Immunotherapies for locally aggressive cancers.

Improving surgical resection outcomes for locally aggressive tumors is key to inducing durable locoregional disease control and preventing progression to metastatic disease. Macroscopically complete resection of the tumor is the standard of care for many cancers, including breast, ovarian, lung, sarcoma, and mesothelioma. Advancements in cancer diagnostics are increasing the number of surgically eligible cases through early detection. Thus, a unique opportunity arises to improve patient outcomes with decreased recurrence rates via intraoperative delivery treatments using local drug delivery strategies after the tumor has been resected. Of the current systemic treatments (e.g., chemotherapy, targeted therapies, and immunotherapies), immunotherapies are the latest approach to offer significant benefits. Intraoperative strategies benefit from direct access to the tumor microenvironment which improves drug uptake to the tumor and simultaneously minimizes the risk of drug entering healthy tissues thereby resulting in fewer or less toxic adverse events. We review the current state of immunotherapy development and discuss the opportunities that intraoperative treatment provides. We conclude by summarizing progress in current research, identifying areas for exploration, and discussing future prospects in sustained remission.

A Pilot Study Using Machine Learning Algorithms and Wearable Technology for the Early Detection of Postoperative Complications After Cardiothoracic Surgery.

OBJECTIVE: To evaluate whether a machine learning algorithm (i.e. the "NightSignal" algorithm) can be used for the detection of postoperative complications prior to symptom onset after cardiothoracic surgery. SUMMARY BACKGROUND DATA: Methods that enable the early detection of postoperative complications after cardiothoracic surgery are needed. METHODS: This was a prospective observational cohort study conducted from July 2021 to February 2023 at a single academic tertiary care hospital. Patients aged 18 years or older scheduled to undergo cardiothoracic surgery were recruited. Study participants wore a Fitbit watch continuously for at least 1 week preoperatively and up to 90-days postoperatively. The ability of the NightSignal algorithm-which was previously developed for the early detection of Covid-19-to detect postoperative complications was evaluated. The primary outcomes were algorithm sensitivity and specificity for postoperative event detection. RESULTS: A total of 56 patients undergoing cardiothoracic surgery met inclusion criteria, of which 24 (42.9%) underwent thoracic operations and 32 (57.1%) underwent cardiac operations. The median age was 62 (IQR: 51-68) years and 30 (53.6%) patients were female. The NightSignal algorithm detected 17 of the 21 postoperative events a median of 2 (IQR: 1-3) days prior to symptom onset, representing a sensitivity of 81%. The specificity, negative predictive value, and positive predictive value of the algorithm for the detection of postoperative events were 75%, 97%, and 28%, respectively. CONCLUSIONS: Machine learning analysis of biometric data collected from wearable devices has the potential to detect postoperative complications-prior to symptom onset-after cardiothoracic surgery.

Multimodality Management of Thoracic Tumors: Initial Experience With a Multidisciplinary Thoracic Ablation Conference.

BACKGROUND: This study aimed to describe lesion-specific management of thoracic tumors referred for consideration of image-guided thermal ablation (IGTA) at a newly established multidisciplinary ablation conference. METHODS: This retrospective single-center cohort study included consecutive patients with non-small cell lung cancer (NSCLC) or thoracic metastases evaluated from June 2020 to January 2022 in a multidisciplinary conference. Outcomes included the management recommendation, treatments received (IGTA, surgical resection, stereotactic body radiation therapy [SBRT], multimodality management), and number of tumors treated per patient. Pearson's chi-square test was used to assess for a change in management, and Poisson regression was used to compare the number of tumors by treatment received. RESULTS: The study included 172 patients (58 % female; median age, 69 years; 56 % thoracic metastases; 27 % multifocal primary lung cancer; 59 % ECOG 0 [range, 0-3]) assessed in 206 evaluations. For the patients with NSCLC, IGTA was considered the most appropriate local therapy in 12 %, equal to SBRT in 22 %, and equal to lung resection in 3 % of evaluations. For the patients with thoracic metastases, IGTA was considered the most appropriate local therapy in 22 %, equal to SBRT in 12 %, and equal to lung resection in 3 % of evaluations. Although all patients were referred for consideration of IGTA, less than one third of patients with NSCLC or thoracic metastases underwent IGTA (p < 0.001). Multimodality management allowed for treatment of more tumors per patient than single-modality management (p < 0.01). CONCLUSIONS: Multidisciplinary evaluation of patients with thoracic tumors referred for consideration of IGTA significantly changed patient management and facilitated lesion-specific multimodality management.

