International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.

Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.

Pioneering the future of cancer therapy: Deciphering the p53-ferroptosis nexus for precision medicine.

The TP53 gene, encoding the p53 protein, has been a focal point of research since its 1979 discovery, playing a crucial role in tumor suppression. Ferroptosis, a distinct form of cell death characterized by lipid peroxide accumulation, has gained prominence since its recognition in 2012. Recent studies have unveiled an intriguing connection between p53 and ferroptosis, with implications for cancer therapy. Recent research underscores p53 as a novel target for cancer therapy, influencing key metabolic processes in ferroptosis. Notably, p53 represses the expression of the cystine-glutamate antiporter SLC7A11, supporting p53-mediated tumor growth suppression. Furthermore, under metabolic stress, p53 mitigates ferroptosis sensitivity, aiding cancer cells in coping and delaying cell death. This dynamic interplay between p53 and ferroptosis has far-reaching implications for various diseases, particularly cancer. This review provides a comprehensive overview of ferroptosis in cancer cells, elucidating p53's role in regulating ferroptosis, and explores the potential of targeting p53 to induce ferroptosis for cancer therapy. Understanding this complex relationship between p53 and ferroptosis offers a promising avenue for developing innovative cancer treatments.

Transoral Laser-Assisted Infrahyoid Supraglottic Laryngectomy for Selected Patients With Supraglottic Cancer.

Supraglottic laryngectomy has evolved from open to transoral endoscopic approaches with advancements in surgical techniques and instruments such as lasers, endoscopes, ultrasonic devices, and robotics. Transoral laser-assisted microsurgery has emerged as an effective treatment option, offering faster functional recovery and serving as an alternative to partial laryngectomy or non-surgical therapies. Traditional endoscopic supraglottic laryngectomy involves resection of both suprahyoid and infrahyoid supraglottic structures. However, in cases where the tumor is limited to the infrahyoid epiglottis, a new technique known as transoral laser-assisted infrahyoid supraglottic laryngectomy allows for tumor removal while preserving the suprahyoid epiglottis, aryepiglottic folds, and vallecula, ensuring optimal preservation of laryngopharyngeal function. This procedure enables patients to swiftly return to their daily routines with minimal complications. This article discusses the surgical technique, potential indications, and advantages and disadvantages of the new approach for infrahyoid epiglottic cancer.

Scarless Excision of Second Branchial Cleft Cyst via Retroauricular Hairline Incision.

BACKGROUND: Second branchial cleft cyst (2nd BCC) is treated by complete excision. Conventional transcervical skin incision on the lesion may leave a prominent scar in the cosmetically sensitive area. The retroauricular hairline incision (RAHI) approach may maintain neurological, mobility, and cosmetic functions of the neck and face after excision. This study evaluated the clinical outcomes and disease control of scarless surgery via RAHI in 57 consecutive patients with 2nd BCC. METHODS: The patients received the prospective evaluation of postoperative neurological, subjective pain, swallowing, neck motion, and cosmetic functions. Postoperative complications, subjective satisfaction, and recurrence were also assessed in each patient. RESULTS: Excision was performed in all cases without injury to the facial nerve or other neurological complications and conversion to other incisions or approaches with a median operation time of 44 min. Complications were minimal, without dysphagia, neurological deficits, or limited neck motion. Postoperative incision scars in the postauricular and hairline region were commonly invisible. Subjective satisfaction with the scar and facial deformity was high after surgery. No patients had a recurrence for a median follow-up of 66 months. CONCLUSION: The RAHI approach for 2nd BCC has excellent cosmetic, functional, and disease control outcomes. This can be safely applied to the treatment of 2nd BCC. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Gland preservation with postauricular sulcus approach for benign parotid tumors.

Gland-preserving surgery has gained popularity for treating benign parotid tumors, offering potential benefits by preserving facial nerve function and salivary secretion while reducing complications. This study aims to evaluate the functional, cosmetic, and disease control outcomes of gland-preserving surgery via a postauricular sulcus incision. METHODS: An observational longitudinal investigation encompassed 46 patients undergoing gland-preserving surgery for benign parotid tumors via the postauricular sulcus incision approach. Patient assessments included cosmetic contentment, functional repercussions, and disease management throughout the follow-up. RESULTS: Predominantly, tumors were situated in the superficial lobe, with successful application observed in 8 instances (17%) within the deep lobe. Notably, no tumor recurrences were detected during the follow-up period. Postoperative pain remained minimal, accentuated by high patient satisfaction regarding the incision scar and facial symmetry. Furthermore, preservation of facial nerve functionality and salivary secretion was observed. CONCLUSION: Gland-preserving surgery via the postauricular sulcus incision technique exemplifies advantageous functional and cosmetic outcomes when addressing benign parotid tumors. This approach presents a secure and efficient alternative, facilitating effective local management.

