Transcriptomic analysis-guided assessment of precision-cut tumor slices (PCTS) as an ex-vivo tool in cancer research.

With cancer immunotherapy and precision medicine dynamically evolving, there is greater need for pre-clinical models that can better replicate the intact tumor and its complex tumor microenvironment (TME). Precision-cut tumor slices (PCTS) have recently emerged as an ex vivo human tumor model, offering the opportunity to study individual patient responses to targeted therapies, including immunotherapies. However, little is known about the physiologic status of PCTS and how culture conditions alter gene expression. In this study, we generated PCTS from head and neck cancers (HNC) and mesothelioma tumors (Meso) and undertook transcriptomic analyses to understand the changes that occur in the timeframe between PCTS generation and up to 72 h (hrs) in culture. Our findings showed major changes occurring during the first 24 h culture period of PCTS, involving genes related to wound healing, extracellular matrix, hypoxia, and IFNγ-dependent pathways in both tumor types, as well as tumor-specific changes. Collectively, our data provides an insight into PCTS physiology, which should be taken into consideration when designing PCTS studies, especially in the context of immunology and immunotherapy.

Red blood cells function as reservoirs of tumor DNA.

Novel screening techniques for early detection of lung cancer are urgently needed. Profiling circulating tumor cell-free DNA (ctDNA) has emerged as a promising tool for biopsy-free tumor genotyping. However, both the scarcity and short half-life of ctDNA substantially limit the sensitivity and clinical utility of ctDNA detection methodologies. Our discovery that red blood cells (RBCs) sequester mitochondrial DNA opens a new avenue for detecting circulating nucleic acids, as RBCs represent an unrecognized reservoir of circulating nucleic acid. Here, we show that RBCs acquire tumor DNA following coculture with lung cancer cell lines harboring Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) mutations. RBC-bound tumor DNA is detectable in patients with early-stage non-small cell lung cancer (NSCLC) but not in healthy controls by qPCR. Our results collectively uncover a previously unrecognized yet easily accessible reservoir of tumor DNA, offering a promising foundation for future RBC-based tumor diagnostics.NEW & NOTEWORTHY We present a novel method for lung cancer detection by revealing RBCs as a reservoir for tumor DNA, overcoming the limitations of current circulating tumor ctDNA methodologies. By demonstrating that RBCs can capture tumor DNA, including critical mutations found in lung cancer, we provide a promising, biopsy-free avenue for early cancer diagnostics. This discovery opens up exciting possibilities for developing RBC-based diagnostic tools, significantly enhancing the sensitivity and clinical utility of noninvasive cancer detection.

Precision Oncology in Lung Cancer Surgery.

Precision in lung cancer surgery is our ability to use the most cutting edge and up to date information to provide personalized and targeted surgical care to our patients. It aims to tailor patient care to patient and tumor characteristics and susceptibilities as well as to optimize the ways treatments are administered. This may include specific perioperative medical treatment, changing operative techniques to more minimally invasive ones if the situation permits, performing sub-anatomical surgeries when possible, and using innovative tumor visualization methods to enhance detection of previously occult disease to ultimately decrease the extent of the planned resection.

Clinical PDT dose dosimetry for pleural Photofrin-mediated photodynamic therapy.

