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Radiotherapy (RT) continues to play a key role in the management of head and neck cancer (HNC). Xerostomia remains a principal detriment to the quality of life (QoL) for 80 % of surviving patients receiving head and neck radiation. Radiation-induced injury to the salivary glands is dose-dependent, and thus efforts have been focused on decreasing radiation to the salivary glands. Decreased saliva production reduces both short-term and long-term quality of life in head and neck survivors by impacting on taste and contributing to dysphagia. Several radioprotective agents to the salivary gland have been investigated. Although not widely practiced, surgical transfer of the submandibular gland prior to RT is the mainstay of surgical options in preventing xerostomia. This review focuses on the strategies to improve xerostomia following radiation therapy in head and neck cancers.
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Neoplasias de Cabeza y Cuello , Xerostomía , Humanos , Xerostomía/etiología , Xerostomía/prevención & control , Calidad de Vida , Glándulas Salivales , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/radioterapia , Glándula SubmandibularRESUMEN
TP53 is the most frequently mutated gene in head and neck squamous cell carcinoma (HNSCC). Patients with HPV-negative TP53 mutant HNSCC have the worst prognosis, necessitating additional agents for treatment. Since mutant p53 causes sustained activation of the PI3K/AKT/mTOR signaling pathway, we investigated the effect of rapalogs RAD001 and CCI-779 on HPV-negative mutTP53 HNSCC cell lines and xenografts. Rapalogs significantly reduced cell viability and colony formation. Interestingly, rapalogs-induced autophagy with no effect on apoptosis. Pretreatment with autophagy inhibitors, 3-methyladenine (3-MA) and ULK-101 rescued the cell viability by inhibiting rapalog-induced autophagy, suggesting that both RAD001 and CCI-779 induce non-apoptotic autophagy-dependent cell death (ADCD). Moreover, rapalogs upregulated the levels of ULK1 and pULK1 S555 with concomitant downregulation of the mTORC1 pathway. However, pretreatment of cells with rapalogs prevented the ULK-101-mediated inhibition of ULK1 to sustained autophagy, suggesting that rapalogs induce ADCD through the activation of ULK1. To further translate our in vitro studies, we investigated the effect of RAD001 in HPV-negative mutTP53 (HN31 and FaDu) tumor cell xenograft model in nude mice. Mice treated with RAD001 exhibited a significant tumor volume reduction without induction of apoptosis, and with a concomitant increase in autophagy. Further, treatment with RAD001 was associated with a considerable increase in pULK1 S555 and ULK1 levels through the inhibition of mTORC1. 3-MA reversed the effect of RAD001 on FaDu tumor growth suggesting that RAD001 promotes ACDC in HPV-negative mutTP53 xenograft. This is the first report demonstrating that rapalogs promote non-apoptotic ADCD in HPV-negative mutTP53 HNSCC via the ULK1 pathway. Further studies are required to establish the promising role of rapalogs in preventing the regrowth of HPV-negative mutTP53 HNSCC.
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Muerte Celular Autofágica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inhibidores mTOR/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Animales , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Everolimus/administración & dosificación , Everolimus/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Inhibidores mTOR/farmacología , Ratones , Mutación , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Sirolimus/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65- to 100-fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B-induced epidermal hyperplasia and hyperproliferation in SKH-1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell-specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan-FGFR inhibitor; AZD4547 significantly decreased cSCC cell-cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR-mediated effects. To further bolster the in vitro studies, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle-only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.
