Toward the scale-up production of polymeric nanotherapeutics for cancer clinical trials.

Nanotherapeutics have gained significant attention for the treatment of numerous cancers, primarily because they can accumulate in and/or selectively target tumors leading to improved pharmacodynamics of encapsulated drugs. The flexibility to engineer the nanotherapeutic characteristics including size, morphology, drug release profiles, and surface properties make nanotherapeutics a unique platform for cancer drug formulation. Polymeric nanotherapeutics including micelles and dendrimers represent a large number of formulation strategies developed over the last decade. However, compared to liposomes and lipid-based nanotherapeutics, polymeric nanotherapeutics have had limited clinical translation from the laboratory. One of the key limitations of polymeric nanotherapeutics formulations for clinical translation has been the reproducibility in preparing consistent and homogeneous large-scale batches. In this review, we describe polymeric nanotherapeutics and discuss the most common laboratory and scale-up formulation methods, specifically those proposed for clinical cancer therapies. We also provide an overview of the major challenges and opportunities for scaling polymeric nanotherapeutics to clinical-grade formulations. Finally, we will review the regulatory requirements and challenges in advancing nanotherapeutics to the clinic.

The 2023 American Association for Thoracic Surgery (AATS) Expert Consensus Document: Management of subsolid lung nodules.

OBJECTIVE: Lung cancers that present as radiographic subsolid nodules represent a subtype with distinct biological behavior and outcomes. The objective of this document is to review the existing literature and report consensus among a group of multidisciplinary experts, providing specific recommendations for the clinical management of subsolid nodules. METHODS: The American Association for Thoracic Surgery Clinical Practice Standards Committee assembled an international, multidisciplinary expert panel composed of radiologists, pulmonologists, and thoracic surgeons with established expertise in the management of subsolid nodules. A focused literature review was performed with the assistance of a medical librarian. Expert consensus statements were developed with class of recommendation and level of evidence for each of 4 main topics: (1) definitions of subsolid nodules (radiology and pathology), (2) surveillance and diagnosis, (3) surgical interventions, and (4) management of multiple subsolid nodules. Using a modified Delphi method, the statements were evaluated and refined by the entire panel. RESULTS: Consensus was reached on 17 recommendations. These consensus statements reflect updated insights on subsolid nodule management based on the latest literature and current clinical experience, focusing on the correlation between radiologic findings and pathological classifications, individualized subsolid nodule surveillance and surgical strategies, and multimodality therapies for multiple subsolid lung nodules. CONCLUSIONS: Despite the complex nature of the decision-making process in the management of subsolid nodules, consensus on several key recommendations was achieved by this American Association for Thoracic Surgery expert panel. These recommendations, based on evidence and a modified Delphi method, provide guidance for thoracic surgeons and other medical professionals who care for patients with subsolid nodules.

Multi-bounce self-mixing in terahertz metasurface external-cavity lasers.

The effects of optical feedback on a terahertz (THz) quantum-cascade metasurface vertical-external-cavity surface-emitting laser (QC-VECSEL) are investigated via self-mixing. A single-mode 2.80 THz QC-VECSEL operating in continuous-wave is subjected to various optical feedback conditions (i.e., feedback strength, round-trip time, and angular misalignment) while variations in its terminal voltage associated with self-mixing are monitored. Due to its large radiating aperture and near-Gaussian beam shape, we find that the QC-VECSEL is strongly susceptible to optical feedback, which is robust against misalignment of external optics. This, in addition to the use of a high-reflectance flat output coupler, results in high feedback levels associated with multiple round-trips within the external cavity-a phenomenon not typically observed for ridge-waveguide QC-lasers. Thus, a new theoretical model is established to describe self-mixing in the QC-VECSEL. The stability of the device under variable optical feedback conditions is also studied. Any mechanical instabilities of the external cavity (such as vibrations of the output coupler), are enhanced due to feedback and result in low-frequency oscillations of the terminal voltage. The work reveals how the self-mixing response differs for the QC-VECSEL architecture, informs other systems in which optical feedback is unavoidable, and paves the way for QC-VECSEL self-mixing applications.

