Abstract
Surgeons must visually distinguish soft-tissues, such as nerves, from surrounding anatomy to prevent complications and optimize patient outcomes. An accurate nerve segmentation and analysis ...tool could provide useful insight for surgical decision-making. Here, we present an end-to-end, automatic deep learning computer vision algorithm to segment and measure nerves. Unlike traditional medical imaging, our unconstrained setup with accessible handheld digital cameras, along with the unstructured open surgery scene, makes this task uniquely challenging. We investigate one common procedure, thyroidectomy, during which surgeons must avoid damaging the recurrent laryngeal nerve (RLN), which is responsible for human speech. We evaluate our segmentation algorithm on a diverse dataset across varied and challenging settings of operating room image capture, and show strong segmentation performance in the optimal image capture condition. This work lays the foundation for future research in real-time tissue discrimination and integration of accessible, intelligent tools into open surgery to provide actionable insights.
Natural killer (NK) cells comprise one subset of the innate lymphoid cell (ILC) family. Despite reported antitumor functions of NK cells, their tangible contribution to tumor control in humans ...remains controversial. This is due to incomplete understanding of the NK cell states within the tumor microenvironment (TME). Here, we demonstrate that peripheral circulating NK cells differentiate down two divergent pathways within the TME, resulting in different end states. One resembles intraepithelial ILC1s (ieILC1) and possesses potent in vivo antitumor activity. The other expresses genes associated with immune hyporesponsiveness and has poor antitumor functional capacity. Interleukin-15 (IL-15) and direct contact between the tumor cells and NK cells are required for the differentiation into CD49a
CD103
cells, resembling ieILC1s. These data explain the similarity between ieILC1s and tissue-resident NK cells, provide insight into the origin of ieILC1s, and identify the ieILC1-like cell state within the TME to be the NK cell phenotype with the greatest antitumor activity. Because the proportions of the different ILC states vary between tumors, these findings provide a resource for the clinical study of innate immune responses against tumors and the design of novel therapy.
Objectives/Hypothesis
Based on current guidelines, surgical and nonsurgical therapies are viable frontline treatment for patients with locoregional oropharyngeal carcinoma (OPC). We sought to compare ...financial parameters between chemoradiation and transoral robotic surgery (TORS) in this patient population.
Study Design
Case‐control study.
Methods
In this study we identified patients with selected American Joint Committee on Cancer 7th Edition stage II to IVa OPC treated with TORS between January 2013 and December 2014. Fifteen patients who underwent TORS were stage matched with 15 patients treated with chemoradiation. Total charges and cost data for each patient were analyzed at 4‐month and 1‐year time points; functional and oncologic outcomes were assessed.
Results
There were no significant differences in functional and oncologic outcomes. Patients undergoing TORS had a longer inpatient hospital stay, and most required a nasogastric tube for an average of 3.5 days. There were no local or regional recurrences. Across all time points, the TORS group had lower charges and costs compared to the chemoradiation group, with 14% lower costs at 1 year. In the chemoradiation group, nearly two‐thirds of costs came from radiation therapy and pharmacy expenses. Chemotherapy accounted for most pharmacy costs. The costs of operating the surgical robot accounted for a about half of surgical costs.
Conclusions
Selected patients with stage II to IVa oropharyngeal carcinoma treated with TORS may incur lower costs than those treated nonsurgically. With rising healthcare spending, the financial impact of treatment might be considered for those patients eligible for treatment regimens with comparable functional and oncologic outcomes.
