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According to recent studies on the trends of BMI worldwide, the prevalence of obesity has doubled in more than 80 countries since 1980. Moreover, nearly every country—excluding parts of sub-Saharan Africa and Asia—has observed an increase in obesity every year since 1975. Worldwide, 10.8% of adult males and 14.8% of adult females have obesity. Overall, this represents 3.4- and 2.3-fold increases in obesity in adult males and females, respectively, in 40 years. However, these trends are heterogeneous across countries with regard to the steepness of increase. The prevalence of a BMI ≥ 30 varies by country from 58% in the Micronesian island of Nauru. This wide range reflects the economic, environmental, ethnic, and social differences throughout the world. Moreover, the tabulation of the prevalence of obesity in each country is not conducted annually, as in the United States and other high-income countries. As a result, this chapter will focus on the trends of obesity in the United States and other affluent countries—defined in this chapter as the top 25 countries according to gross national income.

Background Although real-time localization of gliomas has improved with intraoperative image guidance systems, these tools are limited by brain shift, surgical cavity deformation, and expense. Objective To propose a novel method to perform near-infrared (NIR) imaging during glioma resections based on preclinical and clinical investigations, in order to localize tumors and to potentially identify residual disease. Methods Fifteen patients were identified and administered a Food and Drug Administration-approved, NIR contrast agent (Second Window indocyanine green [ICG], 5 mg/kg) before surgical resection. An NIR camera was utilized to localize the tumor before resection and to visualize surgical margins following resection. Neuropathology and magnetic resonance imaging data were used to assess the accuracy and precision of NIR fluorescence in identifying tumor tissue. Results NIR visualization of 15 gliomas (10 glioblastoma multiforme, 1 anaplastic astrocytoma, 2 low-grade astrocytoma, 1 juvenile pilocytic astrocytoma, and 1 ganglioglioma) was performed 22.7 hours (mean) after intravenous injection of ICG. During surgery, 12 of 15 tumors were visualized with the NIR camera. The mean signal-to-background ratio was 9.5 ± 0.8 and fluorescence was noted through the dura to a maximum parenchymal depth of 13 mm. The best predictor of positive fluorescence was enhancement on T1-weighted imaging; this correlated with signal-to-background ratio (P = .03). Nonenhancing tumors did not demonstrate NIR fluorescence. Using pathology as the gold standard, the technique demonstrated a sensitivity of 98% and specificity of 45% to identify tumor in gadolinium-enhancing specimens (n = 71). Conclusion With the use of Second Window ICG, gadolinium-enhancing tumors can be localized through brain parenchyma intraoperatively. Its utility for margin detection is promising but limited by lower specificity. Abbreviations 5-ALA, 5-aminolevulinic acidEPR, enhanced permeability and retentionFDA, Food and Drug AdministrationGBM, glioblastomaICG, indocyanine greenNIR, near-infraredNPV, negative predictive valuePPV, positive predictive valueROC, receiver operating characteristicROI, region of interestSBR, signal-to-background ratioWHO, World Health Organization.

BACKGROUND Complete tumor resection is the most important predictor of patient survival with non–small cell lung cancer. Methods for intraoperative margin assessment after lung cancer excision are lacking. This study evaluated near-infrared (NIR) intraoperative imaging with a folate-targeted molecular contrast agent (OTL0038) for the localization of primary lung adenocarcinomas, lymph node sampling, and margin assessment. METHODS Ten dogs with lung cancer underwent either video-assisted thoracoscopic surgery or open thoracotomy and tumor excision after an intravenous injection of OTL0038. Lungs were imaged with an NIR imaging device both in vivo and ex vivo. The wound bed was re-imaged for retained fluorescence suspicious for positive tumor margins. The tumor signal-to-background ratio (SBR) was measured in all cases. Next, 3 human patients were enrolled in a proof-of-principle study. Tumor fluorescence was measured both in situ and ex vivo. RESULTS All canine tumors fluoresced in situ (mean Fluoptics SBR, 5.2 [range, 2.7-8.1]; mean Karl Storz SBR 1.9 [range, 1.4-2.6]). In addition, the fluorescence was consistent with tumor margins on pathology. Three positive lymph nodes were discovered with NIR imaging. Also, a positive retained tumor margin was discovered upon NIR imaging of the wound bed. Human pulmonary adenocarcinomas were also fluorescent both in situ and ex vivo (mean SBR, > 2.0). CONCLUSIONS NIR imaging can identify lung cancer in a large-animal model. In addition, NIR imaging can discriminate lymph nodes harboring cancer cells and also bring attention to a positive tumor margin. In humans, pulmonary adenocarcinomas fluoresce after the injection of the targeted contrast agent. Cancer 2016. © 2016 American Cancer Society.

