A feasibility study assessing quantitative indocyanine green angiographic predictors of reconstructive complications following nipple-sparing mastectomy.

Introduction: Immediate post-mastectomy breast reconstruction offers benefits; however, complications can compromise outcomes. Intraoperative indocyanine green fluorescence angiography (ICGFA) may mitigate perfusion-related complications (PRC); however, its interpretation remains subjective. Here, we examine and develop methods for ICGFA quantification, including machine learning (ML) algorithms for predicting complications. Methods: ICGFA video recordings of flap perfusion from a previous study of patients undergoing nipple-sparing mastectomy (NSM) with either immediate or staged immediate (delayed by a week due to perfusion insufficiency) reconstructions were analysed. Fluorescence intensity time series data were extracted, and perfusion parameters were interrogated for overall/regional associations with postoperative PRC. A naïve Bayes ML model was subsequently trained on a balanced data subset to predict PRC from the extracted meta-data. Results: The analysable video dataset of 157 ICGFA featured females (average age 48 years) having oncological/risk-reducing NSM with either immediate (n=90) or staged immediate (n=26) reconstruction. For those delayed, peak brightness at initial ICGFA was lower (p<0.001) and significantly improved (both quicker-onset and brighter p=0.001) one week later. The overall PRC rate in reconstructed patients (n=116) was 11.2%, with such patients demonstrating significantly dimmer (overall, p=0.018, centrally, p=0.03, and medially, p=0.04) and slower-onset (p=0.039) fluorescent peaks with shallower slopes (p=0.012) than uncomplicated patients with ICGFA. Importantly, such relevant parameters were converted into a whole field of view heatmap potentially suitable for intraoperative display. ML predicted PRC with 84.6% sensitivity and 76.9% specificity. Conclusion: Whole breast quantitative ICGFA assessment reveals statistical associations with PRC that are potentially exploitable via ML.

Trends in outcomes of 862 giant hiatus hernia repairs over 30 years.

PURPOSE: Laparoscopic giant hiatus hernia repair is technically difficult with ongoing debate regarding the most effective surgical technique. Repair of small hernia has been well described but data for giant hernia is variable. This study evaluated trends in outcomes of laparoscopic non-mesh repair of giant paraesophageal hernia (PEH) over 30 years. METHODS: Retrospective analysis of a single-surgeon prospective database. Laparoscopic non-mesh repairs for giant PEH between 1991 and 2021 included. Three-hundred-sixty-degree fundoplication was performed routinely, evolving into "composite repair" (esophagopexy and cardiopexy to the right crus). Cases were chronologically divided into tertiles based on operation date (Group 1, 1991-2002; Group 2, 2003-2012; Group 3, 2012-2021) with trends in casemix, operative factors and outcomes evaluated. Hernia recurrence was plotted using weighted moving average and cumulative sum (CUSUM) analysis. RESULTS: 862 giant PEH repairs met selection criteria. There was an increasing proportion of "composite repair" after the first decade (Group 1, 2.7%; Group 2, 81.9%; Group 3, 100%; p < 0.001). There were less anatomical hernia recurrence (Group 1, 36.6%; Group 2, 22.9%; Group 3, 22.7%; p < 0.001) and symptomatic recurrence (Group 1, 34.2%; Group 2, 21.9%; Group 3, 7%; p < 0.001) over time. The incidence of anatomical recurrence declined over time, decreasing from 30.8% and plateauing below 17.6% near the study's end. Median followup (months) in the first decade was higher but followup between the latter two decades comparable (Group 1, 49 [IQR 20, 81]; Group 2, 30 [IQR 15, 65]; Group 3, 24 [14, 56]; p < 0.001). There were 10 (1.2%) Clavien-Dindo grade ≥ III complications including two perioperative deaths (0.2%). CONCLUSION: Hernia recurrence rates decreased with increasing case volume. This coincided with the increasing adoption of "composite repair", supporting the possible improvement in recurrence rates with this approach.

Physical activity during pregnancy is associated with a lower prevalence of gestational diabetes mellitus in Vietnam.

