The Effect of Creatine Nitrate and Caffeine Individually or Combined on Exercise Performance and Cognitive Function: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial.

This study examined the effect of creatine nitrate and caffeine alone and combined on exercise performance and cognitive function in resistance-trained athletes. In a double-blind, randomized crossover trial, twelve resistance-trained male athletes were supplemented with 7 days of creatine nitrate (5 g/day), caffeine (400 mg/day), and a combination of creatine nitrate and caffeine. The study involved twelve resistance-trained male athletes who initially provided a blood sample for comprehensive safety analysis, including tests for key enzymes and a lipid profile, and then performed standardized resistance exercises-bench and leg press at 70% 1RM-and a Wingate anaerobic power test. Cognitive function and cardiovascular responses were also examined forty-five minutes after supplementation. Creatine nitrate and caffeine that were co-ingested significantly enhanced cognitive function, as indicated by improved scores in the Stroop Word-Color Interference test (p = 0.04; effect size = 0.163). Co-ingestion was more effective than caffeine alone in enhancing cognitive performance. In contrast, no significant enhancements in exercise performance were observed. The co-ingestion of creatine nitrate and caffeine improved cognitive function, particularly in cognitive interference tasks, without altering short-term exercise performance. Furthermore, no adverse events were reported. Overall, the co-ingestion of creatine nitrate and caffeine appears to enhance cognition without any reported side effects for up to seven days.

Single-institution experience of 500 pulmonary resections guided by intraoperative molecular imaging.

OBJECTIVE: Intraoperative molecular imaging (IMI) using tumor-targeted optical contrast agents can improve thoracic cancer resections. There are no large-scale studies to guide surgeons in patient selection or imaging agent choice. Here, we report our institutional experience with IMI for lung and pleural tumor resection in 500 patients over a decade. METHODS: Between December 2011 and November 2021, patients with lung or pleural nodules undergoing resection were preoperatively infused with 1 of 4 optical contrast tracers: EC17, TumorGlow, pafolacianine, or SGM-101. Then, during resection, IMI was used to identify pulmonary nodules, confirm margins, and identify synchronous lesions. We retrospectively reviewed patient demographic data, lesion diagnoses, and IMI tumor-to-background ratios (TBRs). RESULTS: Five hundred patients underwent resection of 677 lesions. We found that there were 4 types of clinical utility of IMI: detection of positive margins (n = 32, 6.4% of patients), identification of residual disease after resection (n = 37, 7.4%), detection of synchronous cancers not predicted on preoperative imaging (n = 26, 5.2%), and minimally invasive localization of nonpalpable lesions (n = 101 lesions, 14.9%). Pafolacianine was most effective for adenocarcinoma-spectrum malignancies (mean TBR, 2.84), and TumorGlow was most effective for metastatic disease and mesothelioma (TBR, 3.1). False-negative fluorescence was primarily seen in mucinous adenocarcinomas (mean TBR, 1.8), heavy smokers (>30 pack years; TBR, 1.9), and tumors greater than 2.0 cm from the pleural surface (TBR, 1.3). CONCLUSIONS: IMI may be effective in improving resection of lung and pleural tumors. The choice of IMI tracer should vary by the surgical indication and the primary clinical challenge.

Robotic Extended Right Hepatectomy for Colorectal Liver Metastasis.

BACKGROUND: Advantages of minimally invasive compared with open hepatobiliary surgery include quicker functional recovery, decreased postoperative length of stay, and decreased postoperative opioid use. As more complex operations are approached in minimally invasive fashion, it is imperative to maintain safety and excellent oncologic outcomes. METHODS: In this video, we demonstrate the key principles in performing a safe robotic extended right hepatectomy for colorectal liver metastasis following sound oncologic principles. RESULTS: Key preoperative considerations include (1) early referral to a hepatobiliary surgeon, (2) careful review of cross-sectional imaging to identify the relationship of tumors to major vasculature and any aberrant vascular anatomy, and (3) liver volumetry for every right hepatectomy to determine the need for future liver remnant volume augmentation. Key intraoperative techniques include (1) liberal use of ultrasound before and during transection to determine the relationship of major vasculature to tumor to preserve liver parenchyma without compromising tumor margins, (2) external retraction with vessel loops placed on either side of the transection line as stay sutures to facilitate parenchymal transection, and (3) a crush clamp technique to safely identify and control crossing vessels while dividing liver parenchyma. CONCLUSIONS: With proper preoperative planning and intraoperative use of these techniques, the benefits of a minimally invasive approach can be achieved while maintaining excellence in surgical quality and safety.

