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Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy has been demonstrated to be effective in increasing the number of lymph nodes (LNs) retrieved in laparoscopic gastrectomy for gastric cancer (GC). Previously, we reported the primary outcomes and short-term secondary outcomes of a phase 3, open-label, randomized clinical trial (NCT03050879) investigating the use of ICG for image-guided lymphadenectomy in patients with potentially resectable GC. Patients were randomly (1:1 ratio) assigned to either the ICG or non-ICG group. The primary outcome was the number of LNs retrieved and has been reported. Here, we report the primary outcome and long-term secondary outcomes including three-year overall survival (OS), three-year disease-free survival (DFS), and recurrence patterns. The per-protocol analysis set population is used for all analyses (258 patients, ICG [n = 129] vs. non-ICG group [n = 129]). The mean total LNs retrieved in the ICG group significantly exceeds that in the non-ICG group (50.5 ± 15.9 vs 42.0 ± 10.3, P  < 0.001). Both OS and DFS in the ICG group are significantly better than that in the non-ICG group (log-rank P  = 0.015; log-rank P  = 0.012, respectively). There is a difference in the overall recurrence rates between the ICG and non-ICG groups (17.8% vs 31.0%). Compared with conventional lymphadenectomy, ICG guided laparoscopic lymphadenectomy is safe and effective in prolonging survival among patients with resectable GC. Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy.

The US Food and Drug Administration (FDA) approved 5-aminolevulinic acid (5-ALA; Gleolan ® ; photonamic GmbH and Co. KG) for use as an intraoperative optical imaging agent in patients with suspected high-grade gliomas (HGGs) in 2017. This was the first ever optical imaging agent approved as an adjunct for the visualization of malignant tissue during surgery for brain tumors. The approval occurred a decade after European approval and a multicenter, phase III randomized trial which confirmed that surgeons using 5-ALA fluorescence-guided surgery as a surgical adjunct could achieve more complete resections of tumors in HGG patients and better patient outcomes than with conventional microsurgery. Much of the delay in the US FDA approval of 5-ALA stemmed from its conceptualization as a therapeutic and not as an intraoperative imaging tool. We chronicle the challenges encountered during the US FDA approval process to highlight a new standard for approval of intraoperative optical imaging agents in brain tumors.

Abstract BACKGROUND: Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections of malignant glioma at a dose of 20 mg/kg; yet, it is unknown whether lower doses may also provide efficacy. OBJECTIVE: To perform a double-blinded randomized study comparing 3 different doses of 5-ALA. METHODS: Twenty-one patients with suspected malignant glioma were randomly assigned to 0.2, 2, or 20 mg/kg 5-ALA. Investigators were unaware of dose. Intraoperatively, regions of interest were first defined in tumor core, margin, and adjacent white matter under white light. Under violet–blue illumination, the surgeon's impression of fluorescence was recorded per region, followed by spectrometry and biopsy. Plasma was collected after administration and analyzed for 5-ALA and protoporphyrin IX (PPIX) content. RESULTS: The positive predictive value of fluorescence was 100%. Visual and spectrometric fluorescence assessment showed 20 mg/kg to elicit the strongest fluorescence in tumor core and margins, which correlated with cell density. Spectrometric and visual fluorescence correlated significantly. A 10-fold increase in 5-ALA dose (2-20 mg/kg) resulted in a 4-fold increase of fluorescence contrast between marginal tumor and adjacent brain. tmax for 5-ALA was 0.94 h for 20 mg/kg (0.2 kg: 0.50 h, 2 mg/kg: 0.61 h). Integrated PPIX plasma levels were 255.8 and 779.9 mcg*h/l (2 vs 20 mg/kg). Peak plasma concentrations were observed at 1.89 ± 0.71 and 7.83 ± 0.68 h (2 vs 20 mg/kg; average ± Standard Error of Mean [SEM]). CONCLUSION: The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence.

