Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma.

Thanks to clinically newly introduced inhibitors of the mesenchymal-epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated.

Using clinical parameters to guide fluid therapy in high-risk thoracic surgery. A retrospective, observational study.

BACKGROUND: Despite extensive research, the debate continues as to the optimal way of guiding intraoperative and postoperative fluid therapy. In 2009 we changed our institutional guideline for perioperative fluid therapy in patients undergoing extrapleural pneumonectomy (EPP) and implemented the use of central venous oxygen saturation and intended low urine output to guide therapy in the early postoperative period. Here we evaluate the consequences of our changes. METHODS: Retrospective, observational study of 30 consecutive patients undergoing EPP; 18 who had surgery before and 12 who had surgery after the changes. Data were collected from patient files and from institutional databases. Outcome measures included: Volumes of administered fluids, fluid balances, length of stays and postoperative complications. Dichotomous variables were compared with Fisher's exact test, whereas continuous variables were compared with Student's unpaired t-test or the Wilcoxon Two-Sample Test depending on the distribution of data. RESULTS: The applied changes significantly reduced the volumes of administered fluids, both in the intraoperative (p = 0.01) and the postoperative period (p = 0.04), without increasing the incidence of postoperative complications. Mean length of stay in the intensive care unit (LOSI) was reduced from three to one day (p = 0.04) after the changes. CONCLUSION: The use of clinical parameters to balance fluid restriction and a sufficient circulation in patients undergoing EPP was associated with a reduction in mean LOSI without increasing the incidence of postoperative complications. Due to methodological limitations these results are only hypothesis generating.

Monitoring of Artificial Intelligence in Hospitals.

Monitoring of artificial intelligence (AI)-based algorithms is necessary for safe implementation and will be required in upcoming regulations. This study investigates the potential for monitoring of AI in hospitals. First, by reviewing regulatory requirements and state of the art of monitoring. Then, by conducting a gap analysis of ISO42001, containing industry agnostic requirements harmonized with the EU AI Act. The analysis illustrates the need for comprehensive monitoring capable of capturing deviations in input, performance drifts and unintended interactions. However, hospitals often suffer from a technical debt, and the gap analysis provides qualitative indications on implementation challenges, including data quality, infrastructure and limitations in continuous improvement.

Managing Risk and Quality of AI in Healthcare: Are Hospitals Ready for Implementation?

Artificial intelligence (AI) provides a unique opportunity to help meet the demands of the future healthcare system. However, hospitals may not be well equipped to handle safe and effective development and/or procurement of AI systems. Furthermore, upcoming regulations such as the EU AI Act may enforce the need to establish new management systems, quality assurance and control mechanisms, novel to healthcare organizations. This paper discusses challenges in AI implementation, particularly potential gaps in current management systems (MS), by reviewing the harmonized standard for AI MS, ISO 42001, as part of a gap analysis of a tertiary acute hospital with ongoing AI activities. Examination of the industry agnostic ISO 42001 reveals a technical debt within healthcare, aligning with previous research on digitalization and AI implementation. To successfully implement AI with quality assurance in mind, emphasis should be put on the foundation and structure of the healthcare organizations, including both workforce and data infrastructure.

Data Quality in Healthcare for the Purpose of Artificial Intelligence: A Case Study on ECG Digitalization.

The quantity of data generated within healthcare is increasing exponentially. Following this development, the interest of using data driven methodologies such as machine learning is on a steady rise. However, the quality of the data also needs to be considered, since information generated for human interpretation may not be optimal for quantitative computer-based analysis. This work investigates dimensions of data quality for the purpose of artificial intelligence applications in healthcare. Particularly, ECG is studied which traditionally rely on analog prints for initial examination. A digitalization process for ECG is implemented, together with a machine learning model for heart failure prediction, to quantitatively compare results based on data quality. The digital time series data provide a significant accuracy increase, compared to scans of analog plots.

Enabling Clinical Trials of Artificial Intelligence: Infrastructure for Heart Failure Predictions.

The last decade has seen a large increase in artificial intelligence research within healthcare. However, relatively few attempts of clinical trials have been made for such configurations. One of the main challenges arise in the extensive infrastructure necessary, both for development, but particularly to run prospective studies. In this paper, infrastructural requirements are first presented, together with constraints due to underlying production systems. Then, an architectural solution is presented, with the aim of both enabling clinical trials and streamline model development. Specifically, the suggested design is intended for research of heart failure prediction from ECG, but is generalizable to projects using similar data protocols and installed base.

Fairness in Artificial Intelligence: Regulatory Sanbox Evaluation of Bias Prevention for ECG Classification.