Comparative Experience of Short-wavelength Versus Long-wavelength Fluorophores for Intraoperative Molecular Imaging of Lung Cancer.

BACKGROUND: Intraoperative molecular imaging (IMI) using tumor-targeted optical contrast agents can improve cancer resections. The optimal wavelength of the IMI tracer fluorophore has never been studied in humans and has major implications for the field. To address this question, we investigated 2 spectroscopically distinct fluorophores conjugated to the same targeting ligand. METHODS: Between December 2011 and November 2021, patients with primary lung cancer were preoperatively infused with 1 of 2 folate receptor-targeted contrast tracers: a short-wavelength folate-fluorescein (EC17; λ em =520 nm) or a long-wavelength folate-S0456 (pafolacianine; λ em =793 nm). During resection, IMI was utilized to identify pulmonary nodules and confirm margins. Demographic data, lesion diagnoses, and fluorescence data were collected prospectively. RESULTS: Two hundred eighty-two patients underwent resection of primary lung cancers with either folate-fluorescein (n=71, 25.2%) or pafolacianine (n=211, 74.8%). Most tumors (n=208, 73.8%) were invasive adenocarcinomas. We identified 2 clinical applications of IMI: localization of nonpalpable lesions (n=39 lesions, 13.8%) and detection of positive margins (n=11, 3.9%). In each application, the long-wavelength tracer was superior to the short-wavelength tracer regarding depth of penetration, signal-to-background ratio, and frequency of event. Pafolacianine was more effective for detecting subpleural lesions (mean signal-to-background ratio=2.71 vs 1.73 for folate-fluorescein, P <0.0001). Limit of signal detection was 1.8 cm from the pleural surface for pafolacianine and 0.3 cm for folate-fluorescein. CONCLUSIONS: Long-wavelength near-infrared fluorophores are superior to short-wavelength IMI fluorophores in human tissues. Therefore, future efforts in all human cancers should likely focus on long-wavelength agents.

Iterative Changes in Risk-Stratified Pancreatectomy Clinical Pathways and Accelerated Discharge After Pancreaticoduodenectomy.

BACKGROUND: Previous implementation of risk-stratified pancreatectomy clinical pathways (RSPCPs) decreased length of stay (LOS) following pancreaticoduodenectomy (PD). This study's primary aim was to measure the association of iterative RSPCP revisions with accelerated discharge and early postoperative outcomes. METHODS: This is a retrospective cohort study of a prospectively maintained surgical database (10/2016-9/2020). In February 2019, revised RSPCPs were implemented with earlier nasogastric tube (NGT) removal (postoperative day [POD] 1 for low risk; POD 2 for high risk) and updated drain fluid amylase cutoffs for POD 1/POD 3 removal. Perioperative outcomes between original and revised pathways were compared. Predictors of accelerated discharge (defined as ≤ POD 5 for low risk; ≤ POD 6 for high risk) were identified. RESULTS: There were 233 (36% high risk) patients in original and 131 (32% high risk) in revised RSPCPs. After revision, the rate of POD 1 NGT removal was higher while POD ≤ 3 drain removal was similar. Median LOS decreased for low risk (5 vs. 6 days, p = 0.011) and high risk (6 vs. 9 days, p = 0.005) with no increase in delayed gastric emptying, postoperative pancreatic fistula, or readmissions. With POD 1 NGT removal, diet tolerance was earlier without increased NGT reinsertions. In low-risk patients, younger age, POD 1 NGT removal, and POD ≤ 3 drain removal were independent predictors of accelerated discharge. In high-risk patients, POD 1 NGT removal and POD ≤ 3 drain removal were independent predictors of accelerated discharge. CONCLUSIONS: Following iterative revisions in RSPCPs, LOS after PD decreased further without increasing readmissions, and NGTs were removed earlier without increased reinsertions. Early NGT and drain removal are modifiable practices within RSPCPs that are associated with accelerated discharge.

Introduction to the Special Issue: Urban Mobility and Crime Patterns.

