Prepectoral versus Submuscular Implant-Based Breast Reconstruction: A Matched-Pair Comparison of Outcomes.

BACKGROUND: Implant-based breast reconstruction is the most common reconstructive approach after mastectomy. Prepectoral implants offer advantages over submuscular implants, such as less animation deformity, pain, weakness, and postradiation capsular contracture. However, clinical outcomes after prepectoral reconstruction are debated. The authors performed a matched-cohort analysis of outcomes after prepectoral and submuscular reconstruction at a large academic medical center. METHODS: Patients treated with implant-based breast reconstruction after mastectomy from January of 2018 through October of 2021 were retrospectively reviewed. Patients were propensity score exact matched to control demographic, preoperative, intraoperative, and postoperative differences. Outcomes assessed included surgical-site occurrences, capsular contracture, and explantation of either expander or implant. Subanalysis was done on infections and secondary reconstructions. RESULTS: A total of 634 breasts were included (prepectoral, 197; submuscular, 437). A total of 292 breasts were matched (146 prepectoral:146 submuscular) and analyzed for clinical outcomes. Prepectoral reconstructions were associated with greater rates of SSI (prepectoral, 15.8%; submuscular, 3.4%; P < 0.001), seroma (prepectoral, 26.0%; submuscular, 10.3%; P < 0.001), and explantation (prepectoral, 23.3%; submuscular, 4.8%; P < 0.001). Subanalysis of infections revealed that prepectoral implants have shorter time to infection, deeper infections, and more Gram-negative infections, and are more often treated surgically (all P < 0.05). There have been no failures of secondary reconstructions after explantation in the entire population at a mean follow-up of 20.1 months. CONCLUSIONS: Prepectoral implant-based breast reconstruction is associated with higher rates of infection, seroma, and explantation compared with submuscular reconstructions. Infections of prepectoral implants may need different antibiotic management to avoid explantation. Secondary reconstruction after explantation can result in long-term success. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

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.

Sodium Multivitamin Transporter-Targeted Fluorochrome Facilitates Enhanced Metabolic Evaluation of Tumors Through Coenzyme-R Dependent Intracellular Signaling Pathways.

BACKGROUND: Intraoperative molecular imaging (IMI)-guided resections have been shown to improve oncologic outcomes for patients undergoing surgery for solid malignancies. The technology utilizes fluorescent tracers targeting cancer cells without the use of any ionizing radiation. However, currently available targeted IMI tracers are effective only for tumors with a highly specific receptor expression profile, and there is an unmet need for IMI tracers to label a broader range of tumor types. Here, we describe the development and testing of a novel tracer (CR)-S0456) targeted to the sodium multivitamin transporter (SMVT). METHODS: Preclinical models of fibrosarcoma (HT-1080), lung (A549), breast (4T1), and renal cancers (HEK-293 T) in vitro and in vivo were used for assessment of (CR)-S0456 specific tumor labeling via sodium-mediated SMVT uptake in dipotassium phosphate or choline chloride-containing media buffer. Additionally, pharmacologic inhibition of multiple intracellular coenzyme-R obligate signaling pathways, including holocarboxylase synthetase (sulconazole nitrate), PI3K/AKT/mTOR (omipalisib), and calmodulin-dependent phosphatase (calmidazolium), were investigated to assess (CR)-S0456 uptake kinetics. Human fibrosarcoma-bearing xenografts in athymic nude mice were used for tumor and metabolic-specific labeling. Novel NIR needle confocal laser endomicroscopic (nCLE) intratumoral sampling was performed to demonstrate single-cell specific labeling by CR-S0456. RESULTS: CR-S0456 localization in vitro correlated with highly proliferative cell lines (MTT) and doubling time (p < 0.05) with the highest microscopic fluorescence detected in aggressive human fibrosarcomas (HT-1080). Coenzyme-R-specific localization was demonstrated to be SMVT-specific after competitive inhibition of internal localization with excess administration of pantothenic acid. Inhibiting the activity of SMVT by affecting sodium ion hemostasis prevented the complete uptake of CR-S0456. In vivo validation demonstrated (CR)-S0456 localization to xenograft models with accurate identification of primary tumors as well as margin assessment down to 1 mm3 tumor volume. Systemic treatment of xenograft-bearing mice with a dual PI3K/mTOR inhibitor suppressed intratumoral cell signaling and (CR)-S0456 uptake via a reduction in SMVT expression. Novel analysis of in vivo intratumoral cytologic fluorescence using near-infrared confocal laser endomicroscopy demonstrated the absence of coenzyme-R-mediated NIR fluorescence but not fibroblast activation protein (FAP)-conjugated fluorochrome, indicating specific intracellular inhibition of coenzyme-R obligate pathways. CONCLUSION: These findings suggest that a SMVT-targeted NIR contrast agent can be a suitable tracer for imaging a wide range of malignancies as well as evaluating metabolic response to systemic therapies, similar to PET imaging with immune checkpoint inhibitors.

