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.

Automatic 1-year follow-up appointment creation and reminders can improve long-term follow-up after carotid revascularization.

BACKGROUND: Long-term follow-up (LTFU) following carotid revascularization is important for post-surgical care, stroke risk optimization and post-market surveillance of new technologies. METHODS: We instituted a quality improvement project to improve LTFU rates for carotid revascularizations (primary outcome) by scheduling perioperative and one-year follow-up appointments at time of surgery discharge. A temporal trends analysis (Q1 2019 through Q1 2022), multivariable regression, and interrupted time series (ITS) were performed to compare pre-post intervention LTFU rates. RESULTS: 269 consecutive patients were included (151 pre-intervention, 118 post-intervention; mean 71 â€‹± â€‹12 years-old, 39% female, 77% White). The overall LTFU rate improved (64.9%-78.8%; P â€‹= â€‹0.013) after the intervention. After controlling for patient factors, procedures performed after the intervention were associated with increased odds of being seen for 1-year follow-up (OR: 2.2 95%CI: 1.2-4.0). Quarterly ITS analysis corroborated this relationship (P â€‹= â€‹0.01). CONCLUSIONS: Time-of-surgery appointment creation and automated patient reminders can improve LTFU rates following carotid revascularizations.

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.

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.

Midterm outcomes of isolated thoracic aortic replacement in congenital versus degenerative aortopathy in a 15-year institutional cohort.

BACKGROUND: Open aortic replacement represents the only approved option to address thoracic aortopathy among patients with connective tissue disorders (CTD). The aim of our study was to investigate contemporary midterm outcomes of isolated thoracic aortic replacement in patients with CTD versus degenerative pathology in a large institutional cohort. METHODS: All patients undergoing isolated open thoracic aortic replacement at a single academic center from 2005 to 2020 were included. Patients were classified as having CTD or not having CTD based on documented genetic mutations associated with congenital aortopathy. In-hospital and midterm outcomes, including mortality, paraplegia, development of new arterial pathology on surveillance imaging, and the need for future operations, were compared between groups using descriptive statistics and Kaplan-Meier survival analysis. RESULTS: Overall, 62 patients were included with a median follow-up of 58 months (range, 19-81 months) (59 months for those with CTD vs 51.5 months for those without CTD). CTD was present in 18 patients (29%), with 16 having Marfan syndrome (77.8%). Patients with CTD were younger than patients without CTD (45.8 years vs 60.9 years) and had lower rates of smoking (5.6% vs 56.8%) and hypertension (97.7% vs 72.2%; all P < .01). Patients with CTD were more likely to have a dissection component at the time of repair compared with patients without CTD (100% vs 59.1%) and underwent repair at smaller aortic diameters (5.9 cm vs 6.6 cm; both P < .05). There were no differences in in-hospital outcomes between the two groups, including mortality (4.5% vs 5.6%) and paraplegia (2.3% vs 0%; both P > .05). At 5 years, patients with CTD were more likely to have developed aneurysmal changes distal to their thoracic repair (88.9% vs 47.7%) and extra-aortic arterial aneurysms (41.2% vs 2.3%; both P < .05). However, on survival analysis, there were no differences in freedom from additional vascular procedures (hazard ratio,1.76; P = .333) or, specifically, additional aortic procedures (hazard ratio, 1.81; P = .380) between the two groups. There was only one anastomotic complication identified on longitudinal follow-up, which occurred in a patient without CTD 8 years after the index operation. CONCLUSIONS: Although carrying significant operative risks and the potential for morbidity, open thoracic aortic replacement represents a well-tolerated, durable treatment option for patients with congenitally mediated thoracic aortic disease. Because both patients with and without CTD who required thoracic aortic replacement often need future aortic intervention, vigilant surveillance is warranted. Equivalent intervention rates between the two groups suggest remodeling of the CTD aorta is almost universally characterized by initial postrepair dilation, but the majority of these changes successfully stabilize and do not progress to higher rates of intervention.

A dedicated robotic bedside physician assistant significantly enhances trainee console operating time in general thoracic surgery.

