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.

Reoperative total arch replacement after previous cardiovascular surgery: Outcomes in 426 consecutive patients.

OBJECTIVE: Total aortic arch replacement (TAR) after previous cardiovascular surgery is technically challenging and is becoming more frequent as outcomes for primary arch repair have improved. primary. We analyzed outcomes of reoperative compared with first-time TAR. METHODS: The institutional aortic database was queried to identify consecutive patients undergoing TAR between 1997 and 2022. In total, 426 patients underwent TAR, of whom 150 (35%) had previous cardiovascular surgery (reop TAR) and 276 (65%) underwent their first cardiovascular operation. RESULTS: The reop TAR group was younger (61 ± 13 vs 71 ± 11, P < .001) with more comorbidities such as ischemic heart disease (12% vs 4.3%, P = .006), previous stroke (36% vs 14.5%, P < .001), and renal impairment (24% vs 12.7%, P = .004). Reop TAR had longer cardiac ischemic times (119.3 ± 45.5 minutes vs 98 ± 31.9 minutes, P < .001), a greater operative mortality (3.3% vs 0.4%, P = .040), and incurred a 4-fold increased risk of major adverse event (95% confidence interval [CI], 1.41-11.49, P = .009). Ten-year survival was also lower in the reop TAR cohort (76% vs 82.2%; hazard ratio, 1.79; 95% CI, 1.12-2.86, P = .015) and there was greater need for late reinterventions, mainly on the downstream aorta (hazard ratio, 1.29; 95% CI, 1.03-1.62, P = .024). CONCLUSIONS: Reop TAR is a technically challenging operation and is associated with increased operative mortality and adverse events. Gratifying results can be obtained with meticulous surgical planning and focused attention on end-organ protection. Late reinterventions occur in a significantly greater percentage of patients undergoing reop TAR, and future studies should focus attention on identifying those at-risk groups who may benefit from a more aggressive index procedure.

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.

Short- and long-term results of total arch replacement: Comparison between island and debranching techniques.

Objective: The 2 most acceptable techniques for reimplantation of the supra-aortic vessels in total arch replacement include the branched graft technique (debranching) or en bloc technique (island). We aim to review our experience with total arch replacement and report short- and long-term outcomes from a high-volume center dedicated to surgery for the thoracic aorta. Methods: The aortic surgery database was queried to identify all consecutive patients undergoing total arch replacement between 1997 and 2022. Of the 426 patients who underwent total arch replacement, 303 (71%) received the island technique and 123 (29%) received the debranching approach. Operative and long-term outcomes were compared using multivariable models. Results: The debranching group was younger (64 ± 14 years vs 69 ± 12 years, P = .001), had undergone more previous cardiac operations (54.5% vs 27.4%, P < .001), and had more connective tissue disorder (20.3% vs 4.6%, P < .001). The debranching approach was associated with longer total circulatory arrest time (47 ± 15 minutes vs 37 ± 10 minutes, P < .001) and cardiac ischemic time (116 ± 41 minutes vs 100 ± 37 minutes, P < .001). More patients in the debranching group received blood products intraoperatively or postoperatively (56.1% vs 42.9%, P = .018). All other early outcomes did not differ between groups. Overall operative mortality was 1.4% (2.4% vs 1%, P = .486); the incidence of major postoperative complications was 6.3% (5.7% vs 6.6%, P = .897). Ten-year survival was 80% (78% vs 80.9%, log-rank P = .356). Multivariable Cox regression analysis demonstrated that neither surgical approach was associated with survival advantage (hazard ratio, 1.18; 0.73-1.89; P = .495). Conclusions: Debranching requires a longer operative time, with similar early and long-term outcomes. Preoperative comorbidity, not surgical technique, predicts major adverse events and long-term survival.

Long-term durability of valve-sparing root replacement in patients with and without connective tissue disease.

