Overcoming Resistance to Standard-of-Care Therapies for Head and Neck Squamous Cell Carcinomas.

Although there have been some advances during in recent decades, the treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging. Resistance is a major issue for various treatments that are used, including both the conventional standards of care (radiotherapy and platinum-based chemotherapy) and the newer EGFR and checkpoint inhibitors. In fact, all the non-surgical treatments currently used for HNSCC are associated with intrinsic and/or acquired resistance. Herein, we explore the cellular mechanisms of resistance reported in HNSCC, including those related to epigenetic factors, DNA repair defects, and several signaling pathways. This article discusses these mechanisms and possible approaches that can be used to target different pathways to sensitize HNSCC to the existing treatments, obtain better responses to new agents, and ultimately improve the patient outcomes.

Intraoperative Parathyroid Hormone Monitoring In Normohormonal Primary Hyperparathyroidism: How Low Do You Go?

OBJECTIVE: The primary goal of this study was to determine in patients with normohormonal primary hyperparathyroidism (NHHPT) what percent reduction in post-excision intraoperative parathyroid hormone (IOPTH) from baseline would yield a rate of cure comparable to that in patients with classical primary hyperparathyroidism (PHPT). METHODS: This is a retrospective cohort study of patients who underwent parathyroidectomy between July 2013 and February 2020. Demographic data, preoperative, intraoperative, and postoperative metrics were collected. Patients with NHHPT were compared to those with classical PHPT. Subgroup analyses were performed. RESULTS: Of the 496 patients included in the study, 66 (13.3%) were of the normohormonal variant based on preoperative intact parathyroid hormone (PTH) levels and 28 (5.6%) based on baseline IOPTH levels. The cure rates in the two normohormonal groups were not significantly different from their classical counterparts (98.4% and 100.0% vs. 97.1%, p = 1.000). The median percent decline in post-excision IOPTH from baseline that achieved cure in the normohormonal groups were 82.6% and 80.4% compared to their respective controls at 87.3%, p = 0.011 and p = 0.001. Although the rate of multiglandular disease was higher in one of the normohormonal variant groups, this difference was due to a higher rate of double adenomas, not four-gland hyperplasia. CONCLUSION: Patients with NHHPT undergoing parathyroidectomy can expect cure rates similar to that in patients with classical PHPT. The results of this study indicate that achieving an 80% drop or more in IOPTH levels predicts a high likelihood of cure. This is true irrespective of whether the patient is deemed normohormonal based on preoperative or intraoperative testing. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2480-2484, 2024.

Surgical salvage of human papillomavirus-positive oropharyngeal cancer: Secondary analysis of a randomized controlled trial.

BACKGROUND: Survival outcomes are generally better for human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) than other forms of head and neck cancer. However, less is known about oncologic outcomes, late adverse events, and gastrostomy tube dependence associated with salvage surgery after the failure of definitive chemoradiation in patients with HPV+ OPSCC. METHODS: A secondary analysis of the Radiation Therapy Oncology Group 1016 randomized trial, which compared radiotherapy plus cetuximab to radiotherapy plus cisplatin in patients with HPV+ OPSCC, was performed. The oncologic and adverse event outcomes for patients who underwent salvage surgery were examined. RESULTS: Among the 805 patients who were assigned to treatment and were eligible for analysis, 198 developed treatment failure. Salvage surgery was required for 61 patients (7.6%), with 33 patients undergoing salvage surgery after locoregional failure (LRF) and 28 patients undergoing salvage neck dissection within the 20 weeks after treatment. Patients with LRF who underwent salvage surgery experienced improved overall survival in comparison with patients with LRF who did not undergo surgery (45% vs. 17% at 5 years after treatment; hazard ratio, 0.41; 95% confidence interval [CI], 0.23-0.74). Surgical salvage after LRF was associated with similar frequencies of late grade 3/4 dysphagia in comparison with LRF without surgery (24% [95% CI, 13%-41%] vs. 20% [95% CI, 12%-32%]; p = .64) and with similar gastrostomy tube dependence at 2 years (29% [95% CI, 15%-49%] vs. 13% [95% CI, 5%-28%]; p = .12). CONCLUSIONS: Salvage surgery in patients with HPV+ OPSCC is associated with favorable survival and adverse event outcomes.