Background Re-excision due to positive margins following breast-conserving surgery (BCS) negatively affects patient outcomes and healthcare costs. The inability to visualize margin involvement is a significant challenge in BCS. 5-Aminolevulinic acid hydrochloride (5-ALA HCl), a non-fluorescent oral prodrug, causes intracellular accumulation of fluorescent porphyrins in cancer cells. This single-center Phase II randomized controlled trial evaluated the safety, feasibility, and diagnostic accuracy of a prototype handheld fluorescence imaging device plus 5-ALA for intraoperative visualization of invasive breast carcinomas during BCS. Methods Fifty-four patients were enrolled and randomized to receive no 5-ALA or oral 5-ALA HCl (15 or 30 mg/kg). Forty-five patients (n = 15/group) were included in the analysis. Fluorescence imaging of the excised surgical specimen was performed, and biopsies were collected from within and outside the clinically demarcated tumor border of the gross specimen for blinded histopathology. Results In the absence of 5-ALA, tissue autofluorescence imaging lacked tumor-specific fluorescent contrast. Both 5-ALA doses caused bright red tumor fluorescence, with improved visualization of tumor contrasted against normal tissue autofluorescence. In the 15 mg/kg 5-ALA group, the positive predictive value (PPV) for detecting breast cancer inside and outside the grossly demarcated tumor border was 100.0% and 55.6%, respectively. In the 30 mg/kg 5-ALA group, the PPV was 100.0% and 50.0% inside and outside the demarcated tumor border, respectively. No adverse events were observed, and clinical feasibility of this imaging device-5-ALA combination approach was confirmed. Conclusions This is the first known clinical report of visualization of 5-ALA-induced fluorescence in invasive breast carcinoma using a real-time handheld intraoperative fluorescence imaging device. Trial registration Clinicaltrials.gov identifier NCT01837225 . Registered 23 April 2013.

Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing real-time anatomic and functional imaging, even through intact peritoneum. Here we present the first-in-human experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands. Iatrogenic injury of the ureters is a feared complication of laparoscopic abdominal surgery. Here the authors present the NIR fluorophore ZW800-1 as an intraoperative imaging agent for ureter mapping, showing its safety, pharmacokinetic properties, and efficacy in healthy volunteers and patients undergoing abdominopelvic surgery.

Some neoplastic lesions remain undetected on colonoscopy. To date, no studies have investigated whether combining cap-assisted colonoscopy with chromoendoscopy increases the adenoma detection rate (ADR). This study aimed to compare cap-assisted chromoendoscopy (CAP/CHROMO) with standard colonoscopy (SC) with respect to their efficacy in detecting adenomas. This prospective, multicenter, randomized controlled trial included asymptomatic subjects aged 45-75 years who underwent colonoscopy for the first time at 14 university hospitals. Subjects were randomized to either the CAP/CHROMO group (with 0.09% indigo carmine spraying using a cap-mounted catheter at the tip of the colonoscope) or the SC group. All polyps were resected, but only histologically confirmed neoplastic lesions were considered for analysis. The primary outcome was ADR, defined as the proportion of subjects with at least 1 adenoma. A total of 1,905 subjects were randomized to the CAP/CHROMO (n = 948) or SC (n = 957) group at 14 centers. Subjects' demographic characteristics were similar between both groups. The CAP/CHROMO group had significantly higher ADR than the SC group (54.4% vs 44.9%, P < 0.001). Significantly, more subjects with at least 1 proximal colon adenoma were identified by CAP/CHROMO (38.6%) than by SC (31.2%) (P = 0.001). The proximal serrated polyp detection rate by CAP/CHROMO was significantly higher in the female subgroup vs SC. However, advanced ADR was not different between the CAP/CHROMO and SC groups (9.3% vs 7.6%, P = 0.180). CAP/CHROMO markedly improved the ADR and enhanced the detection of proximal adenoma. CAP/CHROMO is feasible for routine application and will allow for a more effective surveillance program.