Significance: Photodynamic therapy (PDT) is an established cancer treatment utilizing light-activated photosensitizers (PS). Effective treatment hinges on the PDT dose-dependent on PS concentration and light fluence-delivered over time. We introduce an innovative eight-channel PDT dose dosimetry system capable of concurrently measuring light fluence and PS concentration during treatment. Aim: We aim to develop and evaluate an eight-channel PDT dose dosimetry system for simultaneous measurement of light fluence and PS concentration. By addressing uncertainties due to tissue variations, the system enhances accurate PDT dosimetry for improved treatment outcomes. Approach: The study positions eight isotropic detectors strategically within the pleural cavity before PDT. These detectors are linked to bifurcated fibers, distributing signals to both a photodiode and a spectrometer. Calibration techniques are applied to counter tissue-related variations and improve measurement accuracy. The fluorescence signal is normalized using the measured light fluence, compensating for variations in tissue properties. Measurements were taken in 78 sites in the pleural cavities of 20 patients. Results: Observations reveal minimal Photofrin concentration variation during PDT at each site, juxtaposed with significant intra- and inter-patient heterogeneities. Across 78 treated sites in 20 patients, the average Photofrin concentration for all 78 sites is 4.98 µM, with a median concentration of 4.47 µM. The average PDT dose for all 78 sites is 493.17 µMJ/cm2, with a median dose of 442.79 µMJ/cm2. A significant variation in PDT doses is observed, with a maximum difference of 3.1 times among all sites within one patient and a maximum difference of 9.8 times across all patients. Conclusions: The introduced eight-channel PDT dose dosimetry system serves as a valuable real-time monitoring tool for light fluence and PS concentration during PDT. Its ability to mitigate uncertainties arising from tissue properties enhances dosimetry accuracy, thus optimizing treatment outcomes and bolstering the effectiveness of PDT in cancer therapy.

Preoperative predictors of successful tumour localization by intraoperative molecular imaging with pafolacianine in lung cancer to create predictive nomogram.

OBJECTIVES: Intraoperative molecular imaging (IMI) uses cancer-targeted fluorescent probe to locate nodules. Pafolacianine is a Food and Drug Administration-approved fluorescent probe for lung cancer. However, it has a 8-12% false negative rate for localization. Our goal is to define preoperative predictors of tumour localization by IMI. METHODS: We performed a retrospective review of patients who underwent IMI using pafolacianine for lung lesions from June 2015 to August 2019. Candidate predictors including sex, age, body mass index, smoking history, tumour size, distance of tumour from surface, use of neoadjuvant therapy and positron emission tomography avidity were included. The outcome was fluorescence in vivo and comprehensively included those who were true or false positives negatives. Multiple imputation was used to handle the missing data. The final model was evaluated using the area under the receiver operating characteristic curve. RESULTS: Three hundred nine patients were included in our study. The mean age was 64 (standard deviation 13) and 68% had a smoking history. The mean distance of the tumours from the pleural surface was 0.4 cm (standard deviation 0.6). Smoking in pack-years and distance from pleura had an odds ratio of 0.99 [95% confidence interval: 0.98-0.99; P = 0.03] and 0.46 [95% confidence interval: 0.27-0.78; P = 0.004], respectively. The final model had an area under the receiver operating characteristic curve of 0.68 and was used to create a nomogram that gives a probability of fluorescence in vivo. CONCLUSIONS: Primary tumours that are deeper from the pleural surface, especially in patients with a higher pack-years, are associated with a decreased likelihood of intraoperative localization. We identified a nomogram to predict the likelihood of tumour localization with IMI with pafolacianine.

Human Tumor-Associated Macrophages and Neutrophils Regulate Antitumor Antibody Efficacy through Lethal and Sublethal Trogocytosis.

The clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)-expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAMs and TANs regulate tAb response could help improve the efficacy of cancer treatments. Here, we found that myeloid effectors interacting with tAb-opsonized lung cancer cells used antibody-dependent trogocytosis (ADT) but not antibody-dependent phagocytosis. During this process, myeloid cells "nibbled off" tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT was only tumoricidal when the tumor cells expressed high levels of tAg and the effectors were present at high effector-to-tumor ratios. If either of these conditions were not met, which is typical for solid tumors, ADT was sublethal. Sublethal ADT, mainly mediated by CD32hiCD64hi TAM, led to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor that facilitated tumor cell escape from the tumoricidal effects of tAb; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. CD89hiCD32loCD64lo peripheral blood neutrophils (PBN) and TAN stimulated tumor cell growth in the presence of the IgG1 anti-EGFR Ab cetuximab; however, IgA anti-EGFR Abs triggered the tumoricidal activity of PBN and negated the stimulatory effect of TAN. Overall, this study provides insights into the mechanisms by which myeloid effectors mediate tumor cell killing or resistance during tAb therapy. SIGNIFICANCE: The elucidation of the conditions and mechanisms by which human FcR+ myeloid effectors mediate cancer cell resistance and killing during antibody treatment could help develop improved strategies for treating solid tumors.

