CD271 mRNA/hnRNPA2B1 complex promotes proliferation and stemness in oral and head and neck squamous cell carcinoma.

RNAs, such as noncoding RNA, microRNA, and recently mRNA, have been recognized as signal transduction molecules. CD271, also known as nerve growth factor receptor, has a critical role in cancer, although the precise mechanism is still unclear. Here, we show that CD271 mRNA, but not CD271 protein, facilitates spheroid cell proliferation. We established CD271-/- cells lacking both mRNA and protein of CD271, as well as CD271 protein knockout cells lacking only CD271 protein, from hypopharyngeal and oral squamous cell carcinoma lines. Sphere formation was reduced in CD271-/- cells but not in CD271 protein knockout cells. Mutated CD271 mRNA, which is not translated to a protein, promoted sphere formation. CD271 mRNA bound to hnRNPA2B1 protein at the 3'-UTR region, and the inhibition of this interaction reduced sphere formation. In surgical specimens, the CD271 mRNA/protein expression ratio was higher in the cancerous area than in the noncancerous area. These data suggest CD271 mRNA has dual functions, encompassing protein-coding and noncoding roles, with its noncoding RNA function being predominant in oral and head and neck squamous cell carcinoma.

Delta-6 desaturase FADS2 is a tumor-promoting factor in cholangiocarcinoma.

Cholangiocarcinoma is a fatal disease with limited therapeutic options. We screened genes required for cholangiocarcinoma tumorigenicity and identified FADS2, a delta-6 desaturase. FADS2 depletion reduced in vivo tumorigenicity and cell proliferation. In clinical samples, FADS2 was expressed in cancer cells but not in stromal cells. FADS2 inhibition also reduced the migration and sphere-forming ability of cells and increased apoptotic cell death and ferroptosis markers. Lipidome assay revealed that triglyceride and cholesterol ester levels were decreased in FADS2-knockdown cells. The oxygen consumption ratio was also decreased in FADS2-depleted cells. These data indicate that FADS2 depletion causes a reduction in lipid levels, resulting in decrease of energy production and attenuation of cancer cell malignancy.

Preoperative serum interleukin-6 level in head and neck cancer reflects systemic inflammatory response and is a predictor of postoperative prognosis.

BACKGROUND: The outcome of head and neck cancer has improved in recent years but survival is not yet satisfactory. Interleukin (IL)-6 is a representative inflammatory cytokine and inducer of systemic inflammatory response. It is not known whether preoperative serum level of IL-6 is a prognostic factor in head and neck cancer surgery. METHODS: We studied 181 consecutive patients who underwent head and neck surgery with free tissue transfer reconstruction (HNS-FTTR) between September 2016 and December 2020. Whether preoperative serum IL-6 level was a prognostic risk factor was retrospectively investigated by univariate and multivariate analyses. We also investigated the association between preoperative IL-6 level and representative systemic inflammatory response markers. RESULTS: The preoperative IL-6 ≥ 8 pg/mL group had a significantly worse prognosis than the preoperative IL-6 < 8 pg/mL group (overall survival [OS]: hazard ratio [HR] 3.098, P = 0.0006; disease-specific survival [DSS]: HR 3.335, P = 0.0008). In multivariate analysis, IL-6 ≥ 8 pg/mL and age ≥ 70 years were independent poor prognostic factors for OS (HR 1.860, P = 0.0435 and HR 1.883, P = 0.0233, respectively). The only independent poor prognostic factor for DSS was IL-6 ≥ 8 pg/mL (HR 2.052, P = 0.0329). Serum albumin was significantly lower and serum C-reactive protein and neutrophil-to-lymphocyte ratio were significantly higher in the IL-6 ≥ 8 pg/mL group than in the IL-6 < 8 pg/mL group (all P < 0.0001). CONCLUSIONS: Preoperative serum IL-6 level is an independent poor prognostic factor for both OS and DSS after HNS-FTTR, reflecting the degree of preoperative systemic inflammatory response.

Efficacy of an enhanced recovery after surgery pathway to manage pain, nausea and vomiting after head and neck surgeries with free tissue transfer reconstruction.

