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Introduction: Restoring oral intake through oropharyngeal reconstruction is vital for patients undergoing total glossolaryngectomy. Despite its importance, research in this area is limited, leaving clinicians with few guidelines. The debate regarding the optimal shape of the reconstructed oropharynx highlights the need for further research. Methods: This retrospective study analysed data from 16 consecutive patients who underwent primary reconstruction with a free rectus abdominis musculocutaneous flap after total glossolaryngectomy at the University of the Ryukyus Hospital between April 2015 and March 2022. Parameters assessed included reconstructed oropharynx shape (flat or funnel-shaped), demographics, flap characteristics, post-operative course and oral intake outcomes. Results: Among the 16 patients, 10 had flat oropharynx, whereas 6 had a funnel-shaped oropharynx. At 6 months post-surgery, 13 patients resumed oral feeding, whereas 3 did not. Significant differences were observed between the groups in preoperative body mass index (21.1 kg/m² vs 17.8 kg/m², Welch's t-test, p=0.035) and days until the first oral intake (34.2 days vs 19.2 days, Welch's t-test, p=0.01). However, no significant differences were found in the form of oral intake at 6 months after surgery (Fisher's exact test, p=0.518). Conclusion: This study suggests that the shape of the reconstructed oropharynx (flat or funnel-shaped) does not significantly impact long-term post-operative oral intake. These findings provide valuable insights into oropharyngeal reconstruction outcomes after total glossolaryngectomy and offer guidance for future research in this area. Nevertheless, further studies are warranted to elucidate the clinical implications of these findings and address any limitations of this study, particularly those regarding sample size constraints.

In recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC), survival outcomes are significantly better in patients who receive anti-programmed cell death-1 (PD-1) monoclonal antibody therapy than in those who receive standard therapy. However, there is no established biomarker that can predict the anti-PD-1 antibody treatment effect and immune-related adverse events (irAEs) in these patients. This study investigated the inflammatory and nutritional status in 42 patients with R/M-HNSCC and programmed cell death ligand-1 (PD-L1) polymorphisms (rs4143815 and rs2282055) in 35 of the 42 patients. The 1- and 2-year overall survival was 59.5% and 28.6%, respectively; the 1- and 2-year first progression-free survival was 19.0% and 9.5%, respectively, and the respective second progression-free survival was 50% and 27.8%. Performance status and inflammatory and nutritional status (assessed by the geriatric nutritional risk index, modified Glasgow prognostic score, and prognostic nutritional index) were identified as significant indicators of survival outcomes in multivariate analysis. Patients with ancestral alleles in PD-L1 polymorphisms had less frequent irAEs. Performance status and inflammatory and nutritional status before treatment were closely related to survival outcomes after PD-1 therapy. These indicators can be calculated using routine laboratory data. PD-L1 polymorphisms may be biomarkers for predicting irAEs in patients receiving anti-PD-1 therapy.

Abstract Recurrent respiratory papillomatosis (RRP) has a wide range of severity. We investigate the relationship between human papillomavirus (HPV) particle production and severity of RRP. From September 2005 to June 2021, 68 RRP samples (from 29 patients) were included. HPV type was determined. HPV viral load, physical status, and demographic and clinical characteristics were assessed. Immunohistochemistry (IHC) was performed for p16, Ki-67, L1, and E4. We used NanoSuit-CLEM (correlative light and electron microscopy) and transmission electron microscopy (TEM) to examine the samples. The total number of surgeries in HPV-positive and HPV-negative cases were 3.78 (n = 55/68, range: 1–16) and 1.30 (n = 13/68, range: 1–3), respectively (p = 0.02). IHC showed that L1 and E4 were correlated and expressed on the tumour surface. NanoSuit-CLEM and TEM revealed HPV particles in L1-positive nuclei. L1 IHC-positive cases had a shorter surgical interval (p

Abstract Aim Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression‐like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. Methods Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI‐treated group data. Results Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). Conclusion Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant‐like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.

Abstract Prophylactic elective neck dissection (ND) with navigation surgery using radioisotope-based sentinel lymph node biopsy (SLNB) is non-inferior to elective ND in terms of survival but has an advantage in postoperative functional disability. We conducted a subgroup analysis to identify predictive factors for false-negative (FN)-SLNB in patients with early oral cavity cancer. This study is a supplementary analysis using the dataset of a previously reported randomized clinical trial on SLN navigation surgery for oral cancers. This study investigated the association of clinical and SLN-related factors with false-negative cases in the SLNB group. From 2011 to 2016, 275 patients were enrolled and randomly assigned to the ND and SLNB study groups, with 134 patients assigned to the SLNB group. In the SLNB group, seven cases with negative SLNs and neck recurrences were judged as FN-SLNBs according to the general definition. The number of detected SLNs with and without adjusting for the propensity score was significantly associated with FNs in the logistic analysis. FN-SLNB was associated with the number of identified SLNs, suggesting the need for careful postoperative monitoring for neck recurrence in patients with one or two identified SLNs after acquiring sufficient experience in the identification technique.