Three-Dimensional Near-Infrared Specimen Mapping Can Identify the Distance from the Tumor to the Surgical Margin During Resection of Pulmonary Ground Glass Opacities.

BACKGROUND: Lung cancers can recur locally due to inadequate resection margins. Achieving adequate margin distances is challenging in pulmonary ground glass opacities (GGOs) because they are not easily palpable. To improve margin assessment during resection of GGOs, we propose a novel technique, three-dimensional near-infrared specimen mapping (3D-NSM). METHODS: Twenty patients with a cT1 GGO were enrolled and received a fluorescent tracer preoperatively. After resection, specimens underwent 3D-NSM in the operating room. Margins were graded as positive or negative based upon fluorescence at the staple line. Images were analyzed using ImageJ to quantify the distance from the tumor edge to the nearest staple line. This margin distance calculated by 3D-NSM was compared to the margin distance reported on final pathology several days postoperatively. RESULTS: 3D-NSM identified 20/20 GGOs with no false positive or false negative diagnoses. Mean fluorescence intensity for lesions was 110.92 arbitrary units (A.U.) (IQR: 77.77-122.03 A.U.) compared to 23.68 A.U. (IQR: 19.60-27.06 A.U.) for background lung parenchyma (p < 0.0001). There were 4 tumor-positive or close margins in the study cohort, and all 4 (100%) were identified by 3D-NSM. 3D-NSM margin distances were nearly identical to margin distances reported on final pathology (R2 = 0.9362). 3D-NSM slightly under-predicted margin distance, and the median difference in margins was 1.9 mm (IQR 0.5-4.3 mm). CONCLUSIONS: 3D-NSM rapidly localizes GGOs by fluorescence and detects tumor-positive or close surgical margins. 3D-NSM can accurately quantify the resection margin distance as compared to formal pathology, which allows surgeons to rapidly determine whether sublobar resection margin distances are adequate.

Effects of Light-absorbing Carbons in Intraoperative Molecular Imaging-Guided Lung Cancer Resections.

BACKGROUND: One of the novel advancements to enhance the visual aspects of lung cancer identification is intraoperative molecular imaging (IMI), which can reliably detect tumors that would otherwise be missed by standard techniques such as tactile and visual feedback, particularly for sub-centimeter or ground-glass nodules. However, there remains a subset of patients who do not benefit from IMI due to excessive background fluorescence secondary to parenchymal light-absorbing carbon deposition. Our goal was to identify the effects of these carbonaceous materials on the quality of IMI-guided lung cancer resections. STUDY DESIGN AND METHODS: Between July 2014 and May 2021, a total of 311 patients were included in the study. Patients underwent infusion of the study drug OTL38 or ICG up to 24 h prior to VATS for lung cancer. Several factors such as age, tumor subtype, PET SUV, smoking, demographics, chronic lung conditions, patient domicile, and anthracosis were analyzed with respect to lung fluorescence during IMI. P values < 0.05 were considered statistically significant. RESULTS: Variables such as age, sex, and race had no statistical correlation to IMI success. However, smoking status and pack year had a statistically significant correlation with background parenchymal fluorescence and lung inflammation (p < 0.05). MFI of background (lung parenchyma) correlated with smoking history (p < 0.05) which led to decreased tumor-to-background ratio (TBR) measurements for all patients with proven malignancy (p < 0.05). Patients with chronic lung disease appear to have increased background parenchymal fluorescence regardless of smoking history (287 vs. 154, p < 0.01). City dwellers compared to other groups appear to be exposed to higher pollutant load and have higher rates of anthracosis, but living location's impact on fluorescence quantification appears to be not statistically significant. CONCLUSION: Smokers with greater than 10 PPY and those with chronic lung disease appear to have decreased lesion-to-background discrimination, significant anthracosis, and reduced IMI efficacy secondary to light-absorbing carbon deposition.