BACKGROUND: Pain and post-operative nausea and vomiting are the main factors that impair the quality of recovery after surgery. Very few reports have analyzed patient-reported outcomes to investigate the efficacy of an enhanced recovery after surgery protocol to alleviate these symptoms after head and neck surgeries with free tissue transfer reconstruction. METHODS: We investigated post-operative pain and post-operative nausea and vomiting in 47 patients who underwent head and neck surgeries with free tissue transfer reconstruction with enhanced recovery after surgery support between February 2021 and August 2022. Patient-reported outcomes were assessed using the visual analog scale and Japanese version of the Quality of Recovery-40. RESULTS: Significant increases in the mean visual analog scale scores for pain and post-operative nausea and vomiting were observed only on post-operative Day 1 compared with preoperative values (pain: 3.19 ± 2.78 vs. 1.96 ± 2.42, P = 0.0408; post-operative nausea and vomiting: 1.52 ± 2.09 vs. 0.54 ± 1.37, P = 0.0194). From post-operative Day 2, there were no significant differences between the pre- and post-operative visual analog scale scores, and no significant increases in the incidences of moderate or severe pain and post-operative nausea and vomiting compared with preoperatively. The Japanese version of the Quality of Recovery-40 score for post-operative pain showed no significant deterioration compared with preoperatively, while the Japanese version of the Quality of Recovery-40 score for post-operative nausea and vomiting showed significant deterioration compared with the preoperative value on post-operative Days 2, 4 and 7. CONCLUSIONS: The visual analog scale and Japanese version of the Quality of Recovery-40 scores for post-operative pain and visual analog scale score for post-operative nausea and vomiting suggested that the enhanced recovery after surgery strategy favorably controlled pain and post-operative nausea and vomiting after head and neck surgeries with free tissue transfer reconstruction. However, as the post-operative Japanese version of the Quality of Recovery-40 score for post-operative nausea and vomiting was lower than the preoperative value, there is still a need for further improvement of the enhanced recovery after surgery pathway.

Establishment of a monoclonal antibody against glycosylated CD271 specific for cancer cells in immunohistochemistry.

Various proteins are highly expressed in cancer (e.g., epidermal growth factor receptor); however, the majority are also expressed in normal cells, although they may differ in expression intensity. Recently, we reported that CD271 (nerve growth factor receptor), a glycosylated protein, increases malignant behavior of cancer, particularly stemlike phenotypes in squamous cell carcinoma (SCC). CD271 is expressed in SCC and in normal epithelial basal cells. Glycosylation alterations generally occur in cancer cells; therefore, we attempted to establish a cancer-specific anti-glycosylated CD271 antibody. We purified recombinant glycosylated CD271 protein, immunized mice with the protein, and screened hybridomas using an ELISA assay with cancer cell lines. We established a clone G4B1 against CD271 which is glycosylated with O-glycan and sialic acid. The G4B1 antibody reacted with the CD271 protein expressed in esophageal cancer, but not in normal esophageal basal cells. This specificity was confirmed in hypopharyngeal and cervical cancers. G4B1 antibody recognized the fetal esophageal epithelium and Barrett's esophagus, which possess stem cell-like characteristics. In conclusion, G4B1 antibody could be useful for precise identification of dysplasia and cancer cells in SCC.

Pyogenic spondylitis caused by Streptococcus dysgalactiae subspecies equisimilis in a patient with nasopharyngeal cancer.

In the treatment of head and neck cancer, radiation therapy is an effective modality and is often used in routine clinical practice. Although rare, pyogenic spondylitis has been reported as a complication of radiation therapy. Here, we report a case of nasopharyngeal carcinoma resulting in pyogenic spondylitis from a catheter-related bloodstream infection after chemoradiotherapy. The initial symptoms were fever and posterior cervical pain. Streptococcus dysgalactiae subspecies equisimilis was detected in blood cultures. Magnetic resonance imaging showed abnormal enhancement of the C6 and C7 vertebrae and an anterior epidural abscess. The infection was successfully treated with antibacterial therapy.

Discovery of a chemical compound that suppresses expression of BEX2, a dormant cancer stem cell-related protein.