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Benzamidas/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Piperazinas/farmacología , Pirazoles/farmacología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Epidermis/efectos de los fármacos , Epidermis/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Xenoinjertos , Humanos , Queratinocitos/efectos de los fármacos , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: The recent epidemic of head and neck squamous cell carcinomas associated with human papilloma virus (HPV) has not addressed its association with lymphoid tissue in the oropharynx or the potential role of Epstein-Barr virus (EBV)/HPV coinfection. METHODS: The prevalence of HPV and EBV infection/coinfection and CD21 mRNA expression were determined in normal and cancerous tissues from the oropharynx using in situ hybridization (ISH), p16, and quantitative reverse transcriptase PCR (qRT-PCR). The effects of coinfection on tumorigenicity were evaluated using proliferation and invasion assays. RESULTS: Normal oropharynx, tonsil, non-cancer base of tongue (BOT), and BOT from sleep apnea patients demonstrated EBV positivity ranging from 7% to 36% depending on the site and methods of detection used (qRT-PCR or ISH). Among non-malignant BOT samples, HPV positivity was noted only in 20%. The percent of tonsil and BOT cancers positive for HPV (up to 63% and 80%, respectively) or coinfected with HPV/EBV (up to 25% and 70%, respectively) were both significantly associated with cancer status. Notably, HPV/EBV coinfection was observed only in malignant tissue originating in lymphoid-rich oropharynx sites (tonsil, BOT). CD21 mRNA (the major EBV attachment receptor) was detected in tonsil and BOT epithelium, but not in soft-palate epithelium. Coinfected cell lines showed a significant increase in invasiveness (P < 0.01). CONCLUSIONS: There is a high prevalence of HPV/EBV infection and coinfection in BOT and tonsil cancers, possibly reflecting their origins in lymphoid-rich tissue. In vitro, cells modeling coinfection have an increased invasive potential.
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Alphapapillomavirus/fisiología , Carcinogénesis , Coinfección/virología , Infecciones por Virus de Epstein-Barr/virología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/virología , Carcinoma de Células Escamosas/virología , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Herpesvirus Humano 4/inmunología , Humanos , Invasividad Neoplásica , Orofaringe/virología , Neoplasias Palatinas/virología , Paladar Blando/virología , Tonsila Palatina/virología , Receptores de Complemento 3d/análisis , Síndromes de la Apnea del Sueño/virología , Lengua/virología , Neoplasias de la Lengua/virología , Neoplasias Tonsilares/virologíaRESUMEN
A potential role for fibroblast growth factor receptor 2 (FGFR2) in cutaneous squamous cell carcinoma (cSCC) has been reported. To demonstrate the specific role of FGFR2 in UVB-induced skin carcinogenesis and development of cSCC, we generated a keratinocyte specific, tamoxifen inducible mouse model of FGFR2 deficiency. In this mouse model, topical application of 4-hydroxy tamoxifen led to the induction of Cre recombinase to delete FGFR2 in epidermal keratinocytes of both male and female transgenic mice. Analysis of epidermal protein lysates isolated from FGFR2 deficient mice exposed to UVB showed significant reductions of phospho-FGFR (pFGFR; Y653/654) and phospho-fibroblast growth factor receptor substrate 2α as well as downstream effectors of mTORC1 signaling. Phosphorylation of signal transducer and activators of transcription 1/3 was significantly reduced as well as levels of IRF-1, DUSP6, early growth response 1, and PD-L1 compared to the control groups. Keratinocyte-specific ablation of FGFR2 also significantly inhibited epidermal hyperproliferation, hyperplasia, and inflammation after exposure to UVB. Finally, keratinocyte-specific deletion of FGFR2 significantly inhibited UVB-induced cSCC formation. Collectively, the current data demonstrate an important role of FGFR2 in UVB-induced oncogenic signaling as well as development of cSCC. In addition, the current preclinical findings suggest that inhibition of FGFR2 signaling may provide a previously unreported strategy to prevent and/or treat UVB-induced cSCC.
