Sustained Supratherapeutic Paclitaxel Delivery Enhances Irreversible Sarcoma Cell Death.

Risk of locoregional recurrence after sarcoma resection is high, increasing both morbidity and mortality. Intraoperative implantation of paclitaxel (PTX)-eluting polymer films locally delivers sustained, supratherapeutic PTX concentrations to the tumor bed that are not clinically feasible with systemic therapy, thereby reducing recurrence and improving survival in a murine model of recurrent sarcoma. However, the biology underlying increased efficacy of PTX-eluting films is unknown and provides the impetus for this work. In vitro PTX efficacy is time and dose dependent with prolonged exposure significantly decreasing PTX IC50 values for human chondrosarcoma (CS-1) cells (153.9 nmol/L at 4 hours vs. 14.2 nmol/L at 30 hours, P = 0.0001). High-dose PTX significantly inhibits proliferation with in vivo PTX films delivering a dose >130 µmol/L directly to the tumor thereby irreversibly arresting cell cycle and inducing apoptosis in CS-1 as well as patient-derived liposarcoma (LP6) and leiomyosarcoma (LMS20). Supratherapeutic PTX upregulates the expression of p21 in G2-M arrested cells, and irreversibly induces apoptosis followed by cell death, within 4 hours of exposure. Microarray analyses corroborate the finding of poor DNA integrity commonly observed as a final step of apoptosis in CS-1 cells and tumor. Unlike low PTX concentrations at the tumor bed during systemic delivery, supratherapeutic concentrations achieved with PTX-eluting films markedly decrease sarcoma lethality in vivo and offer an alternative paradigm to prevent recurrence.

Obese Patients Undergoing Tracheobronchoplasty Have Excellent Outcomes.

BACKGROUND: Tracheobronchoplasty (TBP) is the gold-standard treatment for severe symptomatic excessive central airway collapse; however outcomes among obese patients are unknown. METHODS: A retrospective, single-center analysis was conducted on consecutive patients undergoing TBP for severe symptomatic excessive central airway collapse from 2003 to 2020. Demographics, comorbidities, functional status, and perioperative complications were collected. Functional status was assessed with a 6-minute walk test (6MWT). Health-related quality of life (HRQOL) was assessed with the St George's Respiratory Questionnaire (SGRQ), Cough-specific Quality of Life Questionnaire, and modified Medical Research Council dyspnea scale (mMRC) at baseline and postoperatively. Wilcoxon rank-sum and χ2 tests were used to compare outcomes between groups. A mixed-effects regression model compared 6MWT and HRQOL over time. RESULTS: One hundred three patients underwent TBP with complete follow-up data. Thirty-four patients (33%) were obese (body mass index ≥ 35 kg/m2). Baseline demographics were similar between obese and nonobese groups, but obese patients had worse preoperative SGRQ and mMRC scores. Overall complication rates were similar (52.9% vs 43.5%, P = .36). At 3 months there was no significant difference in SGRQ, Cough-specific Quality of Life Questionnaire, or 6MWT scores; however mMRC scores were higher in obese patients (P = .04). At 12 months there was no significant difference in SGRQ, Cough-specific Quality of Life Questionnaire, mMRC, or 6MWT scores. Correcting for age, sex, and Charlson Comorbidity Index a mixed-effects regression model demonstrated obesity was not an independent predictor for lower 6MWT scores or HRQOL. CONCLUSIONS: Obese patients achieve similar improvement in HRQOL and functional capacity with comparable morbidity after TBP as nonobese patients. Obesity should not preclude patients with severe symptomatic excessive central airway collapse from TBP.

Finding the "True" N0 Cohort: Technical Aspects of Near-infrared Sentinel Lymph Node Mapping in Non-small Cell Lung Cancer.