Differences in Cardiovascular Health at the Intersection of Race, Ethnicity, and Sexual Identity.

Importance: An understanding of the intersectional effect of sexual identity, race, and ethnicity on disparities in cardiovascular health (CVH) has been limited. Objective: To evaluate differences in CVH at the intersection of race, ethnicity, and sexual identity using the American Heart Association's Life's Essential 8 measure. Design, Setting, and Participants: This cross-sectional study was conducted from July 27 to September 6, 2023, using National Health and Nutrition Examination Survey data from 2007 to 2016. Participants were noninstitutionalized, nonpregnant adults (aged 18-59 years) without cardiovascular disease or stroke. Exposures: Self-reported sexual identity, categorized as heterosexual or sexual minority (SM; lesbian, gay, bisexual, or "something else"), and self-reported race and ethnicity, categorized as non-Hispanic Black (hereafter, Black), Hispanic, non-Hispanic White (hereafter, White), and other (Asian, multiracial, or any other race and ethnicity). Main Outcome and Measures: The primary outcome was overall CVH score, which is the unweighted mean of 8 CVH metrics, assessed from questionnaire, dietary, and physical examination data. Regression models stratified by sex, race, and ethnicity were developed for the overall CVH score and individual CVH metrics, adjusting for age, survey year, and socioeconomic status (SES) factors. Results: The sample included 12 180 adults (mean [SD] age, 39.6 [11.7] years; 6147 [50.5%] male, 2464 [20.2%] Black, 3288 [27.0%] Hispanic, 5122 [42.1%] White, and 1306 [10.7%] other race and ethnicity). After adjusting for age, survey year, and SES, Black (ß, -3.2; 95% CI, -5.8 to -0.6), Hispanic (ß, -5.9; 95% CI, -10.3 to -1.5), and White (ß, -3.3; 95% CI, -6.2 to -0.4) SM female adults had lower overall CVH scores compared with their heterosexual counterparts. There were no statistically significant differences for female adults of other race and ethnicity (ß, -2.8; 95% CI, -9.3 to 3.7) and for SM male adults of any race and ethnicity compared with their heterosexual counterparts (Black: ß, 2.2 [95% CI, -1.2 to 5.7]; Hispanic: ß, -0.9 [95% CI, -6.3 to 4.6]; White: ß, 1.5 [95% CI, -2.2 to 5.2]; other race and ethnicity: ß, -2.2 [95% CI, -8.2 to 3.8]). Conclusions and Relevance: In this cross-sectional study, CVH differed across race and ethnicity categories in SM females, suggesting that different communities within the larger SM population require tailored interventions to improve CVH. Longitudinal studies are needed to identify the causes of CVH disparities, particularly in Black and Hispanic SM females and inclusive of other racial and ethnic identities.

Continuous-wave GaAs/AlGaAs quantum cascade laser at 5.7 THz.

Design strategies for improving terahertz (THz) quantum cascade lasers (QCLs) in the 5-6 THz range are investigated numerically and experimentally, with the goal of overcoming the degradation in performance that occurs as the laser frequency approaches the Reststrahlen band. Two designs aimed at 5.4 THz were selected: one optimized for lower power dissipation and one optimized for better temperature performance. The active regions exhibited broadband gain, with the strongest modes lasing in the 5.3-5.6 THz range, but with other various modes observed ranging from 4.76 to 6.03 THz. Pulsed and continuous-wave (cw) operation is observed up to temperatures of 117 K and 68 K, respectively. In cw mode, the ridge laser has modes up to 5.71 THz - the highest reported frequency for a THz QCL in cw mode. The waveguide loss associated with the doped contact layers and metallization is identified as a critical limitation to performance above 5 THz.

Heterogeneity of State Stroke Center Certification and Designation Processes.