Shortage of thoracic surgeons in the United States: Implications for treatment and survival for stage I lung cancer patients.

OBJECTIVES: To evaluate whether there is a shortage of thoracic surgeons in the United States and whether any potential shortage is impacting lung cancer treatment and outcomes. DESIGN: Using the US Area Health Resources File and Surveillance Epidemiology End Results database, we assessed the number of cardiothoracic surgeons per 100,000 people and the number of stage I non-small cell lung cancer (NSCLC) diagnoses in the US in 2010 versus 2018. Changes in the percentage of patients diagnosed with stage I NSCLC who underwent surgery and stereotactic body radiotherapy and changes in overall survival of patients with stage I NSCLC from 2010 to 2018 in the National Cancer Database were evaluated using multivariable logistic regression and Cox proportional hazards modeling. RESULTS: From 2010 to 2018, the number of cardiothoracic surgeons per 100,000 people in the US decreased by 12% (P < .001), while the number of patients diagnosed with stage I NSCLC increased by 40% (P < .001). Over the same period, the percentage of patients who underwent surgery for stage I NSCLC decreased from 81.0% to 72.3% (adjusted odds ratio, 0.59; 95% confidence interval, 0.55-0.63); this decrease was similarly seen in a subgroup of young and otherwise healthy patients. Greater decreases in the percentage of patients who underwent surgery in nonmetropolitan and underserved regions corresponded with worse improvements in survival among patients in these regions from 2010 to 2018. CONCLUSIONS: Recent declines in the US cardiothoracic surgery workforce may have led to significantly fewer patients undergoing surgery for stage I NSCLC and worsening disparities in survival between different patient populations.

High dose, dual-release polymeric films for extended surgical bed paclitaxel delivery.

While surgery represents a major therapy for most solid organ cancers, local recurrence is clinically problematic for cancers such as sarcoma for which adjuvant radiotherapy and systemic chemotherapy provide minimal local control or survival benefit and are dose-limited due to off-target side effects. We describe an implantable, biodegradable poly(1,2-glycerol carbonate) and poly(caprolactone) film with entrapped and covalently-bound paclitaxel enabling safe, controlled, and extended local delivery of paclitaxel achieving concentrations 10,000× tissue levels compared to systemic administration. Films containing entrapped and covalently-bound paclitaxel implanted in the tumor bed, immediately after resection of human cell line-derived chondrosarcoma and patient-derived xenograft liposarcoma and leiomyosarcoma in mice, improve median 90- or 200-day recurrence-free and overall survival compared to control mice. Furthermore, mice in the experimental film arm show no film-related morbidity. Continuous, extended, high-dose paclitaxel delivery via this unique polymer platform safely improves outcomes in three different sarcoma models and provides a rationale for future incorporation into human trials.

A national survey of occupational musculoskeletal injuries in cardiothoracic surgeons.

