Programmed Death Ligand-1 and Tumor Burden Score Dictate Treatment Responses in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

BACKGROUND: The significance of tumor burden for survival is unknown for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The purpose of our study was to evaluate the prognostic impact of programmed death ligand-1 (PD-L1) and tumor burden score (TBS) in patients with R/M HNSCC. PATIENTS AND METHODS: R/M HNSCC patients who were treated with cisplatin, 5-fluorouracil plus cetuximab (EPF) or pembrolizumab (PPF) as first-line treatment were included in our study. PD-L1 and TBS were estimated and correlated with treatment responses. Kaplan-Meier curves were plotted for outcomes estimation. RESULTS: A total of 252 R/M HNSCC patients were included, with 126 high tumor burden (HTB) and 126 low tumor burden (LTB) patients. Median progression-free survival (PFS) was 7.1 months in LTB and 3.9 months in HTB (p < 0.001) and median overall survival (OS) was 14.2 months in LTB and 9.2 months in HTB (p = 0.001). Patients with LTB had better PFS and OS than those with HTB independent of PD-L1 status. Subgroup analysis showed HTB patients treated with EPF had better survival than those treated with PPF, regardless of PD-L1 expression. For LTB PD-L1 positive patients, there was a longer survival with PPF than EPF, while for LTB PD-L1 negative patients, survival was similar between PPF and EPF. Multivariate analysis exhibited that tumor burden was significantly correlated with OS. CONCLUSIONS: Tumor burden is significantly correlated with survival in patients with R/M HNSCC. PD-L1 and TBS should be taken into consideration to determine first-line treatment.

A Novel Prognostic Model Using Pan-Immune-Inflammation Value and Programmed Death Ligand 1 in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Receiving Immune Checkpoint Inhibitors: A Retrospective Multicenter Analysis.

BACKGROUND: Little is known regarding the prognostication of the Pan-Immune-Inflammation Value (PIV) in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). OBJECTIVES: This study aimed to investigate the prognostic role of PIV in patients with R/M HNSCC receiving immune checkpoint inhibitors (ICI). PATIENTS AND METHODS: Patients who were diagnosed to have R/M HNSCC and treated with ICI were reviewed retrospectively. The cutoff value of PIV was set at the median. Patients were stratified into high PIV and low PIV. Kaplan-Meier curves were estimated for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 192 patients were included in our study for oncologic outcomes evaluation. For the total population, the median PFS was 5.5 months and OS was 18.2 months. After stratification by PIV, median PFS was 11.7 months in the low PIV and 2.8 months in the high PIV groups (p < 0.001). The median OS was 21.8 months in the low PIV and 11.5 months in the high PIV groups (p < 0.001). Multivariate analysis demonstrated that PIV and PD-L1 were independent predictors associated with survival. A prognostic model using both PIV and PD-L1 was constructed. The median PFS was 12.2, 6.4, and 3.0 months for patients with risk scores of 0, 1, and 2, respectively (p < 0.001). The median OS was 23.7, 18.1, and 11.4 months for patients with risk scores of 0, 1, and 2, respectively (p < 0.001). CONCLUSIONS: PIV is a prognostic biomarker in patients with R/M HNSCC treated with ICI. A prognostic model using PIV and PD-L1 could provide outcome prediction and risk stratification.

Comparison of EMG amplitudes recorded by ipsilateral and contralateral electrodes placement during using trans-thyroid cartilage recording method in thyroid surgery.