BACKGROUND: Stroke centers are critical for the timely diagnosis and treatment of acute stroke and have been associated with improved treatment and outcomes; however, variability exists in the definitions and processes used to certify and designate these centers. Our study categorizes state stroke center certification and designation processes and provides examples of state processes across the United States, specifically in states with independent designation processes that do not rely on national certification. METHODS: In this cross-sectional study from September 2022 to April 2023, we used peer-reviewed literature, primary source documents from states, and communication with state officials in all 50 states to capture each state's process for stroke center certification and designation. We categorized this information and outlined examples of processes in each category. RESULTS: Our cross-sectional study of state-level stroke center certification and designation processes across states reveals significant heterogeneity in the terminology used to describe state processes and the processes themselves. We identify 3 main categories of state processes: No State Certification or Designation Process (category A; n=12), State Designation Reliant on National Certification Only (category B; n=24), and State Has Option for Self-Certification or Independent Designation (category C; n=14). Furthermore, we describe 3 subcategories of self-certification or independent state designation processes: State Relies on Self-Certification or Independent Designation for Acute Stroke Ready Hospital or Equivalent (category C1; n=3), State Has Hybrid Model for Acute Stroke Ready Hospital or Equivalent (category C2; n=5), and State Has Hybrid Model for Primary Stroke Center and Above (category C3; n=6). CONCLUSIONS: Our study found significant heterogeneity in state-level processes. A better understanding of how these differences may impact the rigor of each process and clinical performance of stroke centers is worthy of further investigation.

Association between underweight status and chylothorax after esophagectomy for esophageal cancer: A propensity score-matched analysis.

Objective: To use a nationwide database of hospitalizations to investigate underweight status as a risk factor for postesophagectomy complications. Methods: We identified all patients who underwent esophagectomy with a diagnosis of esophageal cancer and known body mass index in the 2018-2020 Nationwide Readmissions Database. All hospital visits for esophagectomy and within 30 days of initial discharge were analyzed for postoperative complications, including chylothorax. Patients who were underweight were propensity score matched with patients who were not. Multivariable logistic regression was performed to identify complications that were significantly associated with underweight status. Results: There were 1877 patients with esophageal cancer meeting inclusion criteria. Following propensity score matching, 433 patients who were underweight were matched to 433 patients who were not. In the multivariable model of the matched sample, which adjusted for age, sex, Charlson Comorbidity Index, history of chemotherapy or radiation therapy, and preoperative surgical feeding access, patients who were underweight were estimated to have 2.06 times the odds for chylothorax (95% confidence interval [CI], 1.07-4.25, P = .035). Underweight status was also significantly associated with acute bleed (odds ratio [OR], 1.52; 95% CI, 1.12-2.05, P = .007), pneumothorax (OR, 2.33; 95% CI, 1.19-4.85; P = .017), pneumonia (OR, 2.30; 95% CI, 1.53-3.50, P < .001), and in-hospital mortality (OR, 2.42; 95% CI, 1.31-4.69, P = .006). Conclusions: Underweight status was found to be a risk factor for chylothorax after esophagectomy, which may have implications for perioperative care of esophageal cancer patients. Future studies should assess whether using feeding tubes or total parenteral nutrition preoperatively or thoracic duct ligation intraoperatively decreases risk of chylothorax among patients who were underweight.

Baseline Stroke Risk and Efficacy of Dual-Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial.

