Assessing the accuracy of a multisection robotic bronchoscope prototype in localization and targeting of small pulmonary lesions.

Objectives: Robotic bronchoscopy (RB) has emerged as a novel technique to address issues with the biopsy of small peripheral lung lesions. The objective of this study was to quantitatively assess the accuracy of a novel multisection robotic bronchoscope compared with current standards of care. Methods: This is a prospective, single-blind, comparative study where the accuracy of a multisection RB was compared against the accuracy of standard electromagnetic navigational bronchoscopy (EM-NB) during lesion localization and targeting. Five blinded subjects of varying bronchoscopy experience were recruited to use both RB and EM-NB in a swine lung model. Accuracy of localization and targeting success was measured as the distance from the center of pulmonary targets at each anatomic location. Subjects used both RB and EM-NB to navigate to 4 pulmonary targets assigned using 1:1 block randomization. Differences in accuracy and time between navigation systems were assessed using Wilcoxon rank-sum test. Results: Of the 40 total attempts per modality, successful targeting was achieved on 90% and 85% of attempts utilizing RB and EM-NB, respectively. Furthermore, RB demonstrated significantly lower median distance to the real-time EM target (1.1 mm; interquartile range [IQR], 0.6-2.0 mm) compared with EM-NB (2.6 mm; IQR, 1.6-3.8) (P < .001). Median target displacement resulting from lung and bronchus deformation during bronchoscopy was found to be significantly lower using RB (0.8 mm; IQR, 0.5-1.2 mm) compared with EM-NB (2.6 mm; IQR, 1.4-6.4 mm) (P < .001). Conclusions: The results of this study demonstrate that the multi-section RB prototype allows for improved localization and targeting of small peripheral lung nodules compared with current nonrobot bronchoscopy modalities.

Synthesis of Amphiphilic Amino Poly-Amido-Saccharide and Poly(lactic) Acid Block Copolymers and Fabrication of Paclitaxel-Loaded Mucoadhesive Nanoparticles.

Drug delivery to the esophagus through systemic administration remains challenging, as minimal drug reaches the desired target. Local delivery offers the potential for improved efficacy while minimizing off-target toxicities but necessitates bioadhesive properties for mucosal delivery. Herein, we describe the synthesis of two new mucoadhesive amphiphilic copolymers prepared by sequential ring-opening copolymerization or postpolymerization click conjugation. Both strategies yield block copolymers containing a hydrophilic amine-functionalized poly-amido-saccharide and either a hydrophobic alkyl derivatized poly-amido-saccharide or poly(lactic acid), respectively. The latter resulting copolymers readily self-assemble into spherical, ≈200 nm diameter, positively charged mucoadhesive nanoparticles. The NPs entrap ultrahigh levels of paclitaxel via encapsulation of free paclitaxel and paclitaxel conjugated to a biodegradable, biocompatible poly(1,2-glycerol carbonate). Paclitaxel-loaded NPs rapidly enter cells, release paclitaxel, are cytotoxic to esophageal OE33 and OE19 tumor cells in vitro, and, importantly, demonstrate improved mucoadhesion compared to conventional poly(ethylene glycol)-poly(lactic acid) nanoparticles to ex vivo esophageal tissue.

Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects.

