Prognostic value of a mandibular canal staging system for primary lesions in patients with lower gingival squamous cell carcinoma: a multicenter, retrospective study.

BACKGROUND: The Union for International Cancer Control and American Joint Committee on Cancer tumor staging system is used globally for treatment planning. As it may be insufficient for tumor staging of lower gingival carcinomas, we proposed the mandibular canal tumor staging system. In this study, we aimed to compare the two systems for such tumor staging and to identify prognostic markers. METHODS: This multicenter, retrospective study included patients with lower gingival squamous cell carcinoma who underwent radical surgery during 2001-2018. We compared survival rates (Kaplan-Meier estimator) and patient stratification according to the two systems. RESULTS: The proposed system yielded more balanced patient stratification than the existing system. Progression in the tumor grade according to the proposed system was associated with a poorer prognosis. The 5-year overall and disease-specific survival rates for the entire cohort were 74.9% and 81.8%, respectively. Independent factors affecting overall survival were tumor stage according to the proposed system, excision margins, and number of positive nodes, whereas those affecting disease-specific survival were excision margins and number of positive nodes. CONCLUSIONS: Subsite-specific tumor classification should be used for patients with oral cancer, and our results suggest that mandibular canal tumor classification may be effective for patients with lower gingival carcinoma.

Assessment of Patient Characteristics Influencing the Analgesic Effects of Ibuprofen Gargle After Mandibular Third Molar Extractions.

Introduction In our previous work, we investigated the analgesic effects of ibuprofen gargle after mandibular third molar extractions. However, a subsequent detailed review of individual patient data revealed variations in postoperative pain reduction among patients. Consequently, the present study was designed to conduct post-hoc subanalyses that identified factors contributing to variation in the analgesic response to ibuprofen gargle after third molar extractions. Materials and methods This study involved thirty-five Japanese patients from a prior randomized, double-blind, placebo-controlled, crossover study, which focused on the analgesic effects of ibuprofen gargle after mandibular third molar extractions. Participants were categorized as responders (n = 13) and non-responders (n = 22) based on the within-subject difference (ibuprofen-placebo, IP) of visual analog scale (VAS) changes. Baseline characteristics were compared, along with variables, such as age, sex, the reason for extraction, extraction site, Pell Gregory (space and depth) classification, Winter's classification, surgeon's experience, and surgery time. Baseline characteristics predicting responder status were examined using multivariate logistic regression. Results In the univariate analysis, variables such as age, sex, and baseline VAS scores with p-values <0.2 were evaluated using a stepwise approach. This analysis identified age (per -10 years) with an odds ratio of 4.163 (95% confidence interval (CI): 1.170-31.952, p = 0.0233) and sex (female) with an odds ratio of 9.977 (95% CI: 1.336-208.256, p = 0.0213) as significant predictors of responder status. Conclusions In young and female patients, ibuprofen gargle decreased postoperative pain after mandibular third molar extractions.

Transcutaneous carbon dioxide suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma.

Cancer cachexia causes skeletal muscle atrophy, impacting the treatment and prognosis of patients with advanced cancer, but no treatment has yet been established to control cancer cachexia. We demonstrated that transcutaneous application of carbon dioxide (CO2) could improve local blood flow and reduce skeletal muscle atrophy in a fracture model. However, the effects of transcutaneous application of CO2 in cancer-bearing conditions are not yet known. In this study, we calculated fat-free body mass (FFM), defined as the skeletal muscle mass, and evaluated the expression of muscle atrophy markers and uncoupling protein markers as well as the cross-sectional area (CSA) to investigate whether transcutaneous application of CO2 to skeletal muscle could suppress skeletal muscle atrophy in cancer-bearing mice. Human oral squamous cell carcinoma was transplanted subcutaneously into the upper dorsal region of nude mice, and 1 week later, CO2 gas was applied to the legs twice a week for 4 weeks and FFM was calculated by bioimpedance spectroscopy. After the experiment concluded, the quadriceps were extracted, and muscle atrophy markers (muscle atrophy F-box protein (MAFbx), muscle RING-finger protein 1 (MuRF-1)) and uncoupling protein markers (uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3)) were evaluated by real-time polymerase chain reaction and immunohistochemical staining, and CSA by hematoxylin and eosin staining. The CO2-treated group exhibited significant mRNA and protein expression inhibition of the four markers. Furthermore, immunohistochemical staining showed decreased MAFbx, MuRF-1, UCP2, and UCP3 in the CO2-treated group. In fact, the CSA in hematoxylin and eosin staining and the FFM revealed significant suppression of skeletal muscle atrophy in the CO2-treated group. We suggest that transcutaneous application of CO2 to skeletal muscle suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma.