Non-small Cell Lung Cancer (NSCLC) remains a deadly disease despite aggressive treatment protocols which incorporate chemotherapy, radiation and surgery. These traditional approaches have reached a plateau in therapeutic benefit. There is emerging evidence suggesting that immunotherapy can serve as an alternative treatment modality for NSCLC. Our group has nearly two decades of experience involving immuno-gene therapy with Ad.hIFN-α and Ad.hIFN-β in human mesothelioma trials, and has observed both safety and efficacy in treatment of Thoracic malignancies. We have expanded the scope of our work and have obtained encouraging pre-clinical evidence suggesting a role for immunotherapy as a surgical adjuvant for NSCLC cancers. By combining immunotherapy with surgery, synergistic results have been observed. Based on these observations, we have prepared a Phase I Clinical Trial that pairs Ad.hIFN-α with surgery for patients with resectable NSCLC. Patient enrollment is likely to begin in the Summer of 2016. We hope that this trial will serve as a platform for future trials aimed at pairing immunotherapy with surgery for patients diagnosed with NSCLC.

Near infrared (NIR) molecular imaging is useful to identify tumor margins during surgery; however, the value of this technology has not been evaluated for tumors that have been pre-treated with chemotherapy. We hypothesized that NIR molecular imaging could locate mediastinal tumor margins in a murine model after neoadjuvant chemotherapy. Flank thymomas were established on mice. Two separate experiments were performed for tumor margin detection. The first experiment compared (i) surgery and (ii) surgery + NIR imaging. The second experiment compared (iii) preoperative chemotherapy + surgery, and (iv) preoperative chemotherapy + surgery + NIR imaging. NIR imaging occurred following systemic injection of indocyanine green. Margins were assessed for residual tumor cells by pathology. NIR imaging was superior at detecting retained tumor cells during surgery compared to standard techniques (surgery alone vs. surgery + NIR imaging, 20% vs. 80%, respectively). Following chemotherapy, the sensitivity of NIR imaging of tumor margins was not significantly altered. The mean in vivo tumor-to-background fluorescence ratio was similar in the treatment-naive and chemotherapy groups ((p = 0.899): 3.79 ± 0.69 (IQR 3.29 - 4.25) vs. 3.79 ± 0.52 (IQR 3.40 – 4.03)). We conclude that chemotherapy does not affect tumor fluorescence or identification of retained cancer cells at margins.

Background More than 80,000 people undergo resection of a pulmonary tumor each year, and the only method to determine if the tumor is malignant is histologic analysis. We propose that a targeted molecular contrast agent could bind lung adenocarcinomas, which could be identified using real-time optical imaging at the time of surgery. Methods Fifty patients with a biopsy-proven lung adenocarcinoma were enrolled. Before surgery, patients were systemically administered 0.1 mg/kg of a fluorescent folate receptor alpha (FRα)–targeted molecular contrast agent by intravenous infusion. During surgery, tumors were imaged in situ and ex vivo, after the lung parenchyma was dissected to directly expose the tumor to the imaging system. Results Tumors ranged from 0.3 to 7.5 cm (mean: 2.6 cm), and 46 of 50 (92%) lung adenocarcinomas were fluorescent. No false uptake occurred, and in 2 cases, intraoperative imaging revealed tumor metastases (3 mm and 6 mm) that were not recognized preoperatively. Four adenocarcinomas were not fluorescent, and immunohistochemistry showed that these adenocarcinomas did not express FRα. Tumor fluorescence was independent of nodule size, uptake of 2-deoxy-2-( 18 F)fluoro-D-glucose, histology, and tumor differentiation. Molecular imaging could identify only 7 of the 50 adenocarcinomas in situ in the patient without bisection. The most important predictor of the success of molecular imaging in locating the tumor in situ was the distance of the nodule from the pleural surface. Conclusions Intraoperative molecular imaging with a targeted contrast agent can identify lung adenocarcinomas, and this technology is currently useful in patients with subpleural tumors, irrespective of size. With further refinements, this tool may prove useful in locating adenocarcinomas that are deeper in the lung parenchyma, in lymph nodes, and at pleural and resection margins.

