Matrix-based molecular mechanisms, targeting and diagnostics in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a head and neck cancer (HNC) with a high mortality rate. OSCC is developed in the oral cavity and it is triggered by many etiologic factors and can metastasize both regionally and distantly. Recent research advances in OSCC improved our understanding on the molecular mechanisms involved in and the initiation of OSCC metastasis. The key roles of the extracellular matrix (ECM) in OSCC are an emerging area of intensive research as the ECM macromolecular network is actively involved in events that regulate cellular morphological and functional properties, transcription and cell signaling mechanisms in invasion and metastasis. The provisional matrix that is formed by cancer cells is profoundly different in composition and functions as compared with the matrix of normal tissue. Fibroblasts are mainly responsible for matrix production and remodeling, but in cancer, the tumor matrix in the tumor microenvironment (TME) also originates from cancer cells. Even though extensive research has been conducted on the role of ECM in regulating cancer pathogenesis, its role in modulating OSCC is less elucidated since there are several issues yet to be fully understood. This critical review is focused on recent research as to present and discuss on the involvement of ECM macromolecular effectors (i.e., proteoglycans, integrins, matrix metalloproteinases) in OSCC development and progression.

Insights into metastatic roadmap of head and neck cancer squamous cell carcinoma based on clinical, histopathological and molecular profiles.

The incidence of head and neck cancer (HNC), constituting approximately one in ten cancer cases worldwide, affects approximately 644,000 individuals annually. Managing this complex disease involves various treatment modalities such as systemic therapy, radiation, and surgery, particularly for patients with locally advanced disease. HNC treatment necessitates a multidisciplinary approach due to alterations in patients' genomes affecting their functionality. Predominantly, squamous cell carcinomas (SCCs), the majority of HNCs, arise from the upper aerodigestive tract epithelium. The epidemiology, staging, diagnosis, and management techniques of head and neck squamous cell carcinoma (HNSCC), encompassing clinical, image-based, histopathological and molecular profiling, have been extensively reviewed. Lymph node metastasis (LNM) is a well-known predictive factor for HNSCC that initiates metastasis and significantly impacts HNSCC prognosis. Distant metastasis (DM) in HNSCC has been correlated to aberrant expression of cancer cell-derived cytokines and growth factors triggering abnormal activation of several signaling pathways that boost cancer cell aggressiveness. Recent advances in genetic profiling, understanding tumor microenvironment, oligometastatic disease, and immunotherapy have revolutionized treatment strategies and disease control. Future research may leverage genomics and proteomics to identify biomarkers aiding individualized HNSCC treatment. Understanding the molecular basis, genetic landscape, atypical signaling pathways, and tumor microenvironment have enhanced the comprehension of HNSCC molecular etiology. This critical review sheds light on regional and distant metastases in HNSCC, presenting major clinical and laboratory features, predictive biomarkers, and available therapeutic approaches.

Horizontal pharyngeal closure during total laryngectomy reduces rates of pharyngocutaneous fistula.

PURPOSE: Pharyngocutaneous fistula (PCF) is a possible complication following total laryngectomy (TL), with a mean incidence of 17%. We intended to investigate the effect of pharyngeal closure type during TL on the prevention of PCF. METHODS: We retrospectively reviewed patients that underwent TL with a horizontal pharyngeal closure over a 10-year period. The frequency of PCF clinically, dysphagia, total oral diet, postoperative dilatation of the neopharynx and voice problems were tabulated. RESULTS: Seventy-seven subjects underwent TL due to laryngeal tumor without pharyngeal extension. Of them, 45 underwent a salvage TL. PCF occurred in 1/77 subjects. The rest of the subjects (76/77) did not develop a PCF, neither in the early nor in the late postoperative phase. All subjects (15/77) that underwent implantation of a voice prosthesis were satisfied with their voice. No subject complained about dysphagia. Every subject achieved total oral diet. CONCLUSION: The horizontal pharyngeal closure is a safe pharyngeal closure technique during TL, reduces PCF rates (< 2%), results in excellent voice rehabilitation and swallowing function, and can also be used during salvage TL instead of a major pectoral flap. This type of closure should be used only in selected patients with laryngeal disease without pharyngeal extension.