Extracapsular dissection versus total excision for benign submandibular gland tumors.

INTRODUCTION: Benign submandibular gland tumors pose challenges in balancing treatment effectiveness and preserving gland function. This study aimed to compare gland-preserving surgery, extracapsular dissection (ECD), with total excision in managing these tumors, focusing on function preservation and recurrence rate. METHODS: Fifty consecutive patients with treatment-naïve benign submandibular gland tumors were alternatively allocated to receive ECD (n = 25) or total excision (n = 25) without randomization procedures. Intraoperative findings, postsurgical complications, subjective satisfaction, and gland function were assessed. Follow-up data were collected for a median duration of 55 months (24-80 months) to monitor recurrences. RESULTS: ECD demonstrated significant advantages, including shorter operation time, reduced bleeding, and preservation of the facial artery and vein (P < 0.05). Both groups exhibited acceptable postsurgical pain and taste sensations. Complications were minimal and similar between the two groups. ECD resulted in superior facial contour satisfaction (P = 0.030) and preserved gland function, as evidenced by salivary scintigraphy. No recurrences were observed in either group during the follow-up period. CONCLUSIONS: ECD is a practical approach for benign submandibular gland tumors, offering favorable functional outcomes, reduced surgical morbidity, shorter operation times, and improved cosmetic results.

Extracapsular dissection via single cervical incision for parotid pleomorphic adenoma.

OBJECTIVES: Surgical management of parotid pleomorphic adenoma ranges from total parotidectomy to extracapsular dissection (ECD). Minimalistic techniques aim to preserve function and minimize the rate of recurrence. This study assesses functional, aesthetic, and disease control outcomes post-ECD through a sole transverse cervical incision for parotid pleomorphic adenoma. MATERIALS AND METHODS: This longitudinal analysis enrolled 36 consecutive patients with pleomorphic adenoma who underwent ECD via a single cervical incision. Complications, satisfaction, salivary function, and tumor recurrence were evaluated. Salivary gland function was assessed using scintigraphy at 6 months post-surgery. RESULTS: Tumors occurred in superficial (83%) or deep (17%) parotid inferior parts according to the European Salivary Gland Society level classification. The median tumor size was 2.8 cm (1.8-6.0 cm); the median operation time was 42 min (30-65 min). No tumor spillage or facial nerve injuries occurred. Facial nerve paralysis was only temporary in two (6%) patients, with minimal other complications. Operated parotid gland function matched the unoperated side. No recurrence was found during the median follow-up of 44 months (24-60 months). CONCLUSIONS: ECD via a single transverse cervical incision is a safe approach for benign parotid tumors, yielding excellent functional and disease control outcomes. CLINICAL RELEVANCE: These findings can provide clinically meaningful minimally invasive recommendations to treat pleomorphic adenoma with minimal complications.

Frey syndrome after conservative parotidectomy: Importance of closing the remnant parotid parenchyma.

BACKGROUND: Frey syndrome (FS) is a typical late complication following parotidectomy. Parotid surgery without proper coverage or reconstruction of exposed parotid parenchyma may contribute to the development of FS. Therefore, this study compared the closure versus the non-closure of exposed parotid parenchyma in the occurrence of FS. METHODS: This study included 195 patients with parotid lesions who underwent partial or superficial parotidectomy plus closure or non-closure of exposed parotid parenchyma, both with the application of fibrin glue. Two surgical methods of closure and non-closure were allocated to patients without randomization and blinding processes. The primary outcome was FS, and the second outcome was other complication rates. RESULTS: The closure and non-closure of exposed parotid parenchyma were performed in 102 and 93 patients, respectively. Early postoperative complications occurred with temporary events: transient facial weakness, 32 (16.4%); hematoma, 13 (6.7%); and wound infection, 2 (1.0%), without statistical difference between the two groups (P > 0.1). However, sialocele occurred in the non-closure group (n = 19) more than in the closure group (n = 7) (P = 0.005). In the first postoperative year, decreased sensation and local pain were found in 16 patients (8.2%) and 9 patients (4.6%), respectively, with no statistical difference between the two groups (P > 0.1). FS was found more in the non-closure group (n = 19, 20.4%) than in the closure group (n = 4, 3.9%) (P < 0.001). CONCLUSION: The closure of exposed parotid parenchyma and covering fascia is preferred over the non-closure to prevent FS.