OBJECTIVE: The goal of this study was to evaluate the long-term outcomes of valve-sparing root replacement in patients with connective tissue disease (CTD) and compare them with patients without CTD who underwent valve-sparing root replacement for root aneurysm. METHODS: Of 487 patients, 380 (78%) did not have CTD and 107 (22%) had CTD; 97 (91%) with Marfan syndrome, 8 (7%) with Loeys-Dietz syndrome, and 2 (2%) with Vascular Ehlers-Danlos syndrome. Operative and long-term outcomes were compared. RESULTS: The CTD group was younger (36 ± 14 years vs 53 ± 12 years; P < .001), had more women (41% vs 10%; P < .001) and had less hypertension (28% vs 78%; P < .001) and bicuspid aortic valve (8% vs 28%; P < .001). Other baseline characteristics did not differ between the groups. Overall operative mortality was nil (P = 1.000); the incidence of major postoperative complications was 1.2% (0.9% vs 1.3%; P = 1.000) and did not differ between groups. Residual mild aortic insufficiency (AI) was more frequent in the CTD group (9.3% vs 1.3%, P < .001) with no difference in moderate or greater AI. Ten-year survival was 97.3% (97.2% vs 97.4%; log-rank P = .801). Of the 15 patients with residual AI, 1 had none, 11 remained mild, 2 had moderate, and 1 had severe AI on follow-up. Ten-year freedom from moderate/severe AI was 89.6% (hazard ratio, 1.05; 95% CI, 0.8-1.37; P = .750) and 10-year freedom from valve reoperation was 94.9% (hazard ratio, 1.21; 95% CI, 0.43-3.39; P = .717). CONCLUSIONS: The operative outcomes as well as long-term durability of valve-sparing root replacement is excellent in patients with or without CTD. Valve function and durability are not influenced by CTD.

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.

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.

Sustainable glycerol terpolycarbonates as temporary bioadhesives.

We describe the synthesis of poly(glycidyl acetate-co-glycidyl butyrate carbonate)s via the terpolymerization of glycidyl acetate (GA), glycidyl butyrate (GB), and CO2 by a cobalt salen complex in high atom economy. These new non-cytotoxic polycarbonates are pressure-sensitive adhesives, and peel testing shows the adhesive strength ranges from Scotch-Tape® to hot-melt glues based on glycidyl butyrate content. The tunable adherence, benign degradation products, and facile application and removal suggest their utility as temporary adhesives, such as those used in biomedical applications or medical devices. One polymer, (GA-co-GB)-87, exhibits the proper adhesive strength to sufficiently adhere a collagen buttress to the jaws of a steel surgical stapler and easily release the buttress after firing to successfully cut, close, and implant the buttress into lung tissue in an ex vivo sheep model.

Pilot-scale production of expansile nanoparticles: Practical methods for clinical scale-up.

One of the foremost challenges in translating nanoparticle technologies to the clinic is the requirement to produce materials on a large-scale. Scaling nanoparticle production methods is often non-trivial, and the success of these endeavors is frequently governed by whether or not an intermediate level of production, i.e., "pilot-scale" production, can be achieved. Pilot-scale production at the one-liter scale serves as a proof-of-concept that large-scale production will be possible. Here, we describe the pilot-scale production of the expansile nanoparticle (eNP) technology including verification of activity and efficacy following scaleup. We describe the challenges of sonication-based emulsification procedures and how these were overcome by use of a Microfluidizer technology. We also describe the problem-solving process that led to pre-polymerization of the nanoparticle polymer-a fundamental change from the lab-scale and previously published methods. Furthermore, we demonstrate good control over particle diameter, polydispersity and drug loading and the ability to sterilize the particles via filtration using this method. To facilitate long-term storage of these larger quantities of particles, we investigated six lyoprotectants and determined that sucrose is the most compatible with the current system. Lastly, we demonstrate that these changes to the manufacturing method do not adversely affect the swelling functionality of the particles, their highly specific localization to tumors, their non-toxicity in vivo or their efficacy in treating established intraperitoneal mesothelioma xenografts.