There is rising evidence that in glioblastoma (GBM) surgery an increase of extent of resection (EoR) leads to an increase of patient's survival. Based on histopathological assessments tumor depiction of Gd-DTPA enhancement and 5-aminolevulinic-acid-fluorescence (5-ALA) might be synergistic for intraoperative resection control. To assess impact of additional use of 5-ALA in intraoperative MRI (iMRI) assisted surgery of GBMs on extent of resection (EoR), progression free survival (PFS) and overall survival (OS). We prospectively enrolled 33 patients with GBMs eligible for gross-total-resection(GTR) and performed a combined approach using 5-ALA and iMRI. As a control group, we performed a retrospective matched pair assessment, based on 144 patients with iMRI-assisted surgery. Matching criteria were, MGMT promotor methylation, recurrent surgery, eloquent location, tumor size and age. Only patients with an intended GTR and primary GBMs were included. We calculated Kaplan Mayer estimates to compare OS and PFS using the Log-Rank-Test. We used the T-test to compare volumetric results of EoR and the Chi-Square-Test to compare new permanent neurological deficits (nPND) and general complications between the two groups. Median follow up was 31 months. No significant differences between both groups were found concerning the matching criteria. GTR was achieved significantly more often (p <0.010) using 5-ALA&iMRI (100%) compared to iMRI alone (82%). Mean EoR was significantly (p<0.004) higher in 5-ALA&iMRI-group (99.7%) than in iMRI-alone-group (97.4%) Rate of complications did not differ significantly between groups (21% iMRI-group, 27%5-ALA&iMRI-group, p<0.518). nPND were found in 6% in both groups. Median PFS (6 mo resp.; p<0.309) and median OS (iMRI:17 mo; 5-ALA&iMRI-group: 18 mo; p<0.708)) were not significantly different between both groups. We found a significant increase of EoR when combining 5-ALA&iMRI compared to use of iMRI alone. Maximizing EoR did not lead to an increase of complications or neurological deficits if used with neurophysiological monitoring in eloquent lesions. No final conclusion can be drawn whether a further increase of EoR benefits patient's progression free survival and overall survival.

During development, coordinated cell behaviors orchestrate tissue and organ morphogenesis. Detailed descriptions of cell lineages and behaviors provide a powerful framework to elucidate the mechanisms of morphogenesis. To study the cellular basis of limb development, we imaged transgenic fluorescently-labeled embryos from the crustacean Parhyale hawaiensis with multi-view light-sheet microscopy at high spatiotemporal resolution over several days of embryogenesis. The cell lineage of outgrowing thoracic limbs was reconstructed at single-cell resolution with new software called Massive Multi-view Tracker (MaMuT). In silico clonal analyses suggested that the early limb primordium becomes subdivided into anterior-posterior and dorsal-ventral compartments whose boundaries intersect at the distal tip of the growing limb. Limb-bud formation is associated with spatial modulation of cell proliferation, while limb elongation is also driven by preferential orientation of cell divisions along the proximal-distal growth axis. Cellular reconstructions were predictive of the expression patterns of limb development genes including the BMP morphogen Decapentaplegic. During early life, animals develop from a single fertilized egg cell to hundreds, millions or even trillions of cells. These cells specialize to do different tasks; forming different tissues and organs like muscle, skin, lungs and liver. For more than a century, scientists have strived to understand the details of how animal cells become different and specialize, and have created many new techniques and technologies to help them achieve this goal. Limbs – such as arms, legs and wings – form from small lumps of cells called limb buds. Scientists use the shrimp-like crustacean, Parhyale hawaiensis, to study development, including limb growth. This species is useful because it is easy to grow, manipulate and observe its developing young in the laboratory. Understanding how its limbs develop offers important new insights into how limbs develop in other animals too. Wolff, Tinevez, Pietzsch et al. have now combined advanced microscopy with custom computer software, called Massive Multi-view Tracker (MaMuT) to investigate this. As limbs develop in Parhyale, the MaMuT software tracks how cells behave, and how they are organized. This analysis revealed that for cells to produce a limb bud, they need to split at an early stage into separate groups. These groups are organized along two body axes, one that goes from head to tail, and one that runs from back to belly. The limb grows perpendicular to these main body axes, along a new ‘proximal-distal’ axis that goes from nearest to furthest from the body. Wolff et al. found that the cells that contribute to the extremities of the limb divide faster than the ones that stay closer to the body. Finally, the results show that when cells in a limb divide, they mostly divide along the proximal-distal axis, producing one cell that is further from the body than the other. These cell activities may help limbs to get longer as they grow. Notably, the groups of cells seen by Wolff et al. were expressing genes that had previously been identified in developing limbs. This helps to validate the new results and to identify which active genes control the behaviors of the analyzed cells. These findings reveal new ways to study animal development. This approach could have many research uses and may help to link the mechanisms of cell biology to their effects. It could also contribute to new understanding of developmental and genetic conditions that affect human health.