Level of Evidence
3b
Laryngoscope, 129:1604–1609, 2019
Background The prognosis for patients with head and neck cancer (HNC) is poor and has improved little in recent decades, partially due to lack of therapeutic options. To identify effective ...therapeutic targets, we sought to identify molecular pathways that drive metastasis and HNC progression, through large-scale systematic analyses of transcriptomic data. Methods We performed meta-analysis across 29 gene expression studies including 2074 primary HNC biopsies to identify genes and transcriptional pathways associated with survival and lymph node metastasis (LNM). To understand the biological roles of these genes in HNC, we identified their associated cancer pathways, as well as the cell types that express them within HNC tumor microenvironments, by integrating single-cell RNA-seq and bulk RNA-seq from sorted cell populations. Results Patient survival-associated genes were heterogenous and included drivers of diverse tumor biological processes: these included tumor-intrinsic processes such as epithelial dedifferentiation and epithelial to mesenchymal transition, as well as tumor microenvironmental factors such as T cell-mediated immunity and cancer-associated fibroblast activity. Unexpectedly, LNM-associated genes were almost universally associated with epithelial dedifferentiation within malignant cells. Genes negatively associated with LNM consisted of regulators of squamous epithelial differentiation that are expressed within well-differentiated malignant cells, while those positively associated with LNM represented cell cycle regulators that are normally repressed by the p53-DREAM pathway. These pro-LNM genes are overexpressed in proliferating malignant cells of TP53 mutated and HPV + ve HNCs and are strongly associated with stemness, suggesting that they represent markers of pre-metastatic cancer stem-like cells. LNM-associated genes are deregulated in high-grade oral precancerous lesions, and deregulated further in primary HNCs with advancing tumor grade and deregulated further still in lymph node metastases. Conclusions In HNC, patient survival is affected by multiple biological processes and is strongly influenced by the tumor immune and stromal microenvironments. In contrast, LNM appears to be driven primarily by malignant cell plasticity, characterized by epithelial dedifferentiation coupled with EMT-independent proliferation and stemness. Our findings postulate that LNM is initially caused by loss of p53-DREAM-mediated repression of cell cycle genes during early tumorigenesis. Keywords: Head and neck cancer, Lymph node metastasis, Transcriptomics, Meta-analysis, Single-cell RNA-Seq, p53-DREAM pathway, Cell cycle, Cellular plasticity, Tumor microenvironment
BackgroundTypical liquid biopsy panels offer a limited understanding of tumor biology, potentially under-representing the heterogeneity of resistance in late-stage cancers. Here, diminished scope can ...result in undetected, therapeutically-relevant biomarkers which respond dynamically to treatment, as well as potentially missed resistance mechanisms and pathway-level events. To address the challenges associated with identifying multiple concurrent heterogeneous resistance mechanisms in individual patients, we evaluated longitudinal exome-scale tumor-informed cell-free DNA (cfDNA) data from head and neck squamous cell carcinoma (HNSCC) patients receiving anti-PD1 therapy.MethodsPre- and post-intervention matched tumor, normal and plasma samples were retrospectively obtained from 15 stage II-IV HNSCC patients. Following baseline sample collection, all patients received a single dose of nivolumab or pembrolizumab. The primary tumor was then resected approximately one month later when possible, or a second biopsy collected where resection was impractical. Paired tumor and normal samples were then profiled using ImmunoID NeXT Platform®, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale cfDNA profiling of matched plasma samples was performed using the NeXT Liquid BiopsyTM platform to detect somatic variants.ResultsPatient neoantigen presentation score (NEOPSTM) rapidly and significantly contracted following therapy (p=.00098). Novel neoantigens arising post-treatment which were predicted to be presented on lost HLA alleles were significantly higher in patients with longer overall survival (p=.019). Variant detection across same-patient serial cfDNA samples revealed significantly correlated VAFs (R=.62, p<.0001) despite significant contraction of mutational burden in solid tumor (p=.0039), suggesting complex clonal/subclonal dynamics. Investigation of the evolving tumor and cfDNA subclonal architecture revealed significant association between decreasing cellular prevalence and NOTCH signaling (q=.001) and the innate immune system (q=.002), while increasing cellular prevalence was associated with p53 signalling (q=.02) and hypoxia (q=.02). These findings were complimented by transcriptomic data which showed significant enrichment of multiple immune pathways across treatment.ConclusionsWe found that immune checkpoint blockade precipitates rapid evolution of the HNSCC tumor microenvironment. By leveraging comprehensive, tumor-informed liquid biopsy data we were able to identify contracting cellular populations enriched for NOTCH pathway mutations. Longer OS following either intervention was associated with an expansion of novel neoantigens predicted to be presented by lost HLA alleles. Our results suggest that tumor-informed liquid biopsy provides a more robust understanding of therapeutic response and resistance mechanisms than that attainable with typical liquid biopsy panels alone.Ethics ApprovalThis study obtained ethics approval from Human Subjects Research at Stanford University. ID number is 40425. All participants gave informed consent prior to enrollment.
