PD-L1 expression, tumor-infiltrating lymphocytes, mismatch repair deficiency, EGFR alteration and HPV infection in sinonasal squamous cell carcinoma.

The antitumor efficacies of immune checkpoint inhibitors (ICIs) and the usefulness of potential predictive markers such as programmed death-ligand 1 (PD-L1) expression, density of tumor-infiltrating lymphocytes (TILs) and microsatellite instability (MSI) in sinonasal squamous cell carcinoma (SNSCC) have not been fully elucidated. We retrospectively analyzed 131 SNSCCs with immunohistochemistry for PD-L1 expression, TIL subpopulations and loss of mismatch repair (MMR) proteins as a surrogate for MSI-high. We also comprehensively evaluated the mutual relationships among these immuno-markers, high-risk human papillomavirus (HPV) infection, epidermal growth factor receptor (EGFR) gene status, and KRAS mutation. PD-L1 expression (tumor proportion score ≥ 1%) was detected in 60 (45.8%) SNSCC cases and was significantly associated with worse overall survival (OS) (p = 0.0240). High density of cluster of differentiation 8 (CD8)-positive TILs was significantly associated with better progression-free survival (PFS) (p = 0.0368), and high density of forkhead box protein P3-positive TILs was significantly associated with better PFS and OS (p = 0.0007 and 0.0143, respectively). With respect to the combination of CD8 + TIL and PD-L1 expression, the high-CD8/PD-L1-negative group showed the most favorable prognosis, whereas the low-CD8/PD-L1-positive group showed the worst prognosis. MMR loss was detected in 3 (2.3%) of the 131 cases. HPV infection (6.1%), EGFR mutation (14.5%), EGFR copy number gain (26%), and MMR loss were essentially mutually exclusive; patients in these molecular groups showed significant differences in prognosis but not in the degree of PD-L1 expression or TILs. Among the nine ICI-treated patients, three (33.3%) were responders, and the EGFR-wild type cases (n = 7) showed better clinical responses to an ICI compared to the EGFR-mutant cases (n = 2). Among the patients with residual/recurrent EGFR-wild type tumors (n = 43), ICI treatment significantly improved OS (p = 0.0281). The results suggest that the evaluation of immuno-markers and molecular subclassification may be helpful for prognostic prediction and selecting an individualized therapeutic strategy for patients with SNSCC.

Non-vascularized bone grafting in scaphoid nonunion: principles and type of fixation.

In scaphoid fractures, delayed diagnosis and nonunion are fairly common as a result of several factors, including the difficulty of radiographic diagnosis of non-displaced fractures and underestimation of the injury by the patient. Main factors to consider when deciding treatment are the type of fracture and fracture stability. In the stable nonunion (Type D1 according to the Filan and Herbert classification, or linear type of Ikeda's classification), percutaneous screw fixation without bone graft is recommended. The indications of non-vascularized bone grafting are as follows: (1) arthroscopic cancellous bone graft in type D1 and cystic type of Ikeda's classification. (2) tricortical bone graft from the iliac crest in type D2 or D3 if the possibility of avascular necrosis of the proximal fragment is excluded. In this paper, our non-vascularized bone grafting for scaphoid nonunion would like to be described mainly about principles and type of fixation.

A case of peritoneal metastasis during treatment for hypopharyngeal squamous cell carcinoma.

BACKGROUND: Advanced head and neck squamous cell carcinomas frequently develop distant metastases to limited organs, including the lungs, bone, mediastinal lymph nodes, brain, and liver. Peritoneal carcinomatosis as an initial distant metastasis from hypopharyngeal squamous cell carcinoma is quite rare. CASE PRESENTATION: A 75-year-old man diagnosed with hypopharyngeal squamous cell carcinoma and his clinical stage was determined as T2N2cM0. Notably, the right retropharyngeal lymph node surrounded more than half of the right internal carotid artery. Concomitant conformal radiation therapy was administered for the primary hypopharyngeal lesion, and the whole neck and tumor response was evaluated at this point according to our algorithm-based chemoradioselection protocol. As the tumor responses at both the primary and lymph nodes were poor, with the right retropharyngeal lymph node in particular demonstrating mild enlargement, we performed a radical surgery: pharyngolaryngectomy, bilateral neck dissection, and reconstruction of the cervical esophagus with a free jejunal flap. Then, postoperative CRT was performed. During these therapies, the patient developed a fever and mild abdominal pain, which was associated with an increased C-reactive protein level. Contrast-enhanced computed tomography from the neck to the pelvis demonstrated mild peritoneal hypertrophy and ascites with no evidence of recurrent and/or metastatic tumor formation. We initially diagnosed acute abdomen symptoms as postoperative ileus. However, cytological examination of the refractory ascites resulted in a diagnosis of peritoneal carcinomatosis. Owing to rapid disease progress, the patient died 1.5 months after abdominal symptom onset. CONCLUSIONS: The present case is the second reported case of head and neck squamous cell carcinoma with peritoneal carcinomatosis as an incipient distant metastasis. Therefore, peritoneal carcinomatosis should be considered a differential diagnosis when acute abdomen is noted during treatment for head and neck cancers.