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Carcinoma de Células Escamosas , Neoplasias Cutáneas , Animales , Femenino , Masculino , Ratones , Carcinogénesis/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Proliferación Celular , Inflamación/metabolismo , Queratinocitos/metabolismo , Ratones Transgénicos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/prevención & control , Tamoxifeno , Rayos Ultravioleta/efectos adversosRESUMEN
BACKGROUND: Dementia, a growing concern among the elderly, has an increased poor postoperative outcome that goes unrecognized by many. Our study aims to establish if dementia plays a role in the outcomes of head and neck cancer patients that undergo resections. METHODS: We queried the National Inpatient Sample (NIS) database from 2016 to 2019 with a primary diagnosis of head and neck cancer who underwent surgical resection. Outcomes analyzed include postoperative delirium, ICU stay, complications, length of stay, and non-routine discharge. RESULTS: A total of 77095 patients were included, of which 1140 patients had dementia. The mean age of the patients with dementia was 77.5 years (±9.1) versus 63.2 years (±12.1) with no dementia. Dementia patients had a higher non-home discharge rate (77.2% vs 46.8%, p = <0.001), extended length of stay (10.9 days ±14.7 vs 7.9 days ±8.8), postoperative delirium (15.4% vs 1.5%, p = <0.001), and longer ICU stay (8.3% vs 5.8%) as compared with patients with no dementia. A higher number of patients with Dementia were placed in long-term facilities (53.5% vs 14.6%) postoperatively. More dementia patients (7.9% vs 0.9%) were transferred in from another health care facility for surgery. Dementia was associated with higher odds of delirium (OR, 6.36; 95% CI, 5.2-7.77), non-routine discharge (OR, 2.05; 95% CI, 1.76-2.3), ventilation (OR, 0.8; 95% CI, 0.6-1.05), and length of stay (estimate 3.01, 95% CI, 1.84-4.184). CONCLUSION: Preoperative dementia significantly impacts postoperative delirium, non-home discharge, and extended length of stay in head and neck cancer patients undergoing surgery. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1258-1264, 2024.
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Demencia , Delirio del Despertar , Neoplasias de Cabeza y Cuello , Humanos , Anciano , Tiempo de Internación , Neoplasias de Cabeza y Cuello/cirugía , Pacientes Internos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Factores de RiesgoRESUMEN
OBJECTIVE: To critically evaluate oncological and functional outcomes following transoral laser microsurgery (TLM) in patients with T3/T4a glottic and supraglottic squamous cell carcinoma (SCC). DATA SOURCES: A comprehensive search of five major databases-PubMed, Embase, Scopus, ScienceDirect, and Web of Science-was conducted using a combination of relevant keywords and MeSH terms. REVIEW METHODS: Systematic review and meta-analysis of odds ratio (OR), hazards ratio (HR), and proportion, focusing on oncological and functional outcomes of TLM in advanced T3/T4a glottic and supraglottic tumors. A random-effects meta-analysis model was employed. RESULTS: The review incorporated 29 cohort studies, representing a total of 1,897 patients undergoing TLM for T3/T4a glottic and supraglottic SCC. The cumulative 5-year disease-free survival (DFS) rate for T3 glottic and supraglottic tumors was 44.4% (95% CI: 47-66%) and 62.8% (95% CI: 63-81%), while the 5-year DFS for T4 glottic and supraglottic tumors was 41.1% (95% CI: 33.4-49.2%) and 32.9% (95% CI: 19.3-50.1%), respectively. T3 glottic tumors exhibited a 2.5-fold significantly higher odds of local recurrence post-TLM compared to their T3 supraglottic tumors (95% CI: 1.6-3.9, p < 0.0001). Laryngeal preservation rates for T3glottic and supraglottic tumors were 68.9% (95% CI: 48.7-83.8%) and 88.4% (95% CI: 79.4-93.8%), respectively. Both groups showed comparable rates of tracheostomy (p = 0.48) and gastrostomy performed (p = 0.17). CONCLUSIONS: This meta-analysis suggests that TLM is a viable larynx preservation approach in select patients with T3/T4a glottic and supraglottic tumors. However, glottic tumors may have less favorable outcomes after TLM compared to those with advanced supraglottic tumors. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024 Laryngoscope, 2024.
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OBJECTIVE: Circulating tumor DNA (ctDNA) detection is an emerging technique that identifies minimal residual disease in patients with solid tumors. ctDNA can act as an adjunct method to help overcome the limitations of positron emission tomography (PET) and select patients who are at high risk for recurrence. STUDY DESIGN: Retrospective Single Institutional Study. SETTING: University Hospital Setting. METHODS: Twenty-nine patients who underwent definitive treatment for squamous cell carcinoma of the head and neck (HNSCC) from 8/2021 to 01/2023 had ctDNA levels analyzed at 1 to 3, 6, 9, and 12 months after definitive treatment. A personalized, tumor-informed, multiplex polymerase chain reaction (PCR) next-generation sequencing (NGS) assay was used to detect the ctDNA levels. The primary outcome was recurrence-free probability (RFP), and the secondary outcomes were overall survival (OS), sensitivity, specificity, and the test's negative (NPV) and positive predictive values (PPV). RESULTS: The median age of patients was 65 years (interquartile range: 56-69), with majority being males (n = 22, 76%). The primary sites were larynx (n = 12), oropharynx (n = 10), and oral cavity (n = 6). Posttreatment ctDNA was detected in 7 patients, all of whom had disease recurrence. ctDNA detection after definitive treatment was associated with a higher risk of disease recurrence (hazard ratio: 9.94, 95% confidence interval: 1.56-63.3, P = .015). ctDNA identified recurrence with 100% specificity and 78% sensitivity. The NPV and PPV were 91% and 100%. PET had 78% sensitivity but only 68% specificity with 86% NPV, and 54% PPV. CONCLUSION: Based on our data, ctDNA can be an excellent adjunct test for posttreatment PET and can help guide physicians in cases where PET results are inconclusive and difficult to interpret.