Objectives: The feasibility and reliability of trans-thyroid cartilage EMG recording method (TCERM) during intraoperative monitoring (IONM) of the recurrent laryngeal nerve (RLN) in thyroid surgery have been established. This study compared two different recording electrode placements on the ipsi-lateral and contra-lateral lamina of the thyroid cartilage (TC). Methods: Fifty consecutive patients undergoing total thyroidectomy with 100 RLNs at risk were enrolled. Two paired subdermal needle electrodes were inserted into the subperichondrium of the bilateral TC lamina to record electromyography (EMG) signals. The channel leads from the TC electrodes were connected to the patient interface with two different modes. In A-mode, the electrode leads were placed ipsi-laterally, and channel 1 monitored the left RLN and channel 2 monitored the right RLN respectively. In B-mode, the electrode leads were placed contra-laterally, and channels 1 and 2 simultaneously monitored the same side of the RLN. The amplitudes of four EMG signals (V1-R1-R2-V2) recorded by A-mode and B-mode were compared. Results: All EMG amplitudes of V1-R1-R2-V2 signals recorded with B-mode were all above 500µV and significantly higher than those with A-mode (p<0.001). No false loss of signal, electrode dislodgement, or needle-related complications were noted during IONM. Postoperatively, all patients had symmetrical vocal cord movement. Lower EMG amplitudes were observed in older and male patients. Histopathology and laterality showed no significant differences in EMG amplitude. Conclusion: During using TCERM in thyroid surgery, the recording electrodes should be placed contra-laterally on the TC lamina. This approach ensures high and stable EMG signals, which are important for high-quality IONM of the RLN.

Proposals for Standardization of Intraoperative Facial Nerve Monitoring during Parotid Surgery.

Intraoperative facial nerve monitoring (FNM) has been widely accepted as an adjunct during parotid surgery to facilitate identification of the facial nerve (FN) main trunk, dissection of FN branches, confirmation of FN function integrity, detection of FN injury and prognostication of facial expression after tumor resection. Although the use of FNM in parotidectomy is increasing, little uniformity exists in its application from the literature. Thus, not only are the results of many studies difficult to compare but the value of FNM technology is also limited. The article reviews the current literature and proposes our standardized FNM procedures during parotid surgery, such as standards in FNM setup, standards in general anesthesia, standards in FNM procedures and application of stimulus currents, interpretation of electrophysiologic signals and prediction of the facial expression outcome and pre-/post-operative assessment of facial expressions. We hope that the FNM standardized procedures will provide greater uniformity, improve the quality of applications and contribute to future research.

Platinum Plus Tegafur-Uracil versus Platinum Alone during Concurrent Chemoradiotherapy in Patients with Nonmetastatic Nasopharyngeal Carcinoma: A Propensity-Score-Matching Analysis.

Concurrent chemoradiotherapy (CCRT) with a cisplatin-based regimen is the standard treatment for patients with nasopharyngeal carcinoma (NPC). Our study was a propensity-score-matching analysis and it aimed to investigate the oncologic outcomes of platinum plus tegafur−uracil versus platinum alone during CCRT in patient with nonmetastatic NPC. Patients with pathologic confirmed NPC in 2018−2022 were reviewed. Patients treated with platinum plus tegafur−uracil (CCRT-UP) or platinum alone (CCRT-P) during CCRT were recruited into this study. A propensity-score-matching analysis was conducted to diminish the selection bias. The recurrence-free survival (RFS) and overall survival (OS) were presented with Kaplan−Meier curves. The treatment-related adverse effects (AEs) were recorded according to the National Cancer Institute's Common Terminology Criteria V3.0. A total of 44 patients with CCRT-UP and 44 patients with CCRT-P were identified after propensity score matching. The median RFS was not reached (NR) in the CCRT-UP group, and it was 12.5 months in the CCRT-P group (p < 0.001). The median OS was NR in the CCRT-UP group, and it was 15.9 months in the CCRT-P group (p < 0.001). The overall response rate and disease-control rate were insignificant between the CCRT-UP and CCRT-P groups. A subgroup analysis showed that the median OS was significantly longer in the CCRT-UP group than in the CCRT-P group, regardless of the clinical stage. A multivariate analysis exhibited that CCRT-UP was independently correlated with survival. The grade 3−4 AEs were insignificant between the CCRT-UP and CCRT-P arms. CCRT-UP had better RFS and OS in nonmetastatic NPC patients with similar toxic profiles. Further larger-scaled prospective randomized control trials are warranted to validate our conclusions.

