Treatment of atopic asthma in primary health care guided by exhaled nitric oxide measurement

Aims: The overall aims of this thesis were to increase knowledge about how patients with asthma rate their health and investigate if we can improve asthma management, with focus on asthma as a chronic inflammatory disease, by use of measurement of the fraction of exhaled nitric oxide (FENO) in monitoring of asthma in primary health care. Methods: Study I included data from a public health questionnaire, which was sent to 8,200 persons (age > 18 years) randomly selected from the population register in Stockholm County. After two reminders, 5,355 persons had responded (67.5 %). Study II was a longitudinal, non-controlled study. Twenty patients with physician-diagnosed atopic asthma and perennial asthma symptoms (age 18 - 50 years) were consecutively recruited from Runby primary health care centre and examined four times during eight weeks (baseline, 2, 4 and 8 weeks). Data for study III and IV were collected in a randomised, controlled study, conducted at 17 primary health care centres in the middle and south of Sweden. A total of 187 non-smoking participants with physician-diagnosed asthma, verified perennial allergy and ongoing inhaled corticosteroid (ICS) treatment (age 18 – 64 years) were randomised to FENO-guided treatment or usual care and were followed up for five visits during one year. Results: Respondents with asthma in study I had approximately three times higher odds of fair/poor self-rated health (SRH) than those in the corresponding sex and age groups who did not have asthma, excepting younger women (18 – 44 years). SRH was associated at least as strong as quality of life to asthma. Study II showed a significant correlation between FENO and IgE-antibody levels against perennial allergens at baseline (r = 0.47, p = 0.04), which disappeared after a step-up in ICS treatment. Nine patients had persistently elevated FENO at last visit (mean 35 ppb vs. 16 ppb). This group was more frequently exposed to relevant allergens or colds (89 % vs. 27 %, p < 0.05) and had higher perennial IgE levels compared with the normalised group (mean 28.9 vs. 10.7 kU/l, p < 0.05). Results from study III showed that total and specific IgE levels decreased 10 – 36 % (p < 0.05 all, except for mugwort) over one year. The changes were not related to any change in allergen exposure, and specific IgG4 levels remained unaltered. The decrease in IgE against perennial allergens related to mean ICS dose (p = 0.030), ii months on leukotriene-receptor antagonist (LTRA) (p = 0.013) and change in FENO (p = 0.003), and interestingly also to change in the Asthma Control Questionnaire (ACQ) score (p = 0.012) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) score (p = 0.009), as well as change in SRH rating (p = 0.041). In study IV, the change in mAQLQ score over one year (primary endpoint) did not differ between the groups (p = 0.197), whereas the mAQLQ symptom domain score (p = 0.041) and the ACQ score (p = 0.045) both improved significantly more in the FENO-guided group. Furthermore, the moderate exacerbation rate was reduced by almost 50 % in the FENO-guided group (p = 0.024). Mean overall ICS use was similar in the two groups (p = 0.95). Conclusions: In Sweden, men > 18 years and women > 45 years with asthma score SRH worse compared with people in corresponding sex and age groups without asthma, which indicates that there is a need to improve asthma management. Exposure to relevant allergens, and type and degree of sensitisa-tion, are important factors to consider when assessing the FENO value. Optimised anti-inflammatory treatment with ICS and LTRA in asthma patients with ongoing treatment at baseline resulted in reduced total and specific IgE levels which were unrelated to the degree of allergen exposure. Using FENO to guide anti-inflammatory treatment within primary care significantly improved asthma symptom control and reduced exacerbation rate in adults with atopic asthma without increasing overall ICS use. FENO-guided anti-inflammatory treatment appears useful to improve the management of patients with atopic asthma

Peroral endoscopic myotomy (POEM) for treating esophageal motility disorders

Review Article on Endoscopic Therapy© Annals of Translational Medicine. All rights reserved. Pneumatic dilatation and Heller myotomy have been thoroughly studied as the most viable treatment options for achalasia. The pendulum, however, is shifting to the minimally invasive approach. Since Inoue et al. published the experience of the first 17 cases of peroral endoscopic myotomy (POEM) in 2010, there have been at least 5,000 cases performed worldwide and the number is increasing exponentially. Experts across the globe have been extending the indications to various esophageal motility disorders, to patients of extremes of age, sigmoidal esophagus and re-operated patients. There are a few variations in technique across different centers in defining the gastroesophageal junction (GEJ) and adequacy of myotomy, the optimal length, site of myotomy and whether the full thickness of the muscle wall should be cut. Large case series demonstrated its promising efficacy & reasonable complication profile. Randomized controlled trial in comparison with the gold standard, Heller myotomy, is ongoing. The future application of submucosal tunnelling technique is thrilling with its extension in tumour resection, antropyloromyotomy and other natural orifice transluminal endoscopic surgery (NOTES).published_or_final_versio

