Targeted imaging in oncologic surgery : preclinical studies utilizing near-infrared fluorescence and radioactivity

Fluorescence-guided surgery (FGS) is an intraoperative imaging technique already introduced and validated in the clinic for sentinel lymph node mapping and biliary imaging. Conjugating a NIR-dye to a specific tumor-targeting vehicle dramatically enhances the specificity of this technique. Hence, a powerful synergy can be achieved when fluorescent imaging is combined with nuclear imaging. The (NIR) fluorescent signal aids the surgeon to accurately recognize and resect malignant tissues and detect (nearby) vital structures in real-time during surgery, while its nuclear counterpart can be used to preoperative assess tumor spread and aid in the surgical planning and guidance. Patients may benefit directly from better tumor detection as the surgical status (R0 or R1) is one of the most import parameters for morbidity and patient survival. This thesis focus on the evaluation of potential targets for image-guided surgery applications and describes the preclinical evaluation of novel tracers for (hybrid) image-guided surgery.  Quest Medical Imaging, Curadel, Chipsoft, Milabs, LUMCLUMC / Geneeskund

Evaluating changes in functioning and psychological distress in visitors of the @ease youth mental health walk-in centres

Background:Highly accessible youth initiatives worldwide aim to prevent worsening of mental health problems, but research into outcomes over time is scarce. Aims:This study aimed to evaluate outcomes and support use in 12- to 15-year-old visitors of the @ease mental health walk-in centres, a Dutch initiative offering free counselling by trained and supervised peers.Method:Data of 754 visitors, collected 2018-2022, included psychological distress (Clinical Outcomes in Routine Evaluation 10 (CORE-10)), social and occupational functioning (Social and Occupational Functioning Assessment Scale (SOFAS)), school absenteeism and support use, analysed with change indicators (first to last visit), and mixed models (first three visits).Results:Among return visitors, 50.5% were female, 79.4% were in tertiary education and 36.9% were born outside of The Netherlands (one-time visitors: 64.7%, 72.9% and 41.3%, respectively). Moreover, 29.9% of return visitors presented with suicidal ideations, 97.1% had clinical psychological distress levels, and 64.1% of the latter had no support in the previous 3 months (one-time visitors: 27.2%, 90.7% and 71.1%, respectively). From visit 1 to 3, psychological distress decreased (β = -3.79, 95% CI -5.41 to -2.18; P &lt; 0.001) and social and occupational functioning improved (β = 3.93, 95% CI 0.51-7.36; P = 0.025). Over an average 3.9 visits, 39.6% improved reliably and 28.0% improved clinically significantly on the SOFAS, which was 28.4% and 8.8%, respectively, on the CORE-10, where 43.2% improved in clinical category. Counselling satisfaction was rated 4.5/5. Conclusions:Reductions in psychological distress, improvements in functioning and high counselling satisfaction were found among @ease visitors, forming a basis for future research with a control group.</p

Evaluating changes in functioning and psychological distress in visitors of the @ease youth mental health walk-in centres

Background:Highly accessible youth initiatives worldwide aim to prevent worsening of mental health problems, but research into outcomes over time is scarce. Aims:This study aimed to evaluate outcomes and support use in 12- to 15-year-old visitors of the @ease mental health walk-in centres, a Dutch initiative offering free counselling by trained and supervised peers.Method:Data of 754 visitors, collected 2018-2022, included psychological distress (Clinical Outcomes in Routine Evaluation 10 (CORE-10)), social and occupational functioning (Social and Occupational Functioning Assessment Scale (SOFAS)), school absenteeism and support use, analysed with change indicators (first to last visit), and mixed models (first three visits).Results:Among return visitors, 50.5% were female, 79.4% were in tertiary education and 36.9% were born outside of The Netherlands (one-time visitors: 64.7%, 72.9% and 41.3%, respectively). Moreover, 29.9% of return visitors presented with suicidal ideations, 97.1% had clinical psychological distress levels, and 64.1% of the latter had no support in the previous 3 months (one-time visitors: 27.2%, 90.7% and 71.1%, respectively). From visit 1 to 3, psychological distress decreased (β = -3.79, 95% CI -5.41 to -2.18; P &lt; 0.001) and social and occupational functioning improved (β = 3.93, 95% CI 0.51-7.36; P = 0.025). Over an average 3.9 visits, 39.6% improved reliably and 28.0% improved clinically significantly on the SOFAS, which was 28.4% and 8.8%, respectively, on the CORE-10, where 43.2% improved in clinical category. Counselling satisfaction was rated 4.5/5. Conclusions:Reductions in psychological distress, improvements in functioning and high counselling satisfaction were found among @ease visitors, forming a basis for future research with a control group.</p

