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.

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.

[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.

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.

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.

[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.

[Evaluation and treatment of patients after caustic ingestion].

This article presents recommendations regarding early management of patients after intake of corrosive chemicals, based on best evidence and clinical experience. Risk assessment built on clinical history, presentation and endoscopy is discussed as well as initial treatment, surgical appraisal and observation. Controversy still surrounds the need for endoscopy in asymptomatic patients, the use of computed tomography in assessing the severity of lesions as well as pharmacological treatment for preventing strictures.

Video-assisted thoracoscopic surgery lobectomy for lung cancer is associated with a lower 30-day morbidity compared with lobectomy by thoracotomy.

OBJECTIVES: Lung cancer is the most common cause of cancer-related deaths worldwide. Survival is highly dependent on surgery. Video-assisted thoracoscopic surgery (VATS) is increasingly chosen over open thoracotomy (OT) because of the possible benefits of the minimally invasive approach. Consequently, our aim was to compare the 30-day morbidity and mortality for lung cancer patients operated by VATS lobectomy or lobectomy by OT. METHOD: Data were obtained from prospective national and regional databases, including patients who underwent lobectomy for lung cancer in the eastern part of Denmark from 1 January 2005 to 31 December 2011. All patients operated before 2009 were re-staged according to the latest International Association for the Study of Lung Cancer lung cancer classification. Patient characteristics, comorbidities, pathology and operative data were assessed using an independent samples t-test, Pearson's χ(2), Fisher's exact test and Mann-Whitney test. Morbidity was assessed using multinomial logistic regression adjusted for gender, age, cancer stage, forced expiratory volume in 1 s (FEV1), year of surgery and Charlson comorbidity score. RESULTS: In total, 1379 patients underwent lobectomy, 785 patients via VATS and 594 patients via thoracotomy. The two groups were similar in gender and FEV1. The patients operated by VATS were older (P < 0.001), and had a lower Charlson comorbidity score (P = 0.034), higher frequency of adenocarcinomas (P < 0.001) and lower cancer stage (P < 0.001). Among the VATS patients, 285 (36.3%) and among the thoracotomy patients, 288 (48.5%) had minor complications (P < 0.001); and 157 (20.0%) VATS patients and 212 (35.7%) thoracotomy patients had major complications (P < 0.001). The 30-day mortality rate was 1% in the VATS group and 1.5% in the thoracotomy group (P = 0.47). Multinomial logistic regression analysis showed that the prevalence of both minor [odds ratio (OR) = 1.51; 95% confidence interval (Cl) = 1.18-1.96] and major complications (OR = 1.91, 95% Cl = 1.44-2.53) was significantly higher for patients who underwent lobectomy via thoracotomy compared with VATS. CONCLUSION: Patients undergoing lobectomy via VATS were less likely to have at least one minor complication within the first 30 postoperative days and less likely to have at least one major complication, compared with patients operated by thoracotomy. These findings remained after adjusting for gender, age, FEV1, cancer stage, year of surgery and Charlson comorbidity score.

Methylation-associated Silencing of microRNA-126 and its Host Gene EGFL7 in Malignant Pleural Mesothelioma.

BACKGROUND/AIM: We recently reported that miR-126 is down-regulated in malignant pleural mesothelioma (MPM) and can be combined into a 4-microRNA-classifier that can accurately diagnose MPM with high sensitivity and specificity. Herein we analyzed the epigenetic regulation of miR-126 and its host gene EGF-like domain, multiple 7 (EGFL7). MATERIALS AND METHODS: Resected formalin-fixed paraffin-embedded MPM tissues from 29 patients, 14 patient-matched non-neoplastic pleura (NNP) specimens, 5 MPM diagnostic biopsies (DB), and 5 samples of pneumothorax-induced benign reactive mesothelial proliferation (PTHX) were analyzed. miR-126 and EGFL7 mRNA were quantified by RT-qPCR. CpG-islands' methylation in the EGFL7 promoter was analyzed using methylation-specific PCR and in the MIR126-containing intron 7 was quantified by pyrosequencing. RESULTS: Relative to NNP, EGFL7 was under-expressed more than 4-fold in MPM (p<0.001). EGFL7 mRNA and miR-126 levels correlated in MPM (p<0.01) and NNP (p<0.001). The EGFL7 promoter region was hypermethylated in 69% of MPM and 80% of DB samples, but not in NNP and PTHX samples. EGFL7 promoter hypermethylation was associated with epithelioid histology (p<0.05) and reduced patient-survival (p<0.05). CONCLUSION: In MPM, DNA-hypermethylation down-regulates miR-126 and its host gene EGFL7, therefore is a poor prognostic factor, and may represent a future therapeutic target for de-methylating strategies re-establishing EGFL7 and miR-126 expression.