With one of the highest mortality rates of all malignancies, the 5-year survival rate for esophageal cancer is under 20%. Depending on the stage and extent of the disease, the current standard of care treatment paradigm includes chemotherapy or chemoradiotherapy followed by surgical esophagogastrectomy, with consideration for adjuvant immunotherapy for residual disease. This regimen has high morbidity, due to anatomic changes inherent in surgery, the acuity of surgical complications, and off-target effects of systemic chemotherapy and immunotherapy. We begin with a review of current treatments, then discuss new and emerging targets for therapies and advanced drug delivery systems. Recent and ongoing preclinical and early clinical studies are evaluating traditional tumor targets (e.g., human epidermal growth factor receptor 2), as well as promising new targets such as Yes-associated protein 1 or mammalian target of rapamycin to develop new treatments for this disease. Due the function and location of the esophagus, opportunities also exist to pair these treatments with a drug delivery strategy to increase tumor targeting, bioavailability, and intratumor concentrations, with the two most common delivery platforms being stents and nanoparticles. Finally, early results with antibody drug conjugates and chimeric antigenic receptor T cells show promise as upcoming therapies. This review discusses these innovations in therapeutics and drug delivery in the context of their successes and failures, with the goal of identifying those solutions that demonstrate the most promise to shift the paradigm in treating this deadly disease.

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.

Decreased Lung Metastasis in Triple Negative Breast Cancer Following Locally Delivered Supratherapeutic Paclitaxel-Loaded Polyglycerol Carbonate Nanoparticle Therapy.

Breast cancer is among the most prevalent malignancies, accounting for 685,000 deaths worldwide in 2020, largely due to its high metastatic potential. Depending on the stage and tumor characteristics, treatment involves surgery, chemotherapy, targeted biologics, and/or radiation therapy. However, current treatments are insufficient for treating or preventing metastatic disease. Herein, we describe supratherapeutic paclitaxel-loaded nanoparticles (81 wt % paclitaxel) to treat the primary tumor and reduce the risk of subsequent metastatic lesions in the lungs. Primary tumor volume and lung metastasis are reduced by day 30, compared to the paclitaxel clinical standard treatment. The ultrahigh levels of paclitaxel afford an immunotherapeutic effect, increasing natural killer cell activation and decreasing NETosis in the lung, which limits the formation of metastatic lesions.

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.

Restructuring lung cancer care to accelerate diagnosis and treatment in patients vulnerable to healthcare disparities using an innovative care model.

The diagnosis and treatment of lung cancer is challenged by complex diagnostic pathways and fragmented care that can lead to disparities for vulnerable patients. Our model involved a multi-institutional, multidisciplinary conference to address the complexity of lung cancer care in vulnerable patient populations. The conference was conducted using a process adapted from the problem-solving method entitled FastTrack, pioneered by General Electric. Conference attendees established critical social determinants of health specific to lung cancer and designed a practical care model to accelerate diagnosis and treatment in this population. The resulting care delivery model, the Lung Cancer Strategist Program (LCSP), was led by a lung cancer trained advanced practice provider (APP) to expedite diagnosis, surgical and oncologic consultation, and treatment of a suspicious lung nodule. We compared the timeliness of care, care efficiency, and oncologic outcomes in 100 LCSP patients and 100 routine referral patients at the same thoracic surgery clinic. Patient triage through our integrated care model transitioned initial referral evaluation to a lung cancer trained APP to coordinate multidisciplinary patient-centered care that was highly individualized and significantly reduced the time to diagnosis and treatment among vulnerable patients at high-risk for treatment delay due to healthcare disparities.•To develop the Lung Cancer Strategist Program care model, we used a three-step (Design, Meeting, and Culmination), team-based, problem-solving process entitled FastTrack.•An advantage of FastTrack is its ability to overcome barriers embedded within hierarchal and institutional social systems, empowering those closest to the relevant issue to propose and enact meaningful change.•Under this framework, we engaged a diverse field of experts to assess systemic barriers in lung cancer care and design an innovative care pathway to improve the timeliness and efficiency of lung cancer care in patients at risk for healthcare disparities.

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.

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.

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.

The American Association for Thoracic Surgery (AATS) 2023 Expert Consensus Document: Staging and multidisciplinary management of patients with early-stage non-small cell lung cancer.

Novel targeted therapy and immunotherapy drugs have recently been approved for use in patients with surgically resectable lung cancer. Accurate staging, early molecular testing, and knowledge of recent trials are critical to optimize oncologic outcomes in these patients.

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.

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.

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.