Acquired tracheobronchomalacia developed following voice prosthesis implantation.

Acquired tracheobronchomalacia (ATBM) is a condition in which the tracheobronchial wall and cartilage progressively lose their rigidity, resulting in dynamic collapse during exhalation. In this report, we present a case of ATBM that developed following voice prosthesis implantation. To the best of our knowledge, this is the first documented case of such a condition in the medical English literature based on a PubMed search. A 63-year-old man was referred to National Kyushu Cancer Center in Japan with complaints of pharyngeal pain and a laryngeal tumor. The tumor was diagnosed as laryngeal cancer, and the patient underwent laryngectomy. Three months after the surgery, we implanted a voice prosthesis through a tracheoesophageal puncture. Two months after implantation, the patient experienced dyspnea. This condition was subsequently diagnosed as ATBM through computed tomography and bronchofiberscope examinations. After the removal of the voice prosthesis, there has been no progression of ATBM for over five years. While ATBM may not be a common occurrence in the practice of head and neck surgeons, it should be considered as a potential complication when patients report dyspnea following voice prosthesis implantation.

Correction: Effectiveness and safety of weekly paclitaxel and cetuximab as a salvage chemotherapy following immune checkpoint inhibitors for recurrent or metastatic head and neck squamous cell carcinoma: a multicenter clinical study.

[This corrects the article DOI: 10.1371/journal.pone.0271907.].

Interobserver and intraobserver reliability of the classification and diagnosis for ossification of the posterior longitudinal ligament of the cervical spine.

PURPOSE: Ossification of the posterior longitudinal ligament (OPLL) of the cervical spine has been classified into four types by lateral plain radiographs, but the reliability of the classification and of the diagnosis of either cervical OPLL or cervical spondylotic myelopathy (CSM) was unknown. We investigated the interobserver and intraobserver reliability of the classification and diagnosis for OPLL by radiographs and computed tomography (CT) images. METHODS: A total of 16 observers classified each patient's images into five groups; OPLL continuous, segmental, mixed, circumscribed type, or CSM. To evaluate interobserver reliability, the observers first classified only radiograph images, and next both radiographs and CT images. On another day they followed the same procedure to evaluate intraobserver reliability. We also evaluated interobserver and intraobserver reliability of the diagnosis of either cervical OPLL or CSM. RESULTS: Interobserver reliability of the classification with radiographs only showed moderate agreement, but interobserver reliability with both radiographs and CT images showed substantial agreement. Intraobserver of reliability the classification was also improved by additional CT images. Interobserver reliability of the diagnosis with both radiographs and CT images was almost similar to with radiographs only. Intraobserver reliability of the diagnosis was improved by additional CT images. CONCLUSIONS: This study suggested that the reliability of the classification and diagnosis for cervical OPLL was improved by additional CT images. We propose that diagnostic criteria for OPLL include both radiographs and CT images.

Novel motion preservation device for atlantoaxial instability.