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ADN Tumoral Circulante , Neoplasias de Cabeza y Cuello , Recurrencia Local de Neoplasia , Tomografía de Emisión de Positrones , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Masculino , Estudios Retrospectivos , Femenino , Recurrencia Local de Neoplasia/diagnóstico por imagen , Persona de Mediana Edad , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/sangre , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Anciano , Medición de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Increased sexual activity is associated with higher human papillomavirus (HPV) rates; however, there is a lack of analysis comparing the sexual history of patients with HPV positive and HPV negative oropharyngeal cancer (OPC). METHODS: In this meta-analysis, PubMed, Scopus, and CINAHL were searched for articles that included patients with OPC and reported information regarding HPV status and either history of oral sex, number of sexual partners, or sexually transmitted infections (STI). RESULTS: A total of 11 studies were included with 3296 patients with OPC. Patients with HPV positive OPC were more likely than patients with HPV negative OPC to report a history of oral sex (92%, 95% CI: 87.0-97.0 vs. 74.5%, 95% CI: 50.6-98.4, p < 0.0001), higher mean number of sexual partners (18.4 partners, 95% CI: 1.5-35.4 vs. 7.2 partners, 95% CI: 1.0-13.4, p < 0.0001), and more frequent history of STI (23.7%, 95% CI: 18.4-29.0 vs. 8.8%, 95% CI: 4.7-12.8, p = 0.0001). CONCLUSIONS: Compared to patients with HPV negative OPC, our analysis shows a larger proportion of patients with HPV positive OPC had participated in oral sex, had a higher number of sexual partners, and had a higher proportion of STI history.
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This study aims to evaluate the functional and prognostic outcomes associated with the internal mammary artery perforator (IMAP) flap in various head and neck defect repairs, given the current lack of clarity on its effectiveness. We performed a systematic review of various databases: PubMed, Embase, Scopus, Web of Science, and ScienceDirect using keywords such as "Internal mammary artery perforator flap" and "IMAP." Screening and data extractions were performed by two individual reviewers. Articles were considered eligible if they included sufficient information on IMAP flap features, their applications in the head and neck, and outcomes. From 264 articles analyzed, 24 studies were included for qualitative analysis. Out of which, 125 patients who received internal mammary artery perforator flaps were included. Most of the patients, 103 (88%), received pedicled IMAP flaps, and 22 (12%) received IMAP free flaps. The second internal mammary artery (IMA) was favored as the single perforator (81.5%), with the combination of the first and second IMA being the primary choice for dual perforators (92.5%). IMAP flaps were predominantly single perforator flaps (65%), with 35% being dual perforator flaps. Among various applications, IMAP flaps are commonly employed in the reconstruction of neck defects (25.5%), pharyngocutaneous fistula repair (20.8%), and burn scar contracture restoration (8%). Only seven (5.6%) patients had flap complications, including venous congestion (1.6%), partial necrosis (1.6%), complete necrosis (1.6%), and incision dehiscence (0.8%). Donor sites were predominantly closed by the primary closure (92%). 3.2% of donor sites had minor complications. The average follow-up was 12.6 (IQR: 6-18) months. This systematic review highlights the effectiveness and safety of IMAP flaps in head and neck reconstruction, with positive outcomes and minimal complications.