Evaluation of OTL38-Generated Tumor-to-Background Ratio in Intraoperative Molecular Imaging-Guided Lung Cancer Resections.

INTRODUCTION: Cancer surgery has multiple challenges including localizing small lesions, ensuring negative margins, and identifying synchronous cancers. One of the tools proposed to address these issues is intraoperative molecular imaging (IMI). An important consideration in IMI is the quantification of the tumor fluorescence during the procedure and using that data to add clinical value. Currently, the most commonly cited measure of quantification is the tumor-to-background ratio (TBR). Our goal was to evaluate the clinical value of TBR measured with OTL38 NIR tracer during a lung cancer resection. METHODS: Intraoperative data was retrospectively reviewed from a prospectively collected 5-year database. Between 2015 and 2020, 279 patients were included in the study. For standardization, all patients underwent infusion of the same targeted molecular optical contrast agent (OTL38) for lung cancer resections; then, the mean fluorescence intensity of the tumors and background tissues were calculated. To evaluate the clinical efficacy of the TBR calculation, the results were correlated with patient, biologic, tumor, and technological factors. RESULTS: For pulmonary surgery, patient factors such as gender, age, smoking history, and time from infusion of OTL38 to surgery did not have any statistical significance in predicting the TBR during surgery. In addition, TBR measurements did not correlate with location of the tumor in the lung (p = 0.123). There was no statistical correlation of preoperative positron emission tomography measurements (standardized uptake value) with intraoperative TBR. However, there was statistically significant negative correlation of in situ TBR measurement and the distance of the lesion from the surface of the organ (p < 0.001). Adenocarcinoma spectrum lesions overall had statistically significant correlation with in situ fluorescence compared to other NSCLC malignancies (p < 0.01) but TBR measurements could not identify histopathologic subtype on univariate analysis (p = 0.089). There was a tendency for in situ fluorescence for moderately and well-differentiated adenocarcinoma spectrum lesions, but this was not statistically significant. When comparing the in situ TBR of benign to malignant nodules in the lung, there was no statistically significant association (p = 0.145). In subset analysis, adenocarcinoma spectrum lesions tend to fluoresce at brighter with OTL38 compared to other histologic subtypes. CONCLUSION: In our various iterations, the results of our retrospective analysis did not show that TBR measurements during OTL38-guided surgery provide clinically useful information about the nature of the nodule or cancer. The true value of IMI is in the ability for the surgeon to use the fluorescence to guide the surgeon to the tumor and margins, but that sophisticated quantification of the amount of fluorescence may not have clinical utility.

Glycoprotein Receptor CEACAM5-Targeted Intraoperative Molecular Imaging Tracer in Non-Small Cell Lung Cancer.