STUDY DESIGN: An in vitro cadaveric biomechanical study. OBJECTIVE: To evaluate the anteroposterior (A-P) stability and the flexibility of our novel motion preservation device (MPD) using cadaveric cervical spines. SUMMARY OF BACKGROUND DATA: The MPD intended to restrict the A-P instability of the C1-C2 complex and to preserve the axial rotation, flexion, extension, and lateral bending was designed and produced. The stability and the flexibility of the MPD was evaluated. METHODS: Ten embalmed cadaveric specimens were loaded with pure A-P translation force and the A-P translational distances were measured. Each specimen was tested for the following 4 models, respectively: Intact (control), the Dens-removed, the MPD instrumented, and a Rod fixation system instrumented. Fifteen specimens were loaded with pure moments (up to 1.5 Nm), and the C1-C2 range of motion (ROM) was measured for flexion, extension, lateral bending, and axial rotation using a stereophotogrammetry motion analysis system. RESULTS: Mean A-P translational distances were 4.26 mm in Intact, 13.1 in the Dens-removed, 5.42 in the MPD, and 2.58 in the Rod fixation. The distance values with the MPD had no significant difference compared with Intact. Mean C1-C2 ROM of Intact, the MPD, and the Rod fixation at 1.5 Nm were: 14.7, 6.96, and 2.11 degrees in flexion, 6.46, 4.72, and 2.84 degrees in extension, 3.29, 4.02, and 1.01 degrees in right lateral bending, 4.92, 4.58, and 1.84 degrees in left lateral bending, 26.4, 15.4, and 1.16 degrees in right axial rotation, and 25.6, 14.3, and 1.21 degrees in left axial rotation, respectively. CONCLUSIONS: The MPD restricted the A-P instability of the C1-C2 complex. In flexion, extension, and axial rotation, the C1-C2 ROM of the MPD was about 50% of the ROM in Intact, whereas equivalent to Intact in lateral bending.

Efficacy of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine for the prevention of mucositis induced by platinum-based chemoradiation in head and neck cancer: A phase II study.

BACKGROUND & AIMS: The current standard treatment modality for advanced head and neck squamous cell carcinoma (HNSCC), namely platinum-based (PB) concurrent chemoradiotherapy (CRT), is associated with frequent severe mucositis which is responsible for the multiple acute and late adverse events. So far, effective preventive methods for this CRT-induced mucositis are not identified. In the current study, we examined the prophylactic effects of beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln) (HMB/Arg/Gln) mixture. METHODS: Patients with HNSCC who were subject to PBCRT were randomly assigned to HMB/Arg/Gln intervention (Group I) and non-intervention (Group NI) cohort. The incidences of ≧ grade 3 mucositis (primary endpoint), ≧ grade 2 mucositis, and opioid usage and the degree of body weight loss (secondary endpoints) were compared between Group I and Group NI. RESULTS: A total of 75 patients were enrolled to this study and 38 patients were assigned to Group I, while 37 patients were to Group NI. After excluding patients who failed to complete CRT (3 in Group I and 2 in Group NI) or withdrew consents (11 in Group I and 1 in Group NI), 24 patients in Group I and 34 patients in Group NI were evaluated. HMB/Arg/Gln failed to reduce the incidences of ≧ grade 2 mucositis, but significantly (p = 0.0003) inhibited grade 3 mucositis in the late phase CRT, reducing the incidence from 64.6% (Group NI) to 25% (Group I) at 70Gy. The degree of body weight loss was significantly (p = 0.0038) lower in Group I (5.6%) compared to Group NI (8.9%), preventing the progression of PBCRT-induced cachexia. CONCLUSIONS: HMB/Arg/Gln administration demonstrated inhibitory effects on the progression of grade 3 mucositis and cancer cachexia in HNSCC patients treated with PBCRT. A larger scale phase III study is encouraged. CLINICAL TRIAL REGISTRATION: This study is registered to the UMIN Clinical Trial Registry: UMIN000050011.

Mesenchymal stem cell isolation and characterization from human spinal ligaments.

Mesenchymal stem cells (MSCs) have a fibroblast-like morphology, multilineage potential, long-term viability and capacity for self-renewal. While several articles describe isolating MSCs from various human tissues, there are no reports of isolating MSCs from human spinal ligaments, and their localization in situ. If MSCs are found in human spinal ligaments, they could be used to investigate hypertrophy or ossification of spinal ligaments. To isolate and characterize MSCs from human spinal ligaments, spinal ligaments were harvested aseptically from eight patients during surgery for lumbar spinal canal stenosis and ossification of the posterior longitudinal ligament. After collagenase digestion, nucleated cells were seeded at an appropriate density to avoid colony-to-colony contact. Cells were cultured in osteogenic, adipogenic or chondrogenic media to evaluate their multilineage differentiation potential. Immunophenotypic analysis of cell surface markers was performed by flow cytometry. Spinal ligaments were processed for immunostaining using MSC-related antibodies. Cells from human spinal ligaments could be extensively expanded with limited senescence. They were able to differentiate into osteogenic, adipogenic or chondrogenic cells. Flow cytometry revealed that their phenotypic characteristics met the minimum criteria of MSCs. Immunohistochemistry revealed the localization of CD90-positive cells in the collagenous matrix of the ligament, and in adjacent small blood vessels. We isolated and expanded MSCs from human spinal ligaments and demonstrated localization of MSCs in spinal ligaments. These cells may play an indispensable role in elucidating the pathogenesis of numerous spinal diseases.

