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PURPOSE: Intraoperative molecular imaging (IMI) uses tumor-targeted optical contrast agents to improve identification and clearance of cancer. Recently, a probe has been developed that only fluoresces when activated in an acidic pH, which is common to many malignancies. We report the first multicenter Phase 2 trial of a pH-activatable nanoprobe (pegsitacianine, ONM-100) for IMI of lung cancer. METHODS: Patients with suspected or biopsy-confirmed lung cancer scheduled for sublobar resection were administered a single intravenous infusion of pegsitacianine (1 mg/kg) one to three days prior to surgery. Intraoperatively, the patients underwent a white light thoracoscopic evaluation, and then were imaged with an NIR thoracoscope to detect tumor fluorescence. The primary study endpoint was the proportion of patients with a clinically significant event (CSE) which was defined as an intraoperative discovery during IMI that led to a change in the surgical procedure. Possible CSEs included (i) localizing the index lung nodule that could not be located by white light, (ii) identifying a synchronous malignant lesion, or (iii) recognizing a close surgical margin (< = 10 mm). Secondary endpoints were sensitivity, specificity, NPV, and PPV of pegsitacianine in detecting tumor-containing tissue. The safety evaluation was based on adverse event reporting, clinical laboratory parameters, and physical examinations. RESULTS: Twenty patients were confirmed as eligible and administered pegsitacianine. Most of the patients were female (n = 12 [60%]), middle-aged (mean age 63.4 years), and former smokers (n = 13 [65%], 28.6 mean pack years). Mean lesion size was 1.9 cm, and most lesions (n = 17 [85%]) were malignant. The most common histologic subtype was adenocarcinoma (n = 9). By utilizing IMI with pegsitacianine, one patient had a CSE in the detection of a close margin and another had localization of a tumor not detectable by traditional surgical means. Six of 19 (31.6%) malignant lesions fluoresced with mean tumor-to-background ratio (TBR) of 3.00, as compared to TBR of 1.20 for benign lesions (n = 3). Sensitivity and specificity of pegsitacianine-based IMI for detecting malignant tissue was 31.6% and 33.3%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of pegsitacianine-based IMI was 75% and 7.1%, respectively. Pegsitacianine-based imaging was not effective in differentiating benign and malignant lymph nodes. From a safety perspective, no drug-related serious adverse events occurred. Four patients experienced mild pegsitacianine-related infusion reactions which required discontinuing the study drug with complete resolution of symptoms. CONCLUSIONS: Pegsitacianine-based IMI, though well tolerated from a safety perspective, does not consistently label lung tumors during resection and does not provide significant clinical benefit over existing standards of surgical care. The biology of lung tumors may not be as acidic as other solid tumors in the body thereby not activating the probe as predicted.
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Neoplasias Pulmonares , Imagem Molecular , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Concentração de Íons de Hidrogênio , Imagem Molecular/métodosRESUMO
Uhl anomaly is characterized by the morphologic absence of right ventricular myocardium and is an exceedingly rare cause of nonischemic cardiomyopathy. We report the first case of a successful heart transplantation in a 41-year-old patient who presented in cardiogenic shock from Uhl anomaly causing decompensated right ventricular failure.
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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.
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Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Eritrócitos , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Eritrócitos/metabolismo , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Mutação , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/sangue , Proteínas Proto-Oncogênicas p21(ras)/genética , Masculino , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , DNA de Neoplasias/sangue , DNA de Neoplasias/genéticaRESUMO
BACKGROUND: We describe use, patients, and outcome of diagnostic lobectomy for suspected lung cancer without pathologic confirmation. METHODS: A retrospective review of consecutive lobectomy or bilobectomy for suspected or confirmed primary pulmonary malignancy was conducted using our participant's sample of The Society of Thoracic Surgeons database. Surgeons performed lobectomy based on clinical diagnosis or confirmation on a biopsy specimen. Lung cancer confirmed by biopsy specimen was compared with cases clinically suspected. Univariate and multivariate analyses identified variables associated with lobectomy without biopsy specimen confirmation. RESULTS: Among 2651 lobectomies performed between 2006 and 2019 in 2617 patients, lung cancer was confirmed by preoperative biopsy specimen in 51.6% (1368 of 2651) or was clinically suspected before the operation in 48.4% (1283 of 2651). The intraoperative biopsy specimen in 585 of 1283 cases (45.6%) proved lung cancer before lobectomy, whereas lobectomy proceeded in 698 cases (54.4%) without a diagnosis. Final pathology proved lung cancer in 90% (628 of 698) without a diagnosis before lobectomy and nonmalignant disease in 10% (70 of 698). Nonneoplastic pathology included granulomas (30 of 70 [43%]), pneumonia (12 of 70 [17%]), bronchiectasis (7 of 70 [10%]), and other lesions (21 of 70 [30%]). Operative mortality was 0.94% (25 of 2651) for the cohort and 1.0% (7 of 698) for diagnostic lobectomy only. Multivariate analysis identified patient age, type of lobectomy (right middle lobe), and the intermediate study tercile as associated with diagnostic lobectomy. CONCLUSIONS: Lobectomy for suspected lung cancer without diagnosis is common, represents practice variation, and infrequently (10% diagnostic, 2.6% all lobectomies) removes nonmalignant disease. Tissue confirmation before lobectomy is preferred, particularly when operative risk is increased. Diagnostic lobectomy is acceptable in carefully selected patients and lesions.