OBJECTIVE: To examine technical-, patient-, tumor-, and treatment-related factors associated with NIR guided SLN identification. BACKGROUND: Missed nodal disease correlates with recurrence in early stage NSCLC. NIR-guided SLN mapping may improve staging and outcomes through identification of occult nodal disease. METHODS: Retrospective analysis of 2 phase I clinical trials investigating NIR-guided SLN mapping utilizing ICG in patients with surgically resectable NSCLC. RESULTS: In total, 66 patients underwent NIR-guided SLN mapping and lymphadenectomy after peritumoral ICG injection. There was significantly increased likelihood of SLN identification with injection dose ≥1 mg compared to <1 mg (65.2% vs 35.0%, P = 0.05), lung ventilation after injection (65.2% vs 35.0%, P = 0.05), and albumin dissolvent (68.1%) compared to fresh frozen plasma (28.6%) and sterile water (20.0%) (P = 0.01). In patients receiving the optimized ICG injection, there was significantly increased likelihood of SLN identification with radiologically solid nodules compared to sub-solid nodules (77.4% vs 33.3%, P = 0.04) and anatomic resection compared to wedge resection (88.2% vs 52.2%, P = 0.04). Disease-free and overall survival are 100% in those with a histologically negative SLN identified (n = 25) compared to 73.6% (P = 0.02) and 63.6% (P = 0.01) in patients with node negative NSCLC established via routine lymphadenectomy alone (n = 22). CONCLUSIONS: SLN(s) are more reliably identified with ICG dose ≥1 mg, albumin dissolvent, post-injection lung ventilation, radiologically solid nodules, and anatomic resections. To date, N0 status when established via NIR SLN mapping seems to be associated with decreased recurrence and improved survival after surgery for NSCLC.

Long-term outcomes after near-infrared sentinel lymph node mapping in non-small cell lung cancer.

OBJECTIVE: To report the first analysis of long-term outcomes using near-infrared (NIR) image-guided sentinel lymph node (SLN) mapping in non-small cell lung cancer (NSCLC). METHODS: Retrospective analysis of patients with NSCLC enrolled in 2 prospective phase 1 NIR-guided SLN mapping trials, including an indocyanine green (ICG) dose-escalation trial, was performed. All patients underwent NIR imaging for SLN identification followed by multistation mediastinal lymph node sampling (MLNS) and pathologic assessment. Disease-free (DFS) and overall survival (OS) were compared between patients with NIR+ SLN (SLN group) and those without (non-SLN group). RESULTS: SLN detection, recurrence, DFS, and OS were assessed in 42 patients with NSCLC who underwent intraoperative peritumoral ICG injection, NIR imaging, and MLNS. NIR+ SLNs were identified in 23 patients (SLN group), whereas SLNs were not identified in 19 patients enrolled before ICG dose and camera optimization (non-SLN group). Median follow-up was 44.5 months. Pathology from NIR+ SLNs was concordant with overall nodal status in all 23 patients. Sixteen patients with SLN were deemed pN0 and no recurrences were, whereas 4 of 15 pN0 non-SLN patients developed nodal or distant recurrent disease. Comparing SLN versus non-SLN pN0 patients, the probability of 5-year OS is 100% versus 70.0% (P = .062) and 5-year DFS is statistically significantly improved at 100% versus 66.1% (P = .036), respectively. Among the 11 pN+ patients, 7 were in the SLN group, with >40% showing metastases in the SLN alone. CONCLUSIONS: Patients with pN0 SLNs showed favorable disease-free and overall survival. This preliminary review of NIR SLN mapping in NSCLC suggests that pN0 SLNs may better represent true N0 status. A larger clinical trial is planned to validate these findings.

A novel technique for tumor localization and targeted lymphatic mapping in early-stage lung cancer.

OBJECTIVE: To investigate safety and feasibility of navigational bronchoscopy (NB)-guided near-infrared (NIR) localization of small, ill-defined lung lesions and sentinel lymph nodes (SLN) for accurate staging in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with known or suspected stage I NSCLC were enrolled in a prospective pilot trial for lesion localization and SLN mapping via NB-guided NIR marking. Successful localization, SLN detection rates, histopathologic status of SLN versus overall nodes, and concordance to initial clinical stage were measured. Ex vivo confirmation of NIR+ SLNs and adverse events were recorded. RESULTS: Twelve patients underwent NB-guided marking with indocyanine green of lung lesions ranging in size from 0.4 to 2.2 cm and located 0.1 to 3 cm from the pleural surface. An NIR+ "tattoo" was identified in all cases. Ten patients were diagnosed with NSCLC and 9 SLNs were identified in 8 of the 10 patients, resulting in an 80% SLN detection rate. SLN pathologic status was 100% sensitive and specific for overall nodal status with no false-negative results. Despite previous nodal sampling, one patient was found to have metastatic disease in the SLN alone, a 12.5% rate of disease upstaging with NIR SLN mapping. SLN were detectable for up to 3 hours, allowing time for obtaining a tissue diagnosis and surgical resection. There were no adverse events associated with NB-labeling or indocyanine green dye itself. CONCLUSIONS: NB-guided NIR lesion localization and SLN identification was safe and feasible. This minimally invasive image-guided technique may permit the accurate localization and nodal staging of early stage lung cancers.