Biomechanical evaluation of an anatomic double-bundle posterior cruciate ligament reconstruction.

PURPOSE: The purpose of this study was to evaluate the effect of the anatomic double-bundle reconstruction (ADBR) of the posterior cruciate ligament (PCL) with 2 femoral tunnels and 2 tibial tunnels. METHODS: Eight fresh-frozen human knees were used. Bone tunnels were created based on the PCL anatomic footprints. A 9-mm looped semitendinosus and gracilis tendon for anterolateral bundle reconstruction (ALR), a 7-mm looped semitendinosus tendon for posteromedial bundle reconstruction (PMR), and the same grafts for the ADBR were used. Under a 100-N posterior tibial load and under a 100-N posterior tibial load and 5 Nm of external tibial torque, the posterior tibial translation (PTT) was measured. RESULTS: Under posterior tibial load, at 0°, the PTT of the ALR was larger than that of the intact knee (P = .04) and the ADBR (P = .03); however, there were no significant differences between the PTT of the PMR and that of the ADBR (P = .28) and intact knee (P = .99). At 30°, the PTT of the ADBR was smaller than that of the ALR (P = .02) and PMR (P = .02). At 60°, the PTT of the PMR was larger than that of the ADBR (P = .02). At 90°, the PTT of the PMR was larger than that of the ADBR (P = .02). Under posterior tibial load and external tibial torque, at 0°, the PTT of the ALR was larger than that of the ADBR (P = .04). CONCLUSIONS: Although the graft size of the ADBR was larger than other reconstructions, the ADBR was better than the ALR at 0° and 30° of knee flexion under the posterior tibial load and at 0° under the combination of posterior tibial load and external tibial torque, as well as better than the PMR at 30°, 60°, and 90° of knee flexion under the posterior tibial load. CLINICAL RELEVANCE: The clinical outcome of PCL reconstruction might improve by reducing posterior knee laxity in knee extension with the ADBR.

The femoral insertion of the anterior cruciate ligament: discrepancy between macroscopic and histological observations.

PURPOSE: To observe the femoral anterior cruciate ligament (ACL) insertion macroscopically, histologically, and immunohistologically. METHODS: We used 20 embalmed cadaveric knees (mean age, 69.8 ± 5.3 years) for this study. The femoral ACL insertion was observed macroscopically, and areas were measured with digital calipers. The morphology of the ACL insertion was subsequently observed, and the areas were measured histologically and immunohistologically (stained for types I and III collagen). Finally, the macroscopic and microscopic measurements were compared. RESULTS: Macroscopically, in 16 knees, the proximal ACL fibers spread in a fanlike manner on the medial aspect of the lateral femoral condyle and the femoral insertion was oval. The lengths of the long and short axes of the insertion were 17.7 ± 2.7 mm and 4.6 ± 0.7 mm, respectively. Microscopically, the insertion was located just behind the lateral intercondylar ridge (resident's ridge) and could be divided into the direct and indirect insertions. The direct insertion was 5.3 ± 1.1 mm wide and did not continue to the posterior cartilage. The indirect insertion was located behind the direct insertion, and the posterior ACL fiber stained for type I collagen blended into the posterior cartilage on immunohistologic observations. Another bony ridge was found at the posterior margin of the direct insertion. The widths of the direct insertion were similar between microscopic and macroscopic measurements. CONCLUSIONS: The femoral ACL insertion observed macroscopically corresponded to the direct insertion observed microscopically. The posterior portion behind the lateral intercondylar posterior ridge was the indirect insertion microscopically and appeared membrane-like macroscopically. CLINICAL RELEVANCE: Findings from observation of the lateral intercondylar posterior ridge during arthroscopy and consideration of the distance from the posterior cartilage border may contribute to surgeons' decisions about femoral tunnel placement during anatomic ACL reconstruction.