Gastrostomy tube dependence and patient-reported quality of life outcomes based on type of treatment for human papillomavirus-associated oropharyngeal cancer: Systematic review and meta-analysis.

We examined the impact of treatment modality on gastrostomy tube dependence and patient-reported outcomes in human papillomavirus-associated oropharyngeal cancer (HPV-OPSCC). We performed systematic review and meta-analysis of functional outcomes 1-3 years after treatment. Twenty-three studies were included, reporting on 3127 patients treated for HPV-OPSCC. Gastrostomy tube dependence failed to show statistically significant difference between surgery with adjuvant therapy and chemoradiotherapy with cisplatin at 12 months (8.3% [95% CI: 3.1-15.9] vs. 4.2% [1.1-9.2], p = 0.37) and 24-36 months (10.5% [95% CI: 3.2-21.5] vs. 3.3% [2.0-4.9], p = 0.06). Surgery with adjuvant therapy was associated with worse University of Washington Quality of Life (UW-QOL) Swallowing (84 [95% CI: 80-88] vs. 89 [87-90], p = 0.03) and UW-QOL Overall scores (76 [95% CI: 72-80] vs. 84 [81-86], p = 0.001) compared to chemoradiotherapy with cisplatin at 12 months. Surgery with adjuvant therapy was associated with worse performance on certain measures of patient-reported swallow and overall function compared to chemoradiotherapy with cisplatin. Further randomized controlled trials are needed to directly compare functional outcomes after treatment for HPV-OPSCC.

Hyperparathyroidism subsequent to radioactive iodine therapy for Graves' disease.

BACKGROUND: The development of primary hyperparathyroidism (PHPT) after radioactive iodine (RAI) treatment for thyroid disease is poorly characterized. The current study is the largest reported cohort and assesses the disease characteristics of patients treated for PHPT with a history of RAI exposure. METHODS: A retrospective analysis comparing patients, with and without a history of RAI treatment, who underwent surgery for PHPT. RESULTS: Twenty-eight of the 469 patients had a history of RAI treatment, all for Graves' disease. Patients with a history of RAI exposure had similar disease characteristics compared to control; however, patients with a history of RAI treatment had a higher rate of recurrence (7.4% vs 1.2%, p = 0.012). CONCLUSION: PHPT in patients with a history of RAI treatment can be approached in the same manner as RAI naive PHPT patients; however, the risk of recurrence of PHPT in RAI exposed patients may be higher.

Diet Significantly Influences the Immunopathology and Severity of Kidney Injury in Male C57Bl/6J Mice in a Model Dependent Manner.

Diet is a leading causative risk factor for morbidity and mortality worldwide, yet it is rarely considered in the design of preclinical animal studies. Several of the nutritional inadequacies reported in Americans have been shown to be detrimental to kidney health; however, the mechanisms responsible are unclear and have been largely attributed to the development of diabetes or hypertension. Here, we set out to determine whether diet influences the susceptibility to kidney injury in male C57Bl/6 mice. Mice were fed a standard chow diet, a commercially available "Western" diet (WD), or a novel Americanized diet (AD) for 12 weeks prior to the induction of kidney injury using the folic acid nephropathy (FAN) or unilateral renal ischemia reperfusion injury (uIRI) models. In FAN, the mice that were fed the WD and AD had worse histological evidence of tissue injury and greater renal expression of genes associated with nephrotoxicity and monocyte infiltration as compared to mice fed chow. Mice fed the AD developed more severe renal hypertrophy following FAN, and gene expression data suggest the mechanism for FAN differed among the diets. Meanwhile, mice fed the WD had the greatest circulating interleukin-6 concentrations. In uIRI, no difference was observed in renal tissue injury between the diets; however, mice fed the WD and AD displayed evidence of suppressed inflammatory response. Taken together, our data support the hypothesis that diet directly impacts the severity and pathophysiology of kidney disease and is a critical experimental variable that needs to be considered in mechanistic preclinical animal studies.

Impact of Race and Socioeconomic Status on Outcomes in Patients Hospitalized with COVID-19.