Molecular Imaging in Precision-Cut Non-Small Cell Lung Cancer Slices.

BACKGROUND: Small animal models remain invaluable for the preclinical study of emerging molecular imaging agents. However, the data obtained in this setting are generated in genetically homogenous animals that do not mimic human pathophysiology. The purpose of this study was to prospectively validate precision-cut lung slices (PCLSs) obtained from patients with lung cancer as a translational tool for the development of targeted fluorophores. METHODS: The lung tissue was gently inflated with 2% Low-Melt Agarose (Fisher, 16520050) to avoid lung damage and minimize inflation pressure. The slices were then loaded into specialized cylindrical cartridges and inserted into a compressotome, and slices 150 to 350 µm thick were cut. Samples were incubated with fluorophore conjugates for ex vivo validation and immunohistochemical staining for receptor expression. RESULTS: A total of 184 unique 3-dimensional, architecturally preserved normal lung and non-small cell lung cancer samples were obtained between 2020 and 2022. The median nodule size was 1.1 ± 0.21 cm for benign lesions and 2.1 ± 0.19 cm for malignant nodules. A total of 101 of 135 (74.8%) malignant lesions were adenocarcinoma spectrum lung cancers. The median viability was 9.78 ± 1.86 days, and 1 µM of FAPL-S0456 (high-affinity fibroblast activation protein [FAP] targeting ligand linked to the near-infrared fluorophore S0456, On Target Laboratories)-targeted near-infrared fluorochrome localization demonstrated correlative labeling of FAP-positive tumor areas with a correlation coefficient of +0.94 (P < .01). There was no FAP fluorochrome uptake in normal lungs (r = -1; P < .001). CONCLUSIONS: PCLSs comprise a novel human tissue-based translational model that can be used to validate the efficacy of molecular imaging fluorochromes. PCLSs preserve the tumor microenvironment and parenchymal architecture that closely resemble the interactions of the immune and stromal components in humans.

Fluorescence-guided surgery with indocyanine green to identify an idiopathic chyle leak-case report.

Background: Chylothorax is the leakage of chyle into the pleural space and is associated with up to 50% morbidity. Although, the identification of traumatic chylothoraces is well described, non-traumatic chylothoraxes, mostly idiopathic, present therapeutic challenges as they are difficult to localize. We describe an attempt at localizing and treating an idiopathic chylothorax refractory to conservative and minimally invasive techniques. This was done using indocyanine green (ICG) and was a joint case between a thoracic surgeon and an interventional radiologist. Case Description: A 50-year-old female with a recent history of coronavirus disease (COVID)-19 presented with shortness of breath. She was found to have a right pleural effusion and was admitted to the hospital, where a chest tube was inserted and pleural fluid analysis confirmed the diagnosis of a chylothorax. Conservative management was attempted but with little success. Initial magnetic resonance lymphangiogram (MRL) revealed abnormal enhancing lymphatic masses in the right paraspinal thoracic space as well as lympho-venous junction obstruction with large neck collaterals. She then underwent percutaneous lympho-venous junction angioplasty followed by multiple rounds of glue embolization without clinical improvement. The decision was then made to proceed with a thoracotomy, identification of the site of thoracic duct (TD) leakage, and a mechanical pleurodesis assisted by intraoperative imaging. Ten mg of ICG was injected into the inguinal lymph nodes. Using a camera capable of detection of near-infrared (NIR) light, we were able to visualize the site from which the ICG was extravasating in the chest. Glue was then injected in that area to further help in reducing the leak. After keeping her nil per os (NPO) and requiring one more ligation, a repeat MRL showed a markedly decreased leak into the right pleural space. Two weeks later, she was seen in clinic and reported significant improvement in her symptoms. Conclusions: This is the case of a 50-year-old female who was found to have a significant right chylothorax. She underwent conservative management, followed by tube thoracostomy, and TD ligation but was refractory to treatment. Fluorescence-guided surgery was pivotal to localize the leakage site and help seal it intraoperatively.