Pulsed Electromagnetic Fields (PEMFs) Trigger Cell Death and Senescence in Cancer Cells.

The currently available anti-cancer therapies, such as gamma-radiation and chemotherapeutic agents, induce cell death and cellular senescence not only in cancer cells but also in the adjacent normal tissue. New anti-tumor approaches focus on limiting the side effects on normal cells. In this frame, the potential anti-tumor properties of Pulsed Electromagnetic Fields (PEMFs) through the irradiation of breast cancer epithelial cells (MCF-7 and MDA-MB-231) and normal fibroblasts (FF95) were investigated. PEMFs had a frequency of 8 Hz, full-square wave type and magnetic flux density of 0.011 T and were applied twice daily for 5 days. The data collected showcase that PEMF application decreases the proliferation rate and viability of breast cancer cells while having the opposite effect on normal fibroblasts. Moreover, PEMF irradiation induces cell death and cellular senescence only in breast cancer cells without any effect in the non-cancerous cells. These findings suggest PEMF irradiation as a novel, non-invasive anti-cancer strategy that, when combined with senolytic drugs, may eliminate both cancer and the remaining senescent cells, while simultaneously avoiding the side effects of the current treatments.

The interplay between tumor and nodal microenvironments for the formation of nodal premetastatic niche in head and neck cancer.

Head and neck cancer (HNC) encompasses a number of malignancies originating in the head and neck area. In patients with HNC, cervical lymph nodes constitute metastatic sites for cancer cells that escape primary tumors. The premetastatic niche (PMN) is a crucial concept in understanding metastatic disease. PMN refers to the microenvironment resulting mainly from primary tumor cells to foster metastatic tumor cell growth at a distant organ. Tumor microenvironment (TME) plays an important part in the pathogenesis of PMN. A significant prognostic factor is the close association between metastases of lymph nodes and organ dissemination in many different malignancies. The nodal premetastatic niche (NPMN) is a particular type of PMN located within the lymph nodes. NPMN formation is specifically important in HNC as regional lymph node metastasis commonly occurs. The formation happens when tumor cells create a supportive microenvironment within lymph nodes, facilitating their survival, growth, spread, and invasion. This complex mechanism involves multiple steps and cellular interactions between the primary tumor and tumor microenvironment. Several extracellular matrix (ECM) macromolecules, cytokines, and growth factors are implicated in this process. The aim of this article is to present the most recent data on the regulation of the lymph node PMN at molecular and cellular levels in HNC, as well as insights with respect to the relationship between primary tumor cells and the microenvironment of lymph nodes, and the formation of NPMN. We also critically discuss on potential targets for preventing or disrupting nodal metastases and identify potential biomarkers for predicting HNC outcomes.

A Rare Cause of Peripheral Facial Nerve Palsy: Chondromyxoid Fibroma of the Temporal Bone.

PURPOSE: To report a rather rare entity of facial palsy due to chondromyxoid fibroma. The authors present a case along with clinico-pathological features, management, treatment options and follow-up. METHODS: The authors present a case of a 29-year-old male who suffered from right facial weakness and numbness for a period of 6-months. imaging studies demonstrated a soft, locally invasive tumor, located mainly in the right temporal bone and extended extracranially. RESULTS: A surgical procedure of local excision followed by cross-facial nerve grafting was performed. CONCLUSIONS: Diagnosis should be based on combination of histo-pathologic and radiographic findings, because of its histological similarities to chondrosarcoma.

The Effect of the Premedication with Systemic Corticosteroids and Antibiotics on Inflammation and Intraoperative Bleeding During Sinonasal Endoscopic Surgery for Chronic Rhinosinusitis with Nasal Polyps (CRSwNP).

