to standard treatment in several studies. While patients with Child C cirrhosis (up to 13 points) clearly benefit from early-TIPSS strategy, it's role in less severe liver disease (Child B) and more severe disease (Child C > 13 points) remains less clear. Moreover, standard of care has improved in the last decade leading to improved 1-year survival in high-risk patients with AVB as compared to earlier "early" TIPSS studies. Lastly in the real world, only a minority of patients with AVB fulfil the stringent criteria for early TIPSS. Therefore, there is unmet need to explore role of early TIPSS in management of AVB in well-designed prospective studies. In this review, we have appraised the role of early TIPSS, patient selection and discussed future directions in the management of patients with AVB
Outcomes and interventions in patients transported to hospital with ongoing CPR after out-of-hospital cardiac arrest - An observational study.
No full textIntroduction
The main objective was to present characteristics and outcome of patients without sustained field return of spontaneous circulation (ROSC) transported to hospital with ongoing cardiopulmonary resuscitation (CPR). Our secondary objectives were to investigate hospital-based interventions and the performance of the universal Termination of Resuscitation-rule (uTOR).
Methods
In this retrospective observational cohort study, out-of-hospital cardiac arrest (OHCA) patients arriving to the emergency department of a university hospital in Sweden during a six-year period (2010-2015) were identified using a prospectively recorded hospital-based registry. Additional data were retrieved from medical records and from the Swedish cardiopulmonary resuscitation registry.
Results
Among 409 patients transported with ongoing CPR, 7 survived to hospital discharge (1.7%). Hospital-based interventions against a suspected cause of arrest were attempted during ongoing resuscitation in 34 patients (8.3%), of whom 3 survived to hospital discharge. The remaining 4 survivors had spontaneous in-hospital ROSC. Survivors presented with either a shockable rhythm ( = 4) or pulseless electrical activity ( = 3). The uTOR identified non-survivors with a positive predictive value (PPV) of 98.4% and a specificity of 71.4% for termination.
Conclusion
Survival after OHCA where sustained prehospital ROSC is not achieved is rare and available in-hospital interventions are rarely utilised. No patient with asystole as the first recorded rhythm survived. The uTOR identified non-survivors with a PPV of 98.4% but showed poor specificity
Author Correction: 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy.
No full textRetrieval of Entrapped Catheter-Mounted Axial Flow Pump From Mitral Subvalvular Apparatus Using a Snare Catheter.
No full textAxial-flow ventricular assist devices are being increasingly used to support hemodynamically compromised patients undergoing percutaneous coronary intervention. Periprocedural valvular complications have been recognized in a few case reports. We present a unique case of entanglement of the Impella within he mitral subvalvular apparatus, retrieved successfully using a snare under fluoroscopic guidance. ()
Effect of benralizumab in a patient with uncontrolled severe eosinophilic asthma and comorbid chronic rhinosinusitis with nasal polyps refractory to mepolizumab treatment.
No full textSevere eosinophilic asthma is associated with a high corticosteroid burden, particularly in patients with comorbid chronic sinusitis/nasal polyps. This case study reports a 33-year-old woman who presented to the severe asthma center with uncontrolled severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Despite maximized asthma treatment, including maintenance oral corticosteroids (OCS) for 7 years, the patient experienced one to two hospitalizations per year, had daily symptoms that substantially impacted her quality of life, and elevated type 2 inflammatory markers (blood eosinophils, 0.72 × 10/L; fractional exhaled nitric oxide, 134 to 300 parts per billion). Her asthma worsened during her first pregnancy, in which she required five hospital admissions despite treatment with maintenance OCS. Mepolizumab treatment was commenced after pregnancy but showed limited efficacy (blood eosinophil levels up to 0.94 × 10/L); treatment was discontinued because of a second pregnancy. The patient's asthma worsened and resulted in four hospitalizations and an increase in monthly OCS dose. Mepolizumab was recommenced after pregnancy, but her asthma remained uncontrolled, symptoms persisted, and one hospitalization and nine OCS courses were required. The patient was switched to benralizumab treatment when it became available. Although her CRSwNP symptoms remained, benralizumab treatment resulted in a marked improvement in asthma control, zero hospitalizations, and suppressed blood eosinophil levels. Notably, the patient was successfully weaned off maintenance OCS after >11 years of treatment. In summary, these findings support the use of benralizumab as a corticosteroid-sparing treatment option in difficult-to-treat severe eosinophilic asthma refractory to mepolizumab treatment
Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control.
No full textAIMS
Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mechanisms, we aimed to reveal the ventricular TBX5-dependent transcriptional network and further test the therapeutic potential of TBX5 level normalization in mice with documented arrhythmias.
METHODS AND RESULTS
We used a mouse model of TBX5 conditional deletion in ventricular cardiomyocytes. Ventricular (v) TBX5 loss in mice resulted in mild cardiac dysfunction and arrhythmias and was associated with a high mortality rate (60%) due to SCD. Upon angiotensin stimulation, vTbx5KO mice showed exacerbated cardiac remodelling and dysfunction suggesting a cardioprotective role of TBX5. RNA-sequencing of a ventricular-specific TBX5KO mouse and TBX5 chromatin immunoprecipitation was used to dissect TBX5 transcriptional network in cardiac ventricular tissue. Overall, we identified 47 transcripts expressed under the control of TBX5, which may have contributed to the fatal arrhythmias in vTbx5KO mice. These included transcripts encoding for proteins implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), in cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5), and cardiac protection upon stress (Fhl2, Gpr22, Fgf16). Interestingly, after TBX5 loss and arrhythmia development in vTbx5KO mice, TBX5 protein-level normalization by systemic adeno-associated-virus (AAV) 9 application, re-established TBX5-dependent transcriptome. Consequently, cardiac dysfunction was ameliorated and the propensity of arrhythmia occurrence was reduced.
CONCLUSIONS
This study uncovers a novel cardioprotective role of TBX5 in the adult heart and provides preclinical evidence for the therapeutic value of TBX5 protein normalization in the control of arrhythmia