Andrew D. Newton

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a review of factors contributing to morbidity and mortality

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with prolonged survival for appropriately selected patients with peritoneal dissemination of abdominal malignancies. CRS and HIPEC has been criticized for perceived high rates of morbidity and mortality. Morbidity and mortality rates of CRS and HIPEC, however, do not appear dissimilar to those of other large abdominal surgeries, particularly when relevant patient and operative factors are accounted for. The risk of morbidity and mortality following this surgery for a given individual can be predicted in part by a variety of patient and operative factors. While strong data are lacking, the limited data that exists on the matter suggests that the independent contribution of the heated intraperitoneal chemotherapy to CRS and HIPEC morbidity is relatively small. A more thorough understanding of the patient and operative factors associated with CRS and HIPEC morbidity and mortality, as well as the specific complications related to the intraperitoneal chemotherapy, can better inform clinicians in multidisciplinary teams and patients alike in the decision-making for this surgery.

Neoadjuvant therapy for gastric cancer: current evidence and future directions

Although surgical resection remains the only potentially curative treatment for gastric cancer (GC), poor long-term outcomes with resection alone compel a multimodality approach to this disease. Multimodality strategies vary widely; while adjuvant approaches are typically favored in Asia and the United States (USA), a growing body of evidence supports neoadjuvant and/or perioperative strategies in locally advanced tumors. Neoadjuvant approaches are particularly attractive given the morbidity associated with surgical management of GC and the substantial risk of omission of adjuvant therapy. The specific advantages of chemoradiotherapy (CRT) compared to chemotherapy have not been well defined, particularly in the preoperative setting and trials aimed at determining the optimal elements and sequencing of therapy are underway. Future studies will also define the role of targeted and biologic therapies.

Intraoperative Molecular Imaging Combined With Positron Emission Tomography Improves Surgical Management of Peripheral Malignant Pulmonary Nodules

Objective: To determine if intraoperative molecular imaging (IMI) can improve detection of malignant pulmonary nodules. Background: 18-Fluorodeoxyglucose positron emission tomography (PET) is commonly utilized in preoperative assessment of patients with solid malignancies; however, false negatives and false positives remain major limitations. Using patients with pulmonary nodules as a study model, we hypothesized that IMI with a folate receptor targeted near-infrared contrast agent (OTL38) can improve malignant pulmonary nodule identification when combined with PET. Methods: Fifty patients with pulmonary nodules with imaging features suspicious for malignancy underwent preoperative PET. Patients then received OTL38 before pulmonary resection. During resection, IMI was utilized to evaluate known pulmonary nodules and identify synchronous lesions. Tumor size, PET standardized uptake value, and IMI tumor-to-background ratios were compared for known and synchronous nodules via paired and unpaired t tests, when appropriate. Test characteristics of PET and IMI with OTL38 were compared. Results: IMI identified 56 of 59 (94.9%) malignant pulmonary nodules identified by preoperative imaging. IMI located an additional 9 malignant lesions not identified preoperatively. Nodules only detected by IMI were smaller than nodules detected preoperatively (0.5 vs 2.4 cm; P < 0.01), but displayed similar fluorescence (tumor-to-background ratio 3.3 and 3.1; P = 0.50). Sensitivity of IMI and PET were 95.6% and 73.5% (P = 0.001), respectively; and positive predictive values were 94.2% and 89.3%, respectively (P > 0.05). Additionally, utilization of IMI clinically upstaged 6 (12%) subjects and improved management of 15 (30%) subjects. Conclusions: These data suggest that combining IMI with PET may provide superior oncologic outcomes for patients with resectable lung cancer.

Early Discharge and Post-Discharge Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer

To assess whether discharging patients early after radical cystectomy (RC) is associated with an increased risk of readmission and post‐discharge complications.

An open label trial of folate receptor-targeted intraoperative molecular imaging to localize pulmonary squamous cell carcinomas

