•Certain oral cavity squamous cell cancer tumors contain a cancer stem cell niche.•Oral cavity cancer stem cell behavior varies by intratumor location.•Cancer stem cell invasive and proliferative ...behaviors are not necessarily coupled.
To describe differences in cancer stem cell (CSC) presence and behavior associated with their intratumor compartment of origin using a patient-derived xenograft (PDX) model of oral cavity squamous cell carcinoma (OCSCC).
Four HPV-negative OCSCC PDX cases were selected (CUHN004, CUHN013, CUHN096, CUHN111) and the percentage of CSCs (ALDH+CD44high) was measured in the tumor Leading Edge (LE) and Core compartments of each PDX tumor case via fluorescence activated cell sorting (FACS). The fraction of cells in the proliferative phase was measured by Ki-67 labelling index of paraffin embedded tissue. The proliferation and invasion of LE versus Core CSCs were compared using sphere and Matrigel invasion assays, respectively.
Both CUHN111 and CUHN004 demonstrate CSC enrichment in their LE compartments while CUHN013 and CUHN096 show no intratumor difference. Cases with LE CSC enrichment demonstrate greater Ki-67 labelling at the LE. CSC proliferative potential, assessed by sphere formation, reveals greater sphere formation in CUHN111 LE CSCs, but no difference between CUHN013 LE and Core CSCs. CUHN111 CSCs do not demonstrate an intratumor difference in invasiveness while CUHN013 LE CSCs are more invasive than Core CSCs.
A discrete intratumor CSC niche is present in a subset of OCSCC PDX tumors. The CSC functional phenotype with regard to proliferation and invasion is associated with the intratumor compartment of origin of the CSC: LE or Core. These individual functional characteristics appear to be modulated independently of one another and independently of the presence of an intratumor CSC niche.
Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to ...diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism has been investigated as an anti-cancer strategy. We have developed STINGel, an extended-release formulation that prolongs the availability of STING agonists, which has demonstrated an enhanced anti-tumor effect in OSCC compared to STING agonist injection. This study investigates the impact of intra-tumoral STINGel on OSCC-induced pain using two separate OSCC models and nociceptive behavioral assays. Intra-tumoral STINGel significantly reduced mechanical allodynia in the orofacial cancer model and alleviated thermal and mechanical hyperalgesia in the hind paw model. To determine the cellular signaling cascade contributing to the antinociceptive effect, we performed an in-depth analysis of immune cell populations via single-cell RNA-seq. We demonstrated an increase in M1-like macrophages and N1-like neutrophils after STINGel treatment. The identified regulatory pathways controlled immune response activation, myeloid cell differentiation, and cytoplasmic translation. Functional pathway analysis demonstrated the suppression of translation at neuron synapses and the negative regulation of neuron projection development in M2-like macrophages after STINGel treatment. Importantly, STINGel treatment upregulated TGF-β pathway signaling between various cell populations and peripheral nervous system (PNS) macrophages and enhanced TGF-β signaling within the PNS itself. Overall, this study sheds light on the mechanisms underlying STINGel-mediated antinociception and anti-tumorigenic impact.
Background
Risk of contralateral nodal metastases in oropharyngeal squamous cell carcinoma (OPSCC) is currently based on clinical risk factors. We propose lymphatic mapping with single photon ...emission computed tomography (SPECT‐CT) for tumor‐specific delineation of lymphatic drainage to guide treatment.
Methods
Retrospective review of lymphatic drainage patterns in cT1‐2 OPSCC and contralateral cN0 neck with a nonoperative, awake injection of 99 m‐Tc sulfur colloid and SPECT‐CT.
Results
Ten patients were reviewed. Primary sites included tonsil (n = 8, 80%) and tongue base (n = 2, 20%). All patients tolerated awake injections with no complications. Nine patients (90%) demonstrated satisfactory migration of radiotracer to neck node(s) with seven (78%) to the ipsilateral lateral neck, one (11%) to the ipsilateral lateral neck and retropharynx, and one (11%) to bilateral lateral neck nodes.
Conclusions
Characterization of lymphatic drainage in OPSCC is feasible using a nonoperative injection technique and SPECT‐CT. Drainage to the contralateral neck is rare, warranting further study to tailor treatment appropriately.
Objectives:
To identify the culturable microbes associated with infectious laryngitis and outline effective treatment strategies.
Methods:
This is a retrospective chart review of adult patients with ...persistent dysphonia plus evidence of laryngeal inflammation who underwent biopsy for culture at a tertiary care medical center. Demographic factors, symptoms as reported on validated patient assessment tools, past medical history, social history, culture results, and treatment duration and response were reviewed.
Results:
Fifteen patients with infectious laryngitis were included in this study. Culture results demonstrated Methicillin-sensitive Staphylococcus aureus (MSSA), Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Serratia marcescens, and “normal respiratory flora.” In most patients, multiple courses of prolonged antibiotics were needed to treat MSSA or MRSA. Infections associated with other microbes resolved with a single course of antibiotics.