Surgery is the most effective method to cure patients with solid tumors, and 50% of all cancer patients undergo resection. Local recurrences are due to tumor cells remaining in the wound, thus we explore near-infrared (NIR) fluorescence spectroscopy and imaging to identify residual cancer cells after surgery. Fifteen canines and two human patients with spontaneously occurring sarcomas underwent intraoperative imaging. During the operation, the wounds were interrogated with NIR fluorescence imaging and spectroscopy. NIR monitoring identified the presence or absence of residual tumor cells after surgery in 14/15 canines with a mean fluorescence signal-to-background ratio (SBR) of ∼16. Ten animals showed no residual tumor cells in the wound bed (mean SBR1-year follow-up. In five animals, the mean SBR of the wound was >15, and histopathology confirmed tumor cells in the postsurgical wound in four/five canines. In the human pilot study, neither patient had residual tumor cells in the wound bed, and both remain disease free at >1.5-year follow up. Intraoperative NIR fluorescence imaging and spectroscopy identifies residual tumor cells in surgical wounds. These observations suggest that NIR imaging techniques may improve tumor resection during cancer operations.

Fluorescence guided surgery (FGS) is a developing field of surgical and oncologic research. Practically, FGS has shown useful applications in urologic surgery, benign biliary surgery, colorectal cancer liver metastasis resection, and ovarian cancer debulking. Most notably in in cancer surgery, FGS allows for the clear delineation of cancerous tissue from benign tissue. FGS requires the utilization of a fluorescent contrast agent and an intraoperative fluorescence imaging device (IFID). Currently available IFIDs are expensive, unable to work with multiple fluorophores, and can be cumbersome. This study aims to describe the development and utility of a small, cost-efficient, and interchangeable IFID made from commercially available components. Extensive research was done to design and construct a light-weight, portable, and cost-effective IFID. We researched the capabilities, size, and cost of several camera types and eventually decided on a near-infrared (NIR) charged couple device (CCD) camera for its overall profile. The small portable interchangeable imager of fluorescence (SPIIF) is a “scout” IFID system for FGS. The main components of the SPIIF are a NIR CCD camera with an articulating light filter. These components and a LED light source with an attached heat sink are mounted on a small metal platform. The system is connected to a laptop by a USB 2.0 cable. Pixielink © software on the laptop runs the system by controlling exposure time, gain, and image capture. After developing the system, we evaluated its utility as an IFID. The system weighs less than two pounds and can cover a large area. Due to its small size, it is easily made sterile by covering it with any sterile plastic sheet. To determine the system’s ability to detect fluorescent signal, we used the SPIIF to detect indocyanine green under ex and in-vivo conditions and fluorescein under ex-vivo conditions. We found the SPIIF was able to detect both ICG and fluorescein under different depths of a semi-opaque colloid. Second, we found that a concentration as low as 0.5 g/ml of indocyanine green dissolved in plasma was detectable. Lastly, in a murine and human cancer model, the SPIIF was able to detect indocyanine green signal within tumors and generate a signal-to-background ratio (SBR) of 3.75. This study shows that a low-cost IFID can be made from commercially available parts. Second, this IFID is capable of in and ex-vivo detection of multiple fluorophores without sacrificing its small size or favorable ergonomics.

