Semi-automatic standardized analysis method to objectively evaluate near-infrared fluorescent dyes in image-guided surgery.

Significance: Near-infrared fluorescence imaging still lacks a standardized, objective method to evaluate fluorescent dye efficacy in oncological surgical applications. This results in difficulties in translation between preclinical to clinical studies with fluorescent dyes and in the reproduction of results between studies, which in turn hampers further clinical translation of novel fluorescent dyes. Aim: Our aim is to develop and evaluate a semi-automatic standardized method to objectively assess fluorescent signals in resected tissue. Approach: A standardized imaging procedure was designed and quantitative analysis methods were developed to evaluate non-targeted and tumor-targeted fluorescent dyes. The developed analysis methods included manual selection of region of interest (ROI) on white light images, automated fluorescence signal ROI selection, and automatic quantitative image analysis. The proposed analysis method was then compared with a conventional analysis method, where fluorescence signal ROIs were manually selected on fluorescence images. Dice similarity coefficients and intraclass correlation coefficients were calculated to determine the inter- and intraobserver variabilities of the ROI selections and the determined signal- and tumor-to-background ratios. Results: The proposed non-targeted fluorescent dyes analysis method showed statistically significantly improved variabilities after application on indocyanine green specimens. For specimens with the targeted dye SGM-101, the variability of the background ROI selection was statistically significantly improved by implementing the proposed method. Conclusion: Semi-automatic methods for standardized quantitative analysis of fluorescence images were successfully developed and showed promising results to further improve the reproducibility and standardization of clinical studies evaluating fluorescent dyes.

Colorectal polyps: Targets for fluorescence-guided endoscopy to detect high-grade dysplasia and T1 colorectal cancer.

BACKGROUND: Differentiating high-grade dysplasia (HGD) and T1 colorectal cancer (T1CRC) from low-grade dysplasia (LGD) in colorectal polyps can be challenging. Incorrect recognition of HGD or T1CRC foci can lead to a need for additional treatment after local resection, which might not have been necessary if it was recognized correctly. Tumor-targeted fluorescence-guided endoscopy might help to improve recognition. OBJECTIVE: Selecting the most suitable HGD and T1CRC-specific imaging target from a panel of well-established biomarkers: carcinoembryonic antigen (CEA), c-mesenchymal-epithelial transition factor (c-MET), epithelial cell adhesion molecule (EpCAM), folate receptor alpha (FRα), and integrin alpha-v beta-6 (αvß6). METHODS: En bloc resection specimens of colorectal polyps harboring HGD or T1CRC were selected. Immunohistochemistry on paraffin sections was used to determine the biomarker expression in normal epithelium, LGD, HGD, and T1CRC (scores of 0-12). The differential expression in HGD-T1CRC components compared to surrounding LGD and normal components was assessed, just as the sensitivity and specificity of each marker. RESULTS: 60 specimens were included (21 HGD, 39 T1CRC). Positive expression (score >1) of HGD-T1CRC components was found in 73.3%, 78.3%, and 100% of cases for CEA, c-MET, and EpCAM, respectively, and in <40% for FRα and αvß6. Negative expression (score 0-1) of the LGD component occurred more frequently for CEA (66.1%) than c-MET (31.6%) and EpCAM (0%). The differential expression in the HGD-T1CRC component compared to the surrounding LGD component was found for CEA in 66.7%, for c-MET in 43.1%, for EpCAM in 17.2%, for FRα in 22.4%, and for αvß6 in 15.5% of the cases. Moreover, CEA showed the highest combined sensitivity (65.0%) and specificity (75.0%) for the detection of an HGD-T1CRC component in colorectal polyps. CONCLUSION: Of the tested targets, CEA appears the most suitable to specifically detect HGD and T1 cancer foci in colorectal polyps. An in vivo study using tumor-targeted fluorescence-guided endoscopy should confirm these findings.

The association between systolic blood pressure and in-hospital mortality in older emergency department patients who are hospitalised with a suspected infection.