BACKGROUND: High-risk transient ischemic attacks and minor ischemic strokes are followed by a variable risk of ischemic stroke. We aimed to determine how baseline stroke risk modified the efficacy of clopidogrel-aspirin (referred to here as dual-antiplatelet therapy [DAPT]) for transient ischemic attack and minor ischemic stroke. METHODS: We performed an unplanned secondary analysis of the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke). We first evaluated the associations of the CHA2DS2-VASc and stroke prognosis instrument II (SPI-II) scores with the risk of incident ischemic stroke and major hemorrhage (intracranial hemorrhage or major systemic hemorrhage). We then tested for heterogeneity of the relative and absolute treatment effect of DAPT relative to aspirin across low- and high-risk patient subgroups. RESULTS: A total of 4841 trial participants were included in this analysis, with 2400 participants assigned to treatment with short-term DAPT and 2430 participants to treatment with aspirin and placebo. The dichotomized SPI-II score, but not the CHA2DS2-VASc score (P=0.18), was associated with the risk of incident ischemic stroke. A high-risk SPI-II score (>3) was associated with greater risk of incident ischemic stroke (hazard ratio of incident ischemic stroke relative to low-risk SPI-II score of 1.84 [95% CI, 1.44-2.35]; P<0.001) and numerically greater risk of major hemorrhage though not meeting statistical significance (hazard ratio, 1.80 [95% CI, 0.90-3.57]; P=0.10). The relative risk reduction with DAPT was similar across SPI-II strata (Pinteraction=0.31). The absolute risk reduction for ischemic stroke with DAPT compared with aspirin was nearly 4-fold higher (2.80% versus 0.76%; number needed to treat, 31 versus 131) in the high-risk SPI-II stratum relative to the low-risk stratum. The absolute risk increase for major hemorrhage with DAPT compared with aspirin was 3-fold higher (0.84% versus 0.30%; number needed to harm, 119 versus 331) in the high-risk SPI-II stratum relative to the low-risk stratum. CONCLUSIONS: Stratification by baseline stroke risk identifies a patient subgroup that derives greater absolute benefit from treatment with DAPT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00991029.

Longer hospitalizations, more complications, and greater readmissions for patients with comorbid psychiatric disorders undergoing pulmonary lobectomy.

OBJECTIVE: To examine the influence of comorbid psychiatric disorders (PSYD) on postoperative outcomes in patients undergoing pulmonary lobectomy. METHODS: A retrospective analysis of the Healthcare Cost and Utilization Project Nationwide Readmissions Database from 2016 to 2018 was performed. Patients with lung cancer with and without psychiatric comorbidities who underwent pulmonary lobectomy were collated and analyzed (International Classification of Diseases, 10th Revision, Clinical Modification Mental, Behavioral and Neurodevelopmental disorders [F01-99]). The association of PSYD with complications, length of stay, and readmissions was assessed using a multivariable regression analysis. Additional subgroup analyses were performed. RESULTS: A total of 41,691 patients met inclusion criteria. Of these, 27.84% (11,605) of the patients had at least 1 PSYD. PSYD was associated with a significantly increased risk of postoperative complications (relative risk, 1.041; 95% CI, 1.015-1.068; P = .0018), pulmonary complications (relative risk, 1.125; 95% CI, 1.08-1.171; P < .0001), longer length of stay (PSYD mean, 6.79 days and non-PSYD mean, 5.68 days; P < .0001), higher 30-day readmission rate (9.2% vs 7.9%; P < .0001), and 90-day readmission rate (15.4% vs 12.9%; P < .007). Among patients with PSYD, those with cognitive disorders and psychotic disorders (eg, schizophrenia) appear to have the highest rates and risks of postoperative morbidity and in-hospital mortality. CONCLUSIONS: Patients with lung cancer with comorbid psychiatric disorders undergoing lobectomy experience worse postoperative outcomes with longer hospitalization, increased rates of overall and pulmonary complications, and greater readmissions suggesting potential opportunities for improved psychiatric care during the perioperative period.

What's new in thoracic oncology.

Many changes have occurred in the field of thoracic surgery over the last several years. In this review, we will discuss new diagnostic techniques for lung cancer, innovations in surgery, and major updates on latest treatment options including immunotherapy. All these have significantly started to change our approach toward the management of lung cancer and have great potential to improve the lives of our patients afflicted with this disease.

Delayed esophagectomy for adenocarcinoma is associated with a negative impact on long-term survival and an increased risk of perioperative morbidity.