OBJECTIVE: There is growing concern that surgeons are at increased risk for work-related orthopedic injuries due to poor ergonomics. We conducted a survey of North American cardiothoracic surgeons to evaluate the prevalence of occupational injury, as well as perceptions and use of ergonomic techniques. METHODS: Cardiothoracic surgeons identified through the Cardiothoracic Surgery Network were asked to complete a 33-question survey assessing their musculoskeletal health, as well as their perceptions and use of ergonomic techniques in the operating room and office. RESULTS: Among 600 cardiothoracic surgeons, the prevalence of occupational musculoskeletal injuries was 64%, with 30% of affected surgeons requiring time away from work and 20% requiring surgery or the use of narcotics. Cervical spine injury (35%, n = 216) was the most common injury due to operating, followed by lumbar spine injury (30%, n = 180). In multivariable-adjusted analysis, cardiac surgeons were more likely than thoracic surgeons to experience occupational musculoskeletal injuries (adjusted odds ratio, 1.8 [1.2-2.8], P < .01). Notably, 90% of surgeons (n = 536) reported thinking that their institution did not provide sufficient ergonomics education or support, and only 35% (n = 205) thought that the cardiothoracic surgical community is supportive of implementing ergonomics techniques in the operating room and office. CONCLUSIONS: In this survey analysis, cardiothoracic surgeons reported experiencing work-related orthopedic injuries at an alarmingly high rate, leading to significant time away from work and for many to retire from surgery over a decade early. These findings underline a critical need for institutions to prioritize ergonomics education and implement ergonomics-directed techniques in the operating room and office.

Efficacy and Safety of Supraclavicular Thoracic Outlet Decompression.

OBJECTIVES: We aimed to report efficacy, safety, and health-related quality of life (HRQoL) outcomes of a multidisciplinary treatment approach including supraclavicular thoracic outlet decompression among patients with thoracic outlet syndrome (TOS). BACKGROUND: TOS is a challenging condition where controversy remains in diagnosis and treatment, primarily given a lack of data exploring various treatment approaches and associated patient outcomes. METHODS: Patients who underwent unilateral, supraclavicular thoracic outlet decompression, or pectoralis minor tenotomy for neurogenic, venous, or arterial TOS were identified from a prospectively maintained database. Demography, use of preoperative botulinum toxin injection, and participation in multidisciplinary evaluation were measured. The primary endpoints were composite postoperative morbidity and symptomatic improvement compared with baseline. RESULTS: Among 2869 patients evaluated (2007-2021), 1032 underwent surgery, including 864 (83.7%) supraclavicular decompressions and 168 (16.3%) isolated pectoralis minor tenotomies. Predominant TOS subtypes among surgical patients were neurogenic (75.4%) and venous TOS (23.4%). Most patients (92.9%) with nTOS underwent preoperative botulinum toxin injection; 56.3% reported symptomatic improvement. Before surgical consultation, few patients reported participation in physical therapy (10.9%). The median time from first evaluation to surgery was 136 days (interquartile range: 55, 258). Among 864 patients who underwent supraclavicular thoracic outlet decompression, complications occurred in 19.8%; the most common complication was chyle leak (8.3%). Four patients (0.4%) required revisional thoracic outlet decompression. At a median follow-up of 420 days (interquartile range: 150, 937) 93.3% reported symptomatic improvement. CONCLUSION: Based on low composite morbidity, need for very few revisional operations, and high rates of symptomatic improvement, a multidisciplinary treatment approach including primarily supraclavicular thoracic outlet decompression is safe and effective for patients with TOS.

Synthesis of Polyethylene Glycol-Poly(glycerol carbonate) Block Copolymeric Micelles as Surfactant-Free Drug Delivery Systems.

We report the synthesis of block copolymers of monomethoxylated polyethylene glycol and poly(glycerol carbonate) (mPEG-b-PGC) via the ring-opening polymerization of benzyl glycidyl ether, monomethoxylated polyethylene glycol, and carbon dioxide using a cobalt salen catalyst. The resulting block copolymers display high polymer/cyclic carbonate selectivity (>99%) and, if two oxirane monomers are used, random incorporation into the polymer feed. The resulting diblock mPEG-b-PGC polymer shows promise as a nanocarrier for surfactant-free, sustained chemotherapeutic delivery. mPEG-b-PGC, with paclitaxel conjugated to the pendant primary alcohol of the glycerol polymer backbone, readily forms 175 nm diameter particles in solution and contains 4.6 wt % paclitaxel (PTX), which is released over 42 days. The mPEG-b-PGC polymer itself is noncytotoxic, whereas the PTX-loaded nanoparticles are cytotoxic to lung, breast, and ovarian cancer cell lines.