Cytocidal Effect of Irradiation on Gastric Cancer Cells Infected with a Recombinant Mammalian Orthoreovirus Expressing a Membrane-Targeted KillerRed.

The outcomes of unresectable gastric cancer (GC) are unfavorable even with chemotherapy; therefore, a new treatment modality is required. The combination of an oncolytic virus and photodynamic therapy can be one of the promising modalities to overcome this. Mammalian orthoreovirus (MRV) is an oncolytic virus that has been used in clinical trials for several cancers. In this study, we developed and evaluated a recombinant MRV strain type 3 Dearing (T3D) that expresses membrane-targeting KillerRed (KRmem), a phototoxic fluorescent protein that produces cytotoxic reactive oxygen species upon light irradiation. KRmem was fused in-frame to the 3' end of the σ2 viral gene in the S2 segment using a 2A peptide linker, enabling the expression of multiple proteins from a single transcript. RNA electrophoresis, Western blotting, and immunofluorescence analyses confirmed functional insertion of KRmem into the recombinant virus. The growth activity of the recombinant virus was comparable to that of the wild-type MRV in a cultured cell line. The recombinant virus infected two GC cell lines (MKN45P and MKN7), and a significant cytocidal effect was observed in MKN45P cells infected with the recombinant virus after light irradiation. Thus, recombinant MRV-expressing KRmem has the potential to serve as a novel treatment tool for GC.

Risk factors associated with prognosis of patients with medication-related osteonecrosis of the jaw.

OBJECTIVES: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect of antiresorptive and/or antiangiogenic agents. As the treatment application for MRONJ is controversial, we aimed to identify the risk factors for poor prognosis and to help determine appropriate management. METHODS: This study included 119 patients. Relevant clinical data were obtained for all the patients. In computed tomography images, osteosclerosis, osteolysis, cortical perforation (buccal or lingual), periosteal reaction, and sequestration were evaluated. RESULTS: Multivariate analyses showed statistically significant associations between poor prognosis in patients with MRONJ and conservative treatment alone (hazard ratio [HR] 1.89), osteolysis (HR 4.67), and the absence of sequestration (HR 5.33). CONCLUSIONS: Conservative treatment alone without clear objectives needs to be avoided, and osteolytic change could be the criteria for surgical intervention. As the boundary between the lesion and vital bone is indistinct, we recommend extensive surgery in cases with unpredictable sequestration.

Efficacy of perioperative oral care management in the prevention of surgical complications in 503 patients after pancreaticoduodenectomy for resectable malignant tumor: A multicenter retrospective analysis using propensity score matching.

BACKGROUND: Pancreaticoduodenectomy has been associated with a high mortality rate and significant postoperative morbidity. Recently, perioperative oral care management has been reported to be effective in preventing postoperative pneumonia and surgical site infection. In this study, we examined the effect of perioperative oral care management in reducing complications after pancreaticoduodenectomy, including surgical site infection. METHODS: This retrospective multicenter study included 503 patients who underwent pancreaticoduodenectomy at 8 facilities between January 2014 and December 2016. Among these, 144 received perioperative oral management by dentists and dental hygienists (oral management group), whereas the remaining 359 did not (control group). The oral care management program included oral health instructions, removal of dental calculus, professional mechanical tooth cleaning, removal of tongue coating, denture cleaning, instructions for gargling, and tooth extraction. The participants were matched using propensity scores to reduce background bias. Various factors were examined for correlation with the development of complications. RESULTS: The incidence of organ/space surgical site infection was significantly lower in the oral management group than in the control group (8.0% vs 19.6%, P = .005). Multivariable logistic regression analysis revealed that hypertension and lack of perioperative oral management were independent risk factors for organ/space surgical site infection. Lack of perioperative oral management had an odds ratio of 2.847 (95% confidence interval 1.335-6.071, P = .007). CONCLUSION: Perioperative oral care management reduces the occurrence of surgical site infections after pancreaticoduodenectomy and should be recommended as a strategy to prevent infections in addition to antibiotic use.