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease characterized by a variety of inflammatory mechanisms. Extensive genetic analyses have shown that among the molecules that are involved in its genetic base, interleukins (ILs) play a critical role in the development and progression of CRSwNP. ILs, such us IL-4 (5q31.1), IL-5 (5q31.1), IL-13 (5q31.11), and IL-25 (14q11.2) are found to be overexpressed. PURPOSE: Our aim is to investigate, through a systemic review, the effect of the premedication with systemic corticosteroids and antibiotics on inflammation and intraoperative bleeding during sinonasal endoscopic surgery for CRSwNP. MATERIALS AND METHODS: The search period covered January 1979 to February 2021, using the scientific databases PubMed, Scien-ceDirect, Scopus, Cochrane Library και Google Scholar. Search terms were "effect, premedication, systemic corticosteroids, antibiotics, intraoperative, bleeding, inflammation, sinonasal, endoscopic surgery, chronic rhinosinusitis, and nasal polyposis." RESULTS: From an initial 80 titles found in the above medline databases, the evaluations led to the final inclusion of 15 papers. Eighty titles found in the above medline databases. Eleven titles were excluded as they did not include a summary and full text in English language. Sixty-nine titles collected and duplicate references were searched. Twelve titles were excluded due to double reporting. Fifty-seven articles remained for systematic review. Fourty-two articles were excluded after systematic review and correlation with the research field. Fifteen articles were eventually included in the literature review. CONCLUSIONS: The effect of corticosteroids and antibiotics on the size of nasal polyps, nasal symptoms, and systemic markers of inflammation is significant. Each of the above factors acts on different pathogenetic inflammatory mechanisms.The use of perioperative corticosteroids reduces blood loss and operation time and improves the quality of the surgical field. There are no other medications that have been shown to improve the surgical field and outcome. Whether there is an additive effect on systemic corticosteroids on top of nasal corticosteroids is unclear. The european position paper on rhinosinusitis and nasal polyps steering group advises to use (nasal) corticosteroids before endoscopic sinus surgery.However, it should be considered in future studies whether some minor differences are due to differences in the initial doses of corticosteroids or during treatment in the preoperative period. It is worth mentioning that although high doses of corticosteroids are required to control the progression of rhinosinusitis with nasal polyps, the optimal initial dosage and the total duration of the treatment have not yet been standardized in patients with CRSwNP and future studies are required to determine the 2 above parameters (optimal dosage and duration of treatment). There are, therefore, known risks from corticosteroid administration, and clinicians should consider them when evaluating each patient. Each patient should be considered as an individual case with individualized treatment.

A Clinical Case of Delayed Posttraumatic Frontal Sinus Cerebrospinal Fluid Leakage Management Via External Surgical Approach.

ABSTRACT: Cerebrospinal fluid rhinorrhea is frequently encountered after a fracture of the skull base. Individual fractures of the posterior wall of the frontal sinus after brain injury are uncommon. The authors present a case of a 33-year-old man with a distant history of skull base injury after a traffic accident, 12 years ago. He presented with intermittent rhinorrhea and reported 2 episodes of bacterial meningitis the last 7 years since the injury. Cerebrospinal fluid leakage was confirmed with ß2-transferrin testing. Computed tomography and magnetic resonance imaging revealed a small defect of the posterior and superior wall of the left frontal sinus and an ipsilateral meningoencephalocele.Finally, there was a communication between intracranial space and frontal sinus that caused meningitis.A coronal incision and frontal craniotomy with preservation of anterior pericranium was performed (frontal sinus cranialization using osteoplastic flap). In order to determine the precise margins of the frontal sinus and allow an accurate anterior table bone osteotomy and complete exposure of the sinus, the authors used a coronal view of skull X-ray. Scissors are then used to cut along the margins of the sinus. An "R" is scratched into the right side of template to record orientation. The template was sterilized and brought onto the surgical field and then placed over the left sinusAn external surgical approach (anterior table bone osteotomy) with the modern technique of osteoplastic flap access was performed. An elevator was used to separate the dura from the posterior table along the entire margin of the defect. Meningoplasty (cauterization of the meningoencephalocele) and closure of the osseous defect was followed. The authors repaired the defect of the posterior wall of the left frontal sinus using a combination of underlay and overlay technique. Femoral fascia from right thigh and fibrin glue were placed in order to cover the leak of the posterior wall of the left frontal sinus, respectively.Patients who present with a short or/ and distant history of traumatic brain injury should be evaluated for complication of a cerebrospinal fluid leak.

Management of paranasal sinus osteomas: A comprehensive narrative review of the literature and an up-to-date grading system.