Synthetic Pressure Sensitive Adhesives for Biomedical Applications.

Pressure sensitive adhesives are components of everyday products found in homes, offices, industries, and hospitals. Serving the general purpose of fissure repair and object fixation, pressure sensitive adhesives indiscriminately bind surfaces, as long as contact pressure is administered at application. With that being said, the chemical and material properties of the adhesive formulation define the strength of a pressure sensitive adhesive to a particular surface. Given our increased understanding of the viscoelastic material requirements as well as the intermolecular interactions at the binding interface required for functional adhesives, pressure sensitive adhesives are now being explored for greater use. New polymer formulations impart functionality and degradability for both internal and external applications. This review highlights the structure-property relationships between polymer architecture and pressure sensitive adhesion, specifically for medicine. We discuss the rational, molecular-level design of synthetic polymers for durable, removable, and biocompatible adhesion to wet surfaces like tissue. Finally, we examine prevalent challenges in biomedical wound closure and the new, innovative strategies being employed to address them. We conclude by summarizing the progress of current research, identifying additional clinical opportunities, and discussing future prospects.

Lobectomy for Suspected Lung Cancer Without Prior Diagnosis.

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.

Boolean logic in synthetic biology and biomaterials: Towards living materials in mammalian cell therapeutics.

BACKGROUND: The intersection of synthetic biology and biomaterials promises to enhance safety and efficacy in novel therapeutics. Both fields increasingly employ Boolean logic, which allows for specific therapeutic outputs (e.g., drug release, peptide synthesis) in response to inputs such as disease markers or bio-orthogonal stimuli. Examples include stimuli-responsive drug delivery devices and logic-gated chimeric antigen receptor (CAR) T cells. In this review, we explore recent manuscripts highlighting the potential of synthetic biology and biomaterials with Boolean logic to create novel and efficacious living therapeutics. MAIN BODY: Collaborations in synthetic biology and biomaterials have led to significant advancements in drug delivery and cell therapy. Borrowing from synthetic biology, researchers have created Boolean-responsive biomaterials sensitive to multiple inputs including pH, light, enzymes and more to produce functional outputs such as degradation, gel-sol transition and conformational change. Biomaterials also enhance synthetic biology, particularly CAR T and adoptive T cell therapy, by modulating therapeutic immune cells in vivo. Nanoparticles and hydrogels also enable in situ generation of CAR T cells, which promises to drive down production costs and expand access to these therapies to a larger population. Biomaterials are also used to interface with logic-gated CAR T cell therapies, creating controllable cellular therapies that enhance safety and efficacy. Finally, designer cells acting as living therapeutic factories benefit from biomaterials that improve biocompatibility and stability in vivo. CONCLUSION: By using Boolean logic in both cellular therapy and drug delivery devices, researchers have achieved better safety and efficacy outcomes. While early projects show incredible promise, coordination between these fields is ongoing and growing. We expect that these collaborations will continue to grow and realize the next generation of living biomaterial therapeutics.

Advancing pressure-sensitive adhesives for internal wound closure.

Pressure sensitive adhesives are familiar household items spanning applications in everyday repair, office supplies, and topical wound care. Through innovations in material and polymer science, pressure sensitive adhesives will advance from current commodity to novel specialty materials with resulting new clinical uses and improved patient care.

Radiolabeled Biodistribution of Expansile Nanoparticles: Intraperitoneal Administration Results in Tumor Specific Accumulation.

