Complication Profiles of Smooth vs Textured Tissue Expanders in Breast Reconstruction: A Systematic Review and Meta-Analysis.

BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a type of non-Hodgkin lymphoma first linked with breast implants in 2011. The correlation between BIA-ALCL and textured devices has led to increased use of smooth devices. However, much of the data surrounding smooth and textured devices investigates breast implants specifically and not tissue expanders. OBJECTIVES: We performed a systematic review and a meta-analysis to compare surgical outcomes for smooth tissue expanders (STEs) and textured tissue expanders (TTEs). METHODS: A search was performed on PubMed, including articles from 2016 to 2023 (n = 419). Studies comparing TTEs and STEs and reported complications were included. A random-effects model was utilized for meta-analysis. RESULTS: A total of 5 articles met inclusion criteria, representing 1709 patients in the STE cohort and 1716 patients in the TTE cohort. The mean duration of tissue expansion with STEs was 221.25 days, while TTEs had a mean time of tissue expansion of 220.43 days.Our meta-analysis found no differences in all surgical outcomes except for explantation risk. STE use was associated with increased odds of explantation by over 50% compared to TTE use (odds ratio = 1.53; 95% CI = 1.15 to 2.02; P = .003). CONCLUSIONS: Overall, STEs and TTEs had similar complication profiles. However, STEs had 1.5 times higher odds of explantation. The incidence of BIA-ALCL is low, and only a single case of BIA-ALCL has been reported with TTEs. This indicates that TTEs are safe and may lower the risk of early complications requiring explantation. Further studies are warranted to further define the relationship between tissue expanders and BIA-ALCL.

Tranexamic acid in burn surgery: A systematic review and meta-analysis.

Burn injury causes a coagulopathy that is poorly understood. After severe burns, significant fluid losses are managed by aggressive resuscitation that can lead to hemodilution. These injuries are managed by early excision and grafting, which can cause significant bleeding and further decrease blood cell concentration. Tranexamic acid (TXA) is an anti-fibrinolytic that has been shown to reduce surgical blood losses; however, its use in burn surgery is not well established. We performed a systematic review and meta-analysis to investigate the influence TXA may have on burn surgery outcomes. Eight papers were included, with outcomes considered in a random-effects model meta-analysis. Overall, when compared to the control group, TXA significantly reduced total volume blood loss (mean difference (MD) = -192.44; 95% confidence interval (CI) = -297.73 to - 87.14; P = 0.0003), the ratio of blood loss to burn injury total body surface area (TBSA) (MD = -7.31; 95% CI = -10.77 to -3.84; P 0.0001), blood loss per unit area treated (MD = -0.59; 95% CI = -0.97 to -0.20; P = 0.003), and the number of patients receiving a transfusion intraoperatively (risk difference (RD) = -0.16; 95% CI = -0.32 to - 0.01; P = 0.04). Additionally, there were no noticeable differences in venous thromboembolism (VTE) events (RD = 0.00; 95% CI = -0.03 to 0.03; P = 0.98) and mortality (RD = 0.00; 95% CI = -0.03 to 0.04; P = 0.86). In conclusion, TXA can potentially be a pharmacologic intervention that reduces blood losses and transfusions in burn surgery without increasing the risk of VTE events or mortality.

Multimodal analysis suggests differential immuno-metabolic crosstalk in lung squamous cell carcinoma and adenocarcinoma.

Immunometabolism within the tumor microenvironment is an appealing target for precision therapy approaches in lung cancer. Interestingly, obesity confers an improved response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC), suggesting intriguing relationships between systemic metabolism and the immunometabolic environment in lung tumors. We hypothesized that visceral fat and 18F-Fluorodeoxyglucose uptake influenced the tumor immunometabolic environment and that these bidirectional relationships differ in NSCLC subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). By integrating 18F-FDG PET/CT imaging, bulk and single-cell RNA-sequencing, and histology, we observed that LUSC had a greater dependence on glucose than LUAD. In LUAD tumors with high glucose uptake, glutaminase was downregulated, suggesting a tradeoff between glucose and glutamine metabolism, while in LUSC tumors with high glucose uptake, genes related to fatty acid and amino acid metabolism were also increased. We found that tumor-infiltrating T cells had the highest expression of glutaminase, ribosomal protein 37, and cystathionine gamma-lyase in NSCLC, highlighting the metabolic flexibility of this cell type. Further, we demonstrate that visceral adiposity, but not body mass index (BMI), was positively associated with tumor glucose uptake in LUAD and that patients with high BMI had favorable prognostic transcriptional profiles, while tumors of patients with high visceral fat had poor prognostic gene expression. We posit that metabolic adjunct therapy may be more successful in LUSC rather than LUAD due to LUAD's metabolic flexibility and that visceral adiposity, not BMI alone, should be considered when developing precision medicine approaches for the treatment of NSCLC.