BACKGROUND: The impact of race and socioeconomic status on clinical outcomes has not been quantified in patients hospitalized with coronavirus disease 2019 (COVID-19). OBJECTIVE: To evaluate the association between patient sociodemographics and neighborhood disadvantage with frequencies of death, invasive mechanical ventilation (IMV), and intensive care unit (ICU) admission in patients hospitalized with COVID-19. DESIGN: Retrospective cohort study. SETTING: Four hospitals in an integrated health system serving southeast Michigan. PARTICIPANTS: Adult patients admitted to the hospital with a COVID-19 diagnosis confirmed by polymerase chain reaction. MAIN MEASURES: Patient sociodemographics, comorbidities, and clinical outcomes were collected. Neighborhood socioeconomic variables were obtained at the census tract level from the 2018 American Community Survey. Relationships between neighborhood median income and clinical outcomes were evaluated using multivariate logistic regression models, controlling for patient age, sex, race, Charlson Comorbidity Index, obesity, smoking status, and living environment. KEY RESULTS: Black patients lived in significantly poorer neighborhoods than White patients (median income: $34,758 (24,531-56,095) vs. $63,317 (49,850-85,776), p < 0.001) and were more likely to have Medicaid insurance (19.4% vs. 11.2%, p < 0.001). Patients from neighborhoods with lower median income were significantly more likely to require IMV (lowest quartile: 25.4%, highest quartile: 16.0%, p < 0.001) and ICU admission (35.2%, 19.9%, p < 0.001). After adjusting for age, sex, race, and comorbidities, higher neighborhood income ($10,000 increase) remained a significant negative predictor for IMV (OR: 0.95 (95% CI 0.91, 0.99), p = 0.02) and ICU admission (OR: 0.92 (95% CI 0.89, 0.96), p < 0.001). CONCLUSIONS: Neighborhood disadvantage, which is closely associated with race, is a predictor of poor clinical outcomes in COVID-19. Measures of neighborhood disadvantage should be used to inform policies that aim to reduce COVID-19 disparities in the Black community.

Perioperative Analgesia for Patients Undergoing Thyroidectomy and Parathyroidectomy: An Evidence-Based Review.

OBJECTIVE: To perform an evidence-based systematic review evaluating perioperative analgesia, including opioid alternatives, used for patients undergoing thyroidectomy and parathyroidectomy. METHODS: A comprehensive literature search from 1997 to January 2018 of Pubmed, Cochrane, and EmBase libraries was performed for studies reporting analgesic administration following thyroid or parathyroid surgery. This systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Studies were evaluated for level of evidence and given a Jadad score to assess for risk of bias. Outcomes gathered included postoperative pain scores, time to rescue analgesia, rescue analgesic consumption, and adverse events. RESULTS: Thirty-eight randomized controlled trials met inclusion criteria. The GRADE criteria determined the overall evidence to be moderate-high. Studies utilizing NSAIDs reported reduced requirements for rescue analgesics. Acetaminophen studies presented with conflicting data on effectiveness. Gabapentinoid studies demonstrated lower pain scores and an increased time to rescue analgesic. Local anesthetics were effective at decreasing Visual Analogue Scale (VAS) and Numeric Rating Scale (NRS) pain scores while also reducing rescue analgesic consumption. Ketamine was shown to increased postoperative nausea and vomiting. NSAIDs and local anesthetic studies had an aggregate grade of evidence A, while all others had grade B evidence. CONCLUSION: There is significant evidence supporting the use of NSAIDs and local anesthetics in the perioperative period for pain management for thyroid and parathyroid surgeries. Acetaminophen, gabapentinoid and ketamine have some supporting evidence and may serve as adequate alternatives. Further multi-institutional RCTs are warranted to delineate optimal analgesic regimens. LEVEL OF EVIDENCE: NA.

HDAC6 regulates DNA damage response via deacetylating MLH1.

MutL homolog 1 (MLH1) is a key DNA mismatch repair protein, which plays an important role in maintenance of genomic stability and the DNA damage response. Here, we report that MLH1 is a novel substrate of histone deacetylase 6 (HDAC6). HDAC6 interacts with and deacetylates MLH1 both in vitro and in vivo Interestingly, deacetylation of MLH1 blocks the assembly of the MutSα-MutLα complex. Moreover, we have identified four novel acetylation sites in MLH1 by MS analysis. The deacetylation mimetic mutant, but not the WT and the acetylation mimetic mutant, of MLH1 confers resistance to 6-thioguanine. Overall, our findings suggest that the MutSα-MutLα complex serves as a sensor for DNA damage response and that HDAC6 disrupts the MutSα-MutLα complex by deacetylation of MLH1, leading to the tolerance of DNA damage.