Potential of exogenous cartilage proteoglycan as a new material for cartilage regeneration.

BACKGROUND: Although proteoglycan (PG) is one of the major components of cartilage matrices, its biological function is not fully elucidated. METHODS: The objectives of this study were to investigate the proliferation and differentiation of chondrocytes embedded in atelocollagen gel with exogenous cartilage PG (PG-atelocollagen gel) in vitro, and also to evaluate the repair of cartilage defects by PG-atelocollagen gel in vivo. In the in vitro study, rabbit chondrocytes were cultured in the PG-atelocollagen gel. Cell proliferation and mRNA expression levels were measured, and gels were histologically evaluated. In the in vivo study, cultured PG-atelocollagen gel containing chondrocytes were transplanted into full-thickness articular cartilage defects in rabbit knees, and evaluated macroscopically and histologically. RESULTS: For the in vitro study, chondrocyte proliferation in 5.0 mg/ml PG-atelocollagen gel was enhanced, and the gene expression of Col2a1 and Aggrecan were decreased. In contrast, chondrocyte proliferation in 0.1 and 1.0 mg/ml PG-atelocollagen gel was not enhanced. The gene expression of Aggrecan in 0.1 and 1.0 mg/ml PG-atelocollagen gel was increased. For the in vivo study, the histological average total score of the 0.1 mg/ml PG-atelocollagen gel was significantly better than that of the group without PG. CONCLUSIONS: Although the appropriate concentration of PG has not been defined, this study suggests the efficacy of PG for cartilage repair.

Post injury changes in the properties of mesenchymal stem cells derived from human anterior cruciate ligaments.

PURPOSE: The anterior cruciate ligament (ACL) rarely heals spontaneously after rupture. Mesenchymal stem cells (MSCs) contribute to healing in various tissues, therefore, they may also have a key role in healing after ACL rupture. The purpose of this study was to investigate the properties of MSCs in ruptured ACLs. METHODS: Human ACL samples were harvested from patients undergoing primary ACL reconstruction, and samples were classified by the number of days post rupture (phase I<21 days; phase II 21­56 days; phase III 57­139 days phase IV≥140 days). We evaluated the characteristics of MSCs, such as colony-forming capacity, differentiation potential and cell-surface markers. RESULTS: There was a tendency for high colony-forming capacity during phases I and II, which tended to decrease in phase III. Chondrogenic, adipogenic and osteogenic differentiation potential was maintained until phase II but decreased in phase III. Most surface-epitope expression was consistent from phase I to III: positive for CD44, CD73, CD90 and CD105; negative for CD11b, CD19, CD34, CD45 and human leukocyte antigen-D-related (HLA-DR). The presence of these surface markers proved the existence of MSCs in ruptured ACL tissue. CONCLUSIONS: Our results suggest that colony-forming and differentiation potential decrease over time. It is important to consider changes in properties of MSCs and use ACL tissue in the acute phase of rupture when biological manipulation is required.

[Laryngeal preservation for hypopharyngeal cancer by radiotherapy with S-1 and vitamin A(TAR therapy)].

The objective of this study was to analyze the outcome of hypopharyngeal cancer patients who underwent triple combination treatment with S-1, vitamin A and radiation(TAR therapy), and to analyze the role of TAR therapy for treating locally advanced hypopharyngeal cancer patients. 146 patients(stage I: 10 cases, stage II : 22 cases, stage III : 23 cases, stage IV: 91 cases)with hypopharyngeal squamous cell carcinoma were treated with TAR therapy(S-1; orally, 65mg/m²day, twice a day; vitamin A(retinol palmitate): 50, 000 I U/day, intra-musculary on each day of radiation; radiation: 1. 5-2 Gy/day, 5 days/week). Histologic complete responders at 30-40 Gy continued TAR therapy up to 60-70 Gy. Nonresponders at 30-40 Gy underwent surgery. The overall 5-year survival and disease-specific 5-year survival rates were 50. 5%and 59%respectively. The cumulative 3-year laryngeal preservation rate for stage I was 100%, 82. 5% for stage II, 66. 6% for stage III, and 35%for stage IV. Laryngeal preservation was fair in T1/T2 patients(81%), but not satisfactory in T3/T4 patients(21. 4%). S- 1 is administered orally, and TAR therapy can be conducted in the clinic with low toxicity. However, protocols with high intensity may be necessary to improve laryngeal preservation for locally advanced(T4)hypopharyngeal cancer.

