Objective
To conduct a prospective cohort study using anakinra, a recombinant IL‐1 receptor antagonist (IL‐1Ra), as first‐line therapy in patients with new‐onset systemic juvenile idiopathic ...arthritis (JIA).
Methods
Therapy with recombinant IL‐1Ra (2 mg/kg) was initiated in 20 patients who fulfilled the International League of Associations for Rheumatology criteria for systemic JIA, before systemic steroid treatment was administered. Patients were monitored clinically and immunologically. The protocol contained a stop strategy for patients who met at least the adapted American College of Rheumatology 90% criteria for improvement in JIA (ACR Pediatric 90 ACR Pedi 90) after 3 months.
Results
We included consecutive patients with new‐onset systemic JIA. The mean followup period was 32 months (range 12–54 months). At the 3‐month time point, 85% of the patients showed an adapted ACR Pedi 90 response or had inactive disease; 75% of the patients achieved this response while receiving recombinant IL‐1Ra alone. After 1 year, 17 of the 20 patients met the criteria for clinically inactive disease, and 13 of these patients met these criteria while receiving monotherapy with recombinant IL‐1Ra. However, because of persistent disease activity, 7 of the 20 patients required additional therapy besides recombinant IL‐1Ra. According to our stop strategy, 73% of patients with at least an adapted ACR Pedi 90 response at 3 months could stop recombinant IL‐1Ra treatment within 1 year. After 2 years, 12 (86%) of 14 patients met the criteria for disease remission, either while receiving (n = 4) or not receiving (n = 8) medication. After 3 years, 10 (91%) of 11 patients met the criteria for disease remission, either while receiving (n = 2) or not receiving (n = 8) medication.
Conclusion
This is the first prospective study in which recombinant IL‐1Ra was used as first‐line therapy in patients with systemic JIA. We observed excellent responses in nearly all patients within 3 months. In the majority of responding patients, treatment with recombinant IL‐1Ra could be stopped within 1 year, with remission being preserved during followup. In approximately one‐third of patients, concomitant therapy was required for maintenance of clinical response.
Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the ...resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer.
This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy.
If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.
To identify factors associated with sudden drops in hearing level after minor head trauma in patients with an enlarged vestibular aqueduct (EVA).
A systematic review of the literature on sudden drops ...in hearing level after minor head trauma in patients with an EVA was conducted. The studies were retrieved from Embase, PubMed, CINAHL, and Cochrane and critically appraised using predefined criteria. Data on all described parameters were collected, and their relation with sudden drops after minor head trauma was statistically analyzed.
Pooled data of 31 articles included 179 patients with 351 EVAs. Drops in hearing level after minor head trauma were experienced by 34% of the patients. We found a significant association between sudden deterioration of hearing after minor head trauma and preexisting fluctuating hearing loss (HL) (odds ratio, 8.6; p < 0.001; 95% confidence interval, 3.9-19.3). The diameter of the VA, type of preexisting HL, severity of HL, preexisting progressive HL, and the diagnosis Pendred syndrome were not significantly associated with sudden drops in hearing levels after head trauma.
Only one-third of the patients with a proven EVA experienced sudden drops in hearing level because of head trauma. There is a significant association between preexisting fluctuating HL and the chance of sudden drops in hearing level caused by trauma. Stringent lifestyle advices, like avoiding activities with a risk of minor head trauma such as contact sports, might be restricted to patients with a fluctuating HL and those with a history of sudden drops on minor head trauma.
Previously, we showed that in 63 (89%) of all 71 non-complete responders, residual tumour cells could be found in the mucosa or submucosa, and only occasionally solely in the deeper layers (six of ...the eight in regional lymph nodes).2 The use of bite-on-bite biopsy theoretically increases the chance of detecting residual cancer cells in the submucosal layer of the oesophagus, compared with regular biopsy. ...we believe that a small amount of residual disease (<10%, TRG2) can initially be missed, as long as this residual disease is detected during active surveillance, while the tumour is still resectable. ...in our opinion an active surveillance strategy should consist of frequent serial clinical investigations using bite-on-bite biopsy samples of the original tumour location, fine-needle aspiration of any suspected lymph node, and PET-CT. Besides molecular markers—such as ALDH1 and GLI1/HH—which might predict response before neoadjuvant chemoradiotherapy, we believe that other molecular markers, such as circulating tumour DNA, that evaluate response after completion of neoadjuvant chemoradiotherapy should be further explored.
To compare overall survival in patients with esophageal adenocarcinoma who underwent transhiatal esophagectomy (THE) with limited lymphadenectomy or transthoracic esophagectomy (TTE) with extended ...lymphadenectomy with or without neoadjuvant chemoradiotherapy (nCRT).
The application of neoadjuvant therapy might change the association between the extent of lymphadenectomy and survival in patients with esophageal adenocarcinoma. This may influence the choice of surgical approach in patients treated with nCRT.
Patients with potentially curable subcarinal esophageal adenocarcinoma treated with surgery alone or nCRT followed by surgery in 7 centers were included. The effect of surgical approach on overall survival, differentiated by the addition or omission of nCRT, was analyzed using a multivariable Cox regression model that included well-known prognostic factors and factors that might have influenced the choice of surgical approach.
In total, 701 patients were included, of whom 318 had TTE with extended lymphadenectomy and 383 had THE with limited lymphadenectomy. TTE had differential effects on survival (P for interaction = 0.02), with a more favorable prognostic effect in patients who were treated with surgery alone hazard ratio (HR) = 0.77, 95% confidence interval (CI) 0.58-1.03. This association was statistically significant in a subgroup of patients with 1 to 8 positive lymph nodes in the resection specimen (HR = 0.62, 95% CI 0.43-0.90). The favorable prognostic effect of TTE over THE was absent in the nCRT and surgery group (HR = 1.16, 95% CI 0.80-1.66) and in the subgroup of nCRT patients with 1 to 8 positive lymph nodes in the resection specimen (HR = 1.00, 95% CI 0.61-1.68).
Compared to surgery alone, the addition of nCRT may reduce the need for TTE with extended lymphadenectomy to improve long-term survival in patients with esophageal adenocarcinoma.
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