OBJECTIVE: Delayed esophagectomy (DE) following chemoradiation therapy (CXRT) for esophageal carcinoma is undertaken in selected patients. This study aimed to assess both short-term outcomes and long-term survival for patients with adenocarcinoma undergoing DE. METHODS: The National Cancer Database was queried for patients with American Joint Committee on Cancer clinical stage II-III esophageal adenocarcinoma undergoing esophagectomy after CXRT. Patients were categorized as (1) DE, ≥90 days between completion of CXRT and surgery or (2) nondelayed esophagectomy (NDE), <90 days. Cox regression was performed to identify factors associated with mortality. RESULTS: A total of 8157 patients met criteria. Age >69, nonwhite race, Medicare/Medicaid insured patients preferentially underwent DE. Five-year overall survival (OS) favored NDE (36% vs. 31%, p = 0.008). Cox regression identified DE, clinical stage >T2, or >N0 as factors associated with mortality. Within the DE group, OS favored early cT-status. DE fared worse than NDE in 30- and 90-day mortality (4.5%/11.1% vs. 2.9%/6.5%, p < 0.01/p < 0.001) and margin positive resection (7.1% vs. 4.2%, p < 0.001). CONCLUSIONS: For esophageal adenocarcinoma, DE is associated with decreased OS compared to NDE. For DE, cT-status is prognostic for OS, while cN-status was not. Increased 30-/90-day mortality and margin positive resection rates for DE question whether patients with locally advanced (cT3/T4) primary esophageal adenocarcinoma should undergo intentional DE.

Impact of Targeting Moiety Type and Protein Corona Formation on the Uptake of Fn14-Targeted Nanoparticles by Cancer Cells.

The TWEAK receptor, Fn14, is a promising candidate for active targeting of cancer nanotherapeutics to many solid tumor types, including metastatic breast and primary brain cancers. Targeting of therapeutic nanoparticles (NPs) has been accomplished using a range of targeting moieties including monoclonal antibodies and related fragments, peptides, and small molecules. Here, we investigated a full-length Fn14-specific monoclonal antibody, ITEM4, or an ITEM4-Fab fragment as a targeting moiety to guide the development of a clinical formulation. We formulated NPs with varying densities of the targeting moieties while maintaining the decreased nonspecific adhesivity with receptor targeting (DART) characteristics. To model the conditions that NPs experience following intravenous infusion, we investigated the impact of serum exposure in relation to the targeting moiety type and surface density. To further evaluate performance at the cancer cell level, we performed experiments to assess differences in cellular uptake and trafficking in several cancer cell lines using confocal microscopy, imaging flow cytometry, and total internal reflection fluorescence microscopy. We observed that Fn14-targeted NPs exhibit enhanced cellular uptake in Fn14-high compared to Fn14-low cancer cells and that in both cell lines uptake levels were greater than observed with control, nontargeted NPs. We found that serum exposure increased Fn14-targeted NP specificity while simultaneously reducing the total NP uptake. Importantly, serum exposure caused a larger reduction in cancer cell uptake over time when the targeting moiety was an antibody fragment (Fab region of the monoclonal antibody) compared with the full-length monoclonal antibody targeting moiety. Lastly, we uncovered that full monoclonal antibody-targeted NPs enter cancer cells via clathrin-mediated endocytosis and traffic through the endolysosomal pathway. Taken together, these results support a pathway for developing a clinical formulation using a full-length Fn14 monoclonal antibody as the targeting moiety for a DART cancer nanotherapeutic agent.

Delays to surgery and worse outcomes: The compounding effects of social determinants of health in non-small cell lung cancer.

