Peripheral lymphocyte fluctuation as an indicator of severe immune-related adverse events in patients treated with immune checkpoint inhibitors.

AIM: Immune checkpoint inhibitors (ICIs) have proven to be effective treatments for various cancers, but can also elicit immune-related adverse events (irAEs). Given that severe irAEs can be life-threatening, biomarkers that can predict the occurrence of irAEs are of paramount importance. ICIs affect the dynamics of lymphocytes, and alterations in these dynamics may play a role in the development and severity of irAEs. The aim of this study was to investigate the correlation between irAEs and changes in lymphocyte counts. METHODS: Information on irAEs was collected from 226 ICI cases from 2014 to 2020. We compared lymphocyte counts before treatment and at the onset of irAE and investigated the association between lymphocyte count fluctuations and the presence and severity of irAE, the course after steroid treatment, and overall survival. RESULTS: Of the 226 cases, 27 patients developed grade 3 or higher irAE. Compared to the other groups, the lymphocyte count in this group was significantly decreased at the time of irAE (p < 0.01). There was a trend toward a rapid increase in lymphocyte count in the steroid responder group compared to the non-responder group. Regarding overall survival, patients with irAE had significantly longer survival than those without irAE (p = 0.0025). However, there was no association between changes in lymphocyte count and survival in patients with irAE. CONCLUSION: The percentage change in lymphocyte count was found to correlate with the incidence of severe irAEs. Close monitoring of the patient's condition is crucial when the lymphocyte count decreases during ICI treatment.

Removal of Large Wharton's Duct Salivary Stones Using a CO2 Laser: A Report of Two Cases.

Introduction: Salivary stones inside the Wharton's duct adjacent to the mylohyoid muscle are often removed by a little incision of the mouth floor under local anesthesia. However, in the case of relatively large salivary stones, a large incision is required, which is commonly accompanied by hemorrhage and the need for surgical hemostasis, resulting in prolonged surgery. Furthermore, troublesome sequelae such as ranula and lingual nerve paralysis can occur after surgical procedures. Methods: Two patients who had relatively large salivary stones (>1 cm diameter) in the Wharton's duct were underwent incision of the mouth floor soft tissues with a CO2 laser. Results: In both patients, the stone was removed in a few minutes without causing abnormal bleeding, nerve injury, or sublingual gland disorders and was completely healed. Conclusion: We report the usefulness and safety of the CO2 laser in two patients with relatively large salivary stones, who underwent successful surgical removal.

Assessment of the association between dysphagia and sarcopenia among elderly patients with cirrhosis: Usefulness of the finger-ring test.

AIM: Sarcopenic dysphagia has become an urgent matter of debate in our aging society. However, little is known about the relationship between sarcopenia and dysphagia in patients with liver cirrhosis. Our aim was to assess sarcopenia and dysphagia among elderly patients with cirrhosis using two easy-to-use screening tests, i.e., the eating assessment tool-10 and the finger-ring test. METHODS: The eating assessment tool-10, handgrip strength, skeletal muscle mass index, computed tomography, and the finger-ring test were included in our analysis. One hundred patients with cirrhosis and without a history of aspiration pneumonia were divided into the elderly (≥75 years) and non-elderly (<75 years) groups. RESULTS: In the elderly group, sarcopenia was identified in 56.5% of the patients; of these, 30.4% and 13.0% had eating assessment tool-10 scores of ≥2 and ≥3, respectively. Sarcopenia-related factors correlated significantly with the eating assessment tool-10 scores (p<0.01). Multivariate regression analysis revealed that sarcopenia was significantly associated with dysphagia (p=0.028; odds ratio, 7.27). Among the elderly patients, the calf size of the non-dominant lower limb was less than the finger-ring circumference in 37.0% of the patients. This group had a significantly higher proportion of patients with an eating assessment tool-10 score of ≥2 than those with a greater calf than finger-ring circumference (p<0.01). CONCLUSIONS: Sarcopenia, rather than the hepatic reserve function, is associated with dysphagia among elderly patients with cirrhosis. The finger-ring test might be useful in screening for dysphagia.

Dental Rehabilitation for Free Fibula Flap-Reconstructed Mandible with Scar Contracture: A Technical Note.