Objective: As trainees rotate through thoracic subspecialties within their curricula, a crucial portion of their robotic training consists of actual console operating time. The more time spent on the surgeon console, the greater the development will be through the course of their training. Implementing a physician assistant at the bedside may increase the operative console time for the trainee and develop robotic skills in a more expeditious rate. The objective was to evaluate the impact a designated robotic physician assistant can have on trainee console learning opportunity. Methods: Operating room data collected consisted of all robotic general thoracic surgical cases that trainees participated in with and without a physician assistant present. Metrics regarding case efficiency included anesthesia ready-to-incision, incision-to-console, and raw resident console times. By using PRISM software, a nonparametric t test was used to analyze each averaged data group compared between when a physician assistant was present and not present. Results: The mean resident console time without and with a physician assistant assist was 45.8 minutes and 80.9 minutes, respectively (P < .0001). The average portion of a case performed by a trainee similarly without and with a physician assistant present was 28.0% and 77.1%, respectively (P < .0001). Case efficiency metrics between physician assistant presence cohorts showed no difference. Conclusions: Thoracic surgical trainees have increased opportunity for robotic skill development within a fellowship or resident program curriculum when a designated robotic physician assistant is present in the operating room. These findings are significant for the improvement of residency and fellowship robotic training models moving forward by incorporating robotic-specialized physician assistants in academic institutions.

The Translational and Regulatory Development of an Implantable Microdevice for Multiple Drug Sensitivity Measurements in Cancer Patients.

OBJECTIVE: The purpose of this article is to report the translational process of an implantable microdevice platform with an emphasis on the technical and engineering adaptations for patient use, regulatory advances, and successful integration into clinical workflow. METHODS: We developed design adaptations for implantation and retrieval, established ongoing monitoring and testing, and facilitated regulatory advances that enabled the administration and examination of a large set of cancer therapies simultaneously in individual patients. RESULTS: Six applications for oncology studies have successfully proceeded to patient trials, with future applications in progress. CONCLUSION: First-in-human translation required engineering design changes to enable implantation and retrieval that fit with existing clinical workflows, a regulatory strategy that enabled both delivery and response measurement of up to 20 agents in a single patient, and establishment of novel testing and quality control processes for a drug/device combination product without clear precedents. SIGNIFICANCE: This manuscript provides a real-world account and roadmap on how to advance from animal proof-of-concept into the clinic, confronting the question of how to use research to benefit patients.

Lung Cancer in Women.

BACKGROUND: Lung cancer is the leading cause of cancer-related death for women in the United States. Clinical characteristics, histology, epidemiology, and treatment responses are unique for women with lung cancer. METHODS: A literature search of Medline publications from 1989 to 2021 was conducted for lung cancer in women. Subsequent narrative review focused on identified differences in risk factors, diagnosis, and treatment of importance to the surgical care of these patients. RESULTS: Studies investigating lung cancer in which sex differences were explored demonstrated differences in risk factors, histology, and treatment response among women, with a significant postsurgical survival advantage over men (41.8 months vs 26.8 months, P = .007) and greater clinical benefit from anti-PD-1 combined with chemotherapy (hazard ratio, 0.44; 95% confidence interval, 0.25-0.76) compared with men (hazard ratio, 0.76; 95% confidence interval, 0.64-0.91). Smoking remains a dominant risk factor, and multiple clinical trials suggest lung cancer screening provides greater benefit for women. However young nonsmoking patients with lung cancer are 2-fold more likely to be female, advocating for broader sex-based screening criteria. Potential roles of genetic mutations, estrogen signaling, and infectious elements in sex-based differences in presentation, histology, prognosis, and treatment response are explored. CONCLUSIONS: Overall much remains unknown regarding how sex influences lung cancer risk, treatment decisions, and outcomes. However evidence of specific differences in presentation, environmental risk, molecular drivers, and mutational burden support the need to better leverage these sex-associated differences to further improve detection, diagnosis, surgical outcomes, and systemic regimens to advance the overall care strategy for women with lung cancer.

Delivery of eupenifeldin via polymer-coated surgical buttresses prevents local lung cancer recurrence.

Lung cancer is the leading cause of cancer deaths worldwide. Unfortunately, high recurrence rates and poor survival remain despite surgical resection and conventional chemotherapy. Local drug delivery systems are a promising intervention for lung cancer treatment with the potential for improved efficacy with reduced systemic toxicity. Here, we describe the development of a chemotherapy-loaded polymer buttress, to be implanted along the surgical margin at the time of tumor resection, for achieving local and prolonged release of a new anticancer agent, eupenifeldin. We prepared five different formulations of buttresses with varying amounts of eupenifeldin, and additional external empty polymer coating layers (or thicknesses) to modulate drug release. The in vitro eupenifeldin release profile depends on the number of external coating layers with the formulation of the greatest thickness demonstrating a prolonged release approaching 90 days. Similarly, the long-term cytotoxicity of eupenifeldin-loaded buttress formulations against murine Lewis lung carcinoma (LLC) and human lung carcinoma (A549) cell lines mirrors the eupenifeldin release profiles and shows a prolonged cytotoxic effect. Eupenifeldin-loaded buttresses significantly decrease local tumor recurrence in vivo and increase disease-free survival in a lung cancer resection model.