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Arterias Mamarias , Colgajo Perforante , Procedimientos de Cirugía Plástica , Humanos , Colgajo Perforante/irrigación sanguínea , Colgajo Perforante/trasplante , Procedimientos de Cirugía Plástica/métodos , Arterias Mamarias/trasplante , Arterias Mamarias/cirugía , Neoplasias de Cabeza y Cuello/cirugía , Femenino , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: Temporal bone resection (TBR) with or without neck dissection (ND) is performed for otologic malignancies with occult or clinical cervical lymph node metastases. To date, characterization of post-operative complications in single institution case series may be non-representative of real-world outcomes. Here, we used data from the National Inpatient Sample (NIS) to comprehensively assess the complications encountered, their frequencies, and to identify underlying risk factors to improve future outcomes. METHODS: The population was patients undergoing TBR and ND derived from the NIS between the years of 2017 and 2019. We utilized ICD-10 diagnosis codes to identify patients with post-operative complications, those discharged to non-home facilities (DNHF), and those with increased length of stay (LOS). Multivariable regression was performed to identify significant variables related to the above outcomes. RESULTS: Ninety of 277 patients that underwent LTBR with ND had postoperative complications. Wound complications were the most frequent complication, occurring in 11 (4%) of patients, followed by CSF leak (n = 6; 2.2%), with acute respiratory failure being the most common medical complication (n = 4; 1.4%). Sixteen percent (45/277) were discharged to a facility besides home. Dementia (OR = 7.96; CI95 3.62-17.48), anemia (OR = 2.39; CI95 1.15-4.99), congestive heart failure (OR = 5.31; CI95 1.82-15.45), COPD (OR = 3.70; CI95 1.35-10.16), and history of prior stroke (OR = 8.50; CI95 1.55-46.68) increased the odds of DNHF. When evaluating LOS (median = 5 days, IQR = 1, 9), anemia (OR = 5.49; CI95 2.86-10.52), and Medicaid insurance (OR = 3.07; CI95 1.06-10.52) were found to increase the LOS. CONCLUSIONS: The vast majority of patients undergoing LTBR with ND have no complications and are discharged within a week. Liver disease is a risk factor for medical complications and increased charges. Patients with dementia or a prior stroke are at risk for DNHF, and those with prior anemia are at risk for a wound complication. LAY SUMMARY: This study identified factors related to worse post-operative outcomes in patients undergoing temporal bone resection and neck dissection. Although safe for most patients, an existing diagnosis of liver disease, stroke, dementia, and anemia specifically are at risk for developing negative outcomes. LEVEL OF EVIDENCE: 3.
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Bases de Datos Factuales , Disección del Cuello , Complicaciones Posoperatorias , Hueso Temporal , Humanos , Disección del Cuello/efectos adversos , Complicaciones Posoperatorias/epidemiología , Femenino , Masculino , Factores de Riesgo , Persona de Mediana Edad , Anciano , Hueso Temporal/cirugía , Estados Unidos/epidemiología , Tiempo de Internación/estadística & datos numéricos , Estudios Retrospectivos , AdultoRESUMEN
To comprehensively evaluate the therapeutic efficacy and safety when utilizing proton therapy (PT) versus intensity-modulated radiation therapy (IMRT) in head and neck cancer patients. Pubmed, ScienceDirect, Embase, Scopus, and Web of Science were systematically searched for studies on comparative PT and IMRT outcomes. We performed a random effect model meta-analysis to estimate the hazard ratio (HR) and odds ratio (OR) for efficacy and safety outcome variables between PT and IMRT. From 641 identified articles, 11 studies met the inclusion criteria, comprising 3087 patients (606 treated with PT and 2481 with IMRT). On toxicity analysis, PT is associated with decreased acute grade 1 nausea (OR = 0.34, 95% CI: 0.13-0.84, p = 0.02) compared to IMRT. In grade 2 toxicity, PT showed significant advantages over IMRT in mucositis (OR = 0.44, p < 0.0001), dysgeusia (OR = 0.35, p = 0.02), dysphagia (OR = 0.36, p < 0.0001), fatigue (OR = 0.29, p = 0.001), pain (OR = 0.34, p = 0.01), and weight loss (OR = 0.54, p = 0.02). Proton therapy also exhibited increased safety in grade 3 dysphagia incidence (OR = 0.44, p < 0.0001) compared to IMRT. PT demonstrated improved overall survival (OS) compared to IMRT across multiple time points: 1-year OS (HR = 0.43, p = 0.02), 2-year OS (HR = 0.44, p < 0.0001), and 5-year OS (HR = 0.78, p = 0.004). In terms of disease-free survival (DFS), PT also showed improved outcomes at 2-year DFS (HR = 0.65, p = 0.03) and 5-year DFS (HR = 0.81, p = 0.03). Proton therapy demonstrated superior overall survival (OS), disease-free survival (DFS), and better local control rate (LCR) compared to IMRT. The data also showed better safety outcomes in PT patients, particularly when involving grade 2 acute toxicity events.