As the use of artificial intelligence within healthcare is on the rise, an increased attention has been directed towards ethical considerations. Defining fairness in machine learning is a well explored topic with an extensive literature. However, such definitions often rely on the existence of metrics on the input data and well-defined outcome measurements, while regulatory definitions use general terminology. This work aims to study fairness within AI, particularly bringing regulation and theoretical knowledge closer. The study is done via a regulatory sandbox implemented on a healthcare case, specifically ECG classification.

New pathogenic germline variants identified in mesothelioma.

BACKGROUND: Mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification of germline pathogenic variants (PVs) in mesothelioma is relevant for identifying potential actionable targets and genetic counseling. METHODS: 44 patients underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Germline variants were selected according to association with inherited cancer using a 168-gene in silico panel, and variants classified according to ACMG/AMP classification as pathogenic (class 5) or likely pathogenic (class 4). RESULTS: In total, 16 patients (36%) were found to carry pathogenic or likely pathogenic variants in 13 cancer associated genes (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The germline PVs occurred in DNA repair pathways, including homologous recombination repair (HRR) (75%), nucleotide excision repair (6%), cell cycle regulatory (7%), base excision repair (6%), and hypoxic pathway (6%). Five (31%) patients with a germline PV had a first or second degree relative with mesothelioma compared to none for patients without a germline PV. Previously undiagnosed BRCA2 germline PVs were identified in two patients. Potential actionable targets based on the germline PVs were found in four patients (9%). CONCLUSION: This study revealed a high frequency of germline PVs in patients with mesothelioma. Furthermore, we identified germline PVs in two genes (NBN & RAD51B) not previously associated with mesothelioma. The data support germline testing in mesothelioma and provide a rationale for additional investigation of the HRR pathway as a potential actionable target.

Preoperative staging of lung cancer with combined PET-CT.

BACKGROUND: Fast and accurate staging is essential for choosing treatment for non-small-cell lung cancer (NSCLC). The purpose of this randomized study was to evaluate the clinical effect of combined positron-emission tomography and computed tomography (PET-CT) on preoperative staging of NSCLC. METHODS: We randomly assigned patients who were referred for preoperative staging of NSCLC to either conventional staging plus PET-CT or conventional staging alone. Patients were followed until death or for at least 12 months. The primary end point was the number of futile thoracotomies, defined as any one of the following: a thoracotomy with the finding of pathologically confirmed mediastinal lymph-node involvement (stage IIIA [N2]), stage IIIB or stage IV disease, or a benign lung lesion; an exploratory thoracotomy; or a thoracotomy in a patient who had recurrent disease or death from any cause within 1 year after randomization. RESULTS: From January 2002 through February 2007, we randomly assigned 98 patients to the PET-CT group and 91 to the conventional-staging group. Mediastinoscopy was performed in 94% of the patients. After PET-CT, 38 patients were classified as having inoperable NSCLC, and after conventional staging, 18 patients were classified thus. Sixty patients in the PET-CT group and 73 in the conventional-staging group underwent thoracotomy (P=0.004). Among these thoracotomies, 21 in the PET-CT group and 38 in the conventional-staging group were futile (P=0.05). The number of justified thoracotomies and survival were similar in the two groups. CONCLUSIONS: The use of PET-CT for preoperative staging of NSCLC reduced both the total number of thoracotomies and the number of futile thoracotomies but did not affect overall mortality. (ClinicalTrials.gov number, NCT00867412.)

Multimodality approach to mediastinal staging in non-small cell lung cancer. Faults and benefits of PET-CT: a randomised trial.

BACKGROUND: Correct mediastinal staging is a cornerstone in the treatment of patients with non-small cell lung cancer. A large range of methods is available for this purpose, making the process of adequate staging complex. The objective of this study was to describe faults and benefits of positron emission tomography (PET)-CT in multimodality mediastinal staging. METHODS: A randomised clinical trial was conducted including patients with a verified diagnosis of non-small cell lung cancer, who were considered operable. Patients were assigned to staging with PET-CT (PET-CT group) followed by invasive staging (mediastinoscopy and/or endoscopic ultrasound with fine needle aspiration (EUS-FNA)) or invasive staging without prior PET-CT (conventional work up (CWU) group). Mediastinal involvement (dichotomising N stage into N0-1 versus N2-3) was described according to CT, PET-CT, mediastinoscopy, EUS-FNA and consensus (based on all available information), and compared with the final N stage as verified by thoracotomy or a conclusive invasive diagnostic procedure. RESULTS: A total of 189 patients were recruited, 98 in the PET-CT group and 91 in the CWU group. In an intention-to-treat analysis the overall accuracy of the consensus N stage was not significantly higher in the PET-CT group than in the CWU group (90% (95% confidence interval 82% to 95%) vs 85% (95% CI 77% to 91%)). Excluding the patients in whom PET-CT was not performed (n=14) the difference was significant (95% (95% CI 88% to 98%) vs 85% (95% CI 77% to 91%), p=0.034). This was mainly based on a higher sensitivity of the staging approach including PET-CT. CONCLUSION: An approach to lung cancer staging with PET-CT improves discrimination between N0-1 and N2-3. In those without enlarged lymph nodes and a PET-negative mediastinum the patient may proceed directly to surgery. However, enlarged lymph nodes on CT needs confirmation independent of PET findings and a positive finding on PET-CT needs confirmation before a decision on surgery is made. CLINICAL TRIAL NUMBER: NCT00867412.