We report the case of a 14-year-old girl with petrous bone cholesteatoma resected through a combined approach from the middle cranial fossa and mastoid process. A favorable outcome can be achieved when applying the transmastoid approach to a cholesteatoma by incorporating the middle fossa approach to preserve inner ear function. We emphasize the utility of integrated three-dimensional image reconstruction as a surgical strategy to determine beneficial routes for facial and inner ear function and accomplishment of radical resection. Visualization by an integrated image of irregular tumor infiltration within the petrous bone facilitates information sharing for better cooperation between surgeons in otolaryngeal and neurosurgical fields.

Abstract Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D2 receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify®). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti®), another D2 receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40 years in the area of antipsychotic drug discovery for dopamine D2 receptor partial agonists.

Abstract Background Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC). Methods The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC. Results The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression. Conclusions These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.

Resumo Dentre os fatores ambientais que influenciam o crescimento vegetal, tem-se a temperatura do ar. A taxa de crescimento de uma planta pode ser determinada a partir de sua temperatura basal inferior (Tb), que corresponde à temperatura abaixo da qual a taxa de expansão foliar é desprezível ou ocorre de maneira reduzida. Este trabalho teve por objetivo determinar a Tb e a soma térmica (ST) da rúcula Rococó, durante o período compreendido entre a germinação e a colheita em sistemas de produção convencional e hidropônico. O experimento foi realizado em Florianópolis, entre abril de 2018 a março de 2020, totalizando cinco e sete safras conduzidas nos sistemas convencional e hidropônico, respectivamente. A Tb foi obtida pela média de três métodos, a saber: menor desvio padrão em dias, desenvolvimento relativo e coeficiente de regressão. Com o valor de Tb, determinou-se a soma térmica (ST), aplicando o método simplificado de graus-dia para cada uma das safras. A partir dos valores de ST determinados foi obtido uma média para estabelecer a ST da rúcula. Durante o período compreendido entre a germinação e colheita, considerando os sistemas de produção convencional e hidropônico, os valores obtidos de Tb foram respectivamente, 4,4 °C e 3,6 °C, enquanto os de ST foram 559 e 490 graus-dia acumulado.

Abstract Background Oropharyngeal cancers associated with high-risk type human papillomavirus (HR-HPV) infection have better prognosis than virus negative cancers. Similarly, the HPV status in laryngeal cancer (LC) may be associated with better outcome. Methods Samples from 88 patients with LC were investigated using the polymerase chain reaction (PCR) and p16 immunohistochemistry for HR-HPV analysis. The cut-off point for p16 overexpression was diffuse (≥75%) tumor expression with at least moderate (+ 2/3) staining intensity. Results The 5-year cumulative survival (CS) rate was 80.7% in all patients with LC. According to a combination of HR-HPV DNA status and p16 overexpression, subjects with LC were divided into four groups: HR-HPV DNA-positive/p16 overexpression-positive (n = 5, 5.7%; CS = 100%), HR-HPV DNA-positive/p16 overexpression-negative (n = 11, 12.5%; CS =81.8%), HR-HPV DNA-negative/p16 overexpression-positive (n = 0), and HR-HPV DNA-negative/p16 overexpression-negative (n = 72, 81.8%; CS = 79.5%). HR-HPV DNA-positive/p16-positive cases tended to have integrated HPV infection and high viral load, compared with HR-HPV DNA-positive/p16 overexpression-negative cases. Conclusions LC patients with HPV infection and high levels of p16 expression might have an improved survival outcome; however, it is necessary to recruit additional LC cases with HPV infection to determine the definitive characteristics of HPV-mediated LC and estimate survival outcome. These results may contribute to the development of a useful method for selecting patients with a potentially fair response to treatment and ensure laryngeal preservation.