BackgroundIntraoperative indocyanine green (ICG) fluorescence imaging has been shown to be a new and innovative way to illustrate the optimal resection margin in hepatectomy for hepatocellular carcinoma. This study investigated its accuracy in resection margin determination by looking into the correlation of ICG intensity gradients with pathological examination results of resected specimens.MethodsThis was a prospective, single-center, non-randomized controlled study. Patients who had liver tumors indicating liver resection were recruited. The hypothesis was that the use of intraoperative near-infrared/ICG fluorescence imaging would be a promising guiding tool for removing hepatocellular carcinoma with a better resection margin. Patients were given ICG (0.25 mg/kg) 1 day before operation. Resected specimens were inspected under a fluorescent imaging system. Biopsies were taken from tumors and normal tissue. Color signals obtained from ICG fluorescence imaging were compared with biopsies for analysis.ResultsTwenty-two patients were recruited for study. The median size of their tumors was 2.25 cm. One patient had resection margin involvement. Under ICG fluorescence, the tumors typically lighted up as yellow color, wrapped by a zone of green color. Tumors of 17 patients (77.3%) displayed yellow color and were confirmed malignancy, while tumors of 12 patients (54.5%) displayed green color and were confirmed malignancy. Receiver operating characteristic curve was used to measure the sensitivity and specificity of the green color to look for a clear resection margin. The area under the curve was 85.3% (p = 0.019, 95% confidence interval 0.696–1.000), with a sensitivity of 0.706 and specificity of 1.000.ConclusionThe use of ICG fluorescence can be helpful in determining resection margins. Resection of tumor should include complete resection of the green zone shown in the fluorescence image.

Background The clinical use of indocyanine green (ICG) in laparoscopic radical gastrectomy for gastric cancer remains at an exploratory stage. Methods Participants with resectable gastric adenocarcinoma were randomly allocated in a 1:1 ratio. The primary outcome is the number of retrieved lymph nodes (LNs) and has been reported. Herein, we report the 5-year overall survival (OS) rate, 5-year disease-free survival (DFS) rate, and related recurrence patterns. Results Total 258 patients (ICG group, 129; non-ICG group, 129) were included in the final per-protocol analysis. The 5-year OS and DFS rate of the ICG group were superior to those of the non-ICG group (all log-rank P  < 0.05). After a 5-year follow-up, the ICG group had a considerably lower cumulative recurrence rate (26/129, 20.2%) than the non-ICG group (44/129, 34.1%) (Gray’s test P  = 0.011), with a risk difference of − 0.140. Stratified by recurrence types, the ICG group exhibited a notably lower cumulative incidence of locoregional recurrence in comparison to the non-ICG group (ICG vs. non-ICG: 1.6% vs. 7.8%; risk difference = − 0.062; Gray’s test P  = 0.019). Dynamic analysis revealed that, in comparison to the ICG group, the non-ICG group had an earlier peak time and higher peak hazard of overall recurrence (ICG vs. non-ICG: peak time: 13.9 vs. 13.1 months; peak hazard: 0.0065 vs. 0.0138). Furthermore, landmark analysis indicated that the early recurrence (within 2 years) rate in the non-ICG group was 26.8%, which was significantly higher than the 13.1% in the ICG group ( P  = 0.006). Conclusions ICG-guided lymphadenectomy not only significantly improved the 5-year OS and DFS but also noticeably reduced the cumulative incidence of early recurrence. These findings support the routine use of ICG fluorescence-guided lymphadenectomy in laparoscopic radical gastrectomy. Trial registration ClinicalTrials.gov, NCT03050879. Key points Question Can indocyanine green (ICG) fluorescence imaging-guided laparoscopic lymphadenectomy during laparoscopic radical gastrectomy in patients with gastric cancer improve the long-term oncological outcomes than conventional lymphadenectomy? Findings In this randomized clinical trial, 5-year OS, DFS, and cumulative incidence of recurrence were better in the ICG group compared with the non–ICG group. Meaning ICG fluorescence imaging-guided lymphadenectomy not only significantly improved the 5-year OS and DFS but also noticeably reduced the recurrence hazard. The routine application of ICG fluorescence-guided lymphadenectomy is recommended for laparoscopic radical gastrectomy.