Gold Nanoparticles Enhance the Tumor Growth-Suppressing Effects of Cetuximab and Radiotherapy in Head and Neck Cancer In Vitro and In Vivo.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) treatment includes surgery, radiotherapy, and immunotherapy with the aim of eradicating cancer cells without affecting normal tissues. HNSCC expresses epidermal growth factor receptor (EGFR) and cetuximab, an IgG1 monoclonal antibody targeting epidermal growth factor receptor, has been approved for the treatment of HNSCC. However, cetuximab has low reactivity and induces serious side effects. Gold nanoparticles (AuNPs) were reported to enhance the local antitumor effects of radiotherapy without damaging normal cells. METHODS AND RESULTS: This study investigated the in vitro effects of single and combination therapy with AuNPs (1.0 nM), cetuximab (30 nM), and radiotherapy (4 Gy) on a human HNSCC cell line, HSC-3. Combination treatment of AuNPs + cetuximab + radiotherapy markedly reduced HSC-3 numbers and proliferation and enhanced apoptosis compared with single and double combination treatments. Furthermore, the in vivo combination treatment (AuNPs + cetuximab + radiotherapy) of a xenograft model of HSC-3 cells transplanted into nude mice (BALB/cAJcl-nu/nu) reduced the tumor volume compared with the controls. Scanning electron microscopy demonstrated the presence of AuNPs in tumor tissues and toxicity analysis indicated that AuNPs had no toxic effect on normal tissues. CONCLUSIONS: This study showed that AuNPs alone do not have a tumor-suppressing effect, but they sensitize tumors to radiotherapy and bind to cetuximab, leading to enhanced antitumor effects.

Is withdrawal of antiresorptive agents necessary before and after tooth extraction? A systematic review.

OBJECTIVES: The need for prevention and management of medication-related osteonecrosis of the jaw (MRONJ) has increased with the growing number of patients using antiresorptive agents. The scope of this systematic review (SR) was to determine whether the withdrawal of antiresorptive agents is necessary for tooth extractions in patients receiving each of the antiresorptive medications. MATERIALS AND METHODS: The searches were performed using the MEDLINE databases. We selected SRs, randomized controlled trials (RCTs), prospective and retrospective non-randomized clinical (observational) studies, and case reports/case series in this order of preference. RESULTS: We included one SR, one RCT, five observational studies, and three case reports. Meta-analyses were not conducted because the RCT had an extremely small sample size and the observational studies had different definitions of intervention and comparison that could not be integrated across studies. In this SR, no studies showed a benefit (i.e., a reduction in the incidence of osteonecrosis of the jaw) of short-term withdrawal of antiresorptive agents for tooth extraction. Additionally, no studies examined the harm (i.e., an increase in femoral and vertebral fractures and skeletal-related events during bone metastasis) of withdrawal for tooth extraction. CONCLUSIONS: We were unable to determine whether withdrawal before and after tooth extraction is necessary with a high certainty of evidence. Future systematic reviews including RCTs with larger samples are expected to provide such evidence. CLINICAL RELEVANCE: This systematic review provides evidence-based information for multidisciplinary collaborations related to patients receiving antiresorptive agents.

The Efficacy of Carbon Dioxide Paste in Alleviating Pain in Patients After Neck Dissection: Protocol for a Double-Blinded, Randomized Controlled Trial.