This Special Issue is a collection of seven papers that seek to better our understanding of how urban mobility relates to crime patterns, and how day to day movement of people in urban spaces (urban mobility) is related to spatio-temporal patterns of crime. It focusses on urban mobility, or the dynamic movement of people in relation to crime risk. Moreover, it questions how to best measure this risk using an appropriate crime denominator. Building on the work of Sarah Boggs, this special issue contends that we need more than an appropriate denominator related to the type of crime we are measuring, for example violence based on the number of potential victims present (the exposed or ambient population), or the number of burglaries per households in an area, or the number of shoplifting offences per number of shops present. It argues that this denominator needs to be both 'crime type' appropriate, and to be spatially and temporally appropriate. When considering urban mobility as flows of people, the challenge is that the denominator can not be considered as a fixed or static concept, and that we need to consider the 'dynamic denominator' challenge. Indeed, crime hot spots which do not account for dynamic denominators may be misleading for resource prioritisation. This special issue explores a range of potential solutions to this including mobile/cell phone data, transportation data, land use data, and other possible measures to address this.

Robotic Completion Radical Cholecystectomy with Fluorescence Guidance.

The application of minimally invasive surgery (MIS) techniques in the treatment of hepatobiliary malignancies offers advantages of shorter length of stay, quicker functional recovery, and decreased need for postoperative opioids. However, MIS completion radical cholecystectomy for incidentally diagnosed gallbladder cancer can be challenging due to a reoperative field and lack of tactile feedback. This video demonstrates the utility of the robotic platform and highlights the ways in which it assists surgeons in overcoming these limitations. These include (1) versatile wristed instruments and excellent visualization that facilitate a thorough regional lymphadenectomy; and (2) built-in fluorescence imaging technology that can be used with intravenous indocyanine green (ICG) to confirm porta hepatis anatomy in a reoperative field. ICG pharmacokinetics enable fluorescence angiography 15-20 s after ICG injection and fluorescence cholangiography 15-20 min after ICG injection as the dye accumulates in the biliary system. Systematic and intentional application of these techniques allows for the safe performance of robotic completion radical cholecystectomy following sound oncologic principles, with excellent perioperative outcomes.

Intraoperative Molecular Imaging Utilizing a Folate Receptor-Targeted Near-Infrared Probe Can Identify Macroscopic Gastric Adenocarcinomas.

PURPOSE: Current methods of assessing disease burden in gastric adenocarcinoma are imperfect. Improved visualization during surgery with intraoperative molecular imaging (IMI) could improve gastric adenocarcinoma staging and guide surgical decision-making. The goal of this study was to evaluate if IMI with a folate receptor-targeted near-infrared fluorescent agent, OTL38, could identify gastric adenocarcinomas during surgery. PROCEDURES: Five patients were enrolled in an IMI clinical trial. Patients received a folate receptor-targeted near-infrared dye (OTL38) 1.5-6 h prior to surgery. During staging laparoscopy and gastric resection, IMI was utilized to identify the primary tumor and any fluorescent lymph nodes. Resected tumors were analyzed for folate receptor alpha (FRα) and CD68 expression using immunohistochemistry. Microscopic OTL38 accumulation was examined with immunofluorescence. RESULTS: Four out of five patients underwent total or subtotal gastrectomy; one had a staging laparoscopy only. All four patients who underwent gastric resection had invasive gastric adenocarcinoma; three had fluorescent tumors, mean tumor to background ratio (TBR) 4.1 ± 2.9. The one patient with a non-fluorescent tumor had a T1a tumor with two 0.4 cm tumor foci within a larger polyp. In each case with a fluorescent tumor, the fluorescence was evident from the exterior of the stomach. Two of the fluorescent tumors had modest FRα expression and no CD68 expression. One fluorescent tumor had high CD68 expression and no FRα expression. CONCLUSIONS: Intraoperative molecular imaging of gastric adenocarcinoma with OTL38 is feasible. Further studies should evaluate the clinical utility of this technique.

Surgical Boot Camps Increases Confidence for Residents Transitioning to Senior Responsibilities.