Nanoparticle biodistribution in vivo is an essential component to the success of nanoparticle-based drug delivery systems. Previous studies with fluorescently labeled expansile nanoparticles, or "eNPs", demonstrated a high specificity of eNPs to tumors that is achieved through a materials-based targeting strategy. However, fluorescent labeling techniques are primarily qualitative in nature and the gold-standard for quantitative evaluation of biodistribution is through radiolabeling. In this manuscript, we synthesize 14C-labeled eNPs to quantitatively evaluate the biodistribution of these particles in a murine model of intraperitoneal mesothelioma via liquid scintillation counting. The results demonstrate a strong specificity of eNPs for tumors that lasts one to 2 weeks postinjection with an overall delivery efficiency to the tumor tissue of 30% of the injected dose which is congruent with prior reports of preclinical efficacy of the technology. Importantly, the route of administration is essential to the eNP's material-based targeting strategy with intraperitoneal administration leading to tumoral accumulation while, in contrast, intravenous administration leads to rapid clearance via the reticuloendothelial system and low tumoral accumulation. A comparison against nanoparticle delivery systems published over the past decade shows that the 30% tumoral delivery efficiency of the eNP is significantly higher than the 0.7% median delivery efficiency of other systems with sufficient quantitative data to define this metric. These results lay a foundation for targeting intraperitoneal tumors and encourage efforts to explore alternative, nonintravenous routes, of delivery to accelerate the translation of nanoparticle therapies to the clinic.

Porous Paclitaxel Mesh Reduces Local Recurrence in Patient-Derived Xenograft Resection Model.

BACKGROUND: Drug-loaded meshes offer a promising delivery strategy for the prevention of local recurrence. Patient-derived xenograft (PDX) models are representative of individual patient tumors and predictive of clinical outcomes. METHODS: A PDX model was established in NSG (NOD-scid IL2Rgammanull) mice using tumor tissue from a patient with aggressive lung adenocarcinoma. Polyglycolic acid (PGA) meshes loaded with paclitaxel (PGA+PTX) were electrospun. Tumor-bearing mice were randomized into 4 groups after macroscopic complete resection: (1) no treatment (n = 10); (2) intraperitoneal PTX at 20 mg/kg (n = 10); (3) PGA mesh without drug (n = 14); and (4) PGA+PTX mesh at 12 mg/kg (n = 14). A 1-cm2 mesh was placed onto the tumor resection beds. Groups were observed for local recurrence for 120 postoperative days. RESULTS: PDX mice treated with PGA+PTX meshes after resection exhibited a >5-fold increase in recurrence-free survival (P < .0001) compared with systemically treated and untreated control groups. Median recurrence-free survival was 24 days for untreated and intraperitoneal PTX groups, 28 days for unloaded PGA mesh group, and undefined for the PGA+PTX mesh group. CONCLUSIONS: Development of a PDX surgical resection model of non-small cell lung cancer permits robust assessment of postresection local recurrence for preclinical studies of patient-derived tumors. Intraoperative placement of drug-loaded meshes demonstrates superior local disease treatment, suggesting that this approach may improve recurrence-free survival in early-stage non-small cell lung cancer patients undergoing limited resection.

First-in-Human Intrathoracic Implantation of Multidrug-Eluting Microdevices for In Situ Chemotherapeutic Sensitivity Testing as Proof of Concept in Nonsmall Cell Lung Cancer.