BACKGROUND: Head and neck cancers that cause severe aesthetic and functional disorders normally metastasize to the cervical lymph nodes. Patients with cervical lymph node metastasis are undergoing neck dissection. Shoulder complaints are common after neck dissection, with patients reporting symptoms such as pain, weakness, shoulder droop, and disability. However, no safe and effective treatment is available for this condition at present. We will conduct a double-blinded, randomized controlled trial to evaluate the efficacy of carbon dioxide (CO2) paste in relieving pain in patients after neck dissection. OBJECTIVE: This will be the first clinical study to compare the efficacy of CO2 paste with placebo in relieving postoperative pain in patients who underwent neck dissection. METHODS: We will perform this trial at the Kobe University Hospital in Japan. Patients will be randomized 1:1 into the CO2 paste and control groups. Patients in the CO2 paste group will have the CO2 paste applied to the cervical surface skin for 10 minutes once per day for 14 consecutive days. The primary end point of the study is a change in the visual analog scale (VAS) scores of neck pain from baseline on day 1 (preapplication) to the end of drug application (day 15). Secondary end points include changes in the following parameters from baseline on day 1 to the end of drug application (day 15) or the study (day 29): neck pain VAS score (days 1-29), grip strength (days 1-15 and 1-29), VAS scores for subjective symptoms (the feeling of strangulation, numbness, swelling, and warmth in the neck and shoulder region) for days 1-15 and 1-29, whether the VAS score improved more than 30% (days 1-15), the arm abduction test (days 1-15 and 1-29), shoulder range of motion (abduction and flexion) for days 1-15 and 1-29, occurrence of skin disorders, and occurrence of serious side effects. Periodic monitoring will be conducted for participants during the trial. This study was approved by the certified review board of Kobe University. RESULTS: The intervention commenced in May 2021 and will continue until March 2024. The collected data will provide information on the efficacy of the CO2 paste treatment. The primary end point will be compared using the Wilcoxon test, with the 1-sided significance level set at 5%. Each evaluation item will be summarized. Secondary efficacy end points will be analyzed to provide additional insights into the primary analysis. Findings based on the treatment effects are expected to be submitted for publication in 2025. CONCLUSIONS: This trial will provide exploratory evidence of the efficacy and safety of CO2 paste in relieving pain in patients after neck dissection. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) identifier: jRCTs051210028; https://jrct.niph.go.jp/en-latest-detail/jRCTs051210028. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50500.

Photodynamic therapy with verteporfin accelerates apoptotic bleb formation in human ameloblastoma.

OBJECTIVE: Although benign, ameloblastoma is a locally aggressive lesion in some patients and the development of additional treatments is needed. Verteporfin (VP) is a photosensitizer exhibiting considerable photocytotoxicity in various tumor cells. We aimed to investigate the effects of verteporfin photodynamic therapy (VP PDT) on ameloblastoma. METHODS: Eighteen patients who underwent surgery for ameloblastoma were randomly selected. We performed an immunohistochemical assessment to investigate the expression of low-density lipoprotein receptor (LDLR) and Yes-associated protein (YAP), targets of VP, in human ameloblastoma tissues and cultured human ameloblastoma cell line (HAM1). The effect of VP PDT on cell proliferation and apoptosis in HAM1 was analyzed. RESULTS: The expression of LDLR and YAP were detected in human ameloblastoma tissues and HAM1. LDLR expression was significantly higher in patients who had previously undergone surgery than in patients who were receiving it for the first time. The cytotoxic effect of the combination of low-concentration VP administration and laser irradiation was comparable to high-concentration VP administration with and without laser irradiation. The addition of laser irradiation to VP administration significantly accelerated apoptotic bleb formation compared with VP administration alone. CONCLUSION: VP PDT has the potential to become an additional treatment for large-sized ameloblastoma.