BACKGROUND: Surgical excision represents the unequivocal treatment modality for symptomatic paranasal sinus osteomas. However, the optimal surgical approach and the extent of the surgery, as well as the management stance in the case of an asymptomatic tumor, remain controversial. METHODS: The MeSH terms 'Osteoma', 'Nasal Cavity', and 'Paranasal Sinuses' were used to retrieve articles concerning the management of paranasal sinus osteomas that were published in the last 30 years, the vast majority of which comprised case reports of one or two cases. Original articles or large series of more than six cases were prioritized. RESULTS: Our review summarizes previous findings and opinions relevant to the management of symptomatic and asymptomatic paranasal sinus osteomas. The recent shifts in trends of their management are thoroughly discussed. Currently, an extension of the lesion through the anterior frontal sinus wall; an erosion of the posterior wall of the frontal sinus; a far-anterior intraorbital extension; an attachment to the orbital roof beyond the midorbital point; and some patient-specific adverse anatomic variations that may restrict access, are considered strong contraindications to a purely endoscopic approach. On the grounds of this thorough review, a new grading system for frontal and frontoethmoidal osteomas is proposed to allow better conformity to recent advancements and current clinical, research, and educational needs. CONCLUSION: Over the past 30 years, endoscopic techniques have emerged as the new standard of care for favorably located paranasal sinus osteomas. Nonetheless, open approaches remain indispensable for the management of the more perplexing cases of frontal sinus osteomas.

Recommendations for head and neck surgical oncology practice in a setting of acute severe resource constraint during the COVID-19 pandemic: an international consensus.

The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.

Chromosomal instability in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) demonstrates an increasing rate due to high risk Human Papilloma Virus (HR-HPV) persistent infection, and also to chronic cigarette and alcohol consumption. Gross chromosomal alterations (polysomy, aneuploidy, intra-chromosome rearrangements) and specific gene aberrations such as amplifications, deletions, point mutations combined or not with epigenetic ones (promoter methylations and miRNA deregulations) are responsible for the progressive transformation of normal squamous cell epithelia to the corresponding malignant. Chromosomal instability (CI) -based on structural or numerical abnormalities- leads to specific abnormal karyotypes combined or not with functional suppressor gene inactivation and oncogene overactivation in solid malignancies, including OSCC. Extensive cytogenetic analyses have shown that gross alterations (gains/losses) in chromosomes 3, 4, 7, 8, 9, 11, 14, 17, 18, 19 and also 20 form different CI patterns in OSCC, which in conjunction with an aggressive phenotype (presence of lymph nodal metastasis) negatively affect the prognosis in the corresponding patients. In the majority of OSCC cases, loss of chromosomal bands are almost equally detected compared with gains regarding the chromosomes referred above. In the current special molecular paper we explored the role of CI in the progression and biological behavior of OSCCs.

Cartilage "shield" tympanoplasty: an effective and practical technique.

The aim of the present study is to report our results with cartilage "shield" tympanoplasty (CST) for total tympanic membrane perforations. A retrospective chart review of patients undergoing CST was performed in tertiary referral centers. One hundred and seventy-seven patients who had undergone CST were identified. Patients' age ranged from 7 to 74 (mean 35) years. The mean postoperative follow-up was 23 (range 6-73) months. The main outcome measures were Graft take, pre and postsurgery audiologic evaluation. Graft take was 97.2%. Three patients developed recurrent cholesteatomas, one an anterior pinhole perforation, and one a minimal graft anterior lateralization. The average pre and postoperative pure-tone air-bone gaps (PTA-ABG) were 32.06 ± 11.21 and 18.69 ± 10.53 dB, respectively. The overall average ABG improvement was 13.37 ± 9.34 dB. An overall postoperative ABG of 25 dB or less was achieved in 140 of the 177 patients (79.1%). Hearing improvement was statistically significant in all cases (p < 0.0001). Cartilage shield tympanoplasty is a very reliable procedure. Graft take is excellent and hearing improvement is significant.

The Value of the Endoscope-Holding Arm in Transoral Pharyngeal Surgery.