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Neoplasias Pulmonares , Pneumonia , Cirurgiões , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia , Estudos Retrospectivos , Pneumonectomia/efeitos adversos , Pneumonia/etiologia , Cirurgia Torácica VídeoassistidaRESUMO
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.
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Neoplasias Pulmonares , Neoplasias Pleurais , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Estudos Retrospectivos , Pulmão/patologia , Imagem Molecular/métodosRESUMO
OBJECTIVES: This study aims to evaluate whether postoperative radiotherapy using newer techniques (intensity-modulated radiotherapy [IMRT]) is associated with improved survival for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) who underwent complete resection. METHODS: The overall survival of patients with stage IIIA-N2 NSCLC who received postoperative IMRT versus no postoperative IMRT following induction chemotherapy and lobectomy in the National Cancer Database from 2010-2018 was assessed via Kaplan-Meier analysis, Cox proportional hazards analysis and propensity score-matched analysis. Additional survival analyses were also conducted in patients with completely resected stage IIIA-pN2 NSCLC who had upfront lobectomy (without induction therapy) followed by adjuvant chemotherapy alone or adjuvant chemotherapy with postoperative IMRT. Only patients receiving IMRT, which is a newer, more conformal radiotherapy technique, were included. Patients with positive surgical margins were excluded. RESULTS: A total of 3203 patients with stage IIA-N2 NSCLC who underwent lobectomy were included. Five hundred eighty-eight (18.4%) patients underwent induction chemotherapy followed by lobectomy, and 2615 (82%) underwent lobectomy followed by chemotherapy. In unadjusted, multivariable-adjusted, and propensity score--matched analyses, there were no significant differences in overall survival between the patients who also received postoperative IMRT versus those who did not. CONCLUSIONS: In this national analysis, the use of postoperative IMRT was not associated with improved survival in patients with completely resected stage IIIA-N2 NSCLC with or without induction chemotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Resultado do Tratamento , Análise de Sobrevida , Quimioterapia Adjuvante , Estadiamento de Neoplasias , Pneumonectomia/efeitos adversos , Radioterapia Adjuvante , Estudos RetrospectivosRESUMO
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.
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Cuidados Intraoperatórios , Neoplasias Pulmonares , Fluoresceínas , Corantes Fluorescentes , Ácido Fólico , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Imagem Molecular/métodosRESUMO
Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach involving local delivery of a replication-deficient adenovirus expressing herpes simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation that promotes immunogenic tumor cell death, antigen-presenting cell activation, and T cell stimulation. This phase I dose-escalation pilot trial assessed bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were candidates for surgery. A single intra-tumoral AdV-tk injection in three dose cohorts (maximum 1012 viral particles) was performed during diagnostic staging, followed by a 14-day course of the prodrug valacyclovir, and subsequent surgery 1 week later. Twelve patients participated after appropriate informed consent. Vector-related adverse events were minimal. Immune biomarkers were evaluated in tumor and blood before and after GMCI. Significantly increased infiltration of CD8+ T cells was found in resected tumors. Expression of activation, inhibitory, and proliferation markers, such as human leukocyte antigen (HLA)-DR, CD38, Ki67, PD-1, CD39, and CTLA-4, were significantly increased in both the tumor and peripheral CD8+ T cells. Thus, intratumoral AdV-tk injection into non-small-cell lung cancer (NSCLC) proved safe and feasible, and it effectively induced CD8+ T cell activation. These data provide a foundation for additional clinical trials of GMCI for lung cancer patients with potential benefit if combined with other immune therapies.
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Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Terapia Genética , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Adenoviridae/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Citotoxicidade Imunológica , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Neoplasias Pulmonares/patologia , Terapia Neoadjuvante , Timidina Quinase/genéticaRESUMO
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.