Platelet- derived growth factor receptor-beta and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study

INTRODUCTION: Systemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) carries a poor prognosis, despite pulmonary vascular dilating therapy. Platelet-derived growth factor receptor-beta (PDGFR-beta) and epidermal growth factor receptor (EGFR) are potential therapeutic targets for PAH because of their proliferative effects on vessel remodelling. To explore their role in SScPAH, we compared PDGFR- and EGFR-mmunoreactivity in lung tissue specimens from SScPAH. We compared staining patterns with idiopathic PAH (IPAH) and pulmonary veno-occlusive disease (PVOD), as SScPAH vasculopathy differs from IPAH and sometimes displays features of PVOD. Immunoreactivity patterns of phosphorylated PDGFR-beta (pPDGFR-beta) and the ligand PDGF-B were evaluated to provide more insight into the patterns of PDGFR-b activation. METHODS: Lung tissue specimens from five SScPAH, nine IPAH, six PVOD patients and five controls were examined. Immunoreactivity was scored for presence, distribution and intensity. RESULTS: All SScPAH and three of nine IPAH cases (P = 0.03) showed PDGFR-beta-immunoreactivity in small vessels (arterioles/venules); of five SScPAH vs. two of nine IPAH cases (P = 0.02) showed venous immunoreactivity. In small vessels, intensity was stronger in SScPAH vs. IPAH. No differences were found between SScPAH and PVOD. One of five normal controls demonstrated focally mild immunoreactivity. There were no differences in PDGF-ligand and pPDGFR-b-immunoreactivity between patient groups; however, pPDGFR-b-immunoreactivity tended to be more prevalent in SScPAH small vasculature compared to IPAH. Vascular EGFR-immunoreactivity was limited to arterial and arteriolar walls, without differences between groups. No immunoreactivity was observed in vasculature of normals. CONCLUSIONS: PDGFR-beta-immunoreactivity in SScPAH is more common and intense in small- and post-capillary vessels than in IPAH and does not differ from PVOD, fitting in with histomorphological distribution of vasculopathy. PDGFR-beta immunoreactivity pattern is not paralleled by pPDGFR-beta or PDGF-B patterns. PDGFR-beta- and EGFR-immunoreactivity of pulmonary vessels distinguishes PAH patients from controls

An outbreak of ST307 extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae in a rehabilitation center: An unusual source and route of transmission

Objective: Nosocomial outbreaks due to multidrug-resistant microorganisms in rehabilitation centers have rarely been reported. We report an outbreak of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae (ESBL-K. pneumoniae) on a single ward in a rehabilitation center in Rotterdam, The Netherlands.Design: Outbreak description.Setting: A 40-bed ward of a rehabilitation center in the Netherlands.Methods: In October 2016, 2 patients were found to be colonized by genetically indistinguishable ESBL-K. pneumoniae isolates. Therefore, an outbreak management team was installed, by whom a contact tracing plan was made. In addition to general outbreak measures, specific measures were formulated to allow continuation of the rehabilitation process. Also, environmental cultures were taken. Multiple-locus variable-number tandem-repeat analysis and amplification fragment-length polymorphism were used to determine strain relatedness. Selected isolates were subjected to whole-genome multilocus sequence typing.Results: The outbreak lasted 8 weeks. In total, 14 patients were colonized with an ESBL-K. pneumoniae, of whom 11 patients had an isolate belonging to

Characterization and Evaluation of the Artemis Camera for Fluorescence-Guided Cancer Surgery