OBJECTIVE: Surgical boot camps enhance the confidence of medical students and surgical interns. The impact of boot camps on the confidence of post-graduate year (PGY) 2 residents is unknown. We hypothesized that a postinternship boot camp would improve the confidence of PGY-2 residents in managing their newfound responsibilities. We also hypothesized that the effect of a tailored high-impact boot camp would persist over time. DESIGN: A 2-hour boot camp at our simulation center was implemented for PGY-2 residents in 2016 and 2017. Confidence in handling boot camp scenarios was measured on a 1 to 5 Likert scale before and after the boot camp. Three-month follow-up was assessed in the 2017 cohort. PARTICIPANTS: Thirty-one PGY-2 residents (n = 16 in 2016, n = 15 in 2017) completed the boot camp. RESULTS: Residents reported increased confidence in placing central lines (p < 0.001), placing chest tubes (p = 0.01), managing emergency airways (p < 0.001), running a code (p = 0.03), and fulfilling the role of in-house senior resident (p < 0.001). Three-month follow-up in 2017 (n = 10) demonstrated no difference in confidence compared to postboot camp results. CONCLUSIONS: Boot camps can durably improve confidence in skills expected of PGY-2 residents assuming in-house senior resident responsibilities.

Intraoperative near-infrared imaging can identify canine mammary tumors, a spontaneously occurring, large animal model of human breast cancer.

INTRODUCTION: Current methods of intraoperative margin assessment in breast conserving surgery are impractical, unreliable, or time consuming. We hypothesized that intraoperative near-infrared (NIR) imaging with an FDA-approved NIR optical contrast agent could identify canine mammary tumors, a spontaneous large animal model of human breast cancer, during surgery. METHODS: Dogs with mammary tumors underwent a standard of care lumpectomy or mastectomy with wide surgical margins 20 hours after indocyanine green administration (3 mg/kg IV). During surgery, NIR imaging was performed on tumors and wound margins in situ and tumors and lymph nodes ex vivo. Following resection, the wound bed was examined for residual fluorescence. Fluorescence intensity was determined by signal-to-background ratio (SBR). All tumors, areas of residual fluorescence, and lymph nodes underwent histopathologic analysis. RESULTS: There were 41 mammary tumors in 16 female dogs. Twenty tumors were malignant and 21 were benign. Twenty-eight tumors were fluorescent (mean SBR 1.5±0.2). Sensitivity of fluorescence for all malignant tumors was 80% (16/20) and 93.3% (14/15) for malignant tumors > 2 cm. Specificity for malignancy was low (< 2cm = 55%; > 2cm = 30%). Tumors > 2 cm were more likely to be fluorescent (OR 6.05, 95% CI 1.50-24.44, P = 0.011) but not more likely to be malignant (OR 3.09, 95% CI 0.86-11.14, P = 0.085) than tumors ≤ 2 cm. Four out of seven inguinal lymph nodes excised in the mastectomy specimen fluoresced. All four drained malignant tumors; however only 2/4 contained metastatic disease. CONCLUSION: Systemic ICG accumulates reliably in malignant canine mammary tumors > 2 cm. Although no tumor margins fluoresced, a wider margin of normal tissue is removed in canine mastectomy, making direct comparisons with breast conserving surgery difficult. Targeted NIR imaging agents are likely required to improve detection of smaller tumors and improve the specificity of NIR imaging for residual disease and metastatic lymph node detection.

Comparison of a Short Versus Long Stokes Shift Near-Infrared Dye During Intraoperative Molecular Imaging.

PURPOSE: Intraoperative molecular imaging (IMI) utilizes optical dyes that accumulate within tumors to assist with detection during a cancer operation. IMI can detect disease not visualized preoperatively, as well as positive margins. However, these dyes are limited by autofluorescence, signal reflection, and photon-scatter. We hypothesize that a novel dye with a wide separation between excitation and emission spectra, SS180, would help overcome these obstacles. PROCEDURES: Two targeted molecular contrast agents, OTL38 and SS180, were selected for this study. Both dyes had the same targeting ligand to folate receptor alpha (FRα). OTL38, a well-annotated IMI agent in human trials, has a Stokes shift of 22 nm, whereas SS180, the new dye, has a Stokes shift of 129 nm. Cell lines were tested for FRα expression and incubated with dyes to demonstrate receptor-dependent binding. Cells were incubated in various concentrations of the dyes to compare dose- and time-dependent binding. Finally, cells tagged with the dyes were injected subcutaneously in a murine model to estimate tumor burden necessary to generate fluorescent signal. RESULTS: Cellular studies demonstrated that SS180 binds cells in a dose-, receptor-, and time-dependent manner and exhibits higher mean fluorescence intensities by flow cytometry when compared with OTL38 for each time point and concentration. In an in vivo flank tumor model, SS180 had a higher tumor-to-background ratio (TBR) than OTL38, though not statistically significant (p = 0.08). Ex vivo, OTL38 had a higher TBR than SS180 (p = 0.02). The subcutaneous model revealed that SS180 had a higher TBR at 5 × 106 cells than OTL38 (p = 0.05). No toxicity was observed in the animals. CONCLUSIONS: SS180 exhibits greater TBRs in vivo, but not ex vivo. These findings suggest that SS180 may have weaker fluorescence, but superior contrast. Studies in large animal models and clinical trials may better elucidate the clinical value of a long Stokes shift.