Objective: To quantify the compounding effects of social determinants of health on time to surgery (T2S) and clinical outcomes. Methods: The National Cancer Database was queried for treatment-naïve patients with cT1-4N0-1M0 non-small cell lung cancer undergoing (bi)lobectomy or pneumonectomy between 2006 and 2016 with 1 to 180 days T2S, the number of days between diagnosis and surgery; surgical delays were defined as statistically significant increased T2S compared with a reference cohort. Social determinants of health factors prognostic for surgical delays were identified using multivariable regression. The 30-/90-day mortality and 5-year survival estimates were calculated using logistic and Cox regressions, respectively. Results: In total, 110,005 patients met inclusionary criteria. Multivariable analysis identified race, insurance, and facility type as factors with significant 3-way interaction: T2S of one depended on the others. Income and education also contributed to delays. Privately insured (private) non-Hispanic White patients at academic medical centers (AMCs) were the reference with T2S of 44.1 days. At AMCs, private Black patients had significant delays to surgery (54.7 days; P < .0001), as did Medicaid and uninsured Black patients (58.5 days; P < .0001, 59.4 days; P < .0001, respectively). The 15-day surgical delays were associated with statistically significant 5% increased 30-day mortality odds (confidence interval [CI], 1.03-1.08), 6% increased 90-day mortality odds (CI, 1.04-1.08), and 4% decrease in hazard of death at 5 years (CI, 1.04-1.05). Conclusions: In treatment-naïve patients with cT1-4N0-1M0 non-small cell lung cancer, Black race, Medicaid, uninsured status, and AMCs generate compounding surgical delays with increased 30-/90-day mortality and decreased 5-year survival. Thoracic surgeons can leverage these facility and demographic-specific insights to standardize time to surgery and begin mitigating underlying disparities.

Early outcomes of lung transplantation with lung allografts from coronavirus disease 2019 (COVID-19)-positive donors.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) can be detected for extended periods of time with nucleic acid amplification test even after transmissibility becomes negligible. Lung allografts from COVID-19-positive donors have been used for transplantation in highly selected cases. This study aimed to clarify the early outcomes of lung transplantation with COVID-19-positive donors. METHODS: The Organ Procurement and Transplantation Network/United Network for Organ Sharing database between April 2020 and June 2022 was retrospectively analyzed. RESULTS: In the study period, 1297 COVID-19-positive donors were identified and the lungs were transplanted from 47 donors (3.6%). Of 47 donors, 44 donors were positive for COVID-19 NAT with nasopharyngeal swabs and the other 3 were positive with bronchoalveolar lavage. The COVID-19-positive lung donors were younger than the COVID-19-negative donors (28.4 ± 11.6 years vs 35.4 ± 13.6 years, P < .001). Recipients of the COVID-19-positive lungs (n = 47) were more likely have a greater lung allocation score (57.1 ± 22.9 vs 50.5 ± 19.7, P = .057) than recipients of COVID-19-negative lungs (n = 5501). The posttransplant length of hospital stay (39.8 ± 43.6 days vs 30.6 ± 34.5 days, P = .181), need for extracorporeal membrane oxygenation support at 72 hours after transplantation (2.6% [1/38] vs 10.4% [541/5184], P = .18), and 1-year overall survival rate (85.6% vs 87.1%, P = .63) were comparable between the 2 groups. CONCLUSIONS: Carefully selected lung allografts from COVID-19-positive donors had comparable early posttransplant outcomes to lung allografts from COVID-19-negative donors.

A Narrative Review: Phentermine and Topiramate for the Treatment of Pediatric Obesity.

The prevalence of pediatric obesity has increased exponentially over the past four decades. The American Academy of Pediatrics recently released updated clinical practice guidelines highlighting the importance of identifying pediatric obesity as a chronic disease. The guidelines support consideration of concurrent treatment with intensive lifestyle interventions, obesity pharmacotherapy, and bariatric surgery. The dramatic rise in pediatric obesity has spurred interest in utilizing obesity pharmacotherapy to support sustained weight reduction in pediatric cohorts, in the hopes of preventing the emergence of later-appearing, significant co-morbidities. Despite the enormous demand, the obstacles posed by performance of needed clinical trials in the pediatric population markedly limits available pharmacotherapy for the treatment of obesity in pediatrics. Currently, there are five medications approved by the Food and Drug Administration for use in youth with obesity. In 2022, the phentermine/topiramate (PHEN/TPM), once-daily, controlled-release, combination product received FDA approval, for the indication of chronic weight management, in youth with obesity, ages 12 years and older. The objectives of this narrative review are to: (1) Review the mechanism of action of phentermine and topiramate, (2) Summarize the safety and efficacy data of topiramate and phentermine use as both monotherapies and in combination, and (3) Discuss clinical practice guidelines and clinical implications, for the use of these agents in youths with obesity.