A pH-Activatable Nanoprobe Labels Diverse Histologic Subtypes of Human Lung Cancer During Resection.

BACKGROUND: Intraoperative molecular imaging (IMI) uses tumor-targeted optical contrast agents to improve identification and clearance of cancer during surgery. Recently, pH-activatable contrast agents have been developed but none has been tested in lung cancer. Here, we report the successful clinical translation of pegsitacianine (ONM-100), a pH-activatable nanoprobe, for fluorescence-guided lung cancer resection. METHODS: We first characterized the pH setpoint for pegsitacianine fluorescence activation in vitro. We then optimized the specificity, dosing, and timing of pegsitacianine in murine flank xenograft models of lung adenocarcinoma and squamous cell carcinoma. Finally, we tested pegsitacianine in humans undergoing lung cancer surgery as part of an ongoing phase 2 trial. RESULTS: We found that the fluorescence activation of pegsitacianine occurred below physiologic pH in vitro. Using preclinical models of lung cancer, we found that the probe selectively labeled both adenocarcinoma and squamous cell carcinoma xenografts (mean tumor-to-background ratio [TBR] > 2.0 for all cell lines). In the human pilot study, we report cases in which pegsitacianine localized pulmonary adenocarcinoma and pulmonary squamous cell carcinoma (TBRs= 2.7 and 2.4) in real time to illustrate its successful clinical translation and potential to improve surgical management. CONCLUSIONS: This translational study demonstrates the feasibility of pegsitacianine as an IMI probe to label the two most common histologic subtypes of human lung cancer.

Strategies to reduce morbidity following pleurectomy and decortication for malignant pleural mesothelioma.

BACKGROUND: Pleurectomy and decortication (PD) in malignant pleural mesothelioma has a high morbidity mostly associated with aspiration pneumonia (PNA), deep vein thrombosis (DVT), and foreign catheter sepsis. We instituted four strategies to reduce these complications and report our experience. METHODS: This was a retrospective review of patients who underwent PD at the University of Pennsylvania between 2015 and 2022. Our patients underwent standard of care PD in addition to tracheostomy and gastrostomy/jejunostomy tube with therapeutic anticoagulation (AC) leading up to surgery. Measured outcomes were postoperative PNA, DVT, and sepsis. The predicted risk of those same outcomes had patients not undergone the interventions was calculated based on the American College of Surgeons (ACS) surgical risk calculator (SRC). A McNemar's test was used to determine whether the risk of having PNA, DVT and sepsis differed between the two subgroups. RESULTS: Fifty-five patients were included in the study. The mean age was 70 years (SD 6.2) with a mean of 21 (SD 19) pack-years of smoking. PNA, DVT, and catheter-related sepsis occurred in 12, four, and seven patients, respectively. Upon using the ACS SRC prediction model of the nonintervention group, PNA, DVT and catheter related sepsis was predicted to occur in 24 (paired data OR 5, 95% CI: 1.4-17.2; McNemar's test p = 0.008), 14 (paired data OR 3.5, 95% CI: 1.15-10.6; McNemar's test p = 0.03), and 17 (paired OR 3, 95% CI: 1.09-8.3; McNemar's test p = 0.04) patients, respectively. DISCUSSION: Patients undergoing tracheostomy creation, therapeutic AC at the time of diagnosis, and gastrostomy tube placement had a reduced risk of aspiration PNA, DVT, and catheter sepsis.

Preclinical Lymph Node Model for Intraoperative Molecular Imaging of Cancer.

