Citations

Introduction and hypothesis Enhanced recovery after surgery (ERAS) evidence-based protocols for perioperative care can lead to improvements in clinical outcomes and cost savings. This article aims to present consensus recommendations for the optimal perioperative management of patients undergoing urogynecological surgery. Methods A review of meta-analyses, randomized clinical trials, large nonrandomized studies, and review articles was conducted via PubMed and other databases for ERAS and urogynecological surgery. ERAS protocol components were established, and then quality of the evidence was both graded and used to form consensus recommendations for each topic. These recommendations were developed and endorsed by the writing group, which is comprised of the American Urogynecologic Society and the International Urogynecological Association members. Results All recommendations on ERAS protocol items are based on best available evidence. The level of evidence for each item is presented accordingly. The components of ERAS with a high level of evidence to support their use include fasting for 6 h and taking clear fluids up to 2 h preoperatively, euvolemia, normothermia, surgical site preparation, antibiotic and antithrombotic prophylaxis, strong antiemetics and dexamethasone to reduce postoperative nausea and vomiting, multimodal analgesia and restrictive use of opiates, use of chewing gum to reduce ileus, removal of catheter as soon as feasible after surgery and avoiding systematic use of drains/vaginal packs. Conclusions The evidence base and recommendations for a urogynecology-relevant ERAS perioperative care pathway are presented in this consensus review. There are several elements of ERAS with strong evidence of benefit in urogynecological surgery.

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by deficient levels and/or activity of glycosaminoglycan (GAG)-degradative enzymes. MPS are characterized by accumulation of the mucopolysaccharides heparan sulfate, dermatan sulfate, keratan sulfate, or chondroitin sulfate in tissues. We report the case of a 38-year-old woman with a history of joint restriction and retinitis pigmentosa who developed bivalvular heart failure requiring surgery. It was not until pathological examination of surgically excised valvular tissue that a diagnosis of MPS I was made. Her musculoskeletal and ophthalmologic symptoms, when placed in the context of MPS I, painted the diagnostic picture of a genetic syndrome that was overlooked until a diagnosis was made in late middle age.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

AbstractBackgroundPreoperative anemia is common and associated with adverse postoperative outcomes. Assessment of hemoglobin concentrations may facilitate optimization prior to surgery. However, phlebotomy‐based hemoglobin measurement may contribute to patient discomfort and iatrogenic blood loss, which makes non‐invasive hemoglobin estimation attractive in this setting.Study Design and MethodsThis is a prospective study of adult patients presenting for preoperative evaluation before elective surgery at a tertiary care medical center. The Masimo Pronto Pulse CO‐Oximeter was utilized to estimate blood hemoglobin concentrations (SpHb), which were then compared with hemoglobin concentrations obtained via complete blood count. Receiver operating curves were used to identify SpHb values maximizing specificity for anemia detection while meeting a minimum sensitivity of 80%.ResultsA total of 122 patients were recruited with a median (interquartile range) age of 66 (58, 72) years. SpHb measurements were obtained in 112 patients (92%). SpHb generally overestimated hemoglobin with a mean (± 1.96 × standard deviation) difference of 0.8 (−2.2, 3.9) g/dL. Preoperative anemia, defined by hemoglobin <12.0 g/dL in accordance with institutional protocol, was present in 22 patients (20%). The optimal SpHb cut‐point to identify anemia was 13.5 g/dL: sensitivity 86%, specificity 81%, negative predictive value 96%, and positive predictive value 53%. Utilizing this cut‐point, 60% (73/122) of patients could have avoided phlebotomy‐based hemoglobin assessment, while an anemia diagnosis would have been missed in <3% (3/122).ConclusionThe use of SpHb devices for anemia screening in surgical patients is feasible with the potential to reliably rule‐out anemia despite limited accuracy.

Importance Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known. Objective To examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials. Design, Setting, and Participants In this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022. Main Outcomes and Measures Immune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses. Results The median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature–adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99). Conclusions and Relevance Results of this study suggest that multiple B-cell–related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

Abstract Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. An emerging area of interest for risk reduction is immunoprevention. MUC1 glycoprotein is aberrantly expressed in adenocarcinomas, including lung cancer and their premalignant lesions. MUC1 vaccine in the premalignant or high-risk setting may be effective in halting neoplastic development and progression. Trial design: Through the NCI-funded Cancer Prevention Network (CPN), we conducted a two-center pilot trial to evaluate immunogenicity of the MUC1 vaccine (assessed at 12 weeks), and safety (assessed at up to 24 weeks) in current and former heavy smokers. 87 participants were screened in order to have at least 40 evaluable for baseline and 12-week immunogenicity assessments. Smoking history of ≥30 pack-years and either current (still smoking or quit &lt; 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules &lt; 6 mm in size (consistent with &lt; 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria were standard for lung cancer screening. Methods: MUC1 peptide plus polyICLC adjuvant (Hiltonol) vaccine was given at week 0, 2 and 10. Blood was collected for safety tests and immune assays pre and 2 weeks post each vaccine, and at week 24. Anti-MUC1 IgG titer was evaluated by ELISA. Based on previous studies of this vaccine, 40 evaluable participants would provide 96% power to detect immune response rate of 15% versus 40%, using a 2-sided test of proportions with type I error rate of 0.05. PBMC were assayed for the presence of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) (secondary endpoint). Circulating levels of inflammatory cytokines and hsCRP were evaluated using commercially available tests (exploratory endpoint). AEs and toxicities were monitored for up to 24 weeks from the first vaccine. Results: 87 individuals were screened and 50 registered. 45 completed the study, 26 current and 19 former smokers (time since last smoked: average 7.8 years; 11 months -13 years). The vaccine was well-tolerated with injection site reactions being the most common AE. Immune response to the vaccine was lower than expected, with 2 current and 2 former smokers developing anti-MUC1 IgG titers ≥2 fold higher at week 12 over baseline (10%). We found high circulating levels of MDSCs in PBMC of both current and former smokers and very low or no serum cytokines. Conclusions: A preventative vaccine trial was feasible in individuals at high risk for lung cancer. However, we discovered a high level of immune suppression, previously documented only in advanced lung cancer. Mitigating the development of lung cancer in heavy smokers through vaccine administration may be limited by related immunosuppression. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Samantha Fatis, John McKolanis, Jia Xue, Pamela Beatty, Camille Jacqueline, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Liz S. Ambulay, Nathan Foster, Ryan McMurray, Carrie Strand, Andres M. Salazar, Lisa Bengtson, Eva Szabo, Paul Limburg, Malgorzata Wojtowicz, David E. Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR002.