Epigenetic modulation of ferroptosis in cancer: Identifying epigenetic targets for novel anticancer therapy.

Ferroptosis is a newly recognized form of oxidative-regulated cell death resulting from iron-mediated lipid peroxidation accumulation. Radical-trapping antioxidant systems can eliminate these oxidized lipids and prevent disrupting the integrity of cell membranes. Epigenetic modifications can regulate ferroptosis by altering gene expression or cell phenotype without permanent sequence changes. These mechanisms include DNA methylation, histone modifications, RNA modifications, and noncoding RNAs. Epigenetic alterations in cancer can control the expression of ferroptosis regulators or related pathways, leading to changes in cell sensitivity to ferroptosis inducers or cancer progression. Epigenetic alterations in cancer are influenced by a wide range of cancer hallmarks, contributing to therapeutic resistance. Targeting epigenetic alterations is a promising approach to overcoming cancer resilience. However, the exact mechanisms involved in different types of cancer remain unresolved. Discovering more ferroptosis-associated epigenetic targets and interventions can help overcome current barriers in anticancer therapy. Many papers on epigenetic modifications of ferroptosis have been continuously published, making it essential to summarize the current state-of-the-art in the epigenetic regulation of ferroptosis in human cancer.

Nrf2 targeting in overcoming ferroptosis evasion in head and neck cancer.

Ferroptosis is a recently identified type of regulated cell death characterized by lipid peroxidation and redox-active iron accumulation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of genes involved in glutathione biosynthesis, antioxidant responses, lipid metabolism, and iron metabolism, contributing to the evasion of ferroptosis. Inhibiting the Nrf2 pathway has been shown to sensitize cancer cells to ferroptosis. In head and neck cancer cells, we found that activation of the Nrf2-antioxidant responsive element pathway leads to ferroptosis resistance, and inhibiting this pathway reverses ferroptosis evasion. Our study suggests that modulating the Nrf2 pathway could be a promising strategy to overcome resistance in cancer therapy for head and neck cancer. Further research is required to investigate the potential of ferroptosis induction in therapy-resistant head and neck cancer. Targeting Nrf2 through ferroptosis-based cancer therapy may be a novel and effective approach to reverse the resistance of head and neck cancer therapy.

Targeting Nrf2 for ferroptosis-based therapy: Implications for overcoming ferroptosis evasion and therapy resistance in cancer.

Ferroptosis is a newly discovered form of programmed cell death caused by redox-active iron-mediated lipid peroxidation. Ferroptosis exhibits a unique morphological phenotype resulting from oxidative damage to membrane lipids. Ferroptosis induction has been shown to be effective in treating human cancers that rely on lipid peroxidation repair pathways. Nuclear factor erythroid 2-related factor 2 (Nrf2) can control the regulatory pathways of ferroptosis, which involve genes associated with glutathione biosynthesis, antioxidant responses, and lipid and iron metabolism. Resistant cancer cells often utilize Nrf2 stabilization by Keap1 inactivation or other somatic alterations in the genes from the Nrf2 pathway, which can confer resistance to ferroptosis induction and other therapies. However, pharmacological inactivation of the Nrf2 pathway can sensitize cancer cells to ferroptosis induction. Inducing lipid peroxidation and ferroptosis through regulating the Nrf2 pathway is a promising strategy for enhancing the anticancer effects of chemotherapy and radiation therapy in therapy-resistant human cancers. Despite promising preliminary studies, clinical trials in human cancer therapy have not yet been realized. A deeper understanding of their exact processes and efficacies in various cancers remains unsolved. Therefore, this article aims to summarize the regulatory mechanisms of ferroptosis, their modulation by Nrf2, and the potential of targeting Nrf2 for ferroptosis-based cancer therapy.

Unleashing Ferroptosis in Human Cancers: Targeting Ferroptosis Suppressor Protein 1 for Overcoming Therapy Resistance.

Ferroptosis, a recently identified form of regulated cell death characterized by the iron-dependent accumulation of lethal lipid peroxidation, has gained increasing attention in cancer therapy. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone oxidoreductase that reduces ubiquinone to ubiquinol, has emerged as a critical player in the regulation of ferroptosis. FSP1 operates independently of the canonical system xc-/glutathione peroxidase 4 pathway, making it a promising target for inducing ferroptosis in cancer cells and overcoming ferroptosis resistance. This review provides a comprehensive overview of FSP1 and ferroptosis, emphasizing the importance of FSP1 modulation and its potential as a therapeutic target in cancer treatment. We also discuss recent progress in developing FSP1 inhibitors and their implications for cancer therapy. Despite the challenges associated with targeting FSP1, advances in this field may provide a strong foundation for developing innovative and effective treatments for cancer and other diseases.