Conclusions:
In this population, infectious laryngitis is defined as colonization with bacteria not found in the previously characterized laryngeal microbiome of benign vocal fold lesions. In suspected cases of infectious laryngitis, culture is recommended, by biopsy if needed. For MSSA- and MRSA-associated laryngitis, an extended course of antibiotics may be necessary for symptom improvement and resolution of laryngeal inflammation. However, the optimal treatment regimen has yet to be defined and will require larger, prospective studies.
Background
Being able to predict negative postoperative outcomes is important for helping select patients for treatment as well for informed decision‐making by patients. Frailty measures are often ...time and resource intensive to use as screening measures, whereas the Braden scale, a commonly used measure to assess patients at risk of developing pressure ulcers after surgery, may be a potential tool to predict postoperative complication rates and longer length of stay (LOS) in patients undergoing major head and neck cancer surgery.
Methods
A retrospective analysis of Braden scale scores was performed on a prospectively collected cohort of patients undergoing major head and neck surgery recruited between December 2011 and April 2014. The association of Braden scale score with the primary outcomes of complications and LOS was analyzed using logistic regression and linear regression models on univariate analysis (UVA), respectively. Multivariate analysis (MVA) was performed based on a backward stepwise selection algorithm.
Results
There were 232 patients with a mean (SD) Braden scale score of 14.9 (2.8) with a range from 9 to 23. The Braden scale (β = −.07 per point; 95% CI −0.09, −0.04, P < .001) was an independent predictor of increased LOS on UVA, but not on MVA when adjusted for other variables. For overall complications, as well as type of complication, the Braden scale score was not a significant predictor of complications on either UVA or MVA.
Conclusion
In the sample population, the Braden scale did not demonstrate an ability to predict negative outcomes in head and neck surgery patients.
Level of Evidence
Level 2b individual cohort study.
Being able to predict negative postoperative outcomes is important for helping select patients for treatment as well for informed decision‐making by patients. The Braden Scale, a commonly used measure to assess patients at risk of developing pressure ulcers after surgery, may be a potential tool to predict postoperative complication rates and longer length of stay in patients undergoing major head and neck cancer surgery. In the sample population the Braden scale did not demonstrate an ability to predict negative outcomes in head and neck surgery patients
Objective
To explore if antiplatelet or anticoagulant therapy increases the risk of transfusion requirement or postoperative hematoma formation in patients undergoing microvascular reconstruction for ...head and neck defects.
Study Design
Retrospective cohort study.
Setting
Departments of Otolaryngology–Head and Neck Surgery at the University of Alabama at Birmingham, the University of Colorado, and the University of California Irvine.
Methods
A multi‐institutional, retrospective review on microvascular reconstruction of the head and neck between August 2013 to July 2021. Perioperative antithrombotic data were collected to examine predictors of postoperative transfusion and hematoma.
Results
A total of 843 free flaps were performed. Preoperative hemoglobin, hematocrit, operative time, and flap type were positive predictors of postoperative transfusion in both bivariate (P < .0001) and multivariate analyses (P < .0001). However, neither anticoagulation nor antiplatelet therapy were predictive of postoperative transfusion rates and hematoma formation.
Conclusion
Antithrombotic regimens do not increase the risk of postoperative transfusion or hematoma in head and neck microvascular reconstruction. Based on this limited data, perioperative antithrombotic regimens can be considered in patients who may otherwise be at risk for these postoperative complications.
Bacterial‐derived compounds from the intestinal microbiome modulate host mucosal immunity. Identification and mechanistic studies of these compounds provide insights into host–microbial mutualism. ...Specific Lactobacillus reuteri strains suppress production of the proinflammatory cytokine, tumor necrosis factor (TNF), and are protective in a mouse model of colitis. Human‐derived L. reuteri strain ATCC PTA 6475 suppresses intestinal inflammation and produces 5,10‐methenyltetrahydrofolic acid polyglutamates. Insertional mutagenesis identified the bifunctional dihydrofolate synthase/folylpolyglutamate synthase type 2 (folC2) gene as essential for 5,10‐methenyltetrahydrofolic acid polyglutamate biosynthesis, as well as for suppression of TNF production by activated human monocytes, and for the anti‐inflammatory effect of L. reuteri 6475 in a trinitrobenzene sulfonic acid‐induced mouse model of acute colitis. In contrast, folC encodes the enzyme responsible for folate polyglutamylation but does not impact TNF suppression by L. reuteri. Comparative transcriptomics between wild‐type and mutant L. reuteri strains revealed additional genes involved in immunomodulation, including previously identified hdc genes involved in histidine to histamine conversion. The folC2 mutant yielded diminished hdc gene cluster expression and diminished histamine production, suggesting a link between folate and histadine/histamine metabolism. The identification of genes and gene networks regulating production of bacterial‐derived immunoregulatory molecules may lead to improved anti‐inflammatory strategies for digestive diseases.