Dental rehabilitation with osseointegrated implants in reconstructed mandibles is a common procedure, but the technique still requires improvement, especially in its reliability and technical simplification. We herein report dental rehabilitation of a free fibula-reconstructed mandible with scar contracture. A vestibuloplasty technique with application of a polyglycolic acid (PGA) sheet is described. The implants were inserted into a viable fibula flap with severe scar contracture of the overlying epithelium resulting from vascular instability in skin paddle. Only the fibula periosteum was sutured after implant insertion; exposed surfaces were covered with a combination of PGA sheet and fibrin sealant. The area with PGA sheet coverage gradually healed with moderate contracture. The epithelium around the almost implants became immobilized. The implant-supported removable partial denture with custom titanium bar was acceptable. Dental rehabilitation is possible for reconstructed mandibles with severe scar contracture. Application of a PGA sheet may be useful for vestibuloplasty in patients with reconstructed mandibles.

Clinical Evaluation of CO2 Laser Vaporization Therapy for Oral Lichen Planus: A Single-Arm Intervention Study.

Objective: The purpose of this study is to evaluate the efficacy of CO2 laser vaporization therapy for oral lichen planus (OLP) refractory to conservative treatments. Methods: The study group comprised 16 patients with clinically and histologically diagnosed OLP. They underwent conservative treatment for 3 months using an adrenal cortex hormone ointment and azulene sulfonate sodium hydrate gargle. Patients who showed no improvement with conservative treatment underwent CO2 laser vaporization therapy (3 W, continuous-wave mode). The assessment was performed using the numerical rating scale (NRS) as a subjective indicator and the Thongprasom sign score (TSS) as an objective indicator of OLP. These two scales were recorded during examinations performed before treatment and then at 7 days, 1, 3, and 6 months, and 1 year after irradiation. Differences between preirradiation and each point of time after irradiation were tested by Wilcoxon's signed-rank tests. Results: Laser irradiation was administered to 9 patients with 11 sites. The NRS score and TSS decreased at all 11 sites (100%) and 10 sites (90.9%) at 1 year after irradiation compared with preirradiation scores. The NRS score and TSS were statistically lower (p < 0.05) at 1 and 3 months (short-term) and 6 months and 1 year (mid-long-term) after irradiation than the preirradiation scores. There were no patients with malignant transformation during the study period. Conclusions: These single-arm clinical trial results show the efficacy of CO2 laser vaporization therapy for OLP refractory to conservative treatment.

Clinical Study of Laser Treatment for Frenectomy of Pediatric Patients.

AIM: To suggest regarding the timing of oral surgery and laser treatment for frenulum abnormalities in the pediatric population. MATERIALS AND METHODS: We investigated the sex, age, frenulum site, reason for consultation, treatment method, and prognosis of 35 patients aged 15 years or younger and who were examined at our hospital for the chief complaint of frenulum abnormality. RESULTS: A total of 21 (mean age, 6.0 years) of the 35 patients underwent frenectomy using a carbon dioxide (CO2) laser. Of these, 7 patients (mean age, 2.8 years) underwent the procedure with general anesthesia and 14 patients (mean age, 7.6 years) underwent the procedure with local anesthesia. The surgical site was the lingual frenulum in 15 patients and the maxillary labial frenulum in 6 patients. No adverse events were intraoperatively reported in any of the patients, and the procedure was quickly and safely performed. The mean postoperative follow-up period was 4.6 months, and readhesion was noted in one patient (4.8%). The most common reason cited for not undergoing frenectomy in the 14 patients (mean age, 3.4 years) was the young age of the child. CONCLUSION: Retrospective study of pediatric patients with frenulum abnormalities demonstrated the usefulness of the CO2 laser in performing frenectomy and offered suggestions regarding the timing of this procedure. CLINICAL SIGNIFICANCE: Frenectomy performed using a CO2 laser for pediatric patients is a useful, simple, and safe treatment method. HOW TO CITE THIS ARTICLE: Komori S, Matsumoto K, Matsuo K, Suzuki H, Komori T. Clinical Study of Laser Treatment for Frenectomy of Pediatric Patients. Int J Clin Pediatr Dent 2017;10(3):272-277.

Single-stage reconstruction for buccal mucosa tumor resection including the labial commissure using a facial artery musculomucosal flap and a vermilion advancement flap.

Resection of buccal mucosa tumors may occasionally involve the labial angle and peripheral skin. Reconstruction is required when the resection involves more than one-third of the lip. We describe a single-stage reconstruction using a facial artery musculomucosal (FAMM) flap and a vermilion advancement flap after buccal mucosa resection including the labial angle. A 62-year-old woman with carcinoma in situ of the buccal mucosa underwent tumor resection. The resection included the right labial angle and peripheral skin. The resection did not lead to a massive lip defect, but a wide defect resulted on the mucosal side. The defect on the mucosal side was reconstructed using a FAMM flap, while the vermilion defect was covered using a vermilion advancement flap. Reconstruction performed using the FAMM flap and vermilion advancement flap produced aesthetically and functionally satisfactory outcomes.