Electromagnetic Pulse Forming of Carbon Steel Sheet Metal

Electromagnetic pulse forming is a promising direct method for a high speed sheet metal forming of materials with high conductivity, like Al- and Cu-alloys. For metallic sheet with low conductivity, like carbon steel sheets, the frequency of the current through the forming coil must increase to create the same forming properties as for materials with high conductivity. Usually this frequency is not easy to change in an existing electromagnetic pulse system without exchanging of the capacitors. Anyway, this project have analysed the formability of two high strength steel sheet material, a carbon steel DP60 and a austenitic stainless steels, with and without a copper driver. The experiments were made on commercial electromagnetic pulse system from Poynting with a predefined current frequency through the forming coil. The geometries that were used for the electromagnetic pulse forming analysis were a cone, rectangular parts, and spherical dome. All physical parts were 3D digitised and the deviation were analysed against nominal reference objects. The spherical dome experiment was used to analyse the increase in formability of the high strength steel sheets compared with conventional stamping in an Erichsén sheet metal testing machine

Intraperitoneal chemotherapy for gastric cancer with peritoneal carcinomatosis: is HIPEC the only answer?

Gastric cancer with peritoneal carcinomatosis is notorious for its dismal prognosis. While the pathophysiology of peritoneal dissemination is still controversial, the rapid downhill course is universal. Patients usually suffer abdominal distension, intestinal obstruction and various complications before they succumb after a median of 3 - 6 months. Although not adopted in most international treatment guidelines, intraperitoneal chemotherapy has growing evidence compared with conventional systemic chemotherapy for the treatment of peritoneal carcinomatosis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is well-established for clinical benefit but is technically demanding with substantial treatment-related morbidities and mortality. On the other hand, normothermic intraperitoneal chemotherapy in the form of bidirectional neoadjuvant treatment is promising with various newer chemotherapeutic agents. Regardless of the treatment technique applied, the essential element of success is meticulous patient selection and availability of expertise. Future direction is along the line of personalized treatment with the application of translational science.published_or_final_versio

Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma: magnifying endoscopy findings

Gastric mucosaâ associated lymphoid tissue lymphoma is uncommon and most patients have an indolent clinical course. The clinical presentation and endoscopic findings can be subtle and diagnosis can be missed on white light endoscopy. Magnifying endoscopy may help identify the abnormal microstructural and microvascular patterns, and target biopsies can be performed. We describe herein the case of a 64-year-old woman with Helicobacter pyloriâ negative gastric mucosaâ associated lymphoid tissue lymphoma diagnosed by screening magnification endoscopy. Helicobacter pyloriâ eradication therapy was given and she received biological therapy. She is in clinical remission after treatment. The use of magnification endoscopy in gastric mucosaâ associated lymphoid tissue lymphoma and its management are reviewed.published_or_final_versio

The Delphi and GRADE methodology used in the PSOGI 2018 consensus statement on Pseudomyxoma Peritonei and Peritoneal Mesothelioma

Pseudomyxoma Peritonei (PMP) and Peritoneal Mesothelioma (PM) are both rare peritoneal malignancies. Currently, affected patients may be treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy offering long-term survival or even cure in selected patients. However, many issues regarding the optimal treatment strategy are currently under debate. To aid physicians involved in the treatment of these patients in clinical decision making, the PSOGI executive committee proposed to create a consensus statement on PMP and PM. This manuscript describes the methodology of the consensus process. The Delphi technique is a reliable method for attaining consensus on a topic that lacks scientific evidence through multiple voting rounds which feeds back responses to the participants in between rounds. The GRADE system provides a structured framework for presenting and grading the available evidence. Separate questionnaires were created for PMP and PM and sent during two voting rounds to 80 and 38 experts, respectively. A consensus threshold of 51.0% was chosen. After the second round, consensus was reached on 92.9%–100.0% of the questions. The results were presented and discussed in the plenary session at the PSOGI 2018 international meeting in Paris. A third round for the remaining issues is currently in progress. In conclusion, using the Delphi technique and GRADE methodology, consensus was reached in many issues regarding the treatment of PM and PMP amongst an international panel of experts. The main results will be published in the near future