BACKGROUND: Transoral pharyngeal surgery is mainly feasible with the use of a microscope or robotic systems. Data about alternative methods, with lower costs and easier availability, are sparse. We intended to examine to what extent the endoscope-holding arm is a suitable alternative to the microscope or robotic systems. MATERIAL AND METHODS: We retrospectively reviewed subjects who underwent pharyngeal tumor resection with the endoscope-holding arm in our university department. RESULTS: We identified 13 subjects who underwent transoral pharyngeal surgery between November 2020 and November 2023. Most subjects presented with an oropharyngeal tumor (6/11 in the lateral wall or tonsil; 4/11 in the tongue base). The oropharyngeal lateral wall or tonsillar tumors were exposed with a standard mouth gag. The tongue-base tumors or hypopharyngeal tumors were exposed with an operating laryngoscope. Advantages over the microscope included an angled view. Advantages over robotic systems included haptic feedback and a faster setup. Advantages over both the microscope and robotic systems included lower costs and easier availability. Visualization with the endoscope was sufficient and similar to that of the microscope. Bimanual action was possible with surgical forceps and a monopolar electrode. CONCLUSIONS: Transoral pharyngeal surgery was feasible with the endoscope-holding arm. The endoscope-holding arm could be a cost-efficient alternative to the microscope or robotic systems.

Parotid Metastasis of Early-Stage Upper Eyelid Sebaceous Carcinoma: A Case Presentation and a Literature Review.

Metastasis from early-stage sebaceous carcinoma of the eyelid to the salivary glands is considered very rare, occurring in less than 3% of early-stage patients. We report the case of a 72-year-old Caucasian man with a parotid tumor. Fine needle aspiration was consistent with a salivary duct carcinoma. A subtotal parotidectomy with ipsilateral neck dissection was performed. The pathology report revealed a sebaceous carcinoma with one parotid and two cervical lymph nodes infiltrated. The patient had a history of an early-stage sebaceous carcinoma of the upper eyelid two years before, which was revealed after the histological examination. An early-stage eyelid sebaceous carcinoma can metastasize to lymph nodes of the parotid glands. A close follow-up should not be neglected.

PTEN Deregulation Mechanisms in Salivary Gland Carcinomas.

Among the tumour suppressor genes that affect critically cell functions and homeostasis, phosphatase and tensin homolog deleted in chromosome 10 (PTEN- gene locus: 10q21) regulates the PI3K/Akt/mTOR signalling pathway. PTEN is deleted, mutated or epigenetically hyper-methylated in a variety of human solid malignancies. Salivary gland carcinomas (SGCs) belong to the head and neck carcinomas (HNCs) super category of solid malignancies. Histo-pathologically, they demonstrate a significant diversity due to a variety of distinct and mixed subtypes. Genetically, they are characterized by a broad spectrum of gene and chromosomal imbalances. Referring specifically to suppressor genes, PTEN deregulation plays a critical role in signaling transduction in the corresponding SGC pre- and malignant epithelia modifying the response rates to potential targeted therapeutic strategies. In the current review, we explored the role of PTEN deregulation mechanisms that are involved in the onset and progression of SGCs.

Intercellular pathways of cancer treatment-related cardiotoxicity and their therapeutic implications: The paradigm of radiotherapy.

Advances in cancer therapeutics have improved patient survival rates. However, cancer survivors may suffer from adverse events either at the time of therapy or later in life. Cardiovascular diseases (CVD) represent a clinically important, but mechanistically understudied complication, which interfere with the continuation of best-possible care, induce life-threatening risks, and/or lead to long-term morbidity. These concerns are exacerbated by the fact that targeted therapies and immunotherapies are frequently combined with radiotherapy, which induces durable inflammatory and immunogenic responses, thereby providing a fertile ground for the development of cardiovascular diseases (CVDs). Stressed and dying irradiated cells produce 'danger' signals including, but not limited to, major histocompatibility complexes, cell-adhesion molecules, proinflammatory cytokines, and damage-associated molecular patterns. These factors activate intercellular signaling pathways which have potentially detrimental effects on the heart tissue homeostasis. Herein, we present the clinical crosstalk between cancer and heart diseases, describe how it is potentiated by cancer therapies, and highlight the multifactorial nature of the underlying mechanisms. We particularly focus on radiotherapy, as a case known to often induce cardiovascular complications even decades after treatment. We provide evidence that the secretome of irradiated tumors entails factors that exert systemic, remote effects on the cardiac tissue, potentially predisposing it to CVDs. We suggest how diverse disciplines can utilize pertinent state-of-the-art methods in feasible experimental workflows, to shed light on the molecular mechanisms of radiotherapy-related cardiotoxicity at the organismal level and untangle the desirable immunogenic properties of cancer therapies from their detrimental effects on heart tissue. Results of such highly collaborative efforts hold promise to be translated to next-generation regimens that maximize tumor control, minimize cardiovascular complications, and support quality of life in cancer survivors.