BACKGROUND: Intraoperative molecular imaging has emerged as a potential tool in addressing challenges faced during lung cancer surgery by localizing small lesions, ensuring negative margins, and identifying synchronous cancers. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) glycoprotein has emerged as a potential target in fluorescent labeling of non-small cell lung cancer given the high antigen density in tumor cells and absence of expression in normal parenchyma. The goal of our study was to determine whether anti-CEACAM5 targeted near-infrared fluorochrome could be a suitable target in non-small cell lung cancer. METHODS: The CEACAM5 expression was evaluated in AB-12 (known negative control), HT29 (known positive control), and H460 (non-small cell lung cancer) cell lines by polymerase chain reaction. SGM-101, a CEACAM5 antibody, coupled with a BM-104 near-infrared fluorescent tracer was evaluated with dose escalation, in vitro cellular localization, and immunofluorescence microscopy. Subsequently, in vivo validation was performed in 52 athymic nude xenografts. RESULTS: Polymerase chain reaction analysis demonstrated 3000x relative expression of CEACAM5 in HT-29 cells compared with AB-12. The H460 cells showed 1000x relative expression compared with AB12 (P < .05). Both HT29 and H460 cells showed tracer internalization with signal to background ratio of 4.5 (SD 0.34) whereas there was minimal uptake by AB12 cells with signal to background ratio 1.1 (SD 0.1; P < .05). There was linear fluorescence increase with increasing tracer dosing in receptor expressing cell lines. In preclinical models, HT-29 and H460 cells lines produced near-infrared fluorescence with average tumor to background ratio of 3.89 (SD 0.25) irrespective of tumor size compared with no fluorescence by AB12 tumors (P < .05). The CEACAM5 expressing tumors had excellent dye uptake compared with AB12 tumors. CONCLUSIONS: CEACAM5 serves as a possible receptor for targeted intraoperative molecular imaging resections in lung cancer. This study sets a path for evaluation of CEACAM5 targets in future clinical trials.

First-in-human results of targeted intraoperative molecular imaging for visualization of ground glass opacities during robotic pulmonary resection.

Background: Identifying ground glass opacities (GGOs) is challenging during robot-assisted thoracic surgery (RATS). Intraoperative molecular imaging (IMI) using tumor-targeted fluorescent tracers may address this clinical problem, but has never been evaluated in RATS. In a pilot study, we sought to determine whether IMI during RATS (RIMI) can localize GGOs. Methods: Ten patients with a cT1 GGO were enrolled. Prior to resection, participants received a folate-receptor targeted fluorescent tracer (OTL38). During RATS, a white-light robotic scope was utilized to identify tumors. RIMI was then conducted using a RATS thoracoscope with a wavelength-specific camera. Finally, a video-assisted thoracic surgery (VATS) thoracoscope designed to detect OTL38 was used as a control to compare to RIMI. The lesions were then resected under RIMI guidance. Results: By white-light robotic scope, 7/10 (70%) GGOs were visually identifiable by pleuroparenchymal distortions. RIMI identified tumor-specific fluorescence in all (100%) subjects. RIMI clearly located the three nodules that could not be seen by robotic white-light imaging. The mean fluorescence intensity (MFI) of tumors was 99.48 arbitrary units (A.U.) (IQR, 75.72-130.49 A.U.), which was significantly higher than background tissue with mean MFI 20.61 A.U. (IQR, 13.49-29.93 A.U., P<0.0001). Mean signal-to-background ratio was 5.71 (range, 2.28-10.13). When compared to VATS-IMI as a control, there were no significant differences in MFI of tumors, background tissue, or signal-to-background ratios. In summary, RIMI compared favorably to VATS-IMI by all measured imaging characteristics. Conclusions: RIMI is feasible for identification of GGOs during robotic resection as compared to white light thoracoscopy and compares favorably to VATS-IMI.

Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer.