Targeting Iron-Sulfur Clusters in Cancer: Opportunities and Challenges for Ferroptosis-Based Therapy.

Iron dysregulation is a hallmark of cancer, characterized by an overexpression of genes involved in iron metabolism and iron-sulfur cluster (ISC) biogenesis. Dysregulated iron homeostasis increases intracellular labile iron, which may lead to the formation of excess cytotoxic radicals and make it vulnerable to various types of regulated cell death, including ferroptosis. The inhibition of ISC synthesis triggers the iron starvation response, increasing lipid peroxidation and ferroptosis in cancer cells treated with oxidative stress-inducing agents. Various methods, such as redox operations, iron chelation, and iron replacement with redox-inert metals, can destabilize or limit ISC formation and function, providing potential therapeutic strategies for cancer treatment. Targeting ISCs to induce ferroptosis represents a promising approach in cancer therapy. This review summarizes the state-of-the-art overview of iron metabolism and ferroptosis in cancer cells, the role of ISC modulation in ferroptosis, and the potential of targeting ISCs for ferroptosis induction in cancer therapy. Further research is necessary to develop and validate these strategies in clinical trials for various cancers, which may ultimately lead to the development of novel and effective treatments for cancer patients.

Early intervention of transoral laser-assisted marsupialization for adult epiglottic abscess.

Epiglottic abscess is a potentially fatal disease by airway compromise. Emergent airway intervention and admission to an intensive care unit are frequently required for patients with epiglottic abscess. Epiglottic abscess also doubles the duration of hospitalization compared to non-abscess epiglottitis. Abscess drainage, antibiotics administration, and airway monitoring are the mainstays of treatment. Spinal needle aspiration has been introduced to treat epiglottic abscess, which shows no significant additional benefit from a comparative study. Marsupialization has been commonly utilized to treat benign cystic diseases. Early surgical intervention of epiglottic abscess may resolve patient symptoms and secure the airway. Early intervention of transoral laser-assisted marsupialization for epiglottic abscess was a safe, simple, and reliable technique that guaranteed early recovery in 12 cases. Therefore, this article presents the procedures, pros, and cons of this method for treating epiglottic abscess.

Promotion of ferroptosis in head and neck cancer with divalent metal transporter 1 inhibition or salinomycin.

Divalent metal transporter 1 (DMT1) inhibitors can selectively kill iron-addicted cancer stem cells by causing lysosomal iron overload, but their role in head and neck cancer (HNC) is unknown. We examined the role of DMT1 inhibition or salinomycin in promoting ferroptosis by lysosomal iron targeting in HNC cells. RNA interference was performed by transfection of siRNA targeting DMT1 or scrambled control siRNA in HNC cell lines. Cell death and viability, lipid peroxidation, iron contents, and molecular expression were compared between the DMT1 silencing or salinomycin group and the control. DMT1 silencing markedly accelerated cell death induced by the ferroptosis inducers. DMT1 silencing marked increases in the labile iron pool, intracellular ferrous and total iron contents, and lipid peroxidation. DMT1 silencing revealed molecular changes in iron starvation response, resulting in increases in TFRC, and decreases in FTH1. Salinomycin treatment also showed similar results to the above DMT1 silencing. DMT1 silencing or salinomycin can promote ferroptosis in HNC cells, suggesting a novel strategy for killing iron-avid cancer cells.

Targeting GPX4 in human cancer: Implications of ferroptosis induction for tackling cancer resilience.

Cancer metabolic alterations have been emphasized to protect cancer cells from cell death. The metabolic reprogramming toward a mesenchymal state makes cancer cells resistant to therapy but vulnerable to ferroptosis induction. Ferroptosis is a new form of regulated cell death based on the iron-dependent accumulation of excessive lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the core regulator of ferroptosis by detoxifying cellular lipid peroxidation using glutathione as a cofactor. GPX4 synthesis requires selenium incorporation into the selenoprotein through isopentenylation and selenocysteine tRNA maturation. GPX4 synthesis and expression can be regulated by multiple levels of its transcription, translation, posttranslational modifications, and epigenetic modifications. Targeting GPX4 in cancer may be a promising strategy for effectively inducing ferroptosis and killing therapy-resistant cancer. Several pharmacological therapeutics targeting GPX4 have been developed constantly to activate ferroptosis induction in cancer. The potential therapeutic index of GPX4 inhibitors remains to be tested with thorough examinations of their safety and adverse effects in vivo and clinical trials. Many papers have been published continuously in recent years, requiring state-of-the-art updates in targeting GPX4 in cancer. Herein, we summarize targeting the GPX4 pathway in human cancer, which leads to implications of ferroptosis induction for tackling cancer resilience.