Near-infrared intraoperative imaging for minimally invasive pulmonary metastasectomy for sarcomas.

BACKGROUND: Complete pulmonary metastasectomy for sarcoma metastases provides patients an opportunity for long-term survival and possible cure. Intraoperative localization of preoperatively identified metastases and identification of occult lesions can be challenging. In this trial, we evaluated the efficacy of near-infrared (NIR) intraoperative imaging using second window indocyanine green during metastasectomy to identify known metastases and to detect occult nodules. METHODS: Thirty patients with pulmonary nodules suspicious for sarcoma metastases were enrolled in an open-label, feasibility study (NCT02280954). All patients received intravenous indocyanine green (5 mg/kg) 24 hours before metastasectomy. Patients 1 through 10 (cohort 1) underwent metastasectomy via thoracotomy to assess fluorescence patterns of nodules detected by traditional methods (preoperative imaging and intraoperative visualization/bimanual palpation). After confirming reliability within cohort 1, patients 11 through 30 (cohort 2) underwent video-assisted thoracic surgery metastasectomy with NIR imaging. RESULTS: In cohort 1, 14 out of 16 preoperatively identified pulmonary metastases (87.5%) displayed tumor fluorescence. Nonfluorescent metastases were deeper than fluorescent metastases (2.1 cm vs 1.3 cm; P = .03). Five out of 5 metastases identified during thoracotomy displayed fluorescence. NIR imaging identified 3 additional occult lesions in this cohort. In cohort 2, 33 out of 37 known pulmonary metastases (89.1%) displayed fluorescence. Nonfluorescent tumors were deeper than 2.0 cm (P = .007). NIR imaging identified 24 additional occult lesions. Of 24 occult lesions, 21 (87.5%) were confirmed metastases and the remaining 3 nodules were lymphoid aggregates. CONCLUSIONS: NIR intraoperative imaging with indocyanine green (5 mg/kg and 24 hours before surgery) localizes known sarcoma pulmonary metastases and identifies otherwise occult lesions. This approach may be a useful intraoperative adjunct to improve metastasectomy.

Intraoperative Near-infrared Imaging Can Identify Neoplasms and Aid in Real-time Margin Assessment During Pancreatic Resection.

OBJECTIVE: To determine if intraoperative near-infrared (NIR) imaging carries benefit in resection of pancreatic neoplasms. BACKGROUND: Resection of pancreatic malignancies is hindered by high rates of local and distant recurrence from positive margins and unrecognized metastases. Improved tumor visualization could improve outcomes. We hypothesized that intraoperative NIR imaging with a clinically approved optical contrast agent could serve as a useful adjunct in assessing margins and extent of disease during pancreatic resections. METHODS: Twenty patients were enrolled in an open-label clinical trial from July 2016 to May 2018. Subjects received second window indocyanine green (ICG) (2.5-5 mg/kg) 24 hours prior to pancreatic resection. NIR imaging was performed during staging laparoscopy and after pancreas mobilization in situ and following resection ex vivo. Tumor fluorescence was quantified using tumor-to-background ratio (TBR). Fluorescence at the specimen margin was compared to pathology evaluation. RESULTS: Procedures included 9 pancreaticoduodenectomies, 10 distal pancreatectomies, and 1 total pancreatectomy; 21 total specimens were obtained. Three out of 8 noninvasive tumors were fluorescent (mean TBR 2.59 ±â€Š2.57). Twelve out of 13 invasive malignancies (n = 12 pancreatic adenocarcinoma, n = 1 cholangiocarcinoma) were fluorescent (mean TBR 4.42 ±â€Š2.91). Fluorescence at the transection margin correlated with final pathologic assessment in 12 of 13 patients. Following neoadjuvant therapy, 4 of 5 tumors were fluorescent; these 4 tumors showed no treatment response on pathology assessment. One tumor had a significant treatment response and showed no fluorescence. CONCLUSIONS: Second window ICG reliably accumulates in invasive pancreatic malignancies and provides real-time feedback during pancreatectomy. NIR imaging may help to assess the response to neoadjuvant therapy.