OBJECTIVE: To evaluate the safety and feasibility of implantation and retrieval of a novel implantable microdevice (IMD) in NSCLC patients undergoing operative resection. BACKGROUND: Adjuvant therapy has limited impact on postsurgical outcomes in NSCLC due to the inability to predict optimal treatment regimens. METHODS: An IMD measuring 6.5 mm by 0.7 mm, containing micro-reservoirs allowing for high-throughput localized drug delivery, was developed and loaded with 12 chemotherapeutic agents. Five patients with peripheral lung lesions larger than 1.0 cm were enrolled in this phase 1 clinical study. IMDs were inserted into tumors intraoperatively under direct vision, removed with the resected specimen, and retrieved in pathology. Surrounding tissues were sectioned, stained, and analyzed for tissue drug response to the IMD-delivered microdoses of these agents by a variety of pharmacodynamic markers. RESULTS: A total of 14 IMDs were implanted intraoperatively with 13 (93%) successfully retrieved. After technique refinement, IMDs were reliably inserted and retrieved in open, Video-Assisted Thoracoscopic Surgery, and robotic cases. No severe adverse reactions were observed. The one retained IMD has remained in place without movement or any adverse effects. Analysis of patient blood revealed no detection of chemotherapeutic agents. We observed differential sensitivities of patient tumors to the drugs on the IMD. CONCLUSIONS: A multi-drug IMD can be safely inserted and retrieved into lung tumors during a variety of surgical approaches. Future studies will encompass preoperative placement to better examine specific tumor responsiveness to therapeutic agents, allowing clinicians to tailor treatment regimens to the microenvironment of each patient.

Global Makeup of Cardiothoracic Surgeons as Represented by Our Major Societies and Associations.

BACKGROUND: Prior efforts to capture the cardiothoracic surgery community rely on survey data with potentially biased or low response rates. Our goal is to better understand our community by assessing the membership directories from The Society of Thoracic Surgeons (STS), American Association for Thoracic Surgery (AATS), European Association for Cardio-Thoracic Surgery (EACTS), and Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS). METHODS: Membership data were obtained from membership directories. Data for STS and EACTS were supplemented by the associations from their internal databases. The inclusion criterion was active membership; trainees and wholly incomplete profiles were excluded. RESULTS: A total of 12 053 membership profiles were included (STS, 6365; EACTS, 3661; AATS, 1495; ASCVTS, 532). Membership is 7% female overall (EACTS, 9%; STS, 6%; AATS, 5%; ASCVTS, 3%), with a median age of 57 years (STS, 60 years; EACTS, 52 years). All societies had a broad scope of practice including members who practiced both adult cardiac and thoracic (20% overall), but most members practiced adult cardiac (31% overall; ASCVTS, 48%; AATS, 36%; EACTS, 30%; STS, 28%) and were in the late stage of their careers. CONCLUSIONS: We present the makeup of our 4 major societies. We are global with a diversity of careers but concerning factors that require immediate attention. The future of our specialty depends on our ability to evolve, to promote the specialty, to attract trainees, and to include and promote female surgeons. It is crucial that we wake up to these issues, change the narrative, and create action on both individual and leadership levels.

Added Value of Magnetic Resonance Over Computed Tomography in Distinguishing Nonneoplastic Complex Thymic Cysts From Malignant Cystic Thymic Neoplasms.

PURPOSE: The aim of the study was to evaluate cystic thymic masses by using computed tomography (CT) and magnetic resonance (MR) scoring systems to differentiate nonneoplastic thymic cysts from cystic thymic neoplasms. METHODS: This retrospective multisite study included adult patients who underwent CT and MR imaging of the chest between 2007 and 2020 with any of the following impressions on cross-sectional imaging studies: "thymic mass with cystic component," "unilocular or multilocular cystic thymic lesion," "complex thymic cyst," "thymic cyst with hemorrhage." Two blinded radiologists reviewed and recorded specific imaging features as well as overall impressions on both CT and MR using a Likert scale scoring system. Data were analyzed, and diagnostic accuracy of CT and MR was compared using areas under the receiver operating characteristic curves (AUC). RESULTS: Fifty-six patients were included, of which 45 (80%) had benign masses. Total of 21 patients (38%) had indeterminate scores on CT of which 3 (14%) were malignant, while only 6 (11%) had indeterminate scores on MR and 1 was malignant. Magnetic resonance scoring system (AUC, 0.95) performed better than CT scoring system (AUC, 0.86) in distinguishing benign versus malignant lesions (P = 0.06). Lack of enhancement within the mass was completely predictive of benign etiology (P < 0.001). Wall thickness of an enhancing cyst was predictive of malignancy, with AUC 0.93. CONCLUSIONS: Magnetic resonance yielded higher specificity allowing a larger number of lesions to be confidently assigned a benign diagnosis. This could help in averting unnecessary follow-up, biopsies, or surgery. The authors recommend follow-up imaging with MR for prevascular masses, even those appearing "solid" on CT.