Inflammation-based Prognostic Score as a Prognostic Biomarker in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma Treated With Nivolumab Therapy.

BACKGROUND/AIM: The inflammation-based prognostic score (IBPS) has attracted attention recently as a prognostic biomarker for head and neck cancer patients. However, as the IBPS often changes after anticancer drug therapy, its independent prognostic value remains controversial. We aimed to investigate the relationship between the IBPS and prognosis in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC) treated with nivolumab, and investigate changes in the IBPS before and after nivolumab treatment. PATIENTS AND METHODS: Total of 164 patients with RMHNSCC received nivolumab therapy were retrospectively analyzed. RESULTS: Univariate analysis among the 164 patients revealed that the performance status (PS), immune-related adverse event (irAE) status, pre- and post-therapy Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), platelet-to-lymphocyte ratio (PLR), and post-eosinophil count, were all significant predictors of overall survival (OS) (p<0.05). A multivariate analysis revealed that PS, irAEs, post-GPS, post-NLR, post-CAR, and post-eosinophil count were independent prognostic factors for overall survival. CONCLUSION: Post-treatment factors were identified as independent prognostic factors for RMHNSCC and can more accurately predict prognosis compared to nivolumab-treated RMHNSCC pre-treatment factors.

Real-world Experience With Pembrolizumab for Advanced-stage Head and Neck Cancer Patients: A Retrospective, Multicenter Study.

BACKGROUND/AIM: This study investigated the effectiveness of pembrolizumab with or without chemotherapy on advanced-stage head and neck cancer (HNC), including nasopharyngeal, sinonasal cavity and external auditory canal cancer, in a real-world setting. PATIENTS AND METHODS: We retrospectively collected data from 97 HNC patients who were treated with pembrolizumab alone (n=60) or with chemotherapy (n=37), and we investigated the association between clinicopathological findings and treatment response or prognosis. RESULTS: Patients treated with pembrolizumab and chemotherapy had a 1-year overall survival (OS) of 72.8%, objective response rate (ORR) of 48.6%, and serious (≥G3) adverse events (AEs) of 29.7%. Patients treated with pembrolizumab alone had a 1-year OS of 51.9%, ORR of 21.7%, and ≥G3 AEs of 6.7%. Both the ORR and disease control rate (DCR) in the pembrolizumab with chemotherapy group were significantly better than those in the pembrolizumab group (p=0.074 and p=0.00101, respectively). Among patients with distant metastasis, patients on pembrolizumab with chemotherapy achieved significantly better OS than pembrolizumab alone (p=0.0039). Among patients in the pembrolizumab group, both AE-positive and better performance status were associated with longer OS (p=0.011 and p=0.0037, respectively). CONCLUSION: Our real-world experience reinforces the durability and effectiveness of pembrolizumab for HNC patients. Additionally, our results suggest that pembrolizumab with chemotherapy might be recommended for patients with distant metastasis and no prior treatment. Further studies are needed to determine the optimal treatment strategy for HNC.

Effectiveness and safety of weekly paclitaxel and cetuximab as a salvage chemotherapy following immune checkpoint inhibitors for recurrent or metastatic head and neck squamous cell carcinoma: A multicenter clinical study.

OBJECTIVES: The benefit of sequential therapy after immune checkpoint inhibitor (ICI) treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has been recently reported. Furthermore, there is a growing interest in the impact of cetuximab (Cmab)-containing salvage chemotherapy (SCT) and the therapeutic efficacy and adverse events (AEs) of Cmab administration prior to ICI administration. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 52 patients with R/M HNSCC treated with SCT (weekly paclitaxel [PTX], n = 7, or weekly PTX and Cmab [PC], n = 45). RESULTS: The objective response rate (ORR) and a disease control rate (DCR) was 53.3% and 91.1% in the PC group and 42.9% and 57.1% in the PTX group, respectively. There was a significant difference in the DCR between the PC and PTX groups (p = 0.0143). The overall survival (OS) and progression-free survival were significantly better in the PC group than in the PTX group. On the other hand, the incidence of drug-induced interstitial pneumonia (DI-IP) in R/M HNSCC patients who received SCT was 21.2%. Patients in the PC group were divided according to whether they received Cmab (Group A) or did not receive Cmab (Group B) as palliative therapy prior to ICIs. Group B had a significantly better OS than Group A. Furthermore, our findings suggest that the incidence rate of DI-IP during SCT might be higher in Group B. CONCLUSION: Although PC following ICIs shows dramatic efficacy, careful monitoring of AEs, including DI-IP, is recommended.