Widespread of horizontal gene transfer in the human genome.

BACKGROUND: A fundamental concept in biology is that heritable material is passed from parents to offspring, a process called vertical gene transfer. An alternative mechanism of gene acquisition is through horizontal gene transfer (HGT), which involves movement of genetic materials between different species. Horizontal gene transfer has been found prevalent in prokaryotes but very rare in eukaryote. In this paper, we investigate horizontal gene transfer in the human genome. RESULTS: From the pair-wise alignments between human genome and 53 vertebrate genomes, 1,467 human genome regions (2.6 M bases) from all chromosomes were found to be more conserved with non-mammals than with most mammals. These human genome regions involve 642 known genes, which are enriched with ion binding. Compared to known horizontal gene transfer regions in the human genome, there were few overlapping regions, which indicated horizontal gene transfer is more common than we expected in the human genome. CONCLUSIONS: Horizontal gene transfer impacts hundreds of human genes and this study provided insight into potential mechanisms of HGT in the human genome.

Should We Perform Carotid Doppler Screening Before Surgical or Transcatheter Aortic Valve Replacement?

BACKGROUND: Screening for internal carotid artery stenosis (ICAS) with Doppler ultrasound is commonly used before cardiovascular surgery. Nevertheless, the relationship between ICAS and procedure-related stroke in isolated aortic valve replacement is unclear. METHODS: We retrospectively reviewed patients with artery stenosis who underwent ICAS screening before surgical (SAVR) or transcatheter aortic valve replacement (TAVR) between January 2007 and August 2014. Logistic regression models were used to determine the relation between post-procedure stroke and total (sum of left and right ICAS) and maximal unilateral ICAS. Age, sex, history of atrial fibrillation, cerebrovascular disease and diabetes, left ventricular ejection fraction, and procedure type were considered as covariates. Two-subgroup analyses were performed in patients who underwent TAVR and SAVR, adjusting for procedure specific details. RESULTS: A total of 996 patients underwent ICAS screening before TAVR (n = 467) or SAVR (n = 529). The prevalence of at least ≥70% ICAS was 5.2% (n = 52) and incidence of 30-day stroke was 3.4% (n = 34). Eight patients who underwent carotid intervention before valve replacement and 6 patients with poor Doppler images were excluded from the final analysis. We found no statistically significant association between stroke and either the total or maximal unilateral ICAS for all patients (p = 0.13 and p = 0.39, respectively) or those undergoing TAVR (p = 0.27 and p = 0.63, respectively) or SAVR (p = 0.21 and p = 0.36, respectively). CONCLUSIONS: We found no statistically significant association between ICAS severity procedure-related stroke after aortic valve replacement. This suggests that universal carotid Doppler screening before isolated TAVR or SAVR is unnecessary.

Does a Higher Society of Thoracic Surgeons Score Predict Outcomes in Transfemoral and Alternative Access Transcatheter Aortic Valve Replacement?

BACKGROUND: Nontransfemoral (non-TF) transcatheter aortic valve replacement (TAVR) is often associated with worse outcomes than TF TAVR. We investigated the relationship between increasing Society of Thoracic Surgeons (STS) predicted risk of mortality (PROM) score and observed mortality and morbidity in TF and non-TF TAVR groups. METHODS: We reviewed 595 patients undergoing TAVR at Emory Healthcare between 2007 and 2014. Clinical outcomes were reported for 337 TF patients (57%) and 258 non-TF patients (43%). We created 3 STS PROM score subgroups: <8%, 8%-15%, and >15%. A composite outcome of postoperative events was defined as death, stroke, renal failure, vascular complications, or new pacemaker implantation. RESULTS: TF patients were older (82.4 ± 8.0 vs 80.8 ± 8.7 years, p = 0.02), whereas the STS PROM was higher in non-TF patients (10.5% ± 5.3% vs 11.7% ± 5.7%, p = 0.01). Observed/expected mortality was less than 1.0 in all groups. The rate of the composite outcome did not differ between STS PROM subgroups in TF (p = 0.68) or non-TF TAVR (p = 0.27). One-year mortality was higher for patients with STS PROM >8% in the non-TF group; however, this difference was not observed in TF patients (p = 0.40). CONCLUSIONS: As expected, non-TF patients were at a higher risk than TF patients for procedural morbidity and death. Although no differences were observed in 30-day deaths or morbidity in different STS PROM subgroups, those undergoing non-TF TAVR at a higher STS PROM (>8%) had higher 1-year mortality. When applicable, TF TAVR remains the procedure of choice in high- or extreme-risk patients undergoing TAVR.