Purpose: Lymph node(LN) dissection is part of most oncologic resections. Intraoperatively identifying a positive LN(+ LN), that harbors malignant cells, can be challenging. We hypothesized that intraoperative molecular imaging(IMI) using a cancer-targeted fluorescent prober can identify + LNs. This study aimed to develop a preclinical model of a + LN and test it using an activatable cathepsin-based enzymatic probe, VGT-309. Procedures: In the first model, we used peripheral blood mononuclear cells (PBMC), representing the lymphocytic composition of the LN, mixed with different concentrations of human lung adenocarcinoma cell line A549. Then, they were embedded in a Matrigel® matrix. A black dye was added to mimic LN anthracosis. Model two was created using a murine spleen, the largest lymphoid organ, injected with various concentrations of A549. To test these models, we co-cultured A549 cells with VGT-309. Mean fluorescence intensity(MFI) was. An independent sample t-test was used to compare the average MFI of each A549:negative control ratio. Results: A significant difference in MFI from our PBMC control was noted when A549 cells were 25% of the LN (p = 0.046) in both 3D cell aggregate models-where the LNs native parenchyma is replaced and the one where the tumor grows over the native parenchyma. For the anthracitic equivalents of these models, the first significant MFI compared to the control was when A549 cells were 9% of the LN (p = 0.002) in the former model, and 16.7% of the LN (p = 0.033) in the latter. In our spleen model, we first noted significance in MFI when A549 cells were 16.67% of the cellular composition.(p = 0.02). Conclusions: A + LN model allows for a granular evaluation of different cellular burdens in + LN that can be assessed using IMI. This first exvivo + LN model can be used in preclinical testing of several existing dyes and in creating more sensitive cameras for IMI-guided LN detection.

Intraoperative molecular imaging: 3rd biennial clinical trials update.

Significance: This third biennial intraoperative molecular imaging (IMI) conference shows how optical contrast agents have been applied to develop clinically significant endpoints that improve precision cancer surgery. Aim: National and international experts on IMI presented ongoing clinical trials in cancer surgery and preclinical work. Previously known dyes (with broader applications), new dyes, novel nonfluorescence-based imaging techniques, pediatric dyes, and normal tissue dyes were discussed. Approach: Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center's third clinical trials update on IMI were selected to discuss their clinical trials and endpoints. Results: Dyes that are FDA-approved or currently under clinical investigation in phase 1, 2, and 3 trials were discussed. Sections on how to move benchwork research to the bedside were also included. There was also a dedicated section for pediatric dyes and nonfluorescence-based dyes that have been newly developed. Conclusions: IMI is a valuable adjunct in precision cancer surgery and has broad applications in multiple subspecialties. It has been reliably used to alter the surgical course of patients and in clinical decision making. There remain gaps in the utilization of IMI in certain subspecialties and potential for developing newer and improved dyes and imaging techniques.

Bioinspired color-near infrared endoscopic imaging system for molecular guided cancer surgery.

Significance: Fluorescently guided minimally invasive surgery is improving patient outcomes and disease-free survival, but biomarker variability hinders complete tumor resection with single molecular probes. To overcome this, we developed a bioinspired endoscopic system that images multiple tumor-targeted probes, quantifies volumetric ratios in cancer models, and detects tumors in ex vivo samples. Aim: We present a new rigid endoscopic imaging system (EIS) that can capture color images while simultaneously resolving two near-infrared (NIR) probes. Approach: Our optimized EIS integrates a hexa-chromatic image sensor, a rigid endoscope optimized for NIR-color imaging, and a custom illumination fiber bundle. Results: Our optimized EIS achieves a 60% improvement in NIR spatial resolution when compared to a leading FDA-approved endoscope. Ratio-metric imaging of two tumor-targeted probes is demonstrated in vials and animal models of breast cancer. Clinical data gathered from fluorescently tagged lung cancer samples on the operating room's back table demonstrate a high tumor-to-background ratio and consistency with the vial experiments. Conclusions: We investigate key engineering breakthroughs for the single-chip endoscopic system, which can capture and distinguish numerous tumor-targeting fluorophores. As the molecular imaging field shifts toward a multi-tumor targeted probe methodology, our imaging instrument can aid in assessing these concepts during surgical procedures.