AIMS: To assess the association between physical activity (PA) during pregnancy and the prevalence of gestational diabetes mellitus (GDM) accounting for sitting time. METHODS: The study used data from a cohort study of 2030 pregnant women in Vietnam. Women were recruited from six hospitals in Ha Noi, Hai Phong, and Ho Chi Minh City. Baseline measurements including PA and GDM were taken at 24-28 weeks of gestation. PA was assessed during the past 3 months before the interview using the interviewer-administered Pregnancy Physical Activity Questionnaire. GDM was diagnosed at 24-28 weeks of gestation using the 2013 World Health Organization criteria. RESULTS: 1987 out of 2030 pregnant women were included in the final analysis, of which 432 had GDM (21.7%). Women undertaking the highest level (upper tertile) of PA during pregnancy appeared to have a lower risk of GDM [odds ratio (OR) 0.70, 95% confidence interval (CI) 0.53-0.94, Ptrend 0.017] when compared to those at the lowest tertile of PA. Similarly, women with increased levels of moderate-intensive activity and household/caregiving activity during pregnancy were associated with reduced risks of GDM (OR 0.66, 95% CI 0.50-0.86, Ptrend 0.002 and OR 0.72, 95% CI 0.55-0.95, Ptrend 0.020, respectively). These apparent inverse associations were not attenuated by their sitting time. There were no significant associations between sitting time, light-intensity activity, vigorous-intensity activity, occupation, sports/exercise, commuting, or meeting exercise guidelines and GDM risk. CONCLUSIONS: High levels of PA, particularly moderate-intensity and household/caregiving activities during pregnancy were associated with a lower prevalence of GDM independent of sitting time.

IL-5-stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8-dependent migration.

BACKGROUND: IL-5 causes suspended eosinophils to polarize with filamentous (F)-actin and granules at one pole and the nucleus in a specialized uropod, the "nucleopod," which is capped with P-selectin glycoprotein ligand-1 (PSGL-1). IL-5 enhances eosinophil adhesion and migration on periostin, an extracellular matrix protein upregulated in asthma by type 2 immunity mediators. OBJECTIVE: Determine how the polarized morphology evolves to foster migration of IL-5-stimulated eosinophils on a surface coated with periostin. METHODS: Blood eosinophils adhering to adsorbed periostin were imaged at different time points by fluorescent microscopy, and migration of eosinophils on periostin was assayed. RESULTS: After 10 minutes in the presence of IL-5, adherent eosinophils were polarized with PSGL-1 at the nucleopod tip and F-actin distributed diffusely at the opposite end. After 30-60 minutes, the nucleopod had dissipated such that PSGL-1 was localized in a crescent or ring away from the cell periphery, and F-actin was found in podosome-like structures. The periostin layer, detected with monoclonal antibody Stiny-1, shown here to recognize the FAS1 4 module, was cleared in wide areas around adherent eosinophils. Clearance was attenuated by metalloproteinase inhibitors or antibodies to disintegrin metalloproteinase 8 (ADAM8), a major eosinophil metalloproteinase previously implicated in asthma pathogenesis. ADAM8 was not found in podosome-like structures, which are associated with proteolytic activity in other cell types. Instead, immunoblotting demonstrated proteoforms of ADAM8 that lack the cytoplasmic tail in the supernatant. Anti-ADAM8 inhibited migration of IL-5-stimulated eosinophils on periostin. CONCLUSIONS AND CLINICAL RELEVANCE: Migrating IL-5-activated eosinophils on periostin exhibit loss of nucleopodal features and appearance of prominent podosomes along with clearance of the Stiny-1 periostin epitope. Migration and epitope clearance are both attenuated by inhibitors of ADAM8. We propose, therefore, that eosinophils remodel and migrate on periostin-rich extracellular matrix in the asthmatic airway in an ADAM8-dependent manner, making ADAM8 a possible therapeutic target.

Loss of T cell-mediated antitumor immunity after construct-specific downregulation of retrovirally encoded T-cell receptor expression in vivo.