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.

Paclitaxel-loaded expansile nanoparticles improve survival following cytoreductive surgery in pleural mesothelioma xenografts.

OBJECTIVE: Malignant pleural mesothelioma is a lethal malignancy with poor survival and high local recurrence rates despite multimodal therapy with cytoreduction and chemoradiation. We evaluated the antitumor efficacy of a paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) in 2 clinically relevant murine xenograft models of malignant pleural mesothelioma. METHODS: Luciferase-transfected MSTO-211H human mesothelioma cells were injected into the thoracic cavity of immunodeficient Nu/J mice. Tumor burden was monitored by bioluminescent imaging. Animals were randomized into 2 models of disease treatment chemotherapy with PTX-eNPs alone delivered locally for early limited disease or cytoreductive surgery plus local PTX-eNP chemotherapy for advanced disease. Within each disease model, anti-tumor efficacy of PTX-eNP was compared against standard formulation paclitaxel and drug-empty nanoparticles. Influence on survival was calculated. Fluorescently labeled PTX-eNPs and immunohistochemistry evaluated in vivo drug localization to tumor. RESULTS: Intrathoracic injection of MSTO-211H resulted in large tumor deposits distributed within the pleural space of the murine thoracic cavity. Local multidose treatment with PTX-eNPs alone in limited stage disease more than doubled survival compared with drug-empty nanoparticles (P ≤ .0001) and standard formulation paclitaxel (P = .0004). In the model of advanced disease, local multidose treatment with PTX-eNPs following cytoreductive surgery also prolonged survival by 126% and 69.4% compared with drug-empty nanoparticles (P = .0018) and standard formulation paclitaxel (P = .03457), respectively. Immunohistology demonstrated PTX-eNP accumulation within tumor cells in vitro and in vivo. CONCLUSIONS: Local delivery of paclitaxel via eNPs confers prolonged survival in a murine model of malignant pleural mesothelioma as single modality treatment for limited disease and in combination with cytoreductive surgery for advanced disease.

Profound autoimmune hemolysis and Evans syndrome in two asplenic patients with babesiosis.

BACKGROUND: Evans syndrome (ES) is characterized by the simultaneous or sequential presence of multiple autoimmune cytopenias. It is often secondary to rheumatologic disorders or lymphoid malignancies, but has not previously been associated with babesiosis. Here we present two cases of severe cytopenias in asplenic patients precipitated by active babesiosis. CASE REPORT: The first patient had a history of Hodgkin's lymphoma in remission and autoimmune hemolytic anemia (AIHA) treated by splenectomy 12 years prior who presented with severe AIHA and thrombocytopenia after Babesia infection. The second patient had a history of ES requiring splenectomy, which relapsed after Babesia infection. RESULTS: The complex presentation and medical histories of both patients made the diagnosis challenging. Both patients' cytopenias responded to therapy, although the use of immunosuppressive agents in patients with active hematologic infections was challenging and required a multidisciplinary approach. CONCLUSION: These two cases illustrate the possibility of babesiosis to not only reactivate ES in asplenic patients, but also precipitate increased levels of immune deregulation, potentially provoking ES, a phenomenon not previously reported.

Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.

Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.

Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response.

T helper type 2 (T(H)2)-mediated immune responses are induced after infection with multicellular parasites and can be triggered by a variety of allergens. The mechanisms of induction and the antigen-presenting cells involved in the activation of T(H)2 responses remain poorly defined, and the innate immune sensing pathways activated by parasites and allergens are largely unknown. Basophils are required for the in vivo induction of T(H)2 responses by protease allergens. Here we show that basophils also function as antigen-presenting cells. We show that although dendritic cells were dispensable for allergen-induced activation of T(H)2 responses in vitro and in vivo, antigen presentation by basophils was necessary and sufficient for this. Thus, basophils function as antigen-presenting cells for T(H)2 differentiation in response to protease allergens.