The bifunctional dihydrofolate synthase/folylpolyglutamate synthase type 2 (folC2) gene is necessary for 5,10‐methenyltetrahydrofolic acid production by Lactobacillus reuteri, while the folC gene encodes the enzyme responsible for polyglutamylation of 5,10‐methenyltetrahydrofolate. The folC2 gene is important for suppression of the proinflammatory cytokine, tumor necrosis factor (TNF), in vitro, and for protection against trinitrobenzene sulfonic acid (TNBS)‐induced colitis and mucosal inflammation in vivo. In addition, there is a link between 5,10‐methenyltetrahydrofolic acid production and histamine, a known potent immunoregulatory molecule produced by probiotics. Specifically, the folC2 mutant yields diminished expression of the hdc gene cluster, which is responsible for the conversion of l‐histidine to histamine as well as diminished histamine production.
Oral squamous cell carcinoma (OSCC) is a capricious cancer with poor survival rates, even for early-stage patients. There is a pressing need to develop more precise risk assessment methods to ...appropriately tailor clinical treatment. Genome-wide association studies have not produced a viable biomarker. However, these studies are limited by using heterogeneous cohorts, not focusing on methylation although OSCC is a heavily epigenetically-regulated cancer, and not combining molecular data with clinicopathologic data for risk prediction. In this study we focused on early-stage (I/II) OSCC and created a risk score called the REASON score, which combines clinicopathologic characteristics with a 12-gene methylation signature, to predict the risk of 5-year mortality.
We combined data from an internal cohort (n = 515) and The Cancer Genome Atlas (TCGA) cohort (n = 58). We collected clinicopathologic data from both cohorts to derive the non-molecular portion of the REASON score. We then analyzed the TCGA cohort DNA methylation data to derive the molecular portion of the risk score.
5-year disease specific survival was 63% for the internal cohort and 86% for the TCGA cohort. The clinicopathologic features with the highest predictive ability among the two the cohorts were age, race, sex, tobacco use, alcohol use, histologic grade, stage, perineural invasion (PNI), lymphovascular invasion (LVI), and margin status. This panel of 10 non-molecular features predicted 5-year mortality risk with a concordance (c)-index = 0.67. Our molecular panel consisted of a 12-gene methylation signature (i.e., HORMAD2, MYLK, GPR133, SOX8, TRPA1, ABCA2, HGFAC, MCPH1, WDR86, CACNA1H, RNF216, CCNJL), which had the most significant differential methylation between patients who survived vs. died by 5 years. All 12 genes have already been linked to survival in other cancers. Of the genes, only SOX8 was previously associated with OSCC; our study was the first to link the remaining 11 genes to OSCC survival. The combined molecular and non-molecular panel formed the REASON score, which predicted risk of death with a c-index = 0.915.
The REASON score is a promising biomarker to predict risk of mortality in early-stage OSCC patients. Validation of the REASON score in a larger independent cohort is warranted.
Abstract Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we ...determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort ( n = 257) and an internal cohort ( n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.
Background: Many antineoplastic (chemotherapeutic) drugs are known or probable human carcinogens, and many have been shown to be reproductive toxicants in cancer patients. Evidence from occupational ...exposure studies suggests that health care workers who have long-term, low-level occupational exposure to antineoplastic drugs have an increased risk of adverse reproductive outcomes. It's recommended that, at minimum, nurses who handle or administer such drugs should wear double gloves and a nonabsorbent gown to protect themselves. But it's unclear to what extent nurses do. Purpose: This study assessed glove and gown use by female pregnant and nonpregnant nurses who administer antineoplastic drugs in the United States and Canada. Methods: We used data collected from more than 40,000 nurses participating in the Nurses' Health Study 3. The use of gloves and gowns and administration of antineoplastic drugs within the past month (among nonpregnant nurses) or within the first 20 weeks of pregnancy (among pregnant nurses) were self-reported via questionnaire. Results: Administration of antineoplastic drugs at any time during their career was reported by 36% of nonpregnant nurses, including 27% who reported administering these drugs within the past month. Seven percent of pregnant nurses reported administering antineoplastic drugs during the first 20 weeks of pregnancy. Twelve percent of nonpregnant nurses and 9% of pregnant nurses indicated that they never wore gloves when administering antineoplastic drugs, and 42% of nonpregnant nurses and 38% of pregnant nurses reported never using a gown. The percentage of nonpregnant nurses who reported not wearing gloves varied by type of administration: 32% of those who administered antineoplastic drugs only as crushed pills never wore gloves, compared with 5% of those who administered such drugs only via infusion. Conclusion: Despite longstanding recommendations for the safe handling of antineoplastic and other hazardous drugs, many nurses-including those who are pregnant-reported not wearing protective gloves and gowns, which are considered the minimum protective equipment when administering such drugs. These findings underscore the need for further education and training to ensure that both employers and nurses understand the risks involved and know which precautionary measures will minimize such exposures.
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