Purpose: Near-infrared (NIR) fluorescence imaging can provide the surgeon with real-time visualization of, e.g., tumor margins and lymph nodes. We describe and evaluate the Artemis, a novel, handheld NIR fluorescence camera.Procedures: We evaluated minimal detectable cell numbers (FaDu-luc2, 7D12-IRDye 800CW), preclinical intraoperative detection of sentinel lymph nodes (SLN) using indocyanine green (ICG), and of orthotopic tongue tumors using 7D12-800CW. Results were compared with the Pearl imager. Clinically, three patients with liver metastases were imaged using ICG.Results: Minimum detectable cell counts for Artemis and Pearl were 2 × 105 and 4 × 104 cells, respectively. In vivo, seven SLNs were detected in four mice with both cameras. Orthotopic OSC-19-luc2-cGFP tongue tumors were clearly identifiable, and a minimum FaDu-luc2 tumor size of 1 mm3 could be identified. Six human malignant lesions were identified during three liver surgery procedures.Conclusions: Based on this study, the Artemis system has demonstrated its utility in fluorescence-guided cancer surgery

Selection of optimal molecular targets for tumor-specific imaging in pancreatic ductal adenocarcinoma

Discrimination of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) or peritumoral inflammation is challenging, both at preoperative imaging and during surgery, but it is crucial for proper therapy selection. Tumor-specific molecular imaging aims to enhance this discrimination and to help select and stratify patients for resection. We evaluated various biomarkers for the specific identification of PDAC and associated lymph node metastases. Using immunohistochemistry (IHC), expression levels and patterns were investigated of integrin avβ6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), Cathepsin E (Cath E), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), thymocyte differentiation antigen 1 (Thy1), and urokinase-type plasminogen activator receptor (uPAR). In a first cohort, multiple types of pancreatic tissue were evaluated (n=62); normal pancreatic tissue (n=8), CP (n=7), PDAC (n=9), tumor associated lymph nodes (n=32), and PDAC after neoadjuvant radiochemotherapy (n=6). In a second cohort, tissues were investigated (n=55) with IHC and immunofluorescence (IF) for concordance of biomarker expression in all tissue types, obtained from an individual patient. Integrin avβ6 and CEACAM5 showed significantly higher expression levels in PDAC versus normal pancreatic tissue (P=0.001 and P < 0.001, respectively) and CP (P=0.003 and P < 0.001, respectively). Avβ6 and CEACAM5 expression identified tumor-positive lymph nodes correctly in 84% and 68%, respectively, and in 100% of tumor-negative nodes for both biomarkers. In conclusion, avβ6 and CEACAM5 are excellent biomarkers to differentiate PDAC from surrounding tissue and to identify lymph node metastases. Individually or combined, these biomarkers are promising targets for tumor-specific molecular imaging of PDAC

EpCAM as multi-tumour target for near-infrared fluorescence guided surgery

Background: Evaluation of resection margins during cancer surgery can be challenging, often resulting in incomplete tumour removal. Fluorescence-guided surgery (FGS) aims to aid the surgeon to visualize tumours and resection margins during surgery. FGS relies on a clinically applicable imaging system in combination with a specific tumour-targeting contrast agent. In this study EpCAM (epithelial cell adhesion molecule) is evaluated as target for FGS in combination with the novel Artemis imaging system. Methods: The NIR fluorophore IRDye800CW was conjugated to the well-established EpCAM specific monoclonal antibody 323/A3 and an isotype IgG1 as control. The anti-EpCAM/800CW conjugate was stable in serum and showed preserved binding capacity as evaluated on EpCAM positive and negative cell lines, using flow cytometry and cell-based plate assays. Four clinically relevant orthotopic tumour models, i.e. colorectal cancer, breast cancer, head and neck cancer, and peritonitis carcinomatosa, were used to evaluate the performance of the anti-EpCAM agent with the clinically validated Artemis imaging system. The Pearl Impulse small animal imaging system was used as reference. The specificity of the NIRF signal was confirmed using bioluminescence imaging and green-fluorescent protein. Results: All tumour types could clearly be delineated and resected 72 h after injection of the imaging agent. Using NIRF imaging millimetre sized tumour nodules were detected that were invisible for the naked eye. Fluorescence microscopy demonstrated the distribution and tumour specificity of the anti-EpCAM agent. Conclusions: This study shows the potential of an EpCAM specific NIR-fluorescent agent in combination with a clinically validated intraoperative imaging system to visualize various tumours during surgery

Inhibition of 14q32 microRNA miR-495 reduces lesion formation, intimal hyperplasia and plasma cholesterol levels in experimental restenosis

Cardiolog