-
Nature Reviews. Disease Primers Nov 2020Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell... (Review)
Review
Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.
Topics: Human papillomavirus 16; Humans; Papillomavirus Infections; Squamous Cell Carcinoma of Head and Neck; Tobacco Use
PubMed: 33243986
DOI: 10.1038/s41572-020-00224-3 -
Experimental and Therapeutic Medicine Oct 2020Ocular cicatricial pemphigoid is a particular form of mucous membrane pemphigoid and it is characterized by a chronic bilateral conjunctivitis with relapsing-remitting... (Review)
Review
Ocular cicatricial pemphigoid is a particular form of mucous membrane pemphigoid and it is characterized by a chronic bilateral conjunctivitis with relapsing-remitting periods. Without therapy 75% of the cases develop visual loss due to major ocular complications (e.g. severe dry-eye syndrome, corneal erosions, corneal keratinization, entropion, symblepharon). Pathogenesis remains uncertain and probably linked to an autoimmune type II hypersensitivity response in patients with a genetic predisposition and exposure to different environmental triggers. With a worldwide distribution, no racial predilection and an estimated incidence that largely varies from 1/10,000-1/60,000, ocular cicatricial pemphigoid predominantly affects women aged ~60 years. Conjunctival biopsy with direct immunofluorescence is the gold standard in diagnosis confirmation, but up to 40% of the patients have a negative biopsy result that does not rule out the diagnosis. The skin and many other mucous membranes (e.g. oral, trachea, esophagus, pharynx, larynx, urethra, vagina and anus) may be involved. The disease grading relies on Foster staging system (based on clinical signs) and Mondino and Brown system (based on the inferior fornix depth loss). The differential diagnosis includes atopy, allergies, trauma, chemical burns, radiation, neoplasia, infectious, inflammatory and autoimmune etiologies. The main goals of the treatment are to stop disease progression, to relieve symptoms and to prevent complications. With long-term systemic therapy 90% of the cases can be efficiently controlled. While Dapsone is the first-line treatment in mild to moderate disease in patients without G6PD deficiency, more severe cases require immunosuppressant therapy with azathioprine, mycophenolate mofetil, methotrexate or cyclosporine. Cyclophosphamide, biologics (etanercept or rituximab) and intravenous immunoglobulin therapy are usually reserved for recalcitrant disease and unsatisfactory results to conventional therapy. Dry eye syndrome requires constant lubricating medication and topical steroids, cyclosporine-A and tacrolimus. Surgery should be planed only in quiescent phase as minor conjunctival trauma can significantly worsen the disease.
PubMed: 32905166
DOI: 10.3892/etm.2020.8972 -
World Journal of Otorhinolaryngology -... Jul 2021This review aims to discuss the basic anatomy and physiology of the palatine and pharyngeal tonsils, with reference to how this foundational understanding may affect... (Review)
Review
OBJECTIVE
This review aims to discuss the basic anatomy and physiology of the palatine and pharyngeal tonsils, with reference to how this foundational understanding may affect patient management and surgical procedures in these regions of the upper airway.
METHODS
A literature search was performed using PubMed and Google Scholar using the MeSH terms tonsils, adenoids, anatomy, physiology, and adenotonsillectomy. Primary sources were excluded if they were abstracts only, non-English language, or non-human studies. Thirty-five sources were included in this review.
RESULTS AND CONCLUSIONS
The pharyngeal and palatine tonsils are compact yet physiologically complex mucosa-associated lymphoid tissues that make up a portion of Waldeyer's ring. As part of the mucosal immune system, these structures function in exogenous antigen sampling and stimulation of immune responses. Aberrant immune activation and/or regulation can lead to a myriad of pathologies, with adenotonsillar hypertrophy, chronic tonsillitis/adenoiditis, and recurrent otitis media among the most commonly encountered conditions by otolaryngologists. While the pathophysiology of these conditions is still incompletely understood, current evidence and future investigations may reveal patterns amenable to targeted medical management. When medical management fails, tonsillectomy and/or adenoidectomy may be indicated for patient care. Though routine procedures, the execution of tonsil and/or adenoid removal requires a thorough understanding of the anatomy of these lymphoepithelial organs so as to minimize the risk for rare serious complications that can occur.
PubMed: 34430822
DOI: 10.1016/j.wjorl.2021.04.003 -
European Journal of Cancer (Oxford,... Sep 2021To update the 2015 clinical practice guideline for the prevention of oral mucositis in pediatric cancer or hematopoietic stem cell transplant (HSCT) patients. (Review)
Review
PURPOSE
To update the 2015 clinical practice guideline for the prevention of oral mucositis in pediatric cancer or hematopoietic stem cell transplant (HSCT) patients.
METHODS
We performed seven systematic reviews of mucositis prevention. Three reviews included randomized controlled trials (RCTs) conducted in pediatric and adult patients evaluating cryotherapy, keratinocyte growth factor (KGF) or photobiomodulation therapy with a focus on efficacy. Three reviews included studies of any design conducted in pediatric patients evaluating these same interventions with a focus on adverse events and feasibility. One review included all RCTs of any intervention for mucositis prevention in pediatric patients. Primary outcome was severe oral mucositis.
