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Type 2 diabetes is a typical lifestyle disease. We aimed to identify the factors affecting glycemic control in 64 outpatients with type 2 diabetes over a 2-year period. We defined poor glycemic control using a change in glycosylated hemoglobin (ΔHbA1c) of ≥ 0.5% over 2 years and/or HbA1c ≥ 7.5% at the end of the study period. We used a questionnaire to collect information on oral health behavior and lifestyle, including eating and smoking habits, and analyzed the relationships between indices of diabetes control and responses to the questionnaire. The mean (SD) HbA1c of the participants was 6.87% (0.77%) at a baseline, and 6.93% (0.69%) after 2 years. Twenty-three participants (36.0%) had poor glycemic control. ΔHbA1c and the change in body mass index (ΔBMI) correlated (Spearman’s rank correlation, r = 0.350, p < 0.01). The HbA1c at baseline was associated with eating slowly / chewing well, and ΔBMI was associated with perceived oral symptoms. Binominal logistic regression analysis revealed that poor glycemic control was associated with ΔBMI and a smoking habit (odds ratio : 1.62, 95% confidence interval : 1.08–2.42 ; and 4.01, 1.12–14.36, respectively). These findings imply that weight gain and a smoking habit are associated with poor glycemic control in patients with type 2 diabetes.

Changes in pelvic tilt angle (PTA) and cup orientation have been reported in patients after total hip arthroplasty, but the current literature generally has a brief follow-up period. This study will be the first to report PTA and cup orientation changes in the supine position for a minimum 18 years after total hip arthroplasty (THA) and investigate the factors associated with pelvic tilt and cup orientation changes.In this study, 101 patients (120 hips) who underwent THA were retrospectively analyzed. The aims of our study were to evaluate the PTA and cup orientation change over 18 years after THA to assess differential PTA, cup inclination, and anteversion. We also investigated whether factors such as gender, body mass index, and age have any influence on PTA and cup orientation after THA.Patients showed a significant incremental change in PTA pre-operatively, immediately post-operatively, and at final follow-up. Cup orientation increased significantly at the final follow-up compared to the immediate post-operative period. Gender subgroup analysis showed that PTA was significantly greater in females than in males at the final follow-up (p = 0.025). Age subgroup analysis showed that PTA was significantly greater in the over 60 years group than in the other groups.Our patients showed significant changes in PTA and cup orientation at a minimum 18 years after surgery, especially in females over 60 years. Female patients over 60 are a risk factor after THA.

Supplementary Data from Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability–High Locally Advanced Rectal Cancer

Supplementary Figure from Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability–High Locally Advanced Rectal Cancer

Purpose:Preoperative chemoradiotherapy (CRT) and surgical resection are the standard treatment for locally advanced rectal cancer (LARC). Combining immune checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC.Patients and Methods:In phase I, we investigated the feasibility of sequentially combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated.Results:Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathologic complete response (pCR) was centrally confirmed in 30% [11/37; 90% confidence interval (CI), 18%–44%] and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30; P = 0.004, Fisher exact test) were observed in those with programmed cell death ligand 1 (PD-L1) tumor proportion score ≥1% and P = 0.003, Fisher exact test) were observed for CD8+ T cell/effector regulatory T cell (CD8/eTreg) ratios of ≥2.5 and Conclusions:CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.

The dual mobility cup (DMC) is designed to extend the longevity of the prosthesis by improving stability, enhancing the range of motion, and decreasing impingement without increasing wear. We hypothesized that DMC would reduce the risk of dislocation in elderly patients. This study aimed to investigate the clinical and radiographic outcomes of DMC-total hip arthroplasty (THA) in elderly patients at high risk of dislocation.From June 2016 to March 2020, 94 patients with a mean age of 77.7 years (97 hips) who underwent a posterolateral approach for DMC-THA in our department were followed up for at least one year. Preoperative and postoperative pelvic tilt angles (PTA) and DMC orientation were prospectively collected for all patients. Intraoperative and postoperative complications were recorded. A parametric test was used for normal distribution, and a non-parametric test was used for non-normal distribution.Abduction and anteversion angles of the cup were 42.4 and 18.0° in the supine position immediately postoperative. The average PTA for patients in the supine and standing positions were 26.5 and 34.5°, respectively. When moving from the supine to the standing position, patients experienced a mean posterior pelvic tilt of 9°. No intraoperative acetabular-related complications were recorded. Postoperative complications included early infection in one patient (1.0%) and dislocation in one patient (1.0%).Our study demonstrates that DMC-THA provides satisfactory short-term outcomes in elderly patients at a high risk of dislocation, regardless of the change in PTA resulting from postural transition.

We investigated whether the proximal circumferential porous coating of cementless stems would make implant survival of20 years possible in young patients.Data for patients younger than 50 years with hip dysplasia who had an anatomic stem implanted with a proximal porous coating with hydroxyapatite/tricalcium phosphate were reviewed. Noncircumferential porous (non-C-type) stems were used in 17 hips (13 cases), and circumferential porous (C-type) stems were used in 87 hips (68 cases). Acetabular components with conventional polyethylene were used for all hips. The mean ages at surgery for patients with non-C-type stems and those with C-type stems were 43.3 and 44.7 years, respectively. Stems that had not loosened were retained at the time of acetabular revision. The average duration of follow-up for patients with non-C-type stems was 26.9 years and was 22.3 years for those with C-type stems.Mean survival rates as determined by the Kaplan-Meier method were 74.9% at 20 years and 59.9% at 25 years for non-C-type stems and were 100% at 20 years and 94.0% at 25 years for C-type stems. The survivorship for C-type stems was significantly higher than that for non-C-type stems (P.01). Focal osteolysis in the shoulder of 37 hips with C-type stems suppressed the spread of osteolysis to the distal femur.Anatomic femoral stems with a circumferential porous coating provide excellent durability in patients with hip dysplasia who are 50 years of age or younger.Therapeutic Level IV.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that affects exocrine glands, such as salivary and lacrimal glands. The Janus kinase (JAK) /signal transducer and activator of transcription (STAT) pathway are activated in various inflammatory diseases including pSS. This study aimed to investigate the expression of JAK1, JAK2, phosphorylated JAK1, and phosphorylated JAK2 in labial salivary gland (LSG) tissues from patients with pSS to evaluate the potential of JAK inhibitors as therapeutic agents for pSS. Immunohistochemical analysis was performed using LSG tissues of patients with pSS (n=10), non-SS (n=5), and healthy controls (n=5). In acinar epithelial cells, JAK1, JAK2, and phosphorylated JAK1 were expressed at significantly lower levels in LSG tissues of patients with pSS than in healthy controls. Significantly higher expression of phosphorylated JAK1 and phosphorylated JAK2 was observed in the ductal epithelial cells of patients with