Cancer stem cells (CSCs) are believed to cause cancer metastasis and recurrence. BEX2 (brain expressed X-linked gene 2) is a CSC-related gene that is expressed in dormant CSCs in cholangiocarcinoma and induces resistance against chemotherapy. The aim of the present study was to identify small compounds that have activity to inhibit BEX2 expression and result in the attenuation of CSC-related phenotypes. We screened 9600 small chemical compounds in high-throughput screening using cholangiocarcinoma cell line HuCCT1 expressing BEX2 protein fused with NanoLuc, and identified a compound, BMPP (1, 3-Benzenediol, [4-(4-methoxyphenyl)-1H-pyrazol-3-yl]). BMPP was found to exert decreasing effects on BEX2 protein expression and G0 phase population of the tumor cells, and increasing effects on ATP levels and chemotherapeutic sensitivity of the cells. These findings indicate that BMPP is a valuable chemical compound for reducing dormant CSC-related phenotypes. Thus, the identification of BMPP as a potential CSC suppressor provides scope for the development of novel therapeutic modalities for the treatment of cancers with BEX2 overexpressing CSCs.

Preoperative prognostic nutritional index as a method to predict postoperative complications after major head and neck surgery with free tissue transfer reconstruction.

BACKGROUND: Head and neck (H&N) cancer patients are often malnourished and have diminished immunity. H&N surgery with free tissue transfer reconstruction (HNS-FTTR) is associated with a relatively high incidence of postoperative complications. METHODS: Associations between possible risk factors and postoperative Clavien-Dindo (C-D) grades ≥ II and ≥ IIIa wound healing- or infection-related complications, postoperative overall complications and prolonged hospital stay were investigated in 188 patients who underwent HNS-FTTR during 2014-2018. The preoperative prognostic nutritional index (PNI) was calculated using the serum albumin level and total lymphocyte count. RESULTS: C-D ≥ II and ≥ IIIa complications were seen in 66 (35.1%) and 37 (19.7%) patients, respectively. Multivariate analysis showed that (i) previous irradiation was significantly associated with C-D ≥ II wound healing- or infection-related complications and prolonged hospital stays [odds ratio (OR) 3.096 and 3.328; P = 0.007 and 0.008, respectively]; and (ii) operation time of ≥9 h 20 min was a significant risk factor for C-D ≥ IIIa wound healing- or infection-related complications, and C-D ≥ IIIa overall complications (OR 2.987 and 2.257; P = 0.021 and 0.047, respectively). (3) Only preoperative PNI ≤ 40 was associated with all occurrences of C-D ≥ II and ≥ IIIa wound healing- or infection-related complications, C-D ≥ II and ≥ IIIa overall complications, and prolonged hospital stays (OR 3.078, 2.918, 2.627, 3.132 and 3.116; P = 0.020, 0.046, 0.036, 0.023 and 0.025, respectively). CONCLUSIONS: PNI, easily calculated, was the lone risk factor significantly predicting all C-D ≥ II and ≥ IIIa postoperative wound healing- or infection-related complications, C-D ≥ II and ≥ IIIa postoperative overall complications and prolonged hospital stay after HNS-FTTR.

Retrospective observational study of occult cervical lymph-node metastasis in T1N0 tongue cancer.

Objective: Delayed neck metastasis is the most significant prognostic factor for early tongue cancer. The main strategies for controlling cervical lymph nodes in Japan are elective neck dissection or watchful waiting. Elective neck dissection offers significantly better survival, but adversely impacts patient quality of life; consequently, here we investigated how to identify high-risk patients warranting elective neck dissection. Methods: We retrospectively evaluated 67 patients with T1N0 oral tongue squamous cell carcinoma who underwent primary treatment in our department from April 2001 to March 2015. All the patients underwent watchful waiting alone for neck management. We investigated the rates of occult neck metastasis, prognosis and circumstances of recurrence, and associations with pathological tumor thickness, depth and muscle invasion by the primary tumor. Correlation between the thickness in pathological specimens and that at magnetic resonance imaging was additionally investigated. Results: Neck recurrence was evident in 20 patients, of which 19 developed within 1 year. Therefore, the rate of occult neck metastasis was 29.9%. Patients with muscle invasion, tumor thickness ≥2 mm or tumor depth ≥2 mm on surgical specimens were significantly more likely to develop delayed neck metastasis. Prognosis was significantly worse for patients with muscle invasion or tumor thickness ≥2 mm. Thickness using magnetic resonance imaging was well correlated with pathological thickness. Conclusions: Patients with tumors ≥2 mm in thickness or muscle invasion developed neck metastasis, suggesting that elective neck dissection may be warranted for patients with these findings. For preoperative assessment of the need for elective neck dissection, magnetic resonance imaging would be a potential modality for T1N0 tongue cancer.