Objectives To evaluate the performance of vision transformer‐derived image embeddings for distinguishing between normal and neoplastic tissues in the oropharynx and to investigate the potential of ...computer vision (CV) foundation models in medical imaging. Methods Computational study using endoscopic frames with a focus on the application of a self‐supervised vision transformer model (DINOv2) for tissue classification. High‐definition endoscopic images were used to extract image patches that were then normalized and processed using the DINOv2 model to obtain embeddings. These embeddings served as input for a standard support vector machine (SVM) to classify the tissues as neoplastic or normal. The model's discriminative performance was validated using an 80–20 train‐validation split. Results From 38 endoscopic NBI videos, 327 image patches were analyzed. The classification results in the validation cohort demonstrated high accuracy (92%) and precision (89%), with a perfect recall (100%) and an F1‐score of 94%. The receiver operating characteristic (ROC) curve yielded an area under the curve (AUC) of 0.96. Conclusion The use of large vision model‐derived embeddings effectively differentiated between neoplastic and normal oropharyngeal tissues. This study supports the feasibility of employing CV foundation models like DINOv2 in the endoscopic evaluation of mucosal lesions, potentially augmenting diagnostic precision in Otorhinolaryngology. Level of Evidence 4 Laryngoscope , 2024
Multiplex immunofluorescence (mIF) assays multiple protein biomarkers on a single tissue section. Recently, high-plex CODEX (co-detection by indexing) systems enable simultaneous imaging of 40+ ...protein biomarkers, unlocking more detailed molecular phenotyping, leading to richer insights into cellular interactions and disease. However, high-plex data can be slower and more costly to collect, limiting its applications, especially in clinical settings. We propose a machine learning framework,
, that can computationally generate in silico 40-plex CODEX at single-cell resolution from a standard 7-plex mIF panel by leveraging cellular morphology. We demonstrate the usefulness of the imputed biomarkers in accurately classifying cell types and predicting patient survival outcomes. Furthermore,
's imputations generalize well across samples from different clinical sites and cancer types.
opens the possibility of in silico CODEX, making insights from high-plex mIF more widely available.
The aim was to assess the effectiveness of fecal microbiota transplantation (FMT) against medical therapy (MT).
FMT has shown good outcomes in the treatment of Clostridium difficile infection (CDI). ...We aimed to conduct a systematic review and meta-analysis to compare the effectiveness of FMT versus MT for CDI.
We performed a comprehensive search to identify randomized controlled trials comparing FMT against MT in patients with CDI. Outcomes of interest were clinical cure as determined by the resolution of diarrhea and/or negative C. difficile testing. Primary CDI is defined as the first episode of CDI confirmed endoscopically or by laboratory analysis. Recurrent C. difficile infection (RCDI) is defined as laboratory or endoscopically confirmed episode of CDI after at least 1 course of approved antibiotic regimen.