Intraoperative EMG recovery patterns and outcomes after RLN traction-related amplitude decrease during monitored thyroidectomy.

Objectives: Traction injury is the most common type of recurrent laryngeal nerve (RLN) injury in thyroid surgery. Intraoperative neuromonitoring (IONM) facilitates early detection of adverse electromyography (EMG) effect, and this corrective maneuver can reduce severe and repeated nerve injury. This study aimed to evaluate intraoperative patterns and outcomes of EMG decrease and recovery by traction injury. Methods: 644 patients received nerve monitored thyroidectomy with 1142 RLNs at risk were enrolled. Intermittent IONM with stimulating dissecting instrument (real-time during surgical procedure) and trans-thyroid cartilage EMG recording method (without electrode malpositioning issue) were used for nerve stimulation and signal recording. When an EMG amplitude showed a decrease of >50% during RLN dissection, the surgical maneuver was paused immediately. Nerve dissection was restarted when the EMG amplitude was stable. Results: 44/1142 (3.9%) RLNs exhibited a >50% EMG amplitude decrease during RLN dissection and all (100%) showed gradual progressive amplitude recovery within a few minutes after releasing thyroid traction (10 recovered from LOS; 34 recovered from a 51-90% amplitude decrease). Three EMG recovery patterns were noted, A-complete EMG recovery (n=14, 32%); B-incomplete EMG recovery with an injury point (n=16, 36%); C-incomplete EMG recovery without an injury point (n=14, 32%). Patients with postoperative weak or fixed vocal cord mobility in A, B, and C were 0(0%), 7(44%), and 2(14%), respectively. Complete EMG recovery was found in 14 nerves, and incomplete recovery was found in another 30 nerves. Temporary vocal cord palsy was found in 6 nerves due to unavoidable repeated traction. Conclusion: Early detection of traction-related RLN amplitude decrease allows monitoring of intraoperative EMG signal recovery during thyroid surgery. Different recovery patterns show different vocal cord function outcomes. To elucidate the recovery patterns can assist surgeons in the intraoperative decision making and postoperative management.

Necessity of Routinely Testing the Proximal and Distal Ends of Exposed Recurrent Laryngeal Nerve During Monitored Thyroidectomy.

Objectives: Intraoperative neuromonitoring (IONM) is a useful tool to evaluate the function of recurrent laryngeal nerve (RLN) in thyroid surgery. This study aimed to determine the necessity and value of routinely testing the proximal and distal ends of RLN. Methods: In total, 796 patients undergoing monitored thyroidectomies with standardized procedures were enrolled. All 1346 RLNs with visual integrity of anatomical continuity were routinely stimulated at the most proximal (R2p signal) and distal (R2d signal) ends after complete RLN dissection. The EMG amplitudes between R2p and R2d signals were compared. If the amplitude of R2p/R2d ratio reduction (RPDR) was over 10% or loss of signal (LOS) occurred, the exposed RLN was mapped to identify the injured point. Pre- and post-operative vocal cord (VC) mobility was routinely examined with video-laryngofiberscope. Results: Nerve injuries were detected in 108 (8%) RLNs, including 94 nerves with incomplete LOS (RPDR between 13%-93%) and 14 nerves with complete LOS. The nerve injuries were caused by traction in 80 nerves, dissecting trauma in 23 nerves and lateral heat spread of energy-based devices in 5 nerves. Symmetric VC mobility was found in 72 nerves with RPDR ≤50%. The occurrence of abnormal VC mobility (weak or fixed) was 14%, 67%, 100%, and 100% among the different RPDR stratifications of 51%-60%, 61%-70%, 71%-80%, and 81-93%, respectively. Of the 14 nerves with complete LOS, all showed fixed VC mobility. Permanent VC palsy occurred in 2 nerves with thermal injury. Conclusion: Routinely testing the proximal and distal ends of exposed RLN helps detect unrecognized partial nerve injury, elucidate the injury mechanism and determine injury severity. The procedure provides accurate information for evaluating RLN function after nerve dissection and should be included in the standard IONM procedure.