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Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.
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BACKGROUND: Tumor dissemination to cervical lymph nodes via lymphatics represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant predictor of tumor recurrence decreasing survival by 50%. The lymphatic suppressing properties of mTOR inhibitors are not yet well understood. METHODS: Lymphatic inhibiting effects of rapamycin were evaluated in vitro using two lymphatic endothelial cell (LEC) lines. An orthotopic mouse model of HNSCC (OSC-19 cells) was used to evaluate anti-lymphangiogenic effects of rapamycin in vivo. The incidence of cervical lymph node metastases, numbers of tumor-free lymphatic vessels and those invaded by tumor cells in mouse lingual tissue, and expression of pro-lymphangiogenic markers were assessed. RESULTS: Rapamycin significantly decreased lymphatic vascular density (p = 0.027), reduced the fraction of lymphatic vessels invaded by tumor cells in tongue tissue (p = 0.013) and decreased metastasis-positive lymph nodes (p = 0.04). Rapamycin also significantly attenuated the extent of metastatic tumor cell spread within lymph nodes (p < 0.0001). We found that rapamycin significantly reduced LEC proliferation and was correlated with decreased VEGFR-3 expression in both LEC, and in some HNSCC cell lines. CONCLUSIONS: The results of this study demonstrate anti-lymphangiogenic properties of mTOR inhibitors in HNSCC. mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing VEGF-C/VEGFR-3 axis and release of soluble VEGFR-2. In a murine HNSCC orthotopic model rapamycin significantly suppressed lymphovascular invasion, decreased cervical lymph node metastasis and delayed the spread of metastatic tumor cells within the lymph nodes.
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Antineoplásicos/farmacología , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Linfangiogénesis/efectos de los fármacos , Metástasis Linfática/patología , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones SCID , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Objectives: The objective of this article is to review options for regional pedicled reconstruction for large head and neck defects in a salvage setting. Methods: Relevant regional pedicled flaps were identified and reviewed. Expert opinion and supporting literature were used to summarize and describe the available options. Results: Specific regional pedicled flap options are presented including the pectoralis major flap, deltopectoral flap, supraclavicular flap, submental flap, latissimus flap, and trapezius flap. Conclusions: Regional pedicled flaps are useful options in a salvage setting even for large defects and should be in the armamentarium of any reconstructive head and neck surgeon. Each flap option carries specific characteristics and considerations.
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In this Special Issue of Cancers, the role of oncogenic human papilloma virus (HPV) with oropharyngeal squamous cell carcinoma is explored [ ].
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TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50-60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. Here, we investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.