Glycolytic expression in lower-grade glioma reveals an epigenetic association between IDH mutation status and PDL1/2 expression.

BACKGROUND: The interplay between glycolysis and immunosuppression in cancer has recently emerged as an intriguing area of research. The aim of this study was to elucidate a potential epigenetic link between glycolysis, isocitrate hydrogenase (IDH) status, and immune checkpoint expression in human lower-grade glioma (LGG). METHODS: Genomic analysis was conducted on 507 LGG samples from The Cancer Genome Atlas (TCGA). Data types analyzed included RNA-seq (IlluminaHiSeq) and DNA methylation (Methylation450K). Unsupervised clustering grouped samples according to glycolytic expression level and IDH status. Global promoter methylation patterns were examined, as well as methylation levels of LDHA/LDHB and immune checkpoint genes. Methylation data from a knock-in IDH1R132H/WT allele in HCT116 cells and ChIP-seq data from immortalized human astrocytes using an inducible IDH1R132H mutation were also assessed. RESULTS: Glycolytic expression distinguished a tumor cluster enriched for wild-type IDH and poorer overall survival (P < .0001). This cluster showed lower levels of LDHA promoter methylation and a higher LDHA/LDHB expression ratio. These samples also displayed lower PDL1/2 promoter methylation and higher PDL1/2 expression, which was more pronounced for PDL2. IDH1R132H/WT cell line data showed that induced changes in methylation were enriched for genes involved in immune regulation, and ChIP-seq data showed that promoter H3K4me3 decreased for LDHA, PDL2, and PDL1 upon induction of IDH1R132H. CONCLUSIONS: These results suggest a previously unrecognized epigenetic link between glycolysis and immune checkpoint expression in LGG. This work advances our understanding of glioma genomics and provides support for further exploration of the metabolic-immune interface in LGG.

Deep Learning Implicitly Handles Tissue Specific Phenomena to Predict Tumor DNA Accessibility and Immune Activity.

DNA accessibility is a key dynamic feature of chromatin regulation that can potentiate transcriptional events and tumor progression. To gain insight into chromatin state across existing tumor data, we improved neural network models for predicting accessibility from DNA sequence and extended them to incorporate a global set of RNA sequencing gene expression inputs. Our expression-informed model expanded the application domain beyond specific tissue types to tissues not present in training and achieved consistently high accuracy in predicting DNA accessibility at promoter and promoter flank regions. We then leveraged our new tool by analyzing the DNA accessibility landscape of promoters across The Cancer Genome Atlas. We show that in lung adenocarcinoma the accessibility perspective uniquely highlights immune pathways inversely correlated with a more open chromatin state and that accessibility patterns learned from even a single tumor type can discriminate immune inflammation across many cancers, often with direct relation to patient prognosis.

An immunogenic NSCLC microenvironment is associated with favorable survival in lung adenocarcinoma.

The tumor microenvironment consists of an intricately organized system through which immune cells and cancer cells may communicate to regulate anti-tumor immunogenicity. To this end, non-small cell lung cancer (NSCLC) has been shown to activate a variety of immunological mechanisms, thereby broadening our understanding of lung cancer immunobiology. However, while recent work has highlighted the importance of NSCLC immunology and prognosis, studies have not yet examined the tumor microenvironment (TME) globally in regards to the survival outcomes between two major NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In the present study, we identify an immunogenic tumor microenvironment state in NSCLC that is enriched for the lung adenocarcinoma subtype. By utilizing TME cell enrichment scores and RNA-seq expression data, we show that the inflamed TME is associated with favorable patient survival in lung adenocarcinoma, but this does not hold true for lung squamous cell carcinoma. Moreover, differentially regulated pathways between immune-inflamed and immune-excluded tumors within LUAD and LUSC were not subtype specific. Instead, immune-inflamed LUSC samples possessed elevated immune checkpoint marker expression when compared to those of the LUAD samples, thereby offering a putative explanation for our prognostic observations. These results shed light on the immunological prognostic effects within lung cancer and may encourage further TME exploration between these two subtypes as the landscape of NSCLC therapy progresses.