P63 and P73 Activation in Cancers with p53 Mutation.

The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.

Treatment Sequences in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Cetuximab Followed by Immunotherapy or Vice Versa.

BACKGROUND: The prognosis was poor when patients had recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Herein, we conducted an observational study of cetuximab followed by immunotherapy (Cet-IO) versus immunotherapy followed by cetuximab (IO-Cet) in patients with R/M HNSCC. METHODS: Patients who were diagnosed with R/M HNSCC and treated with a sequential cetuximab-containing regimen and immunotherapy-containing regimen were enrolled in our study. Kaplan-Meier curves were estimated for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 75 patients were enrolled in our study for oncologic outcomes evaluation, with 40 patients in Cet-IO and 35 patients in IO-Cet. The median PFS1 was 5.1 months in Cet-IO and 4.5 months in IO-Cet (p = 0.777) and the median PFS2 was 16.5 months in Cet-IO and 11.4 months in IO-Cet (p = 0.566). The median OS was 23.7 months versus 22.8 months in Cet-IO and IO-Cet, respectively (p = 0.484). The overall response rate (ORR) were 73% in Cet-IO versus 37% in IO-Cet (p = 0.002). Multivariate analysis demonstrated that the treatment sequences, Cet-IO or IO-Cet, were insignificantly different with survival. CONCLUSION: Both Cet-IO and IO-Cet are effective in R/M HNSCC patients with insignificant survival differences. The higher ORR of Cet-IO might render it to be considered in patients with large tumor burdens and urgent needs for treatment responses. Further prospective studies are merited to validate our conclusions.

The role of induction chemotherapy in patients with locally advanced head and neck squamous cell carcinoma: A nationwide population-based matched study.

INTRODUCTION: Induction chemotherapy (IC) has a proven role in organ preservation and reducing distant failure. However, its ability to prolong survival remains controversy. Herein, our study aimed to investigate the impact of primary tumor location on survival in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) treated with IC. METHODS: Patients who were older than 18 years and diagnosed with LA-HNSCC between 2007 and 2016 were retrospectively identified from Taiwan National Health Insurance Research Database and Taiwan Cancer Registry. Patients were categorized into two group: IC group and CCRT group. In order to reduce the selection bias, IC patients were individually matched with the CCRT patients. The oncologic outcomes were presented with overall survival (OS). RESULTS: A total of 5547 patients were identified. After matching, 2208 patients were analyzed for outcomes comparison, including 1104 patients in each group. In general, median OS were 27.3 months versus 28.5 months in IC and CCRT group, respectively (p = 0.6151). Patients were stratified by primary tumor location. For patients with oral cavity cancers, the median OS was significantly inferior in IC group than those in CCRT group, while for patients with non-oral cavity cancer, the median OS was superior in IC group than those in CCRT group. CONCLUSIONS: Primary tumor location has a significant impact on survival in patients with LA-HNSCC treated with IC. Our study provides a strong evidence that primary tumor location should be taken into consideration during multidisciplinary approach.

Impact of Parenteral Glutamine Supplement on Oncologic Outcomes in Patients with Nasopharyngeal Cancer Treated with Concurrent Chemoradiotherapy.