A cysteine proteinase inhibitor ALLN alleviates bleomycin-induced skin and lung fibrosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that is characterized by fibrosis in the skin and internal organs, such as the lungs. Activated differentiation of progenitor cells, which are mainly resident fibroblasts, into myofibroblasts is considered a key mechanism underlying the overproduction of extracellular matrix and the resultant tissue fibrosis in SSc. Calpains are members of the Ca2+-dependent cysteine protease family, whose enzymatic activities participate in signal transduction and tissue remodeling, potentially contributing to fibrosis in various organs. However, the roles of calpain in the pathogenesis of SSc remain unknown. This study aimed to examine the anti-fibrotic properties of N-acetyl-Leu-Leu-norleucinal (ALLN), one of the cysteine proteinase inhibitors that primarily inhibit calpain, in vitro and in vivo, to optimally translate into the therapeutic utility in human SSc. METHODS: Normal human dermal and lung fibroblasts pretreated with ALLN were stimulated with recombinant transforming growth factor beta 1 (TGF-ß1), followed by assessment of TGF-ß1/Smad signaling and fibrogenic molecules. RESULTS: ALLN treatment significantly inhibited TGF-ß1-induced phosphorylation and nuclear transport of Smad2/3 in skin and lung fibroblasts. TGF-ß1-dependent increases in α-smooth muscle actin (αSMA), collagen type I, fibronectin 1, and some mesenchymal transcription markers were attenuated by ALLN. Moreover, our findings suggest that ALLN inhibits TGF-ß1-induced mesenchymal transition in human lung epithelial cells. Consistent with these in vitro findings, administering ALLN (3 mg/kg/day) three times a week intraperitoneally remarkably suppressed the development of skin and lung fibrosis in a SSc mouse model induced by daily subcutaneous bleomycin injection. The number of skin- and lung-infiltrating CD3+ T cells decreased in ALLN-treated mice compared with that in control-treated mice. Phosphorylation of Smad3 and/or an increase in αSMA-positive myofibroblasts was significantly inhibited by ALLN treatment on the skin and lungs. However, no adverse effects were observed. CONCLUSIONS: Our results prove that calpains can be a novel therapeutic target for skin and lung fibrosis in SSc, considering its inhibitor ALLN.

Relationship of Mitochondrial-Related Protein Expression with the Differentiation, Metastasis, and Poor Prognosis of Oral Squamous Cell Carcinoma.

Mitochondrial dysfunction and respiratory function changes have been consistently associated with the initiation and progression of cancer. The purpose of this study was to retrospectively investigate the expression of mitochondrial tumor-suppressor and DNA-repair proteins in patients with oral squamous cell carcinoma (OSCC) and to evaluate the relationship between their expression and prognosis. We enrolled 197 patients with OSCC who underwent surgical resection between August 2013 and October 2018. Clinical, pathological, and epidemiological data were retrospectively collected from hospital records. The expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A, mitochondrial tumor suppressor gene 1, silent information regulator 3, and 8-hydroxyguanine DNA glycosylase was investigated using immunochemistry. The 3-year disease-specific survival (DSS) rates of patients showing positive expression of all selected proteins were significantly higher than those of patients showing a lack of expression. Multivariate analysis revealed that the expression of PGC-1α (hazard ratio, 4.684) and vascular invasion (hazard ratio, 5.690) can predict the DSS rate (p < 0.001). Low PGC-1α expression and vascular invasion are potential clinically effective predictors of the prognosis of OSCC.

Transcutaneous carbon dioxide application suppresses the expression of cancer-associated fibroblasts markers in oral squamous cell carcinoma xenograft mouse model.

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Cancer-associated fibroblasts (CAFs) are the main stromal cells in the tumor microenvironment (TME). As CAFs promote tumor progression and hypoxia in the TME, regulating the conversion of normal fibroblasts (NFs) into CAFs is essential for improving the prognosis of patients with OSCC. We have previously reported the antitumor effects of transcutaneous carbon dioxide (CO2) application in OSCC. However, the effects of reducing hypoxia in the TME remain unclear. In this study, we investigated whether CO2 administration improves the TME by evaluating CAFs marker expression. Human OSCC cells (HSC-3) and normal human dermal fibroblasts (NHDF) were coinjected subcutaneously into the dorsal region of mice. CO2 gas was applied twice a week for 3 weeks. The tumors were harvested six times after transcutaneous CO2 application. The expression of CAFs markers (α-SMA, FAP, PDPN, and TGF-ß) were evaluated by using real-time polymerase chain reaction and immunohistochemical staining. The expression of α-SMA, FAP, PDPN, and TGF-ß was significantly increased over time after co-injection. In the CO2-treated group, tumor growth was significantly suppressed after treatment initiation. In addition, the mRNA expression of these markers was significantly inhibited. Furthermore, immunohistochemical staining revealed a significant decrease in the protein expression of all CAFs markers in the CO2-treated group. We confirmed that transcutaneous CO2 application suppressed CAFs marker expression and tumor growth in OSCC xenograft mouse model.