Asunto(s)
Everolimus , Neoplasias de Cabeza y Cuello , Ratones , Animales , Humanos , Everolimus/farmacología , Everolimus/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Linfangiogénesis , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratones Desnudos , Proteína p53 Supresora de Tumor/genética , Serina-Treonina Quinasas TOR/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Línea Celular Tumoral , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Transoral Robotic Surgery (TORS) has become widely adopted for the surgical removal of oropharyngeal squamous cell carcinoma (OPSCC), with the most common locations being in the tonsil and base of tongue (BOT). However, it is currently unknown if TORS has equal efficacy and outcomes in patients with tonsillar or BOT OPSCC. Therefore, the aim of this study was to compare the margin status and recurrence rates of tonsillar and BOT OPSCC after TORS. Per PRISMA guidelines, PubMed, Scopus, and CINAHL were systematically searched from inception to 2/28/2022. Articles including the surgical management of OPSCC with TORS that compared margin status, complications, and recurrence between tonsil and BOT were included. Meta-analyses of proportions and odds ratios were performed. A total of 28 studies were included, comprising 1769 patients with tonsillar OPSCC and 1139 patients with BOT OPSCC. HPV positivity was seen in 92.3% of tumors. BOT OPSCC had a higher rate of positive margins compared to tonsillar OPSCC (28.1% [95%CI 15.1-43.3] vs. 7.5% [95%CI 3.3-13.3]). No differences were seen in recurrence between BOT and tonsillar OPSCC (OR 1.1 [95%CI 0.8-1.5], p = 0.480). In addition, no differences in postoperative hemorrhage were seen between tonsillar and BOT OPSCC (10.7% [95%CI 6.1-16.5] vs. 8.8% [95% CI 1.5-21.3]). While a higher rate of positive margins was seen in BOT OPSCC when compared to tonsil OPSCC, this did not translate to a higher recurrence rate in the BOT group. Future research on which subset of patients with BOT is more likely to have positive margins is warranted to improve the utility of TORS further.
RESUMEN
Background: The United States of America is the leading country in confirmed cases of and deaths from severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID-19). In April and May 2020, respectively, 0.2% of patients in a Chinese COVID-19-positive cohort and 20.4% of patients in an Italian COVID-19-positive cohort developed cutaneous abnormalities. Cutaneous abnormalities associated with COVID-19 are not well documented or discussed, and investigation of cutaneous manifestations is necessary to determine if they have any clinical value. Methods: We conducted a retrospective study of COVID-19-positive patients who were admitted to Ochsner-Louisiana State University-Shreveport and Ochsner-Louisiana State University-Monroe facilities in Louisiana. Cutaneous manifestations were determined from clinical notes, descriptions in medical records, and a billing code for skin rashes. Results: Of 1,086 COVID-19-positive patients investigated, 871 were African American and 130 were Caucasian. Only 10 patents exhibited probable COVID-19-induced cutaneous abnormalities: 6 (0.7%) of the 871 African American patients and 4 (3.1%) of the 130 Caucasian patients. Dermatologic abnormalities included pruritic or erythematous rash and hypopigmentation of the face, upper chest, abdomen, and trunk areas. Our data are consistent with the smaller percentage of patients in the Chinese cohort study vs the larger percentage in the Italian cohort study. Conclusion: Our data provide evidence that cutaneous manifestations of COVID-19, especially in African American patients, are rare, but documentation of more cases is necessary to establish a cause and effect for COVID-19-induced skin manifestations.
RESUMEN
OBJECTIVES: Pneumatic compression garment therapy (PCGT) has been established as treatment for postradiotherapy lymphedema, and its use in head and neck patients is becoming more common. Although effects on interstitial edema of the cervical soft tissues have been studied, effects on internal laryngopharyngeal edema, as well as associated symptoms of dysphagia and dysphonia, have yet to be published. METHODS: We surveyed 7 patients treated with radiation for head and neck cancer (HNC) who had also been prescribed PCGT for cervical lymphedema. Patients were asked about subjective experience with the device, and also administered the Eating Assessment Tool-10 (EAT-10) and Voice Handicap Index-10 (VHI-10) surveys regarding their symptoms after using PCGT. Laryngoscopy videos from these same periods were also reviewed and scored using a validated tool for assessing laryngopharyngeal edema. RESULTS: 85% of patients reported at least some improvement in dysphagia and dysphonia following PCGT. Average EAT-10 score after PCGT was 11.4 and average VHI-10 score after PCGT was 8.7. These compare more favorably to historical scores for the same questionnaires in similar patient populations. Laryngeal edema scores on endoscopic examination were not significantly different after at least 3 months of therapy (pre: 20.15, post: 20.21, P = .975); however, the utility of this result is limited by a low inter-rater reliability (Krippendorff α = .513). CONCLUSIONS: While we are unable to show any difference in objective assessment of laryngopharyngeal edema on endoscopic examination in this small pilot study, patients report substantial subjective improvement in postradiotherapy dysphagia and dysphonia following cervical PCGT that warrants more formal investigation.