Birmingham General Hospital was a teaching hospital in Birmingham, England, founded in 1779 and closed in the mid-1990s.
OBJECTIVES:Multiple treatments are described in the literature for the treatment of chronic Eustachian tube dysfunction but high-level quality evidence seems missing to support these treatments. This systematic review aimed to determine and compare the safety and efficacy of Laser Eustachian tuboplasty and Microdebrider Eustachian tuboplasty as a treatment for long-term Eustachian tube dysfunction. DATA SOURCES:A total of 12 electronic databases were searched up to April 2018 for published and unpublished literature in the English language. References of included studies were checked. METHODS:A systematic review was undertaken. Outcomes assessed were: primary outcomes-subjective improvement in symptoms (ETDQ-7), audiometric improvement of hearing, improvement of negative middle ear pressure noticed in tympanometry, objective improvement of tympanic membrane retraction. Secondary outcomes were-the ability to auto-insufflate Eustachian tube i.e. Valsalva manoeuvre, improved quality of life, passive tubal opening, tubomanometry, swallowing test, reduction in mucosal inflammation of Eustachian tube orifice in the nose, complications from the procedure, the need for further procedures. Results are reported in a narrative synthesis as a meta-analysis was not possible due to heterogeneous data. RESULTS:Three studies were included. All included studies were small-scale case series (13-38 participants). Studies were conducted outside the UK. Subjective and objective improvement of Eustachian tube function was reported in all studies. But all included studies were at high risk of bias and subject to multiple limitations. No major complications were reported in either study. CONCLUSIONS:Based on current evidence, it is not possible to recommend the clinical use of either of these two interventions i.e. Laser or Microdebrider Eustachian tuboplasty. Lack of controlled studies was identified as a gap in the evidence. Future research should be directed toward designing randomised controlled trials. These trials should use strict standard methodology and reporting criteria. Future trials should make use of consensus statement document about Eustachian tube dysfunction definition, diagnostic methods, and outcome assessment criteria to design clinical trials.
Introduction: In CLL achieving minimal residual disease (MRD) negativity has a survival advantage compared to MRD positive patients regardless of the approach used to achieve MRD negativity. The UK CLL207 phase II trial assessed consolidation with alemtuzumab following chemotherapy and showed that 38% of patients attained MRD negativity at 6 months post-consolidation. These patients had a significantly improved progression-free survival (PFS) compared to MRD positive patients. However, significant toxicity was associated with alemtuzumab. Obinutuzumab, a type II monoclonal antibody targeting the CD20 antigen has shown greater efficacy in CLL than previous anti-CD20 antibodies with respect to MRD, and appears to be less immune suppressive than alemtuzumab. Methods: The GALACTIC trial was a seamless phase II/III trial, with an overall planned sample size of 188 patients which was designed to test whether consolidation with obinutuzumab is safe and eradicates MRD (phase II) which subsequently leads to prolonged PFS (phase III), in patients with B-CLL who have recently responded to chemotherapy. Patients achieving a complete or partial response (CR/PR) 3-24 months after chemotherapy were eligible. Patients with lymph node >1.5cm were excluded. Eligible patients assessed as MRD positive were randomised to receive either consolidation therapy with obinutuzumab or no consolidation therapy. Obinutuzumab was given 1000mg weekly for first 4 doses (split over two days for first dose) and then 4 further doses fortnightly. Prophylaxis was given to reduce the risk of infusion-related reactions. Simon's 2-stage design was used to define stopping rules in phase II with 80% power, 1-sided sig. level of 10% and minimum efficacy rate of 15%. If 2/9 (stage I) and 6/23 (stage II) participants randomised to obinutuzumab achieved MRD negativity, the trial would continue to phase III. If fewer than 23 MRD assessments were recorded, 6 MRD negative results were still required. Results: GALACTIC opened in March 2015 and passed the stage I stopping rule in April 2016. The trial closed early in February 2017 due to poor recruitment likely due to the advent of novel targeted therapy, such as ibrutinib and venetoclax, for relapsed CLL. A total of 48 patients were enrolled of whom 19 were MRD negative and not entered into the randomisation. The remaining 29 MRD positive participants were randomised to consolidation therapy (n=14; 7 CR, 7 PR) or no consolidation therapy (n=15; 5 CR, 9 PR, 1 N/K). The median age was 69 (46, 82) with 55.2% >65 and 72.4% were male. Overall, 93.1% had received previous rituximab, 41.4% had received 2 or 3 lines of prior therapy and 55.2% had MRD level >0.3% at the time of trial entry. Overall 12 (85.7%) participants randomised to consolidation received all 8 infusions, two participants received 7 doses due to dose limiting toxicity, neutropenia and thrombocytopenia. At 6 months post-randomisation, 10 (71.4%) (80%CI: 50.8, 86.9) consolidation participants achieved MRD negativity by flow cytometry (sensitivity 10-4) in bone marrow passing the stage II stopping rule. 13 (92.6%) achieved MRD negativity in the peripheral blood. In the consolidation arm, response rates were 13 (92.9%) CR and 1 (7.1%) PR, compared to 6 (40.0%) CR and 1 (6.7%) PR with no consolidation therapy. Two consolidated participants experienced 3 severe adverse reactions (serious infection (n=2), neutropenic sepsis (n=1)) which resolved. The most common adverse events in consolidation arm were thrombocytopenia (22.2%), infection (8.9%) and cough (8.4%), only 1% of events were infusion-related reactions. Conclusion: Consolidation therapy with obinutuzumab is highly effective at eradicating MRD by 6 months post-randomisation with 71.4% achieving an MRD negative bone marrow. Obinutuzumab is extremely well-tolerated with minimal infusion reactions and toxicity. Improvement in MRD was demonstrated and it can be postulated that consolidation may result in improvement of PFS and time to next treatment. However, long-term data is needed to establish this hypothesis. Disclosures Munir: Roche: Honoraria; AbbVie: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Janssen: Honoraria; Gilled: Honoraria. Hillmen: Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Rawstron: AbbVie: Consultancy, Honoraria; BD biosciences: Patents & Royalties; Gilead: Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria.
RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.
Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.