Background: Oral mucositis (OM) is a common toxic side effect in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) that has a negative impact on treatment outcomes and patients' survival. Our study aimed to evaluate the impact of parenteral glutamine supplement (dipeptiven) on oncologic outcomes in patients with NPC treated with CCRT. Methods: Patients who were diagnosed with pathologically proved NPC and treated with CCRT were enrolled into our study. Patients were classified as dipeptiven (+) and dipeptiven (−). Oncologic outcomes were measured, and multivariate regression analysis was performed. Grade 3−4 treatment related toxicities were also documented. Results: A total of 144 patients with NPC were recruited in this study to evaluate oncologic outcomes, with 41 dipeptiven (+) and 103 dipeptiven (−). CCRT interruption rate and severe adverse effect (SAE) rate were significant lower in the dipeptiven (+) group than in the dipeptiven (−) group. The median overall survival (OS) was not mature yet in the dipeptiven (+) group and 30 months in the dipeptiven (−) group (p < 0.01). Multivariate analysis demonstrated that dipeptiven supplementation and CCRT interruption were independent predictors associated with better survival. The OS was longest in patients with a dipeptiven supplement and patients who had CCRT interruption had significantly worst OS. As for safety profiles, grade 3 to 4 adverse effects were fewer in dipeptiven (+) than in dipeptiven (−). Conclusion: Dipeptiven supplementation is crucial in NPC patients treated with CCRT, which can ameliorate treatment-related toxicity and augment treatment efficacy. Further prospective clinical trials are warranted to validate our results.

Tegafur-Uracil versus 5-Fluorouracil in Combination with Cisplatin and Cetuximab in Elderly Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Propensity Score Matching Analysis.

There are increasing incidences of elderly patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, the treatment is not yet established. We conducted a propensity score matching analysis to evaluate the efficacy and safety of tegafur-uracil versus 5-fluorouracil in combination with cisplatin plus cetuximab in elderly patients with R/M HNSCC. Elderly patients with R/M HNSCC treated with cetuximab-containing chemotherapy were recruited into this study. In order to reduce the selection bias, propensity score matching was performed. Kaplan-Meier curves were plotted for progression-free survival (PFS) and overall survival (OS). Toxicities were graded according to the National Cancer Institute's Common Terminology Criteria V3.0. After propensity sore matching, 54 patients with tegafur-uracil, cisplatin plus cetuximab (UPEx), and 54 patients with 5-fluorouracil, cisplatin plus cetuximab (EXTREME) were identified. The median PFS was 5.4 months in UPEx and 5.8 months in EXTREME (p = 0.451). The median OS was 10.8 months in UPEx and 10.2 months in EXTREME (p = 0.807). The overall response rate (ORR) and disease control rate (DCR) were insignificant in both arms, accounting for 61% versus 59% (p = 0.680) and 72% versus 70% (p = 0.732) in the UPEx arm and the EXTREME arm, respectively. A multivariate analysis showed that age and ECOG PS were, independently, predictors. Grade 3/4 adverse events were much fewer in UPEx than in EXTREME (p < 0.001). Both cetuximab-containing chemotherapies are effective in elderly patients with R/M HNSCC. Safety profiles are improved when tegafur-uracil is substituted for 5-fluorouracil. Further prospective studies are warranted to validate our conclusions.

Outcomes of patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

Nasopharyngeal cancer shows a good response to intensity-modulated radiotherapy. However, there is no clear evidence for the benefits of routine use of image-guided radiotherapy. The purpose of this study was to perform a retrospective investigation of the treatment outcomes, treatment-related complications and prognostic factors for nasopharyngeal cancer treated with intensity-modulated radiotherapy and image-guided radiotherapy techniques. Retrospective analysis was performed on 326 consecutive nasopharyngeal cancer patients treated between 2004 and 2015. Potentially significant patient-related and treatment-related variables were analyzed. Radiation-related complications were recorded. The 5-year overall survival and disease-free survival rates of these patients were 77.9% and 70.5%, respectively. Age, AJCC (American Joint Committee on Cancer) stage, retropharyngeal lymphadenopathy, treatment interruption and body mass index were independent prognostic factors for overall survival. Age, AJCC stage, retropharyngeal lymphadenopathy, image-guided radiotherapy and body mass index were independent prognostic factors for disease-free survival. In conclusion, intensity-modulated radiotherapy significantly improves the treatment outcomes of nasopharyngeal cancer. With the aid of image-guided radiotherapy, the advantage of intensity-modulated radiotherapy might be further amplified.