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Adenocarcinoma/diagnóstico por imagem , Receptor 1 de Folato/metabolismo , Cuidados Intraoperatórios , Imagem Molecular , Sondas Moleculares/química , Espectroscopia de Luz Próxima ao Infravermelho , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/diagnóstico , Sistemas de Liberação de Medicamentos , Feminino , Fluorescência , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Intraoperative molecular imaging (IMI) may improve surgical outcomes during pulmonary resection for lung cancer. A multiinstitutional phase 2 IMI clinical trial was conducted using a near-infrared, folate receptor-targeted contrast agent for lung adenocarcinomas, OTL38. The primary goal was to determine whether OTL38 improved surgeons' ability to identify difficult to find nodules, occult cancers, and positive margins. METHODS: Patients with lung nodules received OTL38 (0.025 mg/kg) preoperatively. Patients had IMI sequentially during lung inspection, tumor resection, and margin check. Efficacy was evaluated by occurrence of clinically significant events, occurrences that caused the surgeon to modify the operation or upstage the patient's cancer. Safety was assessed for a single intravenous dose of OTL38. RESULTS: Of 110 patients recruited, 92 were eligible for analysis. During lung inspection, IMI found 24 additional nodules, 9 (10%) of which were cancers that had not been known preoperatively. During tumor resection, IMI located 11 (12%) lesions that the surgeon could not find. During the margin check, IMI revealed 8 positive margins (9%) that the surgeon thought were negative. Benefits of IMI were pronounced in patients undergoing sublobar pulmonary resections and in patients with ground-glass opacities. There were no serious adverse events. All surgeons felt comfortable with the procedures by 10 cases. CONCLUSIONS: In this phase 2 clinical trial, IMI improved outcomes for 26% of patients. A randomized, multiinstitutional phase 3 clinical trial is underway.
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Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Imagem Molecular/métodos , Adenocarcinoma de Pulmão/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Cuidados Intraoperatórios , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
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.
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Raios Infravermelhos , Neoplasias Mamárias Animais/diagnóstico por imagem , Neoplasias Mamárias Animais/cirurgia , Imagem Óptica , Animais , Modelos Animais de Doenças , Cães , Humanos , Período Intraoperatório , Metástase Linfática , Neoplasias Mamárias Animais/patologiaRESUMO
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.
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Fluorescência , Corantes Fluorescentes/farmacocinética , Receptor 1 de Folato/metabolismo , Imagem Molecular/métodos , Neoplasias/cirurgia , Cirurgia Assistida por Computador/métodos , Animais , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Humanos , Cuidados Intraoperatórios , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
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Neoplasias Pulmonares/cirurgia , Metastasectomia/métodos , Nódulos Pulmonares Múltiplos/cirurgia , Imagem Óptica/métodos , Pneumonectomia , Sarcoma/cirurgia , Nódulo Pulmonar Solitário/cirurgia , Espectroscopia de Luz Próxima ao Infravermelho , Cirurgia Torácica Vídeoassistida , Toracotomia , Adulto , Idoso , Estudos de Viabilidade , Feminino , Corantes Fluorescentes/administração & dosagem , Humanos , Verde de Indocianina/administração & dosagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Masculino , Metastasectomia/efeitos adversos , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/secundário , Pneumonectomia/efeitos adversos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sarcoma/diagnóstico por imagem , Sarcoma/secundário , Nódulo Pulmonar Solitário/diagnóstico por imagem , Nódulo Pulmonar Solitário/secundário , Cirurgia Torácica Vídeoassistida/efeitos adversos , Toracotomia/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral , Adulto JovemRESUMO
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) (2.5-5âmg/kg) 24âhours 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 2.59â±â2.57). Twelve out of 13 invasive malignancies (n = 12 pancreatic adenocarcinoma, n = 1 cholangiocarcinoma) were fluorescent (mean TBR 4.42â±â2.91). 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.
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Adenocarcinoma/cirurgia , Cuidados Intraoperatórios/métodos , Imagem Óptica/métodos , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Adenocarcinoma/diagnóstico por imagem , Adulto , Idoso , Estudos de Viabilidade , Feminino , Corantes Fluorescentes , Humanos , Verde de Indocianina , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Estudos ProspectivosRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Modelos Animais de Doenças , Neoplasias Pulmonares/patologia , Imagem Óptica/métodos , Cirurgia Assistida por Computador/métodos , Ácido Aminolevulínico/química , Animais , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Linhagem Celular , Linhagem Celular Tumoral , Cães , Fluorescência , Humanos , Neoplasias Pulmonares/cirurgia , Margens de Excisão , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Fármacos FotossensibilizantesRESUMO
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.
Assuntos
Verde de Indocianina/administração & dosagem , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/cirurgia , Imagem Óptica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Período Intraoperatório , Masculino , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Neoplasia Residual , Sensibilidade e EspecificidadeRESUMO
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.