A Retrospective Evaluation of Partial Glossectomy for Early Tongue Cancer Using a Carbon Dioxide Laser.

OBJECTIVE: The purpose of this study was to retrospectively evaluate the postoperative results of partial glossectomy for early tongue cancer using a carbon dioxide laser (CO2 laser). BACKGROUND DATA: CO2 lasers are frequently used for the excision or treatment of soft tissue in a range of diseases, including oral cancer, leukoplakia, mucocele, anomalies of the labial and lingual frenum, and peri-implantitis. MATERIALS AND METHODS: We retrospectively reviewed 31 primary cases of early superficial tongue cancer that were treated using CO2 lasers. In this study, early superficial cancer of the tongue is defined as a T1 or T2 tumor (TNM classification, NOMO; type, superficial spread, or exophytic; depth, <5 mm). The lesions were stained with 10% Lugol's solution and excised with a 5- or 10-mm safety margin from the nonstained area or induration using a CO2 laser. The raw surface was covered with a polyglycolic acid sheet using fibrin glue spray (n = 23), sutures (n = 6), or both (n = 2). Five of the patients showed a bleeding tendency: 1 was taking warfarin 100 mg per day, 1 was taking 350 mg per day, 2 were taking aspirin 100 mg per day, and 1 was taking aspirin 200 mg per day. RESULTS: There were no cases of postoperative bleeding. Regarding postoperative pain, all patients could stop taking analgesic drugs by 1 month after undergoing the operation. In regards to postoperative difficulty to swallow, all could start swallowing rice gruel 2 days after the operation. The surgical margin was unclear in two cases due to the thermal denaturation of the excisional margin. The 2-year local control rate was 100% and subsequent cervical lymph node metastasis rate was 6.5%. CONCLUSIONS: In terms of recurrence, metastasis, postoperative bleeding, postoperative pain, and swallowing, partial glossectomy for early tongue cancer using a CO2 laser might therefore help improve the postoperative course.

Clinical Study of 19 Cases Resulting in Dental Implant Removal.

Dental implant treatment is a highly anticipated therapy with widespread use. However, various accidental symptoms and complications have been reported, and we may reluctantly have to remove an implant body out of necessity. This study evaluated 19 cases (21 jaws) that resulted in removal after the enforcement of implant treatment in our hospital from January 2003 to August 2013 and clarified the details of the removals clinically for the purpose of improvement of future treatment results. Implants were removed at a higher frequency in elderly patients, particularly those 70 years of age or older. The removal rate regarding the tooth missing style was high in edentulous jaw cases in both the maxilla and mandible, and was low in defective cases of middle teeth. Regarding the duration and cause of removal, approximately half of the implants were removed due to defective primary stability within 6 months; for periods greater than 6 months, all cases except 1 jaw were removed within 30 months and many cases were due to peri-implantitis. Preoperation evaluations, primary stability of the implant body at the time of the operation, long-term observation and maintenance, and patient education are crucial to reduce the frequency of removal.

The long-term effects of red light-emitting diode irradiation on the proliferation and differentiation of osteoblast-like MC3T3-E1 cells.

Low level laser therapy (LLLT) affects various biological processes, and it is said that the non-coherent light of the light-emitting diode (LED) has a similar action. The purpose of this study was to examine the effects of LED light on the proliferation and differentiation of osteoblasts-like MC3T3-E1 cells cultured in osteogenic differentiation medium (ODM) over the long term. Cells were irradiated with red LED light of 630 nm at three doses; 0.5J/cm², 1.5J/cm² or 3.0J/cm² for the cell proliferation activity assay, and at 0.5J/cm² for the osteogenic differentiation activity assay. The former activity was checked by counting the number of viable cells using Trypan blue dye. The latter activity was evaluated by alkaline phosphatase (ALP) staining and examining the mRNA expression of the osteopontin (OPN) gene using real-time quantitative PCR. The number of viable MC3T3-E1 cells showed a tendency to increase after the irradiation at all three energy densities in comparison with a non-irradiation group (control group). In particular, there was a remarkable 3.34-fold increase in the group irradiated with 3.0J/cm² on day 7 after starting the culture. On culture day 15, there was a tendency for the red LED irradiation group (0.5 J/cm²) to exhibit more staining for ALP than the control group, and the expression of OPN was significantly higher in the irradiation group on culture day 16. In conclusion, low level red LED light can enhance MC3T3-E1 cell proliferation and osteogenic differentiation when the cells are cultured for a relatively long time.