Background: Early detection and complete resection are important prognostic factors for esophageal cancer (EC). Intraoperative molecular imaging (IMI) using tumor-targeted tracers is effective in many cancer types. However, there are no EC-specific IMI tracers. We sought to test a cathepsin activity-based tracer (VGT-309) for EC resection. Methods: Murine (AKR, HNM007) and human (OE19) EC cell lines were screened for cathepsin expression by western blotting. In vitro binding affinity of VGT-309 was evaluated by fluorescence microscopy. Flank tumor models were developed by injecting EC cells into the flanks of BALB/c or athymic nude mice. Mice pretreated with a cathepsin inhibitor (JPM-OEt) were used to confirm on target binding. Animals were injected with 2 mg/kg VGT-309, underwent IMI, and were sacrificed 24 hours after injection. Results: Cathepsins B, L, S, and X were expressed by EC cell lines, and all cell lines were labeled in vitro with VGT-309. Fluorescent signal was eliminated when cells were pretreated with JPM-OEt. On biodistribution analysis, VGT-309 accumulated in the liver, kidneys, and spleen without other organ involvement. VGT-309 selectively accumulated in flank allografts and xenografts, with mean signal-to-background ratio of 5.21 (IQR: 4.18-6.73) for flank allografts and 4.34 (IQR: 3.75-5.02) for flank xenografts. Fluorescence microscopy and histopathological analysis confirmed the selective accumulation of the tracer in tumors compared to background normal tissues. Conclusions: VGT-309 is an effective tracer for IMI of esophageal cancer. There is potential for clinical translation both as an adjunct to endoscopic detection and for complete removal of disease during esophagectomy.

Targeted detection of cancer cells during biopsy allows real-time diagnosis of pulmonary nodules.

BACKGROUND: The diagnostic yield of biopsies of solitary pulmonary nodules (SPNs) is low, particularly in sub-solid lesions. We developed a method (NIR-nCLE) to achieve cellular level cancer detection during biopsy by integrating (i) near-infrared (NIR) imaging using a cancer-targeted tracer (pafolacianine), and (ii) a flexible NIR confocal laser endomicroscopy (CLE) system that can fit within a biopsy needle. Our goal was to assess the diagnostic accuracy of NIR-nCLE ex vivo in SPNs. METHODS: Twenty patients with SPNs were preoperatively infused with pafolacianine. Following resection, specimens were inspected to identify the lesion of interest. NIR-nCLE imaging followed by tissue biopsy was performed within the lesion and in normal lung tissue. All imaging sequences (n = 115) were scored by 5 blinded raters on the presence of fluorescent cancer cells and compared to diagnoses by a thoracic pathologist. RESULTS: Most lesions (n = 15, 71%) were adenocarcinoma-spectrum malignancies, including 7 ground glass opacities (33%). Mean fluorescence intensity (MFI) by NIR-nCLE for tumor biopsy was 20.6 arbitrary units (A.U.) and mean MFI for normal lung was 6.4 A.U. (p < 0.001). Receiver operating characteristic analysis yielded a high area under the curve for MFI (AUC = 0.951). Blinded raters scored the NIR-nCLE sequences on the presence of fluorescent cancer cells with sensitivity and specificity of 98% and 97%, respectively. Overall diagnostic accuracy was 97%. The inter-observer agreement of the five raters was excellent (κ = 0.95). CONCLUSIONS: NIR-nCLE allows sensitive and specific detection of cancer cells in SPNs. This technology has far-reaching implications for diagnostic needle biopsies and intraprocedural decision-making.

A Cathepsin-Targeted Quenched Activity-Based Probe Facilitates Enhanced Detection of Human Tumors during Resection.

PURPOSE: Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity-based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity-based probe (VGT-309) for fluorescence-guided surgery. EXPERIMENTAL DESIGN: We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of lung cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing lung cancer surgery. RESULTS: In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine tumors, we found that the probe selectively labeled tumors and demonstrated high tumor-to-background ratio (TBR; range: 2.15-3.71). In the Phase I human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase II trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs = 2.83 and 7.18) in real time to illustrate its successful clinical translation and potential to improve surgical management. CONCLUSIONS: This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary tumors during resection. These results may be generalizable to other cancers due to cathepsin overexpression in many solid tumors.

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.

Targeted detection of cancer at the cellular level during biopsy by near-infrared confocal laser endomicroscopy.