OBJECTIVE: In existing risk stratification and resuscitation guidelines for sepsis, a hypotension threshold of systolic blood pressure (SBP) below 90-100 mmHg is typically used. However, for older patients, the clinical relevance of a SBP in a seemingly 'normal' range (>100 mmHg) is still poorly understood, as they may need higher SBP for adequate tissue perfusion due to arterial stiffening. We therefore investigated the association between SBP and mortality in older emergency department (ED) patients hospitalised with a suspected infection. METHODS: In this observational multicentre study in the Netherlands, we interrogated an existing prospective database of consecutive ED patients hospitalised with a suspected infection between 2011 and 2016. We investigated the association between SBP categories (≤100, 101-120, 121-139, ≥140 mmHg) and in-hospital mortality in patients of 70 years and older. We adjusted for demographics, comorbidity, disease severity and admission to ward/intensive care using multivariable logistic regression. RESULTS: In the 833 included older patients, unadjusted in-hospital mortality increased from 4.7% (n=359) in SBP ≥140 mmHg to 20.8% (n=96) in SBP ≤100 mmHg. SBP categories were linearly associated with case-mix-adjusted in-hospital mortality. The adjusted ORs (95% CI) for ≤100, 101-120 and 121-139 mmHgcompared with the reference of ≥140 mmHg were 3.8 (1.8 to 7.8), 2.8 (1.4 to 5.5) and 1.9 (0.9 to 3.7), respectively. CONCLUSION: In older ED patients hospitalised with a suspected infection, we found an inverse linear association between SBP and case-mix-adjusted in-hospital mortality. Our data suggest that the commonly used threshold for hypotension is not clinically meaningful for risk stratification of older ED patients with a suspected infection.

Initial disease severity and quality of care of emergency department sepsis patients who are older or younger than 70 years of age.

OBJECTIVE: Due to atypical symptom presentation older patients are more prone to delayed sepsis recognition. We investigated whether initial disease severity before emergency department (ED) treatment (including treatable acute organ dysfunction), quality of ED sepsis care and the impact on mortality was different between patients older and younger than 70 years. If differences exist, improvements are needed for ED management of older patients at risk for sepsis. METHODS: In this observational multicenter study, ED patients who were hospitalized with a suspected infection were stratified by age <70 and ≥70 years. The presence of treatable and potentially reversible acute organ dysfunction was measured by the RO components of the Predisposition, Infection, Response and Organ dysfunction (PIRO) score, reflecting acute sepsis-related organ dysfunction developed before ED presentation. Quality of care, as assessed by the full compliance with nine quality performance measures and the standardized mortality ratio (SMR: observed/expected in-hospital mortality), was compared between older and younger patients. RESULTS: The RO-components of the PIRO score were 8 (interquartile range; 4-9) in the 833 older patients, twice as high as the 4 (2-8; P<0.001) in the 1537 younger patients. However, full compliance with all nine quality performance measures was achieved in 34.2 (31.0-37.4)% of the older patients, not higher than the 33.0 (30.7-35.4)% in younger patients (P = 0.640). In-hospital mortality was 9.2% (95%-CI, 7.3-11.2) in patients ≥70, twice as high as the 4.6% (3.6-5.6) in patients <70 years, resulting in an SMR (in study period) of ~0.7 in both groups (P>0.05). CONCLUSION: Older sepsis patients are sicker at ED presentation but are not treated more expediently or reliably despite their extra acuity The presence of twice as much treatable acute organ dysfunction before ED treatment suggests that acute organ dysfunction is recognized relatively late by general practitioners or patients in the out of hospital setting.

The most commonly used disease severity scores are inappropriate for risk stratification of older emergency department sepsis patients: an observational multi-centre study.

BACKGROUND: Sepsis recognition in older emergency department (ED) patients is difficult due to atypical symptom presentation. We therefore investigated whether the prognostic and discriminative performance of the five most commonly used disease severity scores were appropriate for risk stratification of older ED sepsis patients (≥70 years) compared to a younger control group (<70 years). METHODS: This was an observational multi-centre study using an existing database in which ED patients who were hospitalized with a suspected infection were prospectively included. Patients were stratified by age < 70 and ≥70 years. We assessed the association with in-hospital mortality (primary outcome) and the area under the curve (AUC) with receiver operator characteristics of the Predisposition, Infection, Response, Organ dysfunction (PIRO), quick Sequential Organ Failure Assessment (qSOFA), Mortality in ED Sepsis (MEDS), and the Modified and National Early Warning (MEWS and NEWS) scores. RESULTS: In-hospital mortality was 9.5% ((95%-CI); 7.4-11.5) in the 783 included older patients, and 4.6% (3.6-5.7) in the 1497 included younger patients. In contrast to younger patients, disease severity scores in older patients associated poorly with mortality. The AUCs of all disease severity scores were poor and ranged from 0.56 to 0.64 in older patients, significantly lower than the good AUC range from 0.72 to 0.86 in younger patients. The MEDS had the best AUC (0.64 (0.57-0.71)) in older patients. In older and younger patients, the newly proposed qSOFA score (Sepsis 3.0) had a lower AUC than the PIRO score (sepsis 2.0). CONCLUSION: The prognostic and discriminative performance of the five most commonly used disease severity scores was poor and less useful for risk stratification of older ED sepsis patients.