Effect of HMB/Arg/Gln on the prevention of radiation dermatitis in head and neck cancer patients treated with concurrent chemoradiotherapy.

OBJECTIVE: This prospective randomized Phase II study was designed to evaluate the preventive effect of an oral nutrition supplement composed of beta-hydroxy-beta-methylbutyrate, arginine and glutamine (beta-hydroxy-beta-methylbutyrate/arginine/glutamine) on radiation dermatitis in head and neck cancer patients. METHODS: Forty patients with histologically proven head and neck cancer, treated with concurrent chemoradiotherapy involving cisplatin were recruited. They were randomly assigned to the beta-hydroxy-beta-methylbutyrate/arginine/glutamine supplement treatment group (Group A) or the control group that received no supplement (Group B). The primary endpoint of this study was the percentage of patients developing ≥Grade 3 dermatitis. The secondary endpoints were the percentage of patients developing ≥Grade 2 dermatitis, and the duration of each grade of dermatitis relative to the observation period. RESULTS: The incidence of ≥Grade 3 dermatitis did not differ between the two groups. However, as secondary endpoints of this study, the incidence of ≥Grade 2 dermatitis was lower in Group A than B (62.6 vs. 94.4%; P < 0.05), and the duration of ≥Grade 1 dermatitis was shorter in Group A than B (44.8 vs. 56.7%; P < 0.01), as was the duration of ≥Grade 2 dermatitis (16.5 vs. 26.5%; P < 0.05). CONCLUSIONS: Our study indicated that beta-hydroxy-beta-methylbutyrate/arginine/glutamine supplementation was potentially effective in the prevention of radiation dermatitis in head and neck cancer patients.

Central-part laryngectomy is a useful and less invasive surgical procedure for resolution of intractable aspiration.

A novel narrow-field laryngectomy procedure known as central-part laryngectomy (CPL) for less invasive laryngeal diversion in patients with intractable aspiration is introduced. We conducted retrospective case reviews of 15 patients who underwent CPL. In this procedure, an area of the glottis including the mid-part of the thyroid cartilage and cricoid cartilage is removed to separate the digestive tract from the air way. The lateral part of the thyroid cartilage, the entire hypopharyngeal mucosa and epiglottis are preserved. The superior laryngeal vessels and nerve are not invaded. All fifteen patients were relieved of aspiration without major complications. In good accordance with cutting of the cricopharyngeal muscles and removal of the cricoid cartilage, postoperative videofluoroscopy demonstrated smooth passages of barium. Ten of 12 patients who had hoped to resume oral food intake became able to do so after CPL and two others also achieved partial oral deglutition. CPL is a useful procedure for treatment of intractable aspiration and offers considerable advantages over other laryngotracheal diversion procedures from the view point of oral food intake.

Enhanced recovery pathways for head and neck surgery with free tissue transfer reconstruction.

The enhanced recovery after surgery (ERAS) pathway is designed to facilitate recovery after surgery by packaging evidence-based protocols specific to each aspect of the perioperative period, including the preoperative, intraoperative, postoperative, and post-discharge periods. The ERAS pathway, which was originally developed for use with colonic resection, is now being expanded to include a variety of surgical procedures, and the ERAS Society has published a consensus review of the ERAS pathway for head and neck surgery with free tissue transfer reconstruction (HNS-FTTR). The ERAS pathway for HNS-FTTR consists of various important protocols, including early postoperative mobilization, early postoperative enteral nutrition, abolition of preoperative fasting, preoperative enteral fluid loading, multimodal pain management, and prevention of postoperative nausea and vomiting. In recent years, meta-analyses investigating the utility of the ERAS pathway in head and neck cancer surgery have also been presented, and all reports showed that the length of the postoperative hospital stay was reduced by the implementation of the ERAS pathway. The ERAS pathway is now gaining traction in the field of head and neck surgery; however, the details of its efficacy remain uncertain. We believe the future direction will require research focused on improving the quality of postoperative patient recovery and patient satisfaction. It will be important to use patient-reported outcomes to determine whether the ERAS pathway is actually beneficial.