Critical roles of interactions among switch I-preceding residues and between switch II and its neighboring alpha-helix in conformational dynamics of the GTP-bound Ras family small GTPases.

GTP-bound forms of Ras family small GTPases exhibit dynamic equilibrium between two interconverting conformations, "inactive" state 1 and "active" state 2. A great variation exists in their state distribution; H-Ras mainly adopts state 2, whereas M-Ras predominantly adopts state 1. Our previous studies based on comparison of crystal structures representing state 1 and state 2 revealed the importance of the hydrogen-bonding interactions of two flexible effector-interacting regions, switch I and switch II, with the γ-phosphate of GTP in establishing state 2 conformation. However, failure to obtain both state structures from a single protein hampered further analysis of state transition mechanisms. Here, we succeed in solving two crystal structures corresponding to state 1 and state 2 from a single Ras polypeptide, M-RasD41E, carrying an H-Ras-type substitution in residue 41, immediately preceding switch I, in complex with guanosine 5'-(ß,γ-imido)triphosphate. Comparison among the two structures and other state 1 and state 2 structures of H-Ras/M-Ras reveal two new structural features playing critical roles in state dynamics; interaction of residues 31/41 (H-Ras/M-Ras) with residues 29/39 and 30/40, which induces a conformational change of switch I favoring its interaction with the γ-phosphate, and the hydrogen-bonding interaction of switch II with its neighboring α-helix, α3-helix, which induces a conformational change of switch II favoring its interaction with the γ-phosphate. The importance of the latter interaction is proved by mutational analyses of the residues involved in hydrogen bonding. These results define the two novel functional regions playing critical roles during state transition.

Structural basis for conformational dynamics of GTP-bound Ras protein.

Ras family small GTPases assume two interconverting conformations, "inactive" state 1 and "active" state 2, in their GTP-bound forms. Here, to clarify the mechanism of state transition, we have carried out x-ray crystal structure analyses of a series of mutant H-Ras and M-Ras in complex with guanosine 5'-(beta,gamma-imido)triphosphate (GppNHp), representing various intermediate states of the transition. Crystallization of H-RasT35S-GppNHp enables us to solve the first complete tertiary structure of H-Ras state 1 possessing two surface pockets unseen in the state 2 or H-Ras-GDP structure. Moreover, determination of the two distinct crystal structures of H-RasT35S-GppNHp, showing prominent polysterism in the switch I and switch II regions, reveals a pivotal role of the guanine nucleotide-mediated interaction between the two switch regions and its rearrangement by a nucleotide positional change in the state 2 to state 1 transition. Furthermore, the (31)P NMR spectra and crystal structures of the GppNHp-bound forms of M-Ras mutants, carrying various H-Ras-type amino acid substitutions, also reveal the existence of a surface pocket in state 1 and support a similar mechanism based on the nucleotide-mediated interaction and its rearrangement in the state 1 to state 2 transition. Intriguingly, the conformational changes accompanying the state transition mimic those that occurred upon GDP/GTP exchange, indicating a common mechanistic basis inherent in the high flexibility of the switch regions. Collectively, these results clarify the structural features distinguishing the two states and provide new insights into the molecular basis for the state transition of Ras protein.

Histological evaluation of artifacts in tongue tissue produced by the CO2 laser and the electrotome.

OBJECTIVE: The purpose of this study was to investigate the clinical usefulness of laser surgery in pathologic diagnosis following excisional biopsy of human oral mucosa by CO(2) laser and electrotome. BACKGROUND DATA: When performing pathologic diagnosis and microscopic analysis of specimens excised by the CO(2) laser, there have been concerns about thermal denaturation of the excisional margin that may prevent diagnosis. MATERIALS AND METHODS: Thirty tongue tissue samples from humans that were surgically resected using a CO(2) laser (continuous wave mode for 10 cases and pulse wave mode for 10 cases) and an electrotome (10 cases) were formalin-fixed and paraffin-embedded. These preserved specimens were then cut into thick sections and subjected to hematoxylin and eosin staining followed by microscopic assessment. RESULTS: Despite the differences between the CO(2) laser and electrotome methods, similar thermal denaturation, such as carbonization, vacuolar degeneration, and elongation of nuclei, were observed at the excisional margins for both methods. Use of the CO(2) laser, particularly in pulse wave mode, reduced the amount of thermal denaturation significantly (p < 0.01) compared to the electrotome. CONCLUSION: These results indicate that the CO(2) laser is better than the electrotome as a means of making excisions for performing pathologic diagnosis.