Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: A stepped-wedge cluster randomised trial

Background: 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. Methods: 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. Discussion: 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

Drie patiënten met massale longembolieën

Three patients presenting with massive venous pulmonary thrombo-embolism are described, who have been selected from a series of 22 patients treated with thrombolysis during a 6-year period. A 23-year-old female presented with tachycardia and dyspnoea. She had pulmonary angiography following scintigraphy with a perfusion deficit of more than 60%. Thrombolysis resulted in open blood vessels and a disappearance of the complaints. A 51-year-old woman presented with profound hypoxemia, probably due to a patent foramen ovale, with shunting and tachycardia. Perfusion defects on scintigraphy combined with a normal chest radiograph in the absence of pre-existent pulmonary disease established the diagnosis. She responded favourably to intravenous streptokinase. The third patient was an 80-year-old woman with hypertension. She developed dyspnoea, tachycardia and shock following immobilisation due to a fractured hip. Despite an initial improvement on streptokinase, she deteriorated and died from right-sided heart failure. The diagnostic tests should be limited and aimed at ruling out left-sided heart failure and pericardial tamponade. Echocardiography is often diagnostic in these patients. Thrombolysis may be life saving but there are no randomised trials to prove that survival rate is indeed better compared to heparin therapy. Streptokinase is less expensive than alteplase and there is no evidence from trials to suggest that it is inferior to more expensive thrombolytics such as alteplase or urokinase

Three patients with massive pulmonary embolism

Three patients presenting with massive venous pulmonary thrombo-embolism are described, who have been selected from a series of 22 patients treated with thrombolysis during a 6-year period. A 23-year-old female presented with tachycardia and dyspnoea. She had pulmonary angiography following scintigraphy with a perfusion deficit of more than 60%. Thrombolysis resulted in open blood vessels and a disappearance of the complaints. A 51-year-old woman presented with profound hypoxemia, probably due to a patent foramen ovale, with shunting and tachycardia. Perfusion defects on scintigraphy combined with a normal chest radiograph in the absence of pre-existent pulmonary disease established the diagnosis. She responded favourably to intravenous streptokinase. The third patient was an 80-year-old woman with hypertension. She developed dyspnoea, tachycardia and shock following immobilisation due to a fractured hip. Despite an initial improvement on streptokinase, she deteriorated and died from right-sided heart failure. The diagnostic tests should be limited and aimed at ruling out left-sided heart failure and pericardial tamponade. Echocardiography is often diagnostic in these patients. Thrombolysis may be life saving but there are no randomised trials to prove that survival rate is indeed better compared to heparin therapy. Streptokinase is less expensive than alteplase and there is no evidence from trials to suggest that it is inferior to more expensive thrombolytics such as alteplase or urokinase.</p

MDR1 polymorphisms are associated with inflammatory bowel disease in a cohort of Croatian IBD patients

BACKGROUND: Inflammatory bowel diseases (IBD) are chronic diseases of unknown etiology and pathogenesis in which genetic factors contribute to development of disease. MDR1/ABCB1 is an interesting candidate gene for IBD. The role of two single nucleotide polymorphisms, C3435T and G2677T remains unclear due to contradictory results of current studies. Thus, the aims of this research were to investigate the association of MDR1 polymorphisms, C3435T and G2677T, and IBD. ----- METHODS: A total of 310 IBD patients, 199 Crohn's disease (CD) patients and 109 ulcerative colitis (UC) patients, and 120 healthy controls were included in the study. All subjects were genotyped for G2677T/A and C3435T polymorphism using RT-PCR. In IBD patients, review of medical records was performed and patients were phenotyped according to the Montreal classification. ----- RESULTS: Significantly higher frequency of 2677T allele (p=0.05; OR 1.46, 95% CI (1.0-2.14)) and of the 3435TT genotype was observed among UC patients compared to controls (p=0.02; OR 2.12; 95% CI (1.11-4.03). Heterozygous carriers for C3435T were significantly less likely to have CD (p=0.02; OR 0.58, 95% CI (0.36-0.91)). Haplotype analysis revealed that carriers of 3435T/2677T haplotype had a significantly higher risk of having UC (p=0.02; OR 1.55; 95% CI (1.06-2.28)). ----- CONCLUSION: MDR1 polymorphisms are associated with both CD and UC with a stronger association with UC