Background Clinical applicability of folate receptor-targeted intraoperative molecular imaging (FR-IMI) has been established for surgically resectable pulmonary adenocarcinoma. A role for FR-IMI in other lung cancer histologies has not been studied. In this study, we evaluate feasibility of FR-IMI in patients undergoing pulmonary resection for squamous cell carcinomas (SCCs). Methods In a human clinical trial (NCT02602119), twelve subjects with pulmonary SCCs underwent FR-IMI with a near-infrared contrast agent that targets the folate receptor-α (FRα), OTL38. Near-infrared signal from tumors and benign lung was quantified to calculate tumor-to-background ratios (TBR). Folate receptor-alpha expression was characterized, and histopathologic correlative analyses were performed to evaluate patterns of OTL38 accumulation. An exploratory analysis was performed to determine patient and histopathologic variables that predict tumor fluorescence. Results 9 of 13 SCCs (in 9 of 12 of subjects) displayed intraoperative fluorescence upon NIR evaluation (median TBR, 3.9). OTL38 accumulated within SCCs in a FRα-dependent manner. FR-IMI was reliable in localizing nodules as small as 1.1 cm, and prevented conversion to thoracotomy for nodule localization in three subjects. Upon evaluation of patient and histopathologic variables, in situ fluorescence was associated with distance from the pleural surface, and was independent of alternative variables including tumor size and metabolic activity. Conclusions This work demonstrates that FR-IMI is potentially feasible in 70% of SCC patients, and that molecular imaging can improve localization during minimally invasive pulmonary resection. These findings complement previous data demonstrating that ∼98% of pulmonary adenocarcinomas are localized during FR-IMI and suggest broad applicability for NSCLC patients undergoing resection.

Utilization of targeted near-infrared molecular imaging to improve pulmonary metastasectomy of osteosarcomas

Abstract. Pulmonary metastasectomy for osteosarcoma provides a select group of patients an opportunity for long-term survival and possible cure. Unfortunately, a complete metastasectomy is challenging due an inability to accurately identify lesions that lay below the threshold of preoperative imaging or intraoperative visual and tactile inspection. Growing evidence suggests that osteosarcomas express a number of unique molecular markers, including the folate receptor alpha. In this case report, we describe the application of a folate receptor-targeted, near-infrared optical contrast agent (OTL38) to improve osteosarcoma localization during minimally invasive pulmonary resection. In addition to localizing preoperatively identified lesions, this technology helped identify additional disease that was undetected on preoperative imaging or with traditional intraoperative techniques. This report marks the first successful utilization of a molecular imaging probe useful for osteosarcomas. This technology may provide a unique approach to improve pulmonary metastasectomy of osteosarcomas.

Near-infrared Intraoperative Molecular Imaging Can Identify Metastatic Lymph Nodes in Prostate Cancer

OBJECTIVE To propose a novel method to perform indocyanine green (ICG) based near-infrared (NIR) fluorescence imaging during pelvic lymph node dissection (PLND) for prostate cancer patients with lymph node metastasis (LNM). MATERIALS AND METHODS A prostate cancer cell line PC3 was used to establish xenograft model in NOD/SCID mice. After tumor growth, the mice were injected with ICG through the tail vein. Xenografts and surrounding tissues were imaged with NIR camera 24 hours after intravenous ICG, and tumor-to-background ratios were calculated. We then performed a pilot human study to evaluate the role of NIR imaging in robotic PLND after systemic ICG in 4 patients with prostate cancer and preoperative lymphadenopathy. RESULTS ICG localized to PC3 xenografts in the mice and all xenografts were highly fluorescent compared with surrounding tissues, with a median tumor-to-background ratio of 2.85 (interquartile range = 2.64-3.90). In the human study, intraoperative in vivo NIR imaging identified 3 of the 4 preoperative lymphadenopathies as fluorescence-positive, and back table ex vivo NIR imaging identified all 4 lymphadenopathies as fluorescence-positive. All the lymphadenopathies were found to be LNMs by pathologic examination. Two of the four cases had additional LNMs, all of which were fluorescence-positive with intraoperative in vivo NIR imaging. CONCLUSION Intravenously administered ICG accumulates in prostate cancers in both a murine model and human patients. NIR fluorescence based on intravenous ICG may serve as a useful tool to facilitate the identification of positive nodes during PLND in patients with higher risk of LNMs.