A Novel Imaging Technique for Analyzing Condylar Movement During Mastication in Patients With Jaw Deformities: Four-Dimensional Computed Tomography.

OBJECTIVE: This study aimed to reveal characteristic condylar movements in patients with jaw deformities. STUDY DESIGN: Thirty patients with jaw deformities before surgery were enrolled and instructed to chew a cookie during 4-dimensional computed tomography (4DCT). The distance between the most anterior and posterior positions of the bilateral condyles on 4DCT images was measured and compared among patients with different skeletal classes. Correlations between the condylar protrusion and cephalometric values were also determined. RESULTS: The distances of condylar protrusion during mastication were significantly greater in the skeletal class II group than in the skeletal class III group ( P =0.0002). Significant correlations were found between the distances of condylar protrusion during mastication and the sella-nasion-B point angle ( r =-0.442, P =0.015), A point-nasion-B point angle ( r =0.516, P =0.004), sella-nasion plane to ramus plane angle ( r =0.464, P =0.01), sella-nasion plane to occlusal plane angle ( r =0.367, P =0.047), and condylion-gonion length ( r =-0.366, P =0.048). CONCLUSION: Motion analysis with 4DCT images revealed that condylar movement in patients with retrognathism was larger than in patients with mandibular prognathism. Skeletal structure was therefore correlated with condylar movement during mastication.

Comparison of the 8th edition of TNM staging of oral cancer with the 7th edition and its prognostic significance using clinical depth of invasion and extranodal extension.

OBJECTIVES: The 8th edition of the International Union Against Cancer Control/American Joint Committee on Cancer Staging System introduced depth of invasion (DOI) and extranodal extension (ENE) into the staging of oral cavity cancer. We evaluated the prognostic ability of this new staging system compared with the 7th edition using clinical DOI (cDOI) and clinical ENE (cENE). MATERIALS AND METHODS: We retrospectively reviewed and restaged 2,118 patients with oral squamous cell carcinoma treated between 2001 and 2018 using cDOI and cENE. Overall and disease-specific survival were used as endpoints to compare the prognostic outcomes of the 7th and 8th editions using Harrell's concordance index (C-index). RESULTS: In total, 305 (14.4 %) cases were upstaged in the T category, 85 (4.0 %) cases were upstaged in the N category, and 280 (13.2 %) cases were upstaged in the overall TNM stage. The introduction of the cDOI increased the C-index and hazard ratio (HR) for each T category. The introduction of cENE increased the N3b category of 85 cases, bringing the total to 94 cases, thereby widening the differences between each N category. In the 8th edition, the C-index and HR for overall TNM stage increased, and the discrimination between stage groups improved. CONCLUSIONS: The 8th edition of the TNM clinical staging system using cDOI and cENE predominantly identified patients with a high mortality rate, thus improving the ability to discriminate and prognosticate oral cancer.

Expression of JCAD and EGFR in Perineurial Cell-Cell Junctions of Human Inferior Alveolar Nerve.

Although perineurium has an important role in maintenance of the blood-nerve barrier, understanding of perineurial cell-cell junctions is insufficient. The aim of this study was to analyze the expression of junctional cadherin 5 associated (JCAD) and epidermal growth factor receptor (EGFR) in the perineurium of the human inferior alveolar nerve (IAN) and investigate their roles in perineurial cell-cell junctions using cultured human perineurial cells (HPNCs). In human IAN, JCAD was strongly expressed in endoneurial microvessels. JCAD and EGFR were expressed at various intensities in the perineurium. In HPNCs, JCAD was clearly expressed at cell-cell junctions. EGFR inhibitor AG1478 treatment changed cell morphology and the ratio of JCAD-positive cell-cell contacts of HPNCs. Therefore, JCAD and EGFR may have a role in the regulation of perineurial cell-cell junctions.

Oncological Impact of the Level of Inferior Mesenteric Artery Ligation in Low Rectal Cancer Surgery.