Suspicious nodules detected by radiography are often investigated by biopsy, but the diagnostic yield of biopsies of small nodules is poor. Here we report a method-NIR-nCLE-to detect cancer at the cellular level in real-time during biopsy. This technology integrates a cancer-targeted near-infrared (NIR) tracer with a needle-based confocal laser endomicroscopy (nCLE) system modified to detect NIR signal. We develop and test NIR-nCLE in preclinical models of pulmonary nodule biopsy including human specimens. We find that the technology has the resolution to identify a single cancer cell among normal fibroblast cells when co-cultured at a ratio of 1:1000, and can detect cancer cells in human tumors less than 2 cm in diameter. The NIR-nCLE technology rapidly delivers images that permit accurate discrimination between tumor and normal tissue by non-experts. This proof-of-concept study analyzes pulmonary nodules as a test case, but the results may be generalizable to other malignancies.

Impact of Intraoperative Molecular Imaging after Fluorescent-Guided Pulmonary Metastasectomy for Sarcoma.

BACKGROUND: Intraoperative molecular imaging (IMI) has been shown to improve lesion detection during pulmonary sarcomatous metastasectomy. Our goal in this study was to evaluate whether data garnered from IMI-guided resection of pulmonary sarcoma metastasis translate to improved patient outcomes. STUDY DESIGN: Fifty-two of 65 consecutive patients with a previous history of sarcomas found to have pulmonary nodules during screening were enrolled in a nonrandomized clinical trial. Patients underwent TumorGlow the day before surgery. Data on patient demographics, tumor biologic characteristics, preoperative assessment, and survival were included in the study analysis and compared with institutional historical data of patients who underwent metastasectomy without IMI. p values < 0.05 were considered significant. RESULTS: IMI detected 42 additional lesions in 31 patients (59%) compared with the non-IMI cohort where 25% percent of patients had additional lesions detected using tactile and visual feedback only (p < 0.05). Median progression-free survival (PFS) for patients with IMI-guided pulmonary sarcoma metastasectomy was 36 months vs 28.6 months in the historical cohort (p < 0.05). IMI-guided pulmonary sarcoma metastasectomy had recurrence in the lung with a median time of 18 months compared with non-IMI group at 13 months (p < 0.05). Patients with synchronous lesions in the IMI group underwent systemic therapy at a statistically higher rate and tended to undergo routine screening at shorter interval. CONCLUSIONS: IMI identifies a subset of sarcoma patients during pulmonary metastasectomy who have aggressive disease and informs the medical oncologist to pursue more aggressive systemic therapy. In this setting, IMI can serve both as a diagnostic and prognostic tool without conferring additional risk to the patient.

A Prostate-Specific Membrane Antigen-Targeted Near-Infrared Conjugate for Identifying Pulmonary Squamous Cell Carcinoma during Resection.

Pulmonary squamous cell carcinoma is the second most common lung cancer subtype and has a low 5-year survival rate at 17.6%. Complete resection with negative margins can be curative, but a high number of patients suffer early postoperative recurrence due to inadequate disease clearance at the index operation. Intraoperative molecular imaging (IMI) with tumor-targeted optical contrast agents is effective in improving resection completeness for other tumor types, but there are no IMI tracers targeted to pulmonary squamous cell carcinoma. In this report, we describe the use of a novel prostate-specific membrane antigen (PSMA)-targeted near-infrared conjugate (OTL78) to identify pulmonary squamous cell carcinoma. We identified PSMA as a viable target by examining its expression in human lung tumor specimens from a surgical cohort. Ninety-four percent of tumors expressed PSMA in either the pulmonary squamous cells or the tumor neovasculature. Using in vitro and in vivo models, we found that OTL78 reliably localized pulmonary squamous cell carcinoma in a PSMA-dependent manner. Finally, we found that IMI with OTL78 markedly improved surgeons' ability to identify residual disease after surgery in a preclinical model. Ultimately, this novel optical tracer may aid surgical resection of pulmonary squamous cell carcinoma and potentially improve long-term outcomes.

3D Specimen Mapping Expedites Frozen Section Diagnosis of Nonpalpable Ground Glass Opacities.