Intraoperative near-infrared imaging of mesothelioma

Though difficult to achieve, complete resection of malignant pleural mesothelioma is paramount to improving patient survival. Surgeons have traditionally been limited to using visual inspection and manual palpation to locate and remove cancerous tissue. However, intraoperative molecular imaging (IMI) is a promising new technology in surgery. Molecular imaging utilizes a fluorescent tracer that selectively accumulates in cancer cells. An imaging device is then used to detect and augment the fluorescent signal emitted from the fluorescent cancer cells. Our group and others have demonstrated that molecular imaging with either indocyanine green (ICG) or a folate receptor alpha (FRα) targeted fluorophore can accurately identify a number of intrathoracic malignancies. Early studies of intraoperative imaging have suggested its efficacy for malignant pleural mesothelioma. In a murine model of mesothelioma, intraoperative imaging was found to have sensitivity of 87% and specificity of 83%. In a pilot human study, eight patients with biopsy-proven epithelial malignant pleural mesothelioma were administered 5 mg/kg of intravenous ICG injection 24 h prior to resection. The following day, a near-infrared (NIR) imaging device was used to detect tumor fluorescence intraoperatively. After what was believed to be complete tumor excision, the wound bed was re-imaged for residual fluorescence indicative of retained tumor. When residual fluorescence was detected, additional tissue was resected, if feasible, and specimens were sent for pathologic correlation. In all cases, intraoperative fluorescence localized to mesothelioma deposits which were confirmed on final pathology. Following resection, fluorescence was confirmed ex vivo with a mean tumor-to-background ratio (TBR) of 3.2 (IQR: 2.9-3.4). It is hoped that this technology will improve outcomes for mesothelioma patients by allowing for a more complete oncologic resection.

The second window ICG technique demonstrates a broad plateau period for near infrared fluorescence tumor contrast in glioblastoma

Introduction Fluorescence-guided surgery has emerged as a powerful tool to detect, localize and resect tumors in the operative setting. Our laboratory has pioneered a novel way to administer an FDA-approved near-infrared (NIR) contrast agent to help surgeons with this task. This technique, coined Second Window ICG, exploits the natural permeability of tumor vasculature and its poor clearance to deliver high doses of indocyanine green (ICG) to tumors. This technique differs substantially from established ICG video angiography techniques that visualize ICG within minutes of injection. We hypothesized that Second Window ICG can provide NIR optical contrast with good signal characteristics in intracranial brain tumors over a longer period of time than previously appreciated with ICG video angiography alone. We tested this hypothesis in an intracranial mouse glioblastoma model, and corroborated this in a human clinical trial. Methods Intracranial tumors were established in 20 mice using the U251-Luc-GFP cell line. Successful grafts were confirmed with bioluminescence. Intravenous tail vein injections of 5.0 mg/kg (high dose) or 2.5 mg/kg (low dose) ICG were performed. The Perkin Elmer IVIS Spectrum (closed field) was used to visualize NIR fluorescence signal at seven delayed time points following ICG injection. NIR signals were quantified using LivingImage software. Based on the success of our results, human subjects were recruited to a clinical trial and intravenously injected with high dose 5.0 mg/kg. Imaging was performed with the VisionSense Iridium (open field) during surgery one day after ICG injection. Results In the murine model, the NIR signal-to-background ratio (SBR) in gliomas peaks at one hour after infusion, then plateaus and remains strong and stable for at least 48 hours. Higher dose 5.0 mg/kg improves NIR signal as compared to lower dose at 2.5 mg/kg (SBR = 3.5 vs. 2.8; P = 0.0624). Although early (≤ 6 hrs) visualization of the Second Window ICG accumulation in gliomas is stronger than late (≥24 hrs) visualization (SBR = 3.94 vs. 2.32; p<0.05) there appears to be a long plateau period of stable ICG NIR signal accumulation within tumors in the murine model. We call this long plateau period the “Second Window” of ICG. In glioblastoma patients, the delayed visualization of intratumoral NIR signal was strong (SBR 7.50 ± 0.74), without any significant difference within the 19 to 30 hour visualization window (R2 = 0.019). Conclusion The Second Window ICG technique allows neurosurgeons to deliver NIR optical contrast agent to human glioblastoma patients, thus providing real-time tumor identification in the operating room. This nonspecific tumor accumulation of ICG within the tumor provides strong signal to background contrast, and is not significantly time dependent between 6 hours to 48 hours, providing a broad plateau for stable visualization. This finding suggests that optimal imaging of the “Second Window of ICG” may be within this plateau period, thus providing signal uniformity across subjects.

Near-Infrared Intraoperative Imaging Can Successfully Identify Malignant Pleural Mesothelioma After Neoadjuvant Chemotherapy

Malignant pleural mesothelioma is a deadly disease. Complete surgical resection provides patients with the best opportunity for long-term survival. Unfortunately, identification of disease during resection can be challenging. In this report, we describe successful intraoperative utilization of the near-infrared imaging agent, indocyanine green, to help the surgeon identify malignant disease in a patient with malignant pleural mesothelioma who had previously received neoadjuvant chemotherapy. This technology may ultimately enhance the thoracic surgeon’s ability to identify small disease deposits at the time of resection.