One-step rapid tracking and isolation of senescent cells in cellular systems, tissues, or animal models via GLF16.

Identification and isolation of senescent cells is challenging, rendering their detailed analysis an unmet need. We describe a precise one-step protocol to fluorescently label senescent cells, for flow cytometry and fluorescence microscopy, implementing a fluorophore-conjugated Sudan Black-B analog, GLF16. Also, a micelle-based approach allows identification of senescent cells in vivo and in vitro, enabling live-cell sorting for downstream analyses and live in vivo tracking. Our protocols are applicable to cellular systems, tissues, or animal models where senescence is present. For complete details on the use and execution of this protocol, please refer to Magkouta et al.1.

Is cartilage better than temporalis muscle fascia in type I tympanoplasty? Implications for current surgical practice.

The aim of this study was to compare the hearing results and graft integration rates in patients undergoing myringoplasty for the reconstruction of the tympanic membrane, with the use of either cartilage or temporalis muscle fascia (TMF). A systematic literature review in Medline and other database sources up to February 2012 was carried out, and the pooled data were meta-analyzed. Twelve studies were systematically analyzed. One represented level I, one level II and ten level III evidence. The total number of treated patients was 1,286. Cartilage reconstruction was used in 536, TMF in 750 cases. Two level III studies showed a significant difference between the pre- and postoperative air-bone gap closure, in favor of cartilage grafting. The mean graft integration rate was 92.4 % in the cartilage group and 84.3 % in the TMF group (p < 0.05). The rates of re-perforations were 7.6 and 15.5 %, respectively (p < 0.05). Among the other complications of type I tympanoplasty, retraction pockets, otitis media with effusion, anterior blunting, and graft lateralization were usually surgically managed, whereas most of the rest were minor and could be dealt with conservatively. The graft integration rate in myringoplasty is higher after using cartilage, in comparison with fascia reconstructions (grade C strength of recommendation), and the rate of re-perforation is significantly lower. Although cartilage is primarily used as grafting material in cases of Eustachian tube dysfunction, adhesive otitis media, and subtotal perforation in everyday surgical practice, a wider utilization for the reconstruction of the tympanic membrane in myringoplasties can be recommended.

Pediatric Laryngopharyngeal Reflux in the Last Decade: What Is New and Where to Next?

BACKGROUND: Laryngopharyngeal reflux may affect people of any age; still, most of the accumulated knowledge concerns adults, and evidence regarding pediatric populations remains relatively restricted. This study aims to review the most recent and emerging aspects of pediatric laryngopharyngeal reflux from the last ten years. It also attempts to identify gaps in knowledge and highlight discrepancies that future research should urgently address. METHODS: An electronic search of the MEDLINE database was conducted, limited to January 2012 through December 2021. Non-English language articles, case reports, and studies that concerned a purely or predominantly adult population were excluded. The information from the articles with the most relevant contribution was initially categorized by theme and subsequently synthesized into a narrative form. RESULTS: 86 articles were included, of which 27 were review articles, eight were surveys, and 51 were original articles. Our review systematically maps the research done in the last decade and provides an updated overview and the current state-of-the-art in this subject. CONCLUSIONS: Despite discrepancies and heterogeneity in accumulating research, evidence gathered so far endorses a need for refining an escalating multiparameter diagnostic approach. A step-wise therapeutic plan appears to be the most reasonable management approach, starting with behavioral changes for mild to moderate, uncomplicated cases and escalating to personalized pharmacotherapy options for severe or nonresponsive cases. Surgical options could be considered in the most severe cases when potentially life-threatening symptoms persist despite maximal medical therapy. Over the past decade, the amount of available evidence has been gradually increasing; however, its strength remains low. Several aspects remain markedly under-addressed, and further adequately powered, multicenter, controlled studies with uniformity in diagnostic procedures and criteria are urgently needed.