Evaluation of Aminolevulinic Acid-Derived Tumor Fluorescence Yields Disparate Results in Murine and Spontaneous Large Animal Models of Lung Cancer.

Fluorescence guided surgery is an emerging technology that may improve accuracy of pulmonary resection for non-small cell lung cancer (NSCLC). Herein we explore optical imaging for NSCLC surgery using the well-studied protoporphyrin IX (PPIX)/5-aminiolevulinic acid (5-ALA) system. More specifically, we evaluate fluorescent patterns observed when using (1) commonly utilized in vitro and murine NSCLC models and with (2) spontaneous canine NSCLCs, which closely mimic human disease. Using flow cytometry and fluorescent microscopy, we confirmed that NSCLC models fluoresce after exposure to 5-ALA in vitro. High levels of fluorescence were similarly observed in murine tumors within 2 hours of systemic 5-ALA delivery. When evaluating this approach in spontaneous canine NSCLC, tumor fluorescence was observed in 6 of 7 canines. Tumor fluorescence, however, was heterogenous owing to intratumoral variations in cellularity and necrosis. Margin and lymph node detection was inaccurate. These data demonstrate the importance of incorporating reliable cancer models into preclinical evaluations of optical agents. Utilization of spontaneous large animal models of cancer may further provide an important intermediate in the path to human translation of optical contrast agents.

A clinical trial of intraoperative near-infrared imaging to assess tumor extent and identify residual disease during anterior mediastinal tumor resection.

BACKGROUND: The management of most solid tumors of the anterior mediastinum involves complete resection. Because of their location near mediastinal structures, wide resection is not possible; therefore, surgeons must use subjective visual and tactile cues to determine disease extent. This clinical trial explored intraoperative near-infrared (NIR) imaging as an approach to improving tumor delineation during mediastinal tumor resection. METHODS: Twenty-five subjects with anterior mediastinal lesions suspicious for malignancy were enrolled in an open-label feasibility trial. Subjects were administered indocyanine green (ICG) at a dose of 5 mg/kg, 24 hours before resection (via a technique called TumorGlow). The NIR imaging systems included Artemis (Quest, Middenmeer, the Netherlands) and Iridium (VisionSense Corp, Philadelphia, Pennsylvania). Intratumoral ICG uptake was evaluated. The clinical value was determined via an assessment of the ability of NIR imaging to detect phrenic nerve involvement or incomplete resection. Clinical and histopathologic variables were analyzed to determine predictors of tumor fluorescence. RESULTS: No drug-related toxicity was observed. Optical imaging added a mean of 10 minutes to case duration. Among the subjects with solid tumors, 19 of 20 accumulated ICG. Fluorescent tumors included thymomas (n = 13), thymic carcinomas (n = 4), and liposarcomas (n = 2). NIR feedback improved phrenic nerve dissection (n = 4) and identified residual disease (n = 2). There were no false-positives or false-negatives. ICG preferentially accumulated in solid tumors; this was independent of clinical and pathologic variables. CONCLUSIONS: NIR imaging for anterior mediastinal neoplasms is safe and feasible. This technology may provide a real-time tool capable of determining tumor extent and specifically identify phrenic nerve involvement and residual disease.

Kinetics of indocyanine green: Optimizing tumor to normal tissue fluorescence in image-guided oral cancer surgery applications.

BACKGROUND: The study aimed to define indocyanine green (ICG) kinetics to determine the optimal ICG dose and surgical time for near-infrared fluorescence-guided oral cancer surgery. METHODS: Spectrometer and grayscale digital imaging were used to quantify the ICG kinetics in 12 patients with oral cancer. The fluorescence intensity and signal-to-background ratio (SBR) of tumor and normal tissue were tested at 1, 6, and 24 hours after ICG injection. RESULTS: The greatest contrast in the fluorescence intensity between tumor and normal tissue was observed at 6 hours (P < .01), and of three dose groups (0.5, 0.75, and 1.0 mg/kg), 0.75 mg/kg showed the highest SBR (2.06 ± 0.23) after ICG injection. CONCLUSIONS: Fluorescence quantification based on spectrometry and grayscale imaging could be effective in determining the optimal ICG dose and surgical time after ICG injection in this cohort of patients with oral cancer.