Aetiology, treatment and mortality after oesophageal perforation in Denmark.

INTRODUCTION: Perforation of the oesophagus into the thoracic cavity is a potentially life-threatening condition. The causes are numerous. Treatment for oesophageal perforation targets mediastinal and pleural contamination. Present knowledge about the causes of perforation and the types of treatment is poor. MATERIAL AND METHODS: A retrospective review was made between 1997 and 2005 based on extracts from the National Patient Registry. RESULTS: A total of 286 patients were diagnosed with perforation of the oesophagus (131 women and 155 men). Their average age was 60 years. A wide spectrum of causes was reported, e.g. instrumentation of the oesophagus 136 (47.6%), spontaneous rupture 89 (31.1%) or procedures otherwise related to surgical intervention 9 (3.1%). One third of the patients started conservative treatment 91 (31.9%). The majority of the patients were transferred to a thoracic surgery department for further treatment: about 25% of patients underwent surgery. The average hospitalization time was 18 days. The mortality rate was 21%. CONCLUSION: Oesophageal perforation remains a diagnostic and therapeutic challenge and the condition requires aggressive treatment. Recent consensus in early treatment with thoracotomy, debridement, irrigation and subsequent parenteral nutrition has improved survival. In this material, most perforations were iatrogenic in nature. In the 2002-2005 period, the study showed that 29% of the iatrogenic perforations were caused by the use of a rigid endoscope which is risky and whose use should therefore be restricted. It is advisable to set up national guidelines for treatment of oesophageal perforation and to centralise treatment.

[Management of thymomas and thymic carcinomas].

This review summarises the diagnostics, staging and treatment of thymic epithelial tumours, of which CT is the current primary imaging. The International Association for the Study of Lung Cancer/International Thymic Malignancy Interest Group TNM staging and the WHO histological classifications are described. Surgery done as total thymectomy with video-assisted thoracoscopic surgery in stage I and open sternotomy in larger stages is the primary treatment if possible. Presurgical tumour reduction with chemotherapy and the possibility of adjuvant radiotherapy after R+ resection is described. Radiotherapy or chemotherapy can be considered, if definite surgery is not possible. Relapse is treated after the same principles as primary disease.

Intrathoracic Splenosis Without Clinical Evidence of Diaphragmatic Rupture.

Intrathoracic splenosis is a rare diagnosis that is usually made after an invasive procedure. Most cases report concomitant rupture of the spleen and left hemidiaphragm with autotransplantation of splenic tissue into the left hemithorax. We report a case of intrathoracic splenosis with no evidence of diaphragmatic rupture. The mechanism may be explained by hematogenous spread. The patient underwent video-assisted thoracoscopic surgery for diagnosis, which could have been avoided if splenosis was suspected.

[Lung volume reduction surgery for severe emphysema treatment].

Lung volume reduction surgery (LVRS) is a treatment option for patients with severe emphysema. A multicentre randomised trial (NETT) found, that LVRS reduced symptoms from emphysema, and in selected patients with heterogen-ous emphysema it improved survival. Since NETT was performed, other studies have demonstrated positive outcomes, both symptomatic and for survival in previously classified high-risk patients. Post-operative mortality after LVRS is now negligible, which is often credited to minimally invasive techniques, greater experience with the patient group and improved operative equipment.

Treatment, no treatment and early death in Danish stage I lung cancer patients.