Retrospective Study of Cisplatin/Carboplatin, 5-Fluorouracil Plus Cetuximab (EXTREME) for Advanced-stage Salivary Gland Cancer.

BACKGROUND/AIM: Surgery remains the standard treatment for salivary gland carcinoma (SGC). Our study investigated the association between epidermal growth factor receptor (EGFR) status in recurrent/metastatic SGC and the effectiveness of treatment with cisplatin/carboplatin and 5-fluorouracil plus cetuximab (EXTREME). PATIENTS AND METHODS: We retrospectively collected 19 SGCs from patients treated with the EXTREME regimen. After analyzing EGFR expression and gene copy number gain, we evaluated the correlation between EGFR status and clinicopathological factors and prognosis. RESULTS: EGFR overexpression was detected in 77.8% cases, but not statistically associated with clinicopathological factors or prognosis. EGFR gene copy number gain was detected in 16.7% cases, and statistically positively correlated with lymph node metastasis (p=0.0291). The best overall response was partial response in two cases, stable disease in 15, and progressive disease in one case. The EXTREME regimen was discontinued in all cases. CONCLUSION: Our results suggest that SGCs are positive for EGFR protein expression but the response rate to the EXTREME regimen was unremarkable.

Treatment Efficacy of PD-1 Inhibitor Therapy in Patients With Recurrent and/or Metastatic Salivary Gland Carcinoma.

BACKGROUND/AIM: The efficacy of programmed cell death 1 (PD-1) inhibitor therapy for patients with recurrent and/or metastatic salivary gland carcinoma (R/M SGC) remains unclear. PATIENTS AND METHODS: We retrospectively analyzed 36 patients with R/M SGC treated with PD-1 inhibitor. The expression of programmed cell death ligand 1 (PD-L1) and mismatch repair (MMR) proteins was also analyzed. RESULTS: The objective response rate (ORR) was 11.1%. The histopathological subtypes of patients who achieved complete response or partial response were salivary duct carcinoma (SDC) in three patients and poorly differentiated carcinoma in one patient, all of whom showed a positive PD-L1 expression. The expression of MMR proteins was not associated with the efficacy of PD-1 inhibitors. CONCLUSION: Although the efficacy of PD-1 inhibitor therapy in R/M SGC is limited, certain patients may respond and achieve long-term disease control. There is a potential therapeutic effect in SDC patients with positive PD-L1 expression.

P2Y1 transient overexpression induced mineralization in spinal ligament cells derived from patients with ossification of the posterior longitudinal ligament of the cervical spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by ectopic bone formation in the spinal ligaments. We previously reported that P2 purinoceptor Y1 (P2Y1) expression is elevated in the spinal ligament cells of OPLL patients, but the role of P2Y1 in the spinal ligament calcification process is unknown. To verify the hypothesis that P2Y1 expression causes ossification of the spinal ligaments, we forced expression of P2Y1 in spinal ligament cells obtained from OPLL and non-OPLL patients using a cytomegaloviral vector. The expression of mRNA and protein was investigated by quantitative real-time polymerase chain reaction and immunofluorescence staining, respectively. After transfection, bone morphogenetic protein-2 (BMP-2) and Sox9 mRNA expression was significantly increased in spinal ligament cells derived from OPLL patients (4.36- and 6.44-fold, respectively) compared with cells from non-OPLL patients (0.57- and 3.64-fold, respectively) 2 days after P2Y1 transient transfection. Furthermore, a statistically significant correlation was observed between BMP-2 and P2Y1 mRNA expression levels in cells obtained from OPLL patients but not from non-OPLL patients. Immunofluorescence analysis showed that BMP-2 and P2Y1 expression was increased in OPLL patients only, while Sox9 expression was increased in OPLL and non-OPLL patients. MRS2279, a selective P2Y1 antagonist, blocked the upregulation of Sox9 and BMP-2 after forced expression of P2Y1. Furthermore, 4 days after transient transfection of P2Y1, mineralization was observed only in spinal ligament cells from OPLL patients. These results suggest that P2Y1 expression plays an important role in ectopic bone formation in the spinal ligaments of OPLL patients.