Nuclear respiratory factor 1 promotes spheroid survival and mesenchymal transition in mammary epithelial cells.

Epithelial cells aggregate into spheroids when deprived of matrix, and the proclivity for spheroid formation and survival is a hallmark of normal and tumorigenic mammary stem cells. We show here that Nuclear Respiratory Factor 1 (NRF1) is a spheroid promoter by in silico identification of this transcription factor as highly connected to top shRNA-hits deduced from re-iterative selections for shRNAs enriched in MCF10A spheroids. NRF1-promoted spheroid survival is linked to its stimulation of mitochondrial OXPHOS, cell migration, invasion, and mesenchymal transition. Conversely, NRF1 knockdown in breast cancer MDA-MB-231 cells reduced spheroids, migration, invasion, and mesenchymal marker expression. NRF1 knockdown also reduced tumor burden in mammary fat pads and lungs of orthotopic- or tail vein-transplanted mice. With the Luminal A subtype of breast cancer, higher NRF1 expression is associated with lower survival. These results show that NRF1, an activator of mitochondrial metabolism, supports mammary spheroid survival and tumor development.

Cell-Free DNA from Ascites and Pleural Effusions: Molecular Insights into Genomic Aberrations and Disease Biology.

Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Herein, we analyzed cfDNA in the ascites and pleural effusions from six individuals with metastatic cancer. In all cases, cfDNA copy number variations (CNV) were discovered within the effusate. One individual had a relevant alteration with a high copy amplification in EGFR in a never smoker with lung cancer, who showed only MDM2 and CDK4 amplification in a prior tissue biopsy. Another subject with metastatic breast cancer had cytology-positive ascites and an activating PIK3CA mutation identified in the tissue, blood, and ascites collectively. This individual had tumor regression after the administration of the mTOR inhibitor everolimus and had evidence of chromotripsis from chromosomal rearrangements noted in the cell-free ascitic fluid. These results indicate that cfDNA from ascites and pleural effusions may provide additional information not detected with tumor and plasma cell-free DNA molecular characterization, and a context for important insights into tumor biology and clonal dynamic change within primary tumor and metastatic deposits. Mol Cancer Ther; 16(5); 948-55. ©2017 AACR.

Strategy for Sustaining Cancer Education Services for Underserved Communities.

Innovative strategies are needed to generate resources to replicate and sustain proven, community-based health promotion programs. Authors describe how civic-minded university students can conduct such programs while simultaneously gaining skills that make them competitive graduate school applicants.

Glucose or Altered Ceramide Biosynthesis Mediate Oxygen Deprivation Sensitivity Through Novel Pathways Revealed by Transcriptome Analysis in Caenorhabditis elegans.

Individuals with type 2 diabetes display metabolic abnormalities, such as hyperglycemia, increased free fatty acids, insulin resistance, and altered ceramide levels, that contribute to vascular dysfunctions and compromised oxygen delivery. Caenorhabditis elegans fed a glucose-supplemented diet or with altered ceramide metabolism, due to a hyl-2 mutation, are sensitive to oxygen deprivation (anoxia). Our experiments showed that the combination of these factors further decreased the anoxia survival. RNA-sequencing analysis was performed to assess how a glucose-supplemented diet and/or a hyl-2 mutation altered the transcriptome. Comparison analysis of transcripts associated with anoxia-sensitive animals [hyl-2(tm2031) mutation or a glucose diet] revealed 199 common transcripts encoded by genes with known or predicted functions involving innate immunity, cuticle function (collagens), or xenobiotic and endobiotic phase I and II detoxification system. Use of RNA interference (RNAi) to target gene products of the xenobiotic and endobiotic phase I and II detoxification system (UDP-glycosyltransferase and Cytochrome p450 genes; ugt-15, ugt-18, ugt-19, ugt-41, ugt-63, cyp-13A12, cyp-25A1, and cyp-33C8) increased anoxia survival in wild-type animals fed a standard diet. Anoxia sensitivity of the hyl-2(tm2031) animals was suppressed by RNAi of cyp-25A1 or cyp-33C8 genes. A glucose diet fed to the P0 hermaphrodite decreased the anoxia survival of its F1 embryos; however, the RNAi of ugt-63 and cyp-33C8 suppressed anoxia sensitivity. These studies provide evidence that the detoxification system impacts oxygen deprivation responses and that C. elegans can be used to model the conserved detoxification system.