BACKGROUND: Pulmonary ground glass opacities (GGOs) are early-stage adenocarcinoma spectrum lesions that are not easily palpable. Challenges in localizing GGOs during intraoperative pathology can lead to imprecise diagnoses and additional time under anesthesia. To improve localization of GGOs during frozen section diagnosis, we evaluated a novel technique, 3-dimensional near-infrared specimen mapping (3D-NSM). METHODS: Fifty-five patients with a cT1 GGO were enrolled and received a fluorescent tracer preoperatively. After resection, specimens were inspected to identify lesions. Palpable and nonpalpable nodules underwent 3D-NSM and the area of highest fluorescence was marked with a suture. Time for 3D-NSM, time for frozen section diagnosis, and number of tissue sections examined were recorded. To compare 3D-NSM with standard-of-care techniques, a control cohort of 20 subjects with identical inclusion criteria were enrolled. Specimens did not undergo 3D-NSM and were sent directly to pathology. RESULTS: 3D-NSM localized 54 of 55 lesions with 1 false negative. All 41 palpable lesions were identified by 3D-NSM. Thirteen (92.8%) of 14 nonpalpable lesions were located by 3D-NSM. Time to diagnosis for the 3D-NSM cohort was 23.5 minutes, compared with 26.0 minutes in the control cohort (P = .04). 3D-NSM did not affect time to diagnosis of palpable lesions (23.2 minutes vs 21.4 minutes; P = .10). 3D-NSM significantly reduced time to diagnosis for nonpalpable lesions (23.3 minutes vs 34.4 minutes; P < .0001). 3D-NSM also reduced the number of tissue sections analyzed in nonpalpable lesions (4.50 vs 11.00; P < .0001). CONCLUSIONS: 3D-NSM accurately localizes GGOs and expedites intraoperative diagnosis by reducing the number of tissue sections analyzed for nonpalpable GGOs.

Targeted Intraoperative Molecular Imaging for Localizing Nonpalpable Tumors and Quantifying Resection Margin Distances.

Importance: Complete (R0) resection is the dominant prognostic factor for survival across solid tumor types. Achieving adequate tumor clearance with appropriate margins is particularly difficult in nonpalpable tumors or in situ disease. Previous methods to address this problem have proven time consumptive, impractical, or ineffective. Objective: To assess the capability of intraoperative molecular imaging (IMI), a novel technology using a fluorescent tracer targeted to malignant cells, to localize visually occult, nonpalpable tumors and quantify margin distances during resection. Design, Setting, and Participants: This nonrandomized open-label trial of IMI using a folate receptor-targeted fluorescent tracer enrolled patients between May 2017 and June 2020 at a single referral center. Eligible patients included those with a small (T1) lung lesion suspicious for malignant neoplasms and with radiographic features suggestive of a nonpalpable lesion. Interventions: Patients were preoperatively infused with a folate receptor-targeted near-infrared tracer. Intraoperatively, surgeons used thoracoscopic visualization and palpation to identify lesions. IMI was performed to detect the lesion in situ, and lesions were imaged ex vivo. Margins were assessed by IMI before comparison with those reported on final histopathologic analysis. Main Outcomes and Measures: The main outcomes were whether IMI could (1) localize nonpalpable lung lesions in situ and (2) quantify margin distance with comparison with final pathology as the criterion standard. Patient demographic information and lesion characteristics were prospectively recorded. Results: Of 40 patients, 26 (65%) were female, and the median (interquartile range) age was 66.5 (62-72) years. Conventional surgical methods localized 22 of 40 lesions (55%), while IMI localized 36 of 40 (90%). Of 18 nonpalpable lesions, 15 (83.3%) were identified by IMI. Both palpable and nonpalpable lesions demonstrated mean signal-to-background ratio more than 2. An IMI margin was able to be calculated for 39 of 40 patients (95%). IMI margins were nearly identical to margins reported on final pathology (R2 = 0.9593), with median (interquartile range) difference of 1.3 (0.7-2.0) mm. IMI detected 2 margins in nonpalpable tumors that were clinically unacceptable and would have had a high probability of recurrence. Conclusions and Relevance: To our knowledge, this study presents the first clinical use of IMI for nonpalpable tumors and provides proof of principle for the utility of IMI across the field of surgical oncology in identifying occult disease and tumor-positive margins.