Adoptive T-cell therapy is clinically efficacious in the treatment of select cancers. However, it is often difficult to obtain adequate numbers of tumor-specific T cells for therapy. One method for overcoming this limitation is to generate tumor-specific T cells by retrovirally mediated T-cell-receptor (TCR) gene transfer. However, despite instances of therapeutic success, major obstacles remain, including attaining the survival of retrovirally modified T cells in vivo as well as inducing long-term and multi-gene retroviral expression. Using a murine model of adoptively transferred retrovirally modified CD8(+) T cells, where antitumor immunity was dependent on sustained, multigene expression, we found that in vitro assays are poor indicators of in vivo efficacy. Despite persisting for over 9 months in a nonlymphopenic environment, genetically modified T cells exhibited discordant retrovirally mediated gene expression in vivo not readily evident from initial in vitro assays. In particular, one of the two TCR subunit genes necessary for antigen specificity was selectively lost in vivo. As this discordant gene expression was associated with the loss of antitumor immunity, consideration of these findings may provide guidance in the design, evaluation and application of retroviral vectors for use in the treatment of cancer and other human disease.

Sustained release of granulocyte-macrophage colony-stimulating factor from a modular peptide-based cancer vaccine alters vaccine microenvironment and enhances the antigen-specific T-cell response.

The recent identification and molecular characterization of tumor antigens provides the opportunity to explore the rational development of peptide-based cancer vaccines. However, the response to these vaccines remains variable, and peptide-based cancer vaccines may even produce tolerance induction and enhanced tumor growth. The authors have developed a unique method for the isolation of a polysaccharide polymer of chemically pure poly- N -acetyl glucosamine (p-GlcNAc). This highly purified polysaccharide can be formulated into a stable gel matrix (designated F2 gel matrix) with unique properties of a sustained-release delivery system that has previously been shown to be an effective immune adjuvant. F2 gel matrix is capable of providing sustained release of antigenic peptide and cytokine in vitro. The purposes of this study were to characterize the ability of F2 gel matrix to provide sustained local release of cytokines in vivo and to test the hypothesis that such sustained release can enhance the microenvironment for antigen presentation, leading to a more effective antitumor response. Subcutaneous administration of F2 gel/cytokine matrix resulted in sustained release of cytokine at the vaccine site for up to 120 hours. Sustained release of granulocyte-macrophage colony-stimulating factor (GM-CSF) was associated with an increased inflammatory infiltrate at the vaccine site and enhanced dendritic cell activation. Further, accination with F2 gel/SIINFEKL/GM-CSF matrix resulted in enhanced antigen-specific immunity. Addition of GM-CSF to the F2 gel matrix resulted in an increase in the percentage of antigen-specific T cells in the draining lymph nodes, enhanced cytotoxicity, a sustained presence of antigen-specific T cells in the peripheral blood, and protection from E.G7 tumor challenge. These results support the potential of an F2 gel matrix modular vaccine delivery system that can provide sustained local release of cytokine in vivo, and confirm the powerful effects of GM-CSF as an immune adjuvant.

Melanoma thickness and histology predict sentinel lymph node status.

BACKGROUND: It remains unclear which patients with melanoma will benefit most from lymphatic mapping and sentinel lymphadenectomy. The purpose of this study is to determine whether primary melanoma histopathologic features could be applied to predict sentinel node status. METHODS: One hundred twelve patients underwent sentinel node biopsy between May 1995 and August 1999. Reported histologic features were assessed for predictive value by univariate and multivariate logistic regression. RESULTS: The sentinel node was located successfully in 105 of the 112 patients (94%). Twenty-one of these 105 patients (20%) had sentinel nodes that were positive for metastatic disease. Multivariate analyses revealed that tumor thickness greater than 1.5 mm (P = 0.01), ulceration (P <0.01), and lymphovascular invasion (P = 0.05) predicted the presence of micrometastases. CONCLUSIONS: The presence of unfavorable histopathology such as ulceration and lymphovascular invasion may identify a group of patients with thin melanomas who would benefit from sentinel lymphadenectomy.

Utilization of natural products for treatment of blood diseases.

This chapter presents an introduction to several diseases of the blood including infectious mononucleosis, leukemia, thrombosis and coagulation, bone marrow disorders, malaria, and anemia. In addition a survey of the recent literature is presented relative to natural products that have been utilized for the treatment of these diseases. The natural products that are reported represent a wide range of structural types and present interesting mechanisms of action. Thus the possibility exists that new drugs may be developed from these natural products which are more effective than those currently on the market.