Abstract The most severe clinical complication of Plasmodium falciparum infection is cerebral malaria (CM). Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice is an established model of CM. Previous work has implied a role for CD8 T cells and perforin expression in fatal stages of PbA infection. We therefore infected C57BL/6 and C57BL/6 Perforin-/- mice with PbA and assessed the CNS for cerebral endothelial cell blood-brain barrier (BBB) disruption using FITC albumin leakage into tissue, confocal microscopy and 3D volumetric T2 and T1 gadolinium enhanced MRI. PbA infected C57BL/6 mice: 1.) had extensive disruption of BBB tight junction proteins Occludin and Claudin 5, 2.) developed severe CNS vascular permeability of FITC albumin and gadolinium leakage, and 3.) became moribund. We also observed increased VEGF cytokine expression coinciding with CNS vascular permeability in these animals. Despite having similar CD8 T cell infiltration into the brain, PbA infected C57BL/6 Perforin-/- mice had intact BBB tight junction, were devoid of CNS vascular permeability, presented with normal brain MRI, and had normal behavioral scores on the rotarod assay. This study is therefore the first to demonstrate the critical importance of perforin expression in promoting BBB tight junction alteration during PbA infection. Therefore, development of therapies to block factors related perforin mediated delivery could have significant benefit to the treatment of CM.

Abstract Thymus organogenesis is dependent on insulin-like growth factor (IGF), but involuted thymi of old mice cannot be reconstituted with infusion of IGF. In adult humans, tumor growth is associated with local upregulation of IGF, but increased incidence of cancer with aging is associated with decreasing levels of serum IGF. We hypothesized that suppression of tissue availability of IGF prevents/delays thymic atrophy and maintains a pool of functionally competent T cells throughout life. Hence, we examined mice with homozygous deletion of PAPPA, a gene encoding for a protease that degrades inhibitory IGF-binding proteins (IGFBP) that limit IGF levels in tissues. PAPPA-/- mice have normal serum IGF levels, indicating maintenance of the endocrine IGF reservoir. They have 40% extension of lifespan; and have reduced burden of spontaneous tumors, the major cause of early mortality of wildtype mice. Strikingly, PAPPA-/- mice aged =18 months have histologically organized thymi densely populated by CD4+CD8+ thymocytes with high TREC levels. Bone marrows of old mutants are enriched with thymus-seeding progenitors. Old mutant mice have a diverse repertoire of T cells that are functionally indistinguishable from young wildtype mice. These data indicate an IGF-immune axis of longevity. We suggest that PAPPA-mediated proteolysis is a potential target for intervention to maintain thymic function and promote healthy aging.

Abstract Trophoblast, the only fetal tissue in direct contact with maternal cells, fails to express the polymorphic HLA class I molecules HLA-A and -B, but does express the nonpolymorphic class I molecule HLA-G. It is thought that HLA-G may provide some of the functions of a class I molecule without stimulating maternal immune rejection of the fetal semiallograft. As a first step in identifying the cis-acting DNA regulatory elements involved in the control of class I expression by extraembryonic tissue, several types of transgenic mice were produced. Two HLA-G genomic fragments were used, 5.7 and 6.0 kb in length. These included the entire HLA-G coding region, 1 kb of 3' flanking sequence, and 1.2 or 1.4 kb of 5' flanking sequence, respectively. A hybrid transgene, HLA-A2/G, was produced by replacing the 5' flanking sequence, first exon, and early first intron of HLA-G with the corresponding elements of HLA-A. Comparison of transgene mRNA expression patterns seen in HLA-A2/G and HLA-G transgenic mice suggests that 5' flanking sequences are largely responsible for the differing patterns of expression typical of the classical class I and HLA-G genes. Studies comparing the extraembryonic HLA-G expression levels of founder embryos transgenic for either the 5.7- or 6.0-kb HLA-G transgene showed that the 6.0-kb transgene directed HLA-G expression far more efficiently than did the 5.7-kb HLA-G transgene, producing extraembryonic HLA-G mRNA levels similar to those seen in human extraembryonic tissues. The results of these studies suggest that the 250-bp fragment present at the extreme 5' end of the 6.0-kb HLA-G transgene and absent from the 5.7-kb HLA-G transgene contains an important positive regulatory element. This 250-bp fragment lies further upstream than any of the previously documented class I regulatory regions and may function as a locus control region.