Management of Sarcoma Metastases to the Lung.

For decades, surgical resection of pulmonary metastases has been performed; despite limited randomized data, surgery is increasingly accepted as an integral part in the management of metastatic disease. Long-term results indicate resection is potentially curative with significantly improved survival following complete resection. Recurrence, however, is not uncommon with many patients undergoing repeat resection. With advancing surgical technique and adjuvant therapies, patients with high or recurrent tumor burden are increasingly afforded disease control and potential cure. In this review, the prognostic characteristics of pulmonary metastases from sarcoma, preoperative evaluation, operative technique, long-term outcomes, and management of complex patients are highlighted.

From Diagnosis to Treatment: Clinical Applications of Nanotechnology in Thoracic Surgery.

Nanotechnology is an emerging field with potential as an adjunct to cancer therapy, particularly thoracic surgery. Therapy can be delivered to tumors in a more targeted fashion, with less systemic toxicity. Nanoparticles may aid in diagnosis, preoperative characterization, and intraoperative localization of thoracic tumors and their lymphatics. Focused research into nanotechnology's ability to deliver both diagnostics and therapeutics has led to the development of nanotheranostics, which promises to improve the treatment of thoracic malignancies through enhanced tumor targeting, controlled drug delivery, and therapeutic monitoring. This article reviews nanoplatforms, their unique properties, and the potential for clinical application in thoracic surgery.

Expanding the indications for laparoscopic retroperitoneal adrenalectomy: experience with 81 resections.

BACKGROUND: Laparoscopic retroperitoneal (RP) adrenalectomy has gained popularity as the preferred approach over transabdominal (TA) method; however, surgeons have been reluctant to offer this operation to obese patients because of the concerns over inadequate working space and overall perceived higher rate of complications. The aim of the present study was to evaluate the feasibility and safety of RP adrenalectomy compared with TA adrenalectomy, specifically in morbidly obese patients. METHODS: All laparoscopic adrenalectomies performed at our institution between 2004 and 2012 were reviewed retrospectively. Presenting features, operative characteristics, and postoperative outcomes were evaluated. Complications were graded using Clavien system. Continuous variables were compared using Student t-test. Categorical variables were compared using χ(2)-test. Prediction models were constructed using linear or logistic regression as appropriate. RESULTS: Eighty-one RP and 130 TA procedures were performed, 26 (12.3%) and 60 (28.4%), respectively in obese patients (BMI > 30). Among the obese patients, operative time and estimated blood loss were less for RP (90 versus 130 min; P < 0.001 and 0 versus 50 mL; P < 0.001). Differences in the length of stay, overall mortality, incidence and severity of postoperative complications, and rates of readmission were not statistically significant between RP and TA procedures for all comers and in the obese patients. Controlling the operative characteristics and patient-specific factors, neither operative approach nor obesity was found to independently predict the postoperative complications. CONCLUSIONS: Laparoscopic RP adrenalectomy is a safe and feasible technique for obese patients. In the obese patients and for all comers, it offers shorter operative time, decreased estimated blood loss, with comparable length of stay and morbidity and mortality rates. We therefore recommend that this technique should be considered for patients undergoing adrenal resection.

Live en face imaging of aortic valve leaflets under mechanical stress.

Soft tissues, such as tendons, skin, arteries, or lung, are constantly subject to mechanical stresses in vivo. None more so than the aortic heart valve that experiences an array of forces including shear stress, cyclic pressure, strain, and flexion. Anisotropic biaxial cyclic stretch maintains valve homeostasis; however, abnormal forces are implicated in disease progression. The response of the valve endothelium to deviations from physiological levels has not been fully characterized. Here, we show the design and validation of a novel stretch apparatus capable of applying biaxial stretch to viable heart valve tissue, while simultaneously allowing for live en face endothelial cell imaging via confocal laser scanning microscopy (CLSM). Real-time imaging of tissue is possible while undergoing highly characterized mechanical conditions and maintaining the native extracellular matrix. Thus, it provides significant advantages over traditional cell culture or in vivo animal models. Planar biaxial tissue stretching with simultaneous live cell imaging could prove useful in studying the mechanobiology of any soft tissue.