Epithelial-mesenchymal plasticity: Implications for ferroptosis vulnerability and cancer therapy.

Cancers polarized to a mesenchymal or poorly differentiated state can often evade cell death induced by conventional therapies. The epithelial-mesenchymal transition is involved in lipid metabolism and increases polyunsaturated fatty acid levels in cancer cells, contributing to chemo- and radio-resistance. Altered metabolism in cancer enables invasion and metastasis but is prone to lipid peroxidation under oxidative stress. Cancers with mesenchymal rather than epithelial signatures are highly vulnerable to ferroptosis. Therapy-resistant persister cancer cells show a high mesenchymal cell state and dependence on the lipid peroxidase pathway, which can respond more sensitively to ferroptosis inducers. Cancer cells may survive under specific metabolic and oxidative stress conditions, and targeting this unique defense system can selectively kill only cancer cells. Therefore, this article summarizes the core regulatory mechanisms of ferroptosis in cancer, the relationship between ferroptosis and epithelial-mesenchymal plasticity, and the implications of epithelial-mesenchymal transition for ferroptosis-based cancer therapy.

Sialocele formation after partial parotidectomy: Dependent on remnant parotid exposure.

BACKGROUND: This study compared the complete closure versus the exposure of remnant parotid parenchyma in sialocele formation. METHODS: This study included 151 patients with benign parotid lesions who underwent partial parotidectomy plus the complete closure or exposure of remnant parotid parenchyma. Two surgical methods of closed or exposed parenchyma were alternatively allocated to consecutive patients without randomization and blinding processes. RESULTS: Complete closure and exposure of the remnant parotid parenchyma were performed in 81 and 70 patients. Early postoperative complications occurred with temporary events: transient facial weakness, 24 (16%); hematoma, 9 (6%); wound infection, 1 (0.7%) without statistical difference between the two groups (p > 0.1). Postoperative sialocele was more frequently found in the exposure group (n = 15) than the closure group (n = 4; p = 0.003). CONCLUSIONS: The complete closure of remnant parotid parenchyma is preferred over the exposure of injured parenchymal parenchyma to prevent postparotidectomy sialocele.

A simple widening technique of postlaryngectomy tracheostomal stenosis: Anchoring to the medial clavicle.

Tracheostomal stenosis is a common distressing problem for surgeons and patients after laryngectomy. The stenosis occurs in up to 44% of laryngectomized patients, according to different contributing factors. Various surgical techniques have been introduced to treat tracheostomal stenosis, showing no clear advantages over the other methods. Only a few studies have reported stomal widening techniques with the preservation of tracheoesophageal puncture (TEP). Tracheostomal restenosis may occur after the stomaplasty, often requiring revision surgery. A new surgical method was developed to preserve TEP and avoid stomal restenosis, including the bilateral vertical incisions of tracheostoma stenosis and anchoring to the clavicle. This operative technique is relatively safe, simple, less invasive and time-consuming, and preserves the TEP and voice prosthesis. Therefore, this article presents the surgical procedure, potential indications, and pros and cons of the new widening method of tracheostomal stenosis.

Altered iron metabolism as a target for ferroptosis induction in head and neck cancer.

Iron is a mineral micronutrient essential for survival and vital functions in many biological processes in living organisms. Iron plays a crucial role as a cofactor of iron-sulfur clusters in energy metabolism and biosynthesis by binding with enzymes and transferring electrons to targets. Iron can also impair cellular functions by damaging organelles and nucleic acids by producing free radicals from redox cycling. Iron-catalyzed reaction products can induce active-site mutations in tumorigenesis and cancer progression. However, the boosted pro-oxidant iron form may contribute to cytotoxicity by increasing soluble radicals and highly reactive oxygen species via the Fenton reaction. An increased redox-active labile iron pool is required for tumor growth and metastasis, but the increased cytotoxic lipid radicals also lead to regulated cell death, such as ferroptosis. Therefore, this may be a major target for selectively killing cancer cells. This review intends to understand altered iron metabolism in cancers and discuss iron-related molecular regulators highly associated with iron-induced cytotoxic radical production and ferroptosis induction, focusing on head and neck cancer.