Doxorubicin-Loaded Polymeric Meshes Prevent Local Recurrence after Sarcoma Resection While Avoiding Cardiotoxicity.

Surgery is the only potentially curative treatment for localized soft-tissue sarcomas. However, for sarcomas arising in the retroperitoneum, locoregional recurrence rates are 35% to 59% despite resection. Doxorubicin (DOX) is the standard first-line systemic chemotherapy for advanced soft-tissue sarcoma, yet its intravenous administration yields limited clinical efficacy and results in dose-limiting cardiotoxicity. We report the fabrication and optimization of a novel electrospun poly(caprolactone) (PCL) surgical mesh coated with layers of a hydrophobic polymer (poly(glycerol monostearate-co-caprolactone), PGC-C18), which delivers DOX directly to the operative bed following sarcoma resection. In xenograft models of liposarcoma and chondrosarcoma, DOX-loaded meshes (DoM) increased overall survival 4-fold compared with systemically administered DOX and prevented local recurrence in all but one animal. Importantly, mice implanted with DoMs exhibited preserved cardiac function, whereas mice receiving an equivalent dose systemically displayed a 23% decrease from baseline in both cardiac output and ejection fraction 20 days after administration. Collectively, this work demonstrates a feasible therapeutic approach to simultaneously prevent post-surgical tumor recurrence and minimize cardiotoxicity in soft-tissue sarcoma. SIGNIFICANCE: A proof-of-principle study in animal models shows that a novel local drug delivery approach can prevent tumor recurrence as well as drug-related adverse events following surgical resection of soft-tissue sarcomas.

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.

Lipid Nanoparticle Delivery of Fas Plasmid Restores Fas Expression to Suppress Melanoma Growth In Vivo.

Fas ligand (FasL), expressed on the surface of activated cytotoxic T lymphocytes (CTLs), is the physiological ligand for the cell surface death receptor, Fas. The Fas-FasL engagement initiates diverse signaling pathways, including the extrinsic cell death signaling pathway, which is one of the effector mechanisms that CTLs use to kill tumor cells. Emerging clinical and experimental data indicate that Fas is essential for the efficacy of CAR-T cell immunotherapy. Furthermore, loss of Fas expression is a hallmark of human melanoma. We hypothesize that restoring Fas expression in tumor cells reverses human melanoma resistance to T cell cytotoxicity. DNA hypermethylation, at the FAS promoter, down-regulates FAS expression and confers melanoma cell resistance to FasL-induced cell death. Forced expression of Fas in tumor cells overcomes melanoma resistance to FasL-induced cell death in vitro. Lipid nanoparticle-encapsulated mouse Fas-encoding plasmid therapy eliminates Fas+ tumor cells and suppresses established melanoma growth in immune-competent syngeneic mice. Similarly, lipid nanoparticle-encapsulated human FAS-encoding plasmid (hCOFAS01) therapy significantly increases Fas protein levels on tumor cells of human melanoma patient-derived xenograft (PDX) and suppresses the established human melanoma PDX growth in humanized NSG mice. In human melanoma patients, FasL is expressed in activated and exhausted T cells, Fas mRNA level positively correlates with melanoma patient survival, and nivolumab immunotherapy increases FAS expression in tumor cells. Our data demonstrate that hCOFAS01 is an effective immunotherapeutic agent for human melanoma therapy with dual efficacy in increasing tumor cell FAS expression and in enhancing CTL tumor infiltration.