Early identification of life-threatening soft-tissue infection using dynamic fluorescence imaging: first-in-kind clinical study of first-pass kinetics.

Necrotizing soft-tissue infections (NSTIs) are aggressive and deadly. Immediate surgical debridement is standard-of-care, but patients often present with non-specific symptoms, thereby delaying treatment. Because NSTIs cause microvascular thrombosis, we hypothesized that perfusion imaging using indocyanine green (ICG) would show diminished fluorescence signal in NSTI-affected tissues, particularly compared to non-necrotizing, superficial infections. Through a first-in-kind clinical study, we performed first-pass ICG fluorescence perfusion imaging of patients with suspected NSTIs. Early results support our hypothesis that ICG signal voids occur in NSTI-affected tissues and that dynamic contrast-enhanced fluorescence parameters reveal tissue kinetics that may be related to disease progression and extent.

Proceduralist criteria for evaluating interface utility of novel imaging modalities in early phase clinical trials: evaluating the need for standardized criteria.

Accelerating innovation in the space of fluorescence imaging for surgical applications has increased interest in safely and expediently advancing these technologies to clinic through Food and Drug Administration-(FDA-) compliant trials. Conventional metrics for early phase trials include drug safety, tolerability, dosing, and pharmacokinetics. Most procedural imaging technologies rely on administration of an exogenous fluorophore and concurrent use of an imaging system; both of which must receive FDA approval to proceed to clinic. Because fluorophores are classified as medical imaging agents, criteria for establishing dose are different, and arguably more complicated, than therapeutic drugs. Since no therapeutic effect is desired, medical imaging agents are ideally administered at the lowest dose that achieves adequate target differentiation. Because procedural imaging modalities are intended to enhance and/or ease proceduralists' identification or assessment of tissues, beneficial effects of these technologies may manifest in the form of qualitative endpoints such as: 1) confidence; 2) decision-making; and 3) satisfaction with the specified procedure. Due to the rapid expansion of medical imaging technologies, we believe that our field requires standardized criteria to evaluate existing and emerging technologies objectively so that both quantitative and qualitative aspects of their use may be measured and useful comparisons to assess their relative value may occur. Here, we present a 15-item consensus-based survey instrument to assess the utility of novel imaging technologies from the proceduralist's standpoint.

Epidemiological, therapeutic, and survival trends in malignant pleural mesothelioma: A review of the National Cancer Database.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive cancer of the cells lining the pleural cavity with a low overall incidence. The National Cancer Database (NCDB) released in August 2022 updated data that reflect the newest trends in MPM. METHODS: The NCDB was queried for patients diagnosed with MPM between 2004 and 2020. Variables collected included demographics, tumor characteristics, and treatment. Student's t-test and independent-samples proportions test were used for means analysis. Survival was assessed by the Kaplan-Meier method using SPSS version 28. RESULTS: A total of 41,074 patients were diagnosed with mesothelioma, with a steady incidence (0.25%) between 2004 and 2017. The mean age of diagnosis was 70 (SD 13). 73.2% of the patients were males, 69% had no comorbidities, and 93.3% were white. More patients were diagnosed at Stage 1 after 2008 (p < 0.001). Since 2010, there has been a significant increase in patients offered treatment with 73.9% receiving some therapy (p < 0.01): 50.5% received chemotherapy, 27.6% surgery, 8.6% radiation, and 5.4% immunotherapy. The median overall survival was 10.3 months from diagnosis [95% CI: 10.2-10.5]. Risk factors associated with 30-day mortality from surgical intervention included age (OR = 1.02, p < 0.001), male gender (OR = 1.3, p = 0.03), poorly differentiated grade (OR = 2.1, p < 0.001), Stage 4 (OR = 1.4, p = 0014), and epithelioid histology (OR = 0.51, p = 0.03). CONCLUSION: The current management of MPM is based on stage and histologic subtype. Due to the small numbers of patients at most academic centers, the NCDB provides a robust dataset to draw upon broad data points in treatment discussions with patients.