BACKGROUND/AIM: This study aimed to evaluate the clinical impact of the level of inferior mesenteric artery (IMA) ligation in patients with advanced low rectal cancer. PATIENTS AND METHODS: All enrolled patients (n=350) underwent curative resection of rectal cancer with D3 lymph node dissection, with either IMA (high-tie) or superior rectal artery (SRA) (low-tie) ligation. RESULTS: There were 27 and 65 patients in the high-tie and low-tie groups, respectively. There was no significant difference in the postoperative complication rate. Postoperative anastomotic leakage developed in five patients in the low-tie group and none in the high-tie group. The overall recurrence rates were 37.0% (n=10) and 40.0% (n=26) in the high-tie and low-tie groups, respectively, with no significant difference between the two groups (p=0.748). Local recurrences and lymph node metastases developed in five and no patients in the high-tie group and in 13 and one patient in the low-tie group, respectively. In the multivariate analysis, pathological T4 and pathological N2 and N3 were independent poor prognostic factors for overall survival (OS), whereas left colic artery (LCA) preservation was not significant. CONCLUSION: No significant difference in oncological outcomes was observed in advanced low rectal cancer surgery with respect to the level of the IMA ligation. Thus, the less complicated high-tie procedure should be adopted as a standard procedure.

Risk factors for pathological fracture in patients with mandibular osteoradionecrosis.

Osteoradionecrosis (ORN) often results in pathological fractures through progression. We aimed to identify the risk factors for pathological fracture in patients with mandibular ORN. Seventy-four patients with mandibular ORN were included in this retrospective study. We investigated various risk factors for pathological fracture in patients with mandibular ORN, including number of mandibular teeth with a poor prognosis each at initial evaluation before radiation therapy (RT) and when fracture occurred, and the proportion of antibiotic administration period in a follow-up duration after RT. The rate of occurrence of pathological fractures in patients with mandibular ORN was 25.7%. The median of duration between RT completion and fracture occurrence was 74.0 months. We found that pathological fracture was significantly associated with a larger number of mandibular teeth with a poor prognosis at initial evaluation before RT (P = 0.024) and when fracture occurred (P = 0.009). Especially, a larger number of mandibular teeth with P4 periodontitis, in other words severe periodontal status, was related to pathological fracture in both timings. The proportion of antibiotic administration period in a follow-up duration was also significant risk factor (P = 0.002). Multivariate analyses showed statistically significant associations between pathological fracture and a larger number of mandibular teeth with a poor prognosis when fracture occurred (hazard ratio 3.669). The patient with a larger number of mandibular teeth with P4 periodontitis may have a risk of not only occurrence of ORN but resulting in pathological fracture by accumulation of infection. Surgeons should consider extraction of those teeth regardless of before/after RT if necessary for infection control.

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with recurrent oral squamous cell carcinoma treated with nivolumab.

The immune checkpoint inhibitor (ICI), nivolumab, has revolutionised the treatment of recurrent and metastatic oral cancer. However, the response rate to ICIs remains low, and identifying predictors of nivolumab response is critical. Although the neutrophil-to-lymphocyte ratio (NLR) has been suggested as a predictive marker of nivolumab response in patients with various types of cancer, its utility in oral squamous cell carcinoma (OSCC) has not been elucidated. In this retrospective multicentre cohort study, we evaluated the association between NLR and outcome of nivolumab treatment in 64 patients with OSCC treated between 2017 and 2020. The objective response and disease control rates were 25.1% and 32.9%, respectively. The rates for complete and partial responses were 15.7% (10/64) and 9.4% (6/64), respectively; stable and progressive disease rates were 7.8% (5/64) and 67.1% (43/64), respectively. Complete and partial responses were classified as responders, and stable and progressive diseases were classified as non-responders. The median (range) pre-treatment NLR among responders was 4.3 (2.8-8.0), which decreased to 4.0 (2.6-6.3) after nivolumab treatment, and the median (range) pre-treatment NLR among non-responders was 5.1 (2.7-7.9), which increased to 6.4 (4.0-14.0) with tumour growth. Moreover, overall survival was significantly worse in the group with a higher post-treatment NLR (≥5) than in the group with a lower NLR (<5). Patients with a post-treatment NLR of ≥6 had worse outcomes for salvage chemotherapy following nivolumab treatment. Thus, post-treatment NLR could be a useful marker for predicting the response to nivolumab treatment or salvage chemotherapy in patients with OSCC.