A total of 7 studies with 238 patients were included in meta-analysis. Compared with MT, FMT did not have a statistically significant difference for clinical cure of combined primary and RCDI after first session risk ratio (RR): 1.52, 95% confidence interval (CI): 0.90, 2.58; P =0.12; I2 =77% and multiple sessions of FMT (RR: 1.68; CI: 0.96, 2.94; P =0.07; I2 =82%). On subgroup analysis, FMT has statistically higher rate of response than MT (RR: 2.41; CI: 1.20, 4.83; I2 =78%) for RCDI. However, for primary CDI there is no statistically significant difference between FMT and MT (RR: 1.00; CI: 0.72, 1.39; I2 =0%).
As per our analysis, FMT should not be utilized for every patient with CDI. It is more effective in RCDI, but the results were not significant in patients with primary CDI.
•TCIP-L SCCHN enriched for β-catenin, Hedgehog pathways, NSD1 mutations, EGFR amplifications.•TCIL-H SCCHN enriched for MAPK/ERK, JAK/STAT pathways, CASP8 mutations, CD274 amplifications.•Combination ...checkpoint blockade and targeting Tregs warranted in HPV+ TCIP-H SCCHN.•Combination checkpoint blockade and targeting M2 macrophages warranted in HPV- TCIP-H SCCHN.
In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors.
Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively). Gene set enrichment and iPANDA analyses were conducted to dissect differences in signaling pathways, somatic mutations and copy number aberrations for TCIP-H versus TCIP-L tumors, stratified by HPV status.
TCIP-H SCCHN tumors were enriched in multiple immune checkpoints irrespective of HPV-status. HPV-positive tumors were enriched in markers of T-regulatory cells (Tregs) and HPV-negative tumors in protumorigenic M2 macrophages. TCIP-L SCCHN tumors were enriched for the β-catenin/WNT and Hedgehog signaling pathways, had frequent mutations in NSD1, amplifications in EGFR and YAP1, as well as CDKN2A deletions. TCIP-H SCCHN tumors were associated with the MAPK/ERK, JAK/STAT and mTOR/AKT signaling pathways, and were enriched in CASP8, EP300, EPHA2, HRAS mutations, CD274, PDCD1LG2, JAK2 amplifications.
Our findings support that combinatorial immune checkpoint blockade and depletion strategies targeting Tregs in HPV-positive and M2 macrophages in HPV-negative tumors may lead to improved antitumor immune responses in patients with TCIP-H SCCHN. We highlight novel pathways and genetic events that may serve as candidate biomarkers and novel targeted therapies to enhance the efficacy of immunotherapy in SCCHN patients.
Background: Dural puncture epidural (DPE) is a method in which a dural hole is created prior to epidural injection. This study was planned to evaluate whether dural puncture improves onset and ...duration of labor analgesia when compared to conventional epidural technique. Methods and Materials: Sixty term primigravida parturients of ASA grade I and II were randomly assigned to two groups of 30 each (Group E for conventional epidural and Group DE for dural puncture epidural). In group E, epidural space was identified and 18-gauge multi-orifice catheter was threaded 5 cm into the epidural space. In group DE, dura was punctured using the combines spinal epidural (CSE) spinal needle and epidural catheter threaded as in group E followed by 10 ml of injection of Ropivacaine (0.2%) with 20 mcg of Fentanyl (2 mcg/ml) in fractions of 2.5 ml. Later, Ropivacaine 10 ml was given as a top-up on patient request. Onset, visual analouge scale (VAS), sensory and motor block, haemodynamic variables, duration of analgesia of initial dose were noted along with mode of delivery and the neonatal outcome. Results: Six parturients in group DE achieved adequate analgesia in 5 minutes while none of those in group E (P < 0.05) achieved adequate analgesia. The mean VAS score was 4.97 ± 0.85 in group E and 4.33 ± 0.922 in group DE at 5 min (P < 0.05). Duration of analgesia of initial bolus dose was 99.37 ± 23.175 min in group E and 98.77 ± 24.955 min in group DE (P > 0.05). Conclusions: Both techniques of labor analgesia are efficacious; dural puncture epidural has the potential to fasten onset and improve quality of labor analgesia when compared with conventional epidural technique.
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