Standardized uptake value (SUV) in PET/CT for esophageal cancer correlates with pathological stage and predicts R-category of resection

postprin

Use of flow cytometry in the analysis of stage III squamous cell carcinoma of the oesophagus and its association with MIB-1

Aims - To examine the prognostic and pathobiological importance of DNA content in oesophageal squamous cell carcinomas in Hong Kong Chinese subjects; to evaluate its association with the immunohistochemical proliferative marker MIB-1. Methods - Paraffin wax embedded tumour tissue and adjacent normal tissue (control tissue) samples from 45 resected stage III oesophageal squamous cell carcinomas were studied using flow cytometric analysis. The DNA content and the clinicopathological data of these patients were analysed together with the MIB-1 labelling index. Results - DNA aneuploidy was present in 14 (31%) of the 45 cases. However, the DNA content did not correlate significantly with the age, sex, or survival of the patients, nor the length, location, differentiation and MIB-1 labelling index of the oesophageal carcinomas. The synthetic (S) phase fraction of diploid tumours bore no relation to the patients' survival or MIB-1 score. Conclusions - Flow cytometry was not as useful as the MIB-1 labelling index in predicting the biological characteristics of the tumours and the prognosis of patients with oesophageal squamous cell carcinomas. This study does not support the routine use of DNA flow cytometric analysis in oesophageal cancers.published_or_final_versio

MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor

Background: To understand the involvement of micro- RNA (miRNA) in the development and progression of oesophageal squamous cell carcinoma (ESCC), miRNA profiles were compared between tumour and corresponding non-tumour tissues. Methods: miRCURY LNA array was used to generate miRNA expressing profile. Real-time quantitative PCR was applied to detectthe expression of miR-375 in ESCC samples and its correlation with insulin-like growth factor 1 receptor (IGF1R). Methylation-specific PCR was used to study the methylation status in the promoter region of miR-375. The tumour-suppressive effect of miR-375 was determined by both in-vitro and in-vivo assays. Results: The downregulation of miR-375 was frequently detected in primary ESCC, which was significantly correlated with advanced stage (p=0.003), distant metastasis (p<0.0001), poor overall survival (p=0.048) and disease-free survival (p=0.0006). Promoter methylation of miR-375 was detected in 26 of 45 (57.8%) ESCC specimens. Functional assays demonstrated that miR-375 could inhibit clonogenicity, cell motility, cell proliferation, tumour formation and metastasis in mice. Further study showed that miR-375 could interact with the 39-untranslated region of IGF1R and downregulate its expression. In clinical specimens, the expression of IGF1R was also negatively correlated with miR-375 expression (p=0.008). Conclusions: This study demonstrates that miR-375 has a strong tumour-suppressive effect through inhibiting the expression of IGF1R. The downregulation of miR-375, which is mainly caused by promoter methylation, is one of the molecular mechanisms involved in the development and progression of ESCC.published_or_final_versio

A Versatile Orthotopic Nude Mouse Model for Study of Esophageal Squamous Cell Carcinoma

Increasing evidence indicates tumor-stromal interactions play a crucial role in cancer. An in vivo esophageal squamous cell carcinoma (ESCC) orthotopic animal model was developed with bioluminescence imaging established with a real-time monitoring platform for functional and signaling investigation of tumor-stromal interactions. The model was produced by injection of luciferase-labelled ESCC cells into the intraesophageal wall of nude mice. Histological examination indicates this orthotopic model is highly reproducible with 100% tumorigenesis among the four ESCC cell lines tested. This new model recapitulates many clinical and pathological properties of human ESCC, including esophageal luminal stricture by squamous cell carcinoma with nodular tumor growth, adventitia invasion, lymphovascular invasion, and perineural infiltration. It was tested using an AKT shRNA knockdown of ESCC cell lines and the in vivo tumor suppressive effects of AKT knockdown were observed. In conclusion, this ESCC orthotopic mouse model allows investigation of gene functions of cancer cells in a more natural tumor microenvironment and has advantages over previous established models. It provides a versatile platform with potential application for metastasis and therapeutic regimen testing.published_or_final_versio