Background Over 80,000 people undergo pulmonary resection for a lung nodule in the United States each year. Small nodules are frequently missed or difficult to find despite preoperative imaging. We hypothesized that near-infrared (NIR) imaging technology could be used to identify and locate lung nodules during surgery. Methods We enrolled 18 patients who were diagnosed with a pulmonary nodule that required resection. All patients had a fine-cut 1-mm computed tomography scan preoperatively. The patients were given systemic 5 mg/kg indocyanine green and then underwent an open thoracotomy 24 hours later. The NIR imaging was used to identify the primary nodule and search for additional nodules that were not found by visual inspection or manual palpation of the ipsilateral lung. Results Manual palpation and visual inspection identified all 18 primary pulmonary nodules and no additional lesions. Intraoperative NIR imaging detected 16 out of the 18 primary nodules. The NIR imaging also identified 5 additional subcentimeter nodules; 3 metastatic adenocarcinomas and 2 metastatic sarcomas. This technology could identify nodules as small as 0.2 cm and as deep as 1.3 cm from the pleural surface. This approach discovered 3 nodules that were in different lobes than the primary tumor. Nodule fluorescence was independent of size, metabolic activity, histology, tumor grade and vascularity. Conclusions This is the first-in-human demonstration of identifying pulmonary nodules during thoracic surgery with NIR imaging without a priori knowledge of their location or existence. The NIR imaging can detect pulmonary nodules during lung resections that are poorly visualized on computed tomography and difficult to discriminate on finger palpation.

Introduction Defining tumor from non-tumor tissue is one of the major challenges of cancer surgery. Surgeons depend on visual and tactile clues to select which tissues should be removed from a patient. Recently, we and others have hypothesized near-infrared (NIR) imaging can be used during surgery to differentiate tumors from normal tissue. Methods We enrolled 8 canines and 5 humans undergoing cancer surgery for NIR imaging. The patients were injected with indocyanine green (ICG), an FDA approved non-receptor specific NIR dye that accumulates in hyperpermeable tissues, 16–24 hours prior to surgery. During surgery, NIR imaging was used to discriminate the tumor from non-tumor tissue. Results NIR imaging identified all tumors with a mean signal-to-background ratio of 6.7. Optical images were useful during surgery in discriminating normal tissue from cancer. In 3 canine cases and 1 human case, the tissue surrounding the tumor was inflamed due to obstruction of the vascular supply due to mass effect. In these instances, NIR imaging could not distinguish tumor tissue from tissue that was congested, edematous and did not contain cancer. Conclusions This study shows that NIR imaging can identify tumors from normal tissues, provides excellent tissue contrast, and it facilitates the resection of tumors. However, in situations where there is significant peritumoral inflammation, NIR imaging with ICG is not helpful. This suggests that non-targeted NIR dyes that accumulate in hyperpermeable tissues will have significant limitations in the future, and receptor-specific NIR dyes may be necessary to overcome this problem.

Background Transforming growth factor (TGF)-β is a potent immunosuppressive cytokine necessary for cancer growth. Animal and human studies have shown that pharmacologic inhibition of TGF-β slows the growth rate of established tumors and occasionally eradicates them altogether. We observed, paradoxically, that inhibiting TGF-β before exposing animals to tumor cells increases tumor growth kinetics. We hypothesized that TGF-β is necessary for the anti-tumor effects of cytotoxic CD8+ T lymphocytes (CTLs) during the early stages of tumor initiation. Methods BALB/c mice were pretreated with a blocking soluble TGF-β receptor (sTGF-βR, TGF-β-blockade group, n=20) or IgG2a (Control group, n=20) before tumor inoculation. Tumor size was followed for 6 weeks. In vivo lymphocyte assays and depletion experiments were then performed to investigate the immunological basis of our results. Lastly, animals were pretreated with either sTGF-βR (n=6) or IgG2a (n=6) prior to immunization with an adenoviral vector encoding the human papillomavirus E7 gene (Ad.E7). One week later, flow cytometry was utilized to measure the number of splenic E7-specific CD8+ T cells. Results Inhibition of TGF-β before the injection of tumor cells resulted in significantly larger average tumor volumes on days 11, 17, 22, 26 and 32 post tumor-inoculation (p