Intraoperative molecular imaging clinical trials: a review of 2020 conference proceedings.

SIGNIFICANCE: Surgery is often paramount in the management of many solid organ malignancies because optimal resection is a major factor in disease-specific survival. Cancer surgery has multiple challenges including localizing small lesions, ensuring negative surgical margins around a tumor, adequately staging patients by discriminating positive lymph nodes, and identifying potential synchronous cancers. Intraoperative molecular imaging (IMI) is an emerging potential tool proposed to address these issues. IMI is the process of injecting patients with fluorescent-targeted contrast agents that highlight cancer cells prior to surgery. Over the last 5 to 7 years, enormous progress has been achieved in tracer development, near-infrared camera approvals, and clinical trials. Therefore, a second biennial conference was organized at the University of Pennsylvania to gather surgical oncologists, scientists, and experts to discuss new investigative findings in the field. Our review summarizes the discussions from the conference and highlights findings in various clinical and scientific trials. AIM: Recent advances in IMI were presented, and the importance of each clinical trial for surgical oncology was critically assessed. A major focus was to elaborate on the clinical endpoints that were being utilized in IMI trials to advance the respective surgical subspecialties. APPROACH: Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center's second clinical trials update on IMI were selected to discuss their clinical trials and endpoints. RESULTS: Multiple phase III, II, and I trials were discussed during the conference. Since the approval of 5-ALA for commercial use in neurosurgical malignancies, multiple tracers and devices have been developed to address common challenges faced by cancer surgeons across numerous specialties. Discussants also presented tracers that are being developed for delineation of normal anatomic structures that can serve as an adjunct during surgical procedures. CONCLUSIONS: IMI is increasingly being recognized as an improvement to standard oncologic surgical resections and will likely advance the art of cancer surgery in the coming years. The endpoints in each individual surgical subspecialty are varied depending on how IMI helps each specialty solve their clinical challenges.

Using disability adjusted life years to value the treatment of thirty chronic conditions in the U.S. from 1987 to 2010: a proof of concept.

Health care spending in the U.S. grew two trillion dollars from 1987 to 2010, a 400% increase, but our understanding of the value of that increase is limited. In this paper we estimate the net value of spending for thirty chronic diseases between 1987 and 2010 by assigning a monetary value to changes in health outcomes and relating it to the costs of treating each disease. Changes in health outcomes are measured using a newly-available time series of disability adjusted life years (DALYs) data from the Institute for Health Metrics and Evaluation. Spending on treatments are determined using health care expenditure data from nationally representative surveys. We find the net value of treatment has grown substantially for several diseases. Overall, 20 of the 30 chronic conditions studied experienced an increase in health outcomes over the period, with 8 of those 20 showing a decrease in per-patient spending. Our estimates of net value of health spending using DALYs data are simple to apply and results are generally consistent with previous estimates which usually involve onerous data collection methods to study a single disease. The DALYs data have potential to be a useful, low-cost way to measure changes in health outcomes. However, challenges remain in using DALYs data to accurately measure the changing value of health care spending on the treatment of disease.

Targeting Prion-like Cis Phosphorylated Tau Pathology in Neurodegenerative Diseases.

Tau is a microtubule-associated protein heavily implicated in neurodegenerative diseases collectively known as tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Phosphorylation of tau at Thr231 allows for the isomerization of phosphorylated tau (p-tau) into distinct cis and trans conformations. Cis, but not trans, p-tau is detectable not only in Alzheimer's disease and chronic traumatic encephalopathy, but also right after traumatic brain injury depending on injury severity and frequency both in humans and animal models. Cis p-tau is not only neurotoxic but also spreads from a neuron to another in a prion-like fashion, functioning as a primary driver of neurodegeneration, which can be effectively neutralized by cis p-tau antibody. This represents an exciting new opportunity for understanding disease development and developing early biomarkers and effective therapies of tauopathies.