A Clinical Trial of TumorGlow to Identify Residual Disease During Pleurectomy and Decortication.

BACKGROUND: Macroscopic complete resection can improve survival in a select group of patients with malignant pleural mesothelioma. During resection, differentiating residual tumor from inflammation or scar can be challenging. This trial evaluated near-infrared (NIR) intraoperative imaging using TumorGlow (a novel NIR imaging approach utilizing high-dose indocyanine green and delayed imaging) technology to improve detection of macroscopic residual disease. METHODS: Twenty subjects were enrolled in an open-label clinical trial of NIR intraoperative imaging with TumorGlow (Indocyanine Green for Solid Tumors [NCT02280954]). Twenty-four hours before pleural biopsy or pleurectomy and decortication (P/D), patients received intravenous indocyanine green. All specimens identified during standard-of-care surgical resection and with NIR imaging underwent histopathologic profiling and correlative microscopic fluorescent tomographic evaluation. For subjects undergoing P/D (n = 13), the hemithorax was evaluated with NIR imaging during P/D to assess for residual disease. When possible, additional fluorescent lesions were resected. RESULTS: Of 203 resected specimens submitted for evaluation, indocyanine green accumulated within 113 of 113 of resected mesothelioma specimens, with a mean signal-to-background fluorescence ratio of 3.1 (SD, 2.2 to 4.8). The mean signal-to-background fluorescence ratio of benign tissues was 2.2 (SD, 1.4 to 2.4), which was significantly lower than in malignant specimens (p = 0.001). NIR imaging identified occult macroscopic residual disease in 10 of 13 subjects. A median of 5.6 resectable residual deposits per patient (range, 0 to 11 deposits per patient), with a mean size of 0.3 cm (range, 0.1 to 1.5 cm), were identified. CONCLUSIONS: TumorGlow for malignant pleural mesothelioma is safe and feasible. Excellent sensitivity allows for to reliable detection of macroscopic residual disease during cytoreductive surgical procedures.

Optimization of Second Window Indocyanine Green for Intraoperative Near-Infrared Imaging of Thoracic Malignancy.

BACKGROUND: Near-infrared (NIR) imaging using the second time window of indocyanine green (ICG) allows localization of pulmonary, pleural, and mediastinal malignancies during surgery. Based on empirical evidence, we hypothesized that different histologic tumor types fluoresce optimally at different ICG doses. STUDY DESIGN: Patients with thoracic tumors biopsy-proven or suspicious for malignancy were enrolled in an NIR imaging clinical trial. Patients received a range of ICG doses 1 day before surgery: 1 mg/kg (n = 8), 2 mg/kg (n = 8), 3 mg/kg (n = 13), 4 mg/kg (n = 8), and 5 mg/kg (n = 8). Intraoperatively, NIR imaging was performed. The endpoint was to identify the highest tumor-to-background fluorescence ratio (TBR) for each tumor type at each dose. Final pathology confirmed tumor histology. RESULTS: Of 45 patients, 41 had malignancies (18 non-small cell lung cancers [NSCLC], 3 pulmonary neuroendocrine tumors, 13 thoracic metastases, 4 thymomas, 3 mesotheliomas). At doses of 4 to 5 mg/kg, the TBR from primary NSCLC vs other malignancies was no different (2.70 vs 3.21, p = 1.00). At doses of 1 to 3 mg/kg, the TBR was greater for the NSCLCs (3.19 vs 1.49, p = 0.0006). Background fluorescence from the heart or ribs was observed in 1 of 16 cases at 1 to 2 mg/kg, 5 of 13 cases at 3 mg/kg, and 14 of 16 cases at 4 to 5 mg/kg; this was a major determinant of dose optimization. CONCLUSIONS: This is the first study to demonstrate that the optimal NIR contrast agent dose varies by tumor histology. Lower dose ICG (2 to 3 mg/kg) is superior for nonprimary lung cancers, and high dose ICG (4 to 5 mg/kg) is superior for lung cancers. This will have major implications as more intraoperative imaging trials surface in other specialties, will significantly reduce costs and may facilitate wider application.