CAD/POLD2 gene expression is associated with poor overall survival and chemoresistance in bladder urothelial carcinoma.

Somatic mutations in DNA repair genes have been clinically associated with chemosensitivity, although few studies have interrogated the nucleotide synthesis pathways that supply DNA repair processes. Previous work suggests that bladder urothelial carcinoma is uniquely enriched for mutations in nucleotide excision repair genes, and that these mutations are associated with response to platinum-based therapy and favorable survival. Conversely, the de novo pyrimidine synthesis pathway has recently emerged as a putative clinical target. This anabolic process is thought to supply DNA repair processes such as nucleotide excision repair; that is, DNA repair enzymes may require a sufficient nucleotide supply available to reverse the intended genotoxic damage of systemic chemotherapy in rapidly proliferating cancer cells. Therefore, we explored the prognostic complementarity between de novo pyrimidine synthesis and nucleotide excision repair expression in a total of 570 bladder urothelial carcinoma patients. Ultimately, we show that the de novo pyrimidine synthesis gene CAD is associated with poor survival (P = 0.008) and is co-altered with the nucleotide excision repair gene POLD2. High expression of POLD2 was also associated with poor overall survival (P = 0.019) and was significantly correlated with CAD expression in pre-treatment patient tumor samples (P = 2.44e-4). Expression of each gene was associated with cisplatin-based therapy resistance, and accordingly, CADhighPOLD2high patients were associated with worse survival than CADhighPOLD2low and CADlowPOLD2high patients. Together, these biomarkers could help elucidate mechanisms of chemoresistance to further personalize therapeutic strategies in bladder urothelial carcinoma.

Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples.

Immune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival. We therefore analyzed RNA-seq data of Treg-enriched tumor samples to derive a pan-cancer gene signature able to help reconcile the inconsistent results of Treg studies, by better understanding the variable clinical association of Tregs across alternative tumor contexts. We show that increased expression of a 32-gene signature in Treg-enriched tumor samples (n = 135) is able to distinguish a cohort of patients associated with chemosensitivity and overall survival. This cohort is also enriched for CD8+ T cell abundance, as well as the antitumor M1 macrophage subtype. With a subsequent validation in a larger TCGA pool of Treg-enriched patients (n = 626), our results reveal a gene signature able to produce unsupervised clusters of Treg-enriched patients, with one cluster of patients uniquely representative of an immunogenic tumor microenvironment. Ultimately, these results support the proposed gene signature as a putative biomarker to identify certain Treg-enriched patients with immunogenic tumors that are more likely to be associated with features of favorable clinical outcome.

Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma.

Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS). MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor/anti-resistance factor Raf-1 kinase inhibitor protein (RKIP) is poorly expressed in the majority of cancers and is often almost absent in metastatic tumors. RKIP inhibits the Raf/MEK/ERK1/2 and the NF-κB pathways. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our recent findings demonstrated that RKIP is overexpressed primarily in its inactive phosphorylated form in MM cell lines and patient-derived tumor tissues. The underlying mechanism of RKIP overexpression in MM, in contrast to other tumors, is not known. We examined transcriptomic datasets on Oncomine platform (Life Technologies) for the co-expression of RKIP and other gene products in both pre-MM and MM. The transcription of several gene products was found to be either commonly overexpressed (i.e., RKIP, Bcl-2, and DR5) or underexpressed (i.e., Bcl-6 and TNFR2) in both pre-MM and MM. Noteworthy, a significant inverse correlation of differentially expressed pro-apoptotic genes was observed in pre-MM: overexpression of Fas and TNF-α and underexpression of YY1 versus expression of anti-apoptotic genes in MM: overexpression of YY1 and underexpression of Fas and TNF-α. Based on the analysis on mRNA levels and reported studies on protein levels of the above various genes, we have constructed various schemes that illustrate the possible cross-talks between RKIP (active/inactive) and the identified gene products that underlie the mechanism of RKIP overexpression in MM. Clearly, such cross-talks would need to be experimentally validated in both MM cell lines and patient-derived tumor tissues. If validated, the differential molecular signatures between pre-MM and MM might lead to a more precise diagnosis/prognosis of the disease and disease stages and will also identify novel molecular therapeutic targets for pre-MM and MM.