Breastfeeding among Mothers on Opioid Maintenance Treatment: A Literature Review.

Although there is an abundance of interventional studies to increase breastfeeding rates, little is known about how to support and promote breastfeeding among mothers on opioid maintenance treatment (OMT). The studies on maternal OMT mainly focus on medication excreted in breast milk and breastfeeding benefits for infants with neonatal abstinence syndrome (NAS). We aim to review interventions to improve breastfeeding outcomes among mothers on OMT to make recommendations for practice and future research. We searched CINAHL, PubMed, PsycINFO, and the Cochrane Database of Systematic Reviews for articles, preferably experimental/quasi-experimental studies published within the past 10 years, that examined interventions to increase rates of breastfeeding initiation and duration among mothers on OMT. Nine studies met our inclusion criteria, comprising 5 categories: 4 combined obstetric and addiction care, 1 rooming-in, 1 Baby-Friendly hospital, 2 inpatient/outpatient NAS treatment, and 1 divided methadone dose. Breastfeeding rates were relatively higher for divided methadone dose (81% initiated any breastfeeding) and rooming-in (62% initiated any breastfeeding); lower in Baby-Friendly hospital (24%) and inpatient/outpatient NAS treatment (45% and 24%, respectively); and mixed in combined obstetric and addiction care programs (2 studies reported 70% and 76%; 2 studies reported 17% and 28%). Studies that included both methadone and buprenorphine did not specify breastfeeding results by medication. We recommend future research to differentiate breastfeeding types and duration by OMT medication. Qualitative studies are needed to explore maternal view on breastfeeding regarding need, barrier, and motivating factors in order to develop effective interventions to promote breastfeeding among mothers on OMT.

Intensive Glycemic Control in Cardiac Surgery.

Hyperglycemia has been found to be associated with increased morbidity and mortality in surgical patients, yet, the optimal glucose management strategy during the perioperative setting remains undetermined. While much has been published about hyperglycemia and cardiac surgery, most studies have used widely varying definitions of hyperglycemia, methods of insulin administration, and the timing of therapy. This has only allowed investigators to make general conclusions in this challenging clinical scenario. This review will introduce the basic pathophysiology of hyperglycemia in the cardiac surgery setting, describe the main clinical consequences of operative hyperglycemia, and take the reader through the published material of intensive and conservative glucose management. Overall, it seems that intensive control has modest benefits with adverse effects often outweighing these advantages. However, some studies have indicated differing results for certain patient subgroups, such as non-diabetics with acute operative hyperglycemia. Future studies should focus on distinguishing which patient populations, if any, would optimally benefit from intensive insulin therapy.

Minimalist transcatheter aortic valve replacement: The new standard for surgeons and cardiologists using transfemoral access?

BACKGROUND: A minimalist approach for transcatheter aortic valve replacement (MA-TAVR) utilizing transfemoral access under conscious sedation and transthoracic echocardiography is increasing in popularity. This relatively novel technique may necessitate a learning period to achieve proficiency in performing a successful and safe procedure. This report evaluates our MA-TAVR cohort with specific characterization between our early, midterm, and recent experience. METHODS: We retrospectively reviewed 151 consecutive patients who underwent MA-TAVR with surgeons and interventionists equally as primary operator at Emory University between May 2012 and July 2014. Our institution had performed 300 TAVR procedures before implementation of MA-TAVR. Patient characteristics and early outcomes were compared using Valve Academic Research Consortium 2 definitions among 3 groups: group 1 included the first 50 patients, group 2 included patients 51 to 100, and group 3 included patients 101 to 151. RESULTS: Median age for all patients was 84 years and similar among groups. The majority of patients were men (56%) and the median ejection fraction for all patients was 55% (interquartile range, 38.0%-60.0%). The majority of patients were high-risk surgical candidates with a median Society of Thoracic Surgeons Predicted Risk of Mortality of 10.0% and similar among groups. The overall major stroke rate was 3.3%, major vascular complications occurred in 3% of patients, and greater-than-mild paravalvular leak rate was 7%. In-hospital mortality and morbidity were similar among all 3 groups. CONCLUSIONS: In a high-volume TAVR center, transition to MA-TAVR is feasible with acceptable outcomes and a diminutive procedural learning curve. We advocate for TAVR centers to actively pursue the minimalist technique with equal representation by cardiologists and surgeons.