Laryngeal papilloma (LP), which is associated with infection by human papillomavirus (HPV)-6 or -11, displays aggressive growth. The precise molecular mechanism underlying the tumorigenesis of LP has yet to be uncovered. Building on our earlier research into HPV-6, in this study, the viral gene expression of HPV-11 was investigated by quantitative PCR and DNA/RNA in situ hybridization. Additionally, newly developed antibodies against the E4 protein of HPV-6 and HPV-11 were evaluated by immunohistochemistry. The average viral load of HPV-11 in LP was 1.95 ± 0.66 × 105 copies/ng DNA, and 88% of HPV mRNA expression was found to be E4, E5a, and E5b mRNAs. According to RNA in situ hybridization, E4 and E5b mRNAs were expressed from the middle to upper part of the epithelium. E4 immunohistochemistry revealed a wide positive reaction in the upper cell layer in line with E4 mRNA expression. Other head and neck lesions with HPV-11 infection also showed a positive reaction in E4 immunohistochemistry. The distribution pattern of HPV DNA, viral mRNA, and E4 protein in LP with HPV-11 infection was quite similar to that of HPV-6. Therefore, it might be possible to apply these E4-specific antibodies in other functional studies as well as clinical applications, including targeted molecular therapies in patients with HPV-6 and HPV-11 infection.

Laryngeal papilloma (LP) associated with human papillomavirus (HPV)-6 or -11 infection shows aggressive growth. However, the detailed molecular mechanism of virus-driven tumorigenesis has not been uncovered fully. HPV-6 viral gene expression and dynamic alterations were investigated with in situ localization of viral DNA and RNA in 13 patients with HPV-6-infected laryngeal papilloma. The average viral load was 4.80 × 105 ± 1.86 × 105 copies/ng DNA. E4, E5a, and E5b mRNAs accounted for 96% of the expression of 9 mRNAs. The alteration of viral DNA load during recurrence paralleled the mRNA expression levels, and the expression of all mRNAs showed a similar curve. E4, E5a, and E5b were expressed in the middle to upper part of the epithelium and were co-expressed in the same cells. E4 immunohistochemistry demonstrated an extensively positive reaction in the upper cell layer in accordance with E4 mRNA expression. These results suggest that individual viral genes are coordinately expressed for viral replication, virus release, and immunosurveillance avoidance. The newly developed E4-specific monoclonal antibody can be applied to further functional studies and clinical applications such as targeted molecular therapies.