Pafolacianine for intraoperative molecular imaging of cancer in the lung: The ELUCIDATE trial.

OBJECTIVE: The study objective was to determine the clinical utility of pafolacianine, a folate receptor-targeted fluorescent agent, in revealing by intraoperative molecular imaging folate receptor α positive cancers in the lung and narrow surgical margins that may otherwise be undetected with conventional visualization. METHODS: In this Phase 3, 12-center trial, 112 patients with suspected or biopsy-confirmed cancer in the lung scheduled for sublobar pulmonary resection were administered intravenous pafolacianine within 24 hours before surgery. Participants were randomly assigned to surgery with or without intraoperative molecular imaging (10:1 ratio). The primary end point was the proportion of participants with a clinically significant event, reflecting a meaningful change in the surgical operation. RESULTS: No drug-related serious adverse events occurred. One or more clinically significant event occurred in 53% of evaluated participants compared with a prespecified limit of 10% (P < .0001). In 38 participants, at least 1 event was a margin 10 mm or less from the resected primary nodule (38%, 95% confidence interval, 28.5-48.3), 32 being confirmed by histopathology. In 19 subjects (19%, 95% confidence interval, 11.8-28.1), intraoperative molecular imaging located the primary nodule that the surgeon could not locate with white light and palpation. Intraoperative molecular imaging revealed 10 occult synchronous malignant lesions in 8 subjects (8%, 95% confidence interval, 3.5-15.2) undetected using white light. Most (73%) intraoperative molecular imaging-discovered synchronous malignant lesions were outside the planned resection field. A change in the overall scope of surgical procedure occurred for 29 of the subjects (22 increase, 7 decrease). CONCLUSIONS: Intraoperative molecular imaging with pafolacianine improves surgical outcomes by identifying occult tumors and close surgical margins.

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.

Neuromodulation for the Treatment of Refractory Ventricular Arrhythmias.

BACKGROUND: Neuromodulation is increasingly recognized as a therapeutic strategy for patients with refractory ventricular arrhythmias (VAs). Percutaneous stellate ganglion blockade (SGB), transcutaneous magnetic stimulation (TcMS), and surgical cardiac sympathetic denervation (CSD) have all been utilized in this setting. OBJECTIVES: This study sought to characterize contemporary use and outcomes of these neuromodulation techniques for patients with refractory VA. METHODS: This retrospective cohort study included all patients at the Hospital of the University of Pennsylvania with antiarrhythmic drug (AAD)-refractory VA from 2019 to 2021 who were treated with SGB, TcMS, or CSD. RESULTS: A total of 34 patients (age 61 ± 14 years, 15 polymorphic VAs [44%], refractory to 1.8 ± 0.8 AADs) met inclusion criteria. SGB was performed on 11 patients (32%), TcMS on 19 (56%), and CSD on 7 (21%). Neuromodulation was associated with a reduction in the number of episodes of sustained VAs from 7 [IQR: 4-12] episodes in the 24 hours before the initial neuromodulation strategy to 0 [IQR: 0-1] episodes in the subsequent 24 hours (P < 0.001). During 1.2 ± 1.1 years of follow-up, 21 (62%) experienced recurrent VAs, and among those patients, the median time to recurrence was 3 [IQR: 1-25] days. Outcomes were similar among patients with monomorphic and polymorphic VAs. Among patients who had an acute myocardial infarction within 30 days before neuromodulation, the burden of VAs decreased from 11 [IQR: 7-12] episodes to 0 episodes in the 24 hours after treatment. CONCLUSIONS: Autonomic neuromodulation with SGB, TcMS, or CSD in patients with AAD-refractory VAs is safe and results in substantial acute reduction of VA although recurrent arrhythmias are common, and not all patients experience a reduction in arrhythmia burden.