BACKGROUND: Stage I lung cancer is curable with surgery as the treatment of choice. Other effective and curative treatments exist. Nevertheless, some patients only receive palliative treatment and some receive no treatment at all. MATERIALS AND METHODS: Using the Danish Lung Cancer Registry (DLCR), we assessed treatment distribution for a population-based Danish cohort of stage I lung cancer patients diagnosed from 2011 to 2014. We assessed one-year mortality according to treatment. Furthermore, in a nested case-control study based on data from medical records, we assessed the reason for not undergoing treatment among patients in favourable performance status (PS) with no treatment registration in the DLCR. RESULTS: We identified 2985 patients, 68% (n = 2021) were treated surgically and 17% (n = 508) were managed with curative oncological therapy. The unadjusted odds ratio (OR) for death within one year was 2.5 (95% CI, 1.8-3.3) for the oncologically managed vs. the surgically treated. After adjusting for age, lung function and PS, the OR was 1.2 (95% CI, 0.8-1.9). Among 129 patients with a PS of 0-1 and no treatment registration, we established the reason for not undergoing treatment in 122 (95%). The majority (70%) were misclassified and did either not have lung cancer, had more advanced disease or were curatively treated. The 36 (30%) patients that did not undergo treatment, had a lower prevalence of adenocarcinomas (17 vs. 51%, p = 0.003), more comorbidites (median Charlson comorbidity index score 2 vs. 1, p < 0.001) and high alcohol intake (19 vs. 7%, p = 0.04) as compared to surgically treated controls. The primary reasons for no treatment were; comorbidity, patient decision and disease progression. CONCLUSION: Difference in outcome between the two major treatment groups was confounded by age, lung function and PS. Comorbidity, high alcohol intake and histology were associated with not undergoing curative treatment in spite of a favourable PS.

[The first 25 years of lung transplantations in Denmark].

Lung transplantation (LTx) has been performed in Denmark since 1992, and chronic obstructive pulmonary disease and interstitial lung diseases are the major indications. All candidates are subject to an intensive evaluation before being accepted for LTx. Follow-up after transplantation is life-long and includes immunosuppressive medication with a high risk of side effects. The median survival in Denmark is 7.0 years. Chronic rejection is common, diagnosed by declining lung function, and it is the most important factor for morbidity and mortality. LTx requires dedicated personnel in an interdisciplinary organisation.

Advanced trauma life support, 8th edition, the evidence for change.

The American College of Surgeons Committee on Trauma's Advanced Trauma Life Support Course is currently taught in 50 countries. The 8th edition has been revised following broad input by the International ATLS subcommittee. Graded levels of evidence were used to evaluate and approve changes to the course content. New materials related to principles of disaster management have been added. ATLS is a common language teaching one safe way of initial trauma assessment and management.

[Surgery in patients with lung cancer].

This review is about the initial diagnostic workup and the surgical treatment of patients with lung cancer in Denmark. Due to the development of international and national clinical guidelines for diagnosis and treatment of lung cancer, survival has increased. Data from 2005-2016 in the National Danish Lung Cancer Registry show an increase in: 1) the number of women being diagnosed, 2) the part of surgical candidates being thoracoscopically treated, 3) the number of patients being referred to surgery and 4) the survival rate.

Oxidized resorbable cellulose (Gelita-cel) causing foreign body reaction in the mediastinum.

Different types of oxidized cellulose have been used for haemorrhage control in thoracic surgery, abdominal surgery and neurosurgery. Oxidized resorbable cellulose (Gelita-cel) is a new haemostatic agent. Once saturated with blood, it swells and makes a gelatinous mass that formats as a fibrin clot. We have performed a prospective observational cohort study of patients operated for lung cancer or suspected lung cancer using Gelita-cel as a haemostatic agent. Between October 2010 and April 2012, 477 patients were operated in our department for lung cancer. Gelita-cel was used in 200 patients due to minor intraoperative haemorrhage after lymph node resection from Stations 2 to 11. During follow-up for lung cancer, computed tomography, which was performed 4-60 months after the primary operation, showed enlarged lymph nodes in the mediastinum in 16 patients. Endoscopic bronchial ultrasonographic biopsies of the lymph nodes showed foreign body material and granulomatous inflammation, and no sign of lung cancer recurrence. Gelita-cel has a high risk of causing granuloma and should not be used as a haemostatic agent in thoracic surgery.

Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)-validation in two independent cohorts.

INTRODUCTION: Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented. METHODS: The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n = 71) or no adjuvant treatment (OBS, n = 62) and 2) formalin-fixed paraffin-embedded (FFPE) tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine. RESULTS: The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079-0.889, p = 0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08-1.04, p = 0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR = 0.138 (95% CI:0.035-0.537), p = 0.004) and multivariate analysis (HR = 0.14 (95% CI:0.030-0.6), p = 0.0081). No discrimination was found in the OBS cohort (HR = 1.328, p = 0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12-1.15, p = 0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03-0.59, p = 0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis. CONCLUSIONS: Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.