RESULTS
We included 107 unique studies of cryotherapy (22 RCTs and 4 pediatric studies); KGF (15 RCTs and 12 pediatric studies); photobiomodulation therapy (29 RCTs and 8 pediatric studies) and any intervention (31 pediatric RCTs). Effects on severe mucositis reduction from RCTs were cryotherapy risk ratio (RR) 0.49 and 95% confidence interval (CI) 0.31-0.76; palifermin RR 0.81 and 95% CI 0.69-0.95 and photobiomodulation therapy RR 0.40 and 95% CI 0.27-0.60. Cryotherapy was not feasible in young children while photobiomodulation therapy was feasible across age groups. Palifermin was associated with adverse effects.
CONCLUSIONS
Cryotherapy should be used for older cooperative pediatric patients who will receive short infusions of melphalan or 5-fluorouracil. Intraoral photobiomodulation therapy (620-750 nm spectrum) should be used in pediatric patients undergoing autologous or allogeneic HSCT and for pediatric head and neck carcinoma patients undergoing radiotherapy. Palifermin should not be used routinely in pediatric cancer or HSCT patients.
Topics: Adult; Child; Cryotherapy; Hematopoietic Stem Cell Transplantation; Humans; Low-Level Light Therapy; Neoplasms; Oropharynx; Practice Guidelines as Topic; Radiotherapy; Stomatitis
PubMed: 34252760
DOI: 10.1016/j.ejca.2021.05.013 -
Nature Communications Jan 2020Cancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid...
Cancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid metabolism sustains cells enriched with CSCs and its ablation induces anti-tumor immune responses in mice. Notably, Arf1 ablation in cancer cells induces mitochondrial defects, endoplasmic-reticulum stress, and the release of damage-associated molecular patterns (DAMPs), which recruit and activate dendritic cells (DCs) at tumor sites. The activated immune system finally elicits antitumor immune surveillance by stimulating T-cell infiltration and activation. Furthermore, TCGA data analysis shows an inverse correlation between Arf1 expression and T-cell infiltration and activation along with patient survival in various human cancers. Our results reveal that Arf1-pathway knockdown not only kills CSCs but also elicits a tumor-specific immune response that converts dying CSCs into a therapeutic vaccine, leading to durable benefits.
Topics: ADP-Ribosylation Factor 1; Alarmins; Animals; Antineoplastic Agents; Cell Line, Tumor; Dendritic Cells; Endoplasmic Reticulum Stress; Female; Gastrointestinal Neoplasms; Gene Knockdown Techniques; Humans; Lipid Metabolism; Lipolysis; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Neoplastic Stem Cells; T-Lymphocytes; Tamoxifen; Vaccination
PubMed: 31924786
DOI: 10.1038/s41467-019-14046-9 -
The Journal of Clinical Investigation Mar 2021BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT01443936 and NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).
Topics: Adenoviruses, Human; Administration, Oral; Adolescent; Adult; Antibodies, Neutralizing; Antibodies, Viral; Antigens, Viral; Female; Genetic Vectors; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Immunity, Cellular; Immunity, Humoral; Immunity, Mucosal; Influenza A Virus, H5N1 Subtype; Influenza Vaccines; Influenza, Human; Male; Nasal Sprays; Palatine Tonsil; Virus Replication; Virus Shedding; Young Adult
PubMed: 33529172
DOI: 10.1172/JCI140794 -
Nature Mar 2023Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes. On infection, immune cells release...
Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes. On infection, immune cells release a 'storm' of cytokines and other mediators, many of which are detected by neurons; yet, the responding neural circuits and neuro-immune interaction mechanisms that evoke sickness behaviour during naturalistic infections remain unclear. Over-the-counter medications such as aspirin and ibuprofen are widely used to alleviate sickness and act by blocking prostaglandin E2 (PGE2) synthesis. A leading model is that PGE2 crosses the blood-brain barrier and directly engages hypothalamic neurons. Here, using genetic tools that broadly cover a peripheral sensory neuron atlas, we instead identified a small population of PGE2-detecting glossopharyngeal sensory neurons (petrosal GABRA1 neurons) that are essential for influenza-induced sickness behaviour in mice. Ablating petrosal GABRA1 neurons or targeted knockout of PGE2 receptor 3 (EP3) in these neurons eliminates influenza-induced decreases in food intake, water intake and mobility during early-stage infection and improves survival. Genetically guided anatomical mapping revealed that petrosal GABRA1 neurons project to mucosal regions of the nasopharynx with increased expression of cyclooxygenase-2 after infection, and also display a specific axonal targeting pattern in the brainstem. Together, these findings reveal a primary airway-to-brain sensory pathway that detects locally produced prostaglandins and mediates systemic sickness responses to respiratory virus infection.
Topics: Animals; Humans; Mice; Behavior, Animal; Blood-Brain Barrier; Brain; Brain Stem; Dinoprostone; Drinking; Eating; Influenza, Human; Movement; Nasopharynx; Orthomyxoviridae; Orthomyxoviridae Infections; Sensory Receptor Cells; Survival Rate
PubMed: 36890237
DOI: 10.1038/s41586-023-05796-0