JUSTIFICATIVA E OBJETIVOS: Os pacientes que vão ser submetidos a um procedimento cirúrgico experimentam ansiedade. A ansiedade e a depressão são os distúrbios mais associados às doenças físicas. Na Escala Hospitalar de Ansiedade e Depressão (HADS) não figuram itens que poderiam estar presentes em doenças físicas e na ansiedade e na depressão. O objetivo deste estudo foi medir a freqüência e o nível da ansiedade e da depressão em pacientes no pré-operatório e em um grupo-controle. MÉTODO: Setenta e nove pacientes internados no Departamento de Cirurgia da Santa Casa de São Paulo e 56 acompanhantes responderam a um questionário de dados sociodemográficos e a HADS. RESULTADOS: A avaliação dos sintomas mostrou que 35 (44,3%) pacientes e 36 (64,3%) acompanhantes foram considerados com ansiedade (teste Exato de Fisher - p = 0,03) e 21 (26,6%) pacientes e 23 (41,1%) acompanhantes foram considerados com depressão (p = 0,09). Com relação ao impacto das variáveis sociodemográficas sobre a medida da ansiedade e da depressão, foi observado apenas que os pacientes desempregados apresentaram nível mais elevado de ansiedade. CONCLUSÕES: Este estudo confirmou a possibilidade do uso da escala HADS de ansiedade e depressão em pacientes cirúrgicos internados. Ele mostrou também que a avaliação da ansiedade no período pré-operatório deve ser realizada, independentemente de o paciente apresentar ou não doença clínica e/ou cirúrgica grave, pois a freqüência de pacientes com ansiedade é relevante e estes merecem algum tipo de cuidado diferenciado no mínimo o uso de medicação ansiolítica antes da intervenção cirúrgica. Foram encontrados níveis muito maiores de ansiedade entre os acompanhantes dos pacientes. Essas pessoas, avaliadas sem que houvesse um concomitante problema clínico, possivelmente demonstraram estar expostas a um considerável nível de estresse, o que resultou em estado ansioso maior do que os pacientes que seriam submetidos a procedimento cirúrgico.JUSTIFICATIVA Y OBJETIVOS: Los pacientes que serán sometidos a un procedimiento quirúrgico tuvieron ansiedad. La ansiedad y la depresión son los disturbios más asociados a las enfermedades físicas. En la Escala Hospitalaria de Ansiedad y Depresión (HADS) no figuran ítems que podrían estar presentes en enfermedades físicas y en la ansiedad y en la depresión. El objetivo de este estudio fue medir la frecuencia y el nivel de la ansiedad y de la depresión en pacientes en el preoperatorio y en un grupo control. MÉTODO: Setenta y nueve pacientes internados en el Departamento de Cirugía de la Santa Casa de São Paulo y 56 acompañantes respondieron a un cuestionario de datos socio demográficos y la HADS. RESULTADOS: La evaluación de los síntomas mostró que 35 (44,3%) pacientes y 36 (64,3%) acompañantes fueron considerados con ansiedad (teste exacto de Fisher - p = 0,03) y 21 (26,6%) pacientes y 23 (41,1%) acompañantes fueron considerados con depresión (p = 0,09). En relación al impacto de las variables socio demográficas sobre la medida de la ansiedad y de la depresión, se observó apenas que los pacientes sin empleo presentaron un nivel más elevado de ansiedad. CONCLUSIONES: Este estudio confirmó la posibilidad del uso de la escala HADS de ansiedad y depresión en pacientes quirúrgicos internados. También nos mostró que la evaluación de la ansiedad en el período preoperatorio debe ser realizada, independientemente de que el paciente presente o no enfermedad clínica y/o quirúrgica grave, pues la frecuencia de pacientes con ansiedad es relevante y ellos merecen algún tipo de cuidado diferenciado, como mínimo el uso de medicación ansiolítica antes de la intervención quirúrgica. Fueron encontrados niveles significativamente mayores de ansiedad entre los acompañantes de los pacientes. Esas personas, evaluadas sin que existiese un concomitante problema clínico, posiblemente demostraron estar expuestas a un nivel ostensible de estrés, lo que conllevó a un estado de ansiedad mayor que el que tendrían los pacientes que serían sometidos a procedimiento quirúrgico.BACKGROUND AND OBJECTIVES: Patients scheduled for surgeries experience anxiety. Anxiety and depression are the disorders most commonly associated with organic diseases. The Hospital Anxiety and Depression Scale (HADS) does not include items that could be present in organic diseases and in anxiety and depression. The objective of this study was to measure the frequency and the level of anxiety and depression in preoperative patients and in a control group. METHODS: Seventy-nine patients admitted to the Surgical Department of Santa Casa de São Paulo and 56 caretakers answered a questionnaire on socio-demographic data and the HADS. RESULTS: The evaluation of the symptoms showed that 35 (44.3%) patients and 36 (64.3%) caretakers had anxiety (Fisher Exact test - p = 0.03) and 21 (26.6%) patients and 23 (41.1%) caretakers had depression (p = 0.09). Regarding the impact of the socio-demographic data on the measurement of anxiety and depression, it was only observed that patients that were unemployed had higher anxiety levels. CONCLUSIONS: This study confirmed that the HADS could be used in hospitalized surgical patients. It also showed that patients should be evaluated preoperatively for anxiety and depression, regardless of the presence of severe clinical and/or surgical disorders, because the frequency of patients with anxiety is relevant and they deserve a differentiated approach - at least the administration of tranquilizers before surgery. Caretakers presented significantly higher levels of anxiety. Those people, evaluated in the absence of concomitant clinical problems, probably demonstrated to be exposed to a considerable level of stress, resulting in a higher anxiety state than the patients scheduled for surgeries.

To map comprehensively the methylation status of the CpG sites within the HPV16 long control region (LCR) in HPV-positive cancer cells, and to explore further the effects of methylation status of HPV16 LCR on cell bioactivity and E6 and E7 expression. In addition, to analyze the methylation status of the LCR in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) patients.Methylation patterns of HPV16 LCR in UM-SCC47, CaSki, and SiHa cells and HPV16-positiive OPSCC specimens were detected by bisulfite-sequencing PCR and TA cloning. For cells treated with 5-aza-2'-deoxycytidine and E6 and E7 knockdown, MTS and trypan blue staining, annexin-V and 7-AAD staining, and prodidium iodide were used to evaluate cell growth and cell proliferation, cell apoptosis, and cell cycle arrest, respectively. E6 and E7 mRNA and protein expression were analyzed by quantitative real-time PCR and immunocytochemistry, respectively.Hypermethylation status of the LCR in UM-SCC47 (79.8%) and CaSki cells (90.0%) and unmethylation status of the LCR in SiHa cells (0%) were observed. Upon demethylation, the cells with different methylation levels responded differently during growth, apoptosis, and cell cycle arrest, as well as in terms of their E6 and E7 expression. In HPV16-positive OPSCC patients, the methylation rates were 9.5% in the entire LCR region, 13.9% in the 5'-LCR, 6.0% in the E6 enhancer, and 9.5% in the p97 promoter, and hypermethylation of p97 promoter was found in a subset of cases (20.0%, 2/10).Our study revealed two different methylation levels of the LCR in HPV16-positive cancer cells and OPSCC patients, which may represent different carcinogenesis mechanisms of HPV-positive cancers cells. Demethylating the meCpGs in HPV16 LCR might be a potential target for a subgroup of HPV16-positive patients with head and neck squamous cell carcinoma.