Neck dissection for treatment of supraglottic carcinoma associated with deep-seated intermuscular lipoma in the neck: A case report.

Lipomas are superficial tumors that occur primarily in the subcutaneous region and very rarely occur deeply within or between the muscle layers. No reports to date have described cervical lipomas in patients with head and neck cancer who underwent neck dissection. We herein report a case involving a 72-year-old woman with supraglottic carcinoma complicated by a cervical lipoma who underwent simultaneous neck dissection and lipoma removal. The lipoma was a deep-seated intermuscular lipoma arising in the longus cervicis muscle. We initially considered that the lipoma would be removed en bloc with neck dissection, but the imaging findings clearly indicated that the tumor was located more deeply than the prevertebral layer of the deep cervical fascia and outside the range of neck dissection. The lipoma was removed by incision of the prevertebral fascial layer following neck dissection, and no complications occurred.

Preoperative assessment of hyperactive delirium risk after head and neck surgery with free tissue transfer reconstruction.

OBJECTIVE: Hyperactive delirium with agitation following head and neck surgeries with free tissue transfer reconstruction (HNS-FTTR) represents a critical and potentially life-threatening postoperative complication. Although preoperative risk assessment is important, no established risk screening tool has been developed to accurately predict its occurrence. METHODS: In this retrospective observational study, we examined 192 consecutive patients who underwent HNS-FTTR between August 2019 and January 2024. We assessed the effectiveness of the existing delirium risk screening system, the DELirium Team Approach program which includes factors such as age ≥ 70 years, presence of brain disorders, dementia, alcohol consumption habits, a history of delirium, and use of benzodiazepines. Additionally, we explored the association between each risk factor and the onset of delirium. RESULTS: Delirium occurred in 43 patients (22.4 %). The risk screening tool effectively predicted the occurrence of hyperactive delirium after HNS-FTTR (OR: 8.316; 95 % CI: 2.205-36.060; p = 0.004), with a sensitivity of 95.3 % and a specificity of 28.9 %. Multivariate analysis revealed age ≥ 70 years (OR: 2.179; 95 % CI: 1.058-4.662; p = 0.0383) and alcohol consumption habits (OR: 2.554; 95 % CI: 1.260-5.268; p = 0.0098) as significant independent risk factors. CONCLUSION: Our findings suggest that the risk screening system evaluated in this study appears to be sensitive, simple, and effective for the preoperative prediction of hyperactive postoperative delirium following HNS-FTTR.

Effect of acute kidney injury and overall survival in patients with postoperative head and neck cancer who received chemoradiotherapy with cisplatin: A supplementary analysis of the phase II/III trial of JCOG1008.

BACKGROUND: In a randomized phase II/III trial (JCOG1008), weekly cisplatin (40 mg/m2) was non-inferior to 3-weekly cisplatin (100 mg/m2) for postoperative high-risk head and neck cancer. We investigated how acute kidney injury (AKI), a major dose-limiting toxicity effect of cisplatin, affects overall survival (OS). METHODS: We analyzed 251 patients from JCOG1008 receiving chemoradiotherapy. AKI was defined based on AKI Network criteria (serum creatinine increase of ≥0.3 mg/dL or ≥1.5-fold [≥ stage I]) within 30 days after completing chemoradiotherapy. OS in the two arms was compared according to AKI development using the log-rank test. RESULTS: The total incidence of AKI was lower in the weekly arm than in the 3-weekly arm (38/122 [31.1%] vs. 56/129 [43.4%]). Additionally, stage II/III AKI occurred less frequently in the weekly arm than in the 3-weekly arm (8/122 [6.6%] vs. 19/129 [14.7%]). Cisplatin doses were similar in the weekly arm for patients with and without AKI (median, 238.6 mg/m2 vs. 239.2 mg/m2; p = 0.94), but lower in the 3-weekly arm for those who developed AKI (median, 276.3 mg/m2 vs. 297.4 mg/m2; p = 0.007). In the weekly arm, there was no difference in OS between patients with and without AKI (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.53 to 2.10). However, in the 3-weekly arm, patients with AKI had poorer OS than those without AKI (HR, 1.83; 95% CI, 1.04 to 3.21). CONCLUSIONS: In this supplementary analysis of JCOG1008 data, AKI impacted the OS of patients with head and neck cancer undergoing postoperative chemoradiotherapy in the 3-weekly arm but not in the weekly arm. Our results further endorse the utilization of weekly cisplatin at 40 mg/m2 in this setting.

Risk prediction model for cisplatin-induced acute kidney injury in patients with head and neck cancer receiving chemoradiotherapy: A re-analysis of a phase II/III JCOG1008 trial.

OBJECTIVES: Acute kidney injury (AKI) represents a major toxicity associated with cisplatin. We developed a risk prediction model for cisplatin-induced AKI in patients with postoperative high-risk head and neck cancer who received chemoradiotherapy during a randomized phase II/III trial, JCOG1008. MATERIALS AND METHODS: Two hundred and fifty-one patients received radiotherapy with weekly cisplatin at 40 mg/m2 (weekly arm) or 3-weekly cisplatin at 100 mg/m2 (3-weekly arm). AKI was defined using the AKI Network classification/staging system as increased serum creatinine of ≥0.3 mg/dL or a ≥1.5-fold increase from baseline 30 days after completing chemoradiotherapy. The Akaike information criterion was used to explore the optimal model by combining explanatory variables at registration. RESULTS: Among the 251 patients (210 men and 41 women (median age; 62 years)), 94 (37.5 %) developed cisplatin-induced AKI. The optimal cisplatin-induced AKI risk prediction model comprised four factors, including a primary site of hypopharynx/larynx (vs. oral cavity/oropharynx), 3-weekly arm (vs. weekly arm), serum albumin of ≤3.5 g/dL (vs. >3.5 g/dL) and creatinine clearance (CCr) of <90 mL/min (vs. ≥90 mL/min). The incidence of cisplatin-induced AKI rose with cumulative count of the four factors. When the cumulative count was ≥2, the positive predictive value for cisplatin-induced AKI was 50.3 %. CONCLUSIONS: We developed a risk prediction model for cisplatin-induced AKI in patients with head and neck cancer who received postoperative chemoradiotherapy using primary site, cisplatin administration method, serum albumin, and CCr. Patients with risk factors unrelated to the cisplatin administration method should adopt a weekly cisplatin regimen.

Extent of thyroidectomy and paratracheal lymph node dissection in total pharyngolaryngectomy for pyriform sinus cancer, and recurrence, survival, and postoperative hypoparathyroidism: A multicenter retrospective study.

BACKGROUND: Total pharyngolaryngectomy (TPL) is standard treatment for hypopharyngeal cancer. However, extensive thyroidectomy and paratracheal nodal dissection (PTND) can cause hypoparathyroidism. We sought to determine the optimum extent of resection. METHODS: We analyzed the clinicopathological information of 161 pyriform sinus cancer patients undergoing TPL from 25 Japanese institutions. Rates of recurrence and risk factors for hypoparathyroidism, as well as incidence of pathological contralateral level VI nodal metastasis and stomal recurrence, were investigated. RESULTS: The extent of thyroidectomy and nodal dissection were not independent risk factors for recurrence. Incidences of contralateral level VI nodal involvement and stomal recurrence were 1.8% and 1.2%, respectively. Patients undergoing hemithyroidectomy/ipsilateral PTND did not develop stomal recurrence and had the lowest incidence of hypoparathyroidism. Prognosis in patients without tracheostomy prior to hemithyroidectomy/ipsilateral PTND was comparable to that with more extensive resections. CONCLUSIONS: Hemithyroidectomy/ipsilateral PTND may be sufficient for pyriform sinus cancer cases without tracheostomy.

Incidence and risk factors associated with the development of hypothyroidism after postoperative chemoradiotherapy for head and neck cancer patients with high-risk features: Supplementary analysis of JCOG1008.

BACKGROUND AND PURPOSE: Hypothyroidism is a recognized late adverse event following radiotherapy for head and neck cancer (HNC). In the JCOG1008 trial, we treated patients with high-risk HNC with postoperative chemoradiotherapy. We aimed to elucidate factors associated with hypothyroidism by analyzing the JCOG1008 data. MATERIALS AND METHODS: In 2012-2018, 261 patients from 28 institutions were enrolled in JCOG1008. Thyroid function tests were conducted to assess hypothyroidism, including free thyroxine (FT4) and thyroid-stimulating hormone assays. Hypothyroidism was defined as Grade 2 or higher in CTCAE v4.0. Various clinical and dosimetric parameters were analyzed. In radiotherapy, there were no dose constraints for the thyroid. Multivariable analysis was conducted on these variables to identify predictive factors for hypothyroidism. RESULTS: The analysis included 162 patients (57 with 3D-CRT and 105 with IMRT), with a median follow-up of 4.7 years (0.3-9.3 years). Among these, 27 (16.7 %) developed hypothyroidism within 2 years after radiotherapy. In a multivariable analysis, the weekly cisplatin [OR=7.700 (CI: 1.632-36.343, p = 0.010)] and baseline FT4 [OR=0.009 (CI: <0.001-0.313, p = 0.010)] were significantly associated with hypothyroidism in the IMRT group. Regarding dosimetric characteristics, V60Gy [OR=1.069 (CI: 0.999-1.143, p = 0.054)] was potentially associated with the development of hypothyroidism. CONCLUSION: The study revealed that the incidence of hypothyroidism within 2 years after postoperative chemoradiotherapy for high-risk HNC was 16.7 % based on analytical results from prospective clinical trials.

Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma.

Background: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

Postoperative serum interleukin-6 level as a risk factor for development of hyperactive delirium with agitation after head and neck surgery with free tissue transfer reconstruction.

OBJECTIVE: Occurrence of hyperactive postoperative delirium (POD) with agitation after head and neck surgery with free tissue transfer reconstruction (HNS-FTTR) is associated with the risk of life-threatening complications. The relationships between occurrence of hyperactive POD after HNS-FTTR and inflammatory markers reflecting the surgical stress response, represented by postoperative interleukin-6 levels, are not fully understood. METHODS: A retrospective study was conducted on 221 consecutive patients who underwent HNS-FTTR at our department between September 2016 and December 2021. Potential risk factors for POD were examined, including age, operation time, intraoperative blood loss, and postoperative serum levels of blood parameters such as interleukin-6, C-reactive protein, and neutrophil-to-lymphocyte ratio. RESULTS: Hyperactive POD with agitation was observed in 54 subjects (24.4%). The postoperative hospital stay in the POD group was significantly longer than that in the non-POD group (median: 32.5 days vs. 28 days; p=0.0129). Multivariate logistic regression analysis identified age (in years) (odds ratio: 1.102; p<0.0001), operation time (min) (odds ratio: 1.004; p=0.0359), and postoperative serum interleukin-6 level (pg/mL) (odds ratio: 1.005; p=0.0384) as significant risk factors for development of POD. In a receiver operating characteristic curve and area under the curve analysis, the cut-off value for postoperative serum interleukin-6 level to predict POD development was 82.5 pg/mL. The postoperative serum interleukin-6 ≥82.5 pg/mL group developed hyperactive POD with agitation significantly more often than the postoperative serum IL-6 <82.5 pg/mL group (odds ratio: 4.400; p<0.0001). The postoperative serum IL-6 ≥82.5 pg/mL group also had significantly longer postoperative hospital stay (41.58 ± 33.42 days vs. 31.73 ± 22.89 days; p=0.0151), older age (68.60 ± 9.99 years vs. 64.30 ± 12.58 years; p=0.0054), and longer operation time (625.4 ± 114.05 min vs. 575.5 ± 98.73 min; p=0.0009) than the postoperative serum IL-6 <82.5 pg/mL group. CONCLUSION: Postoperative serum interleukin-6 level, as well as age and operation time, were identified as significant independent risk factors for development of hyperactive POD with agitation after HNS-FTTR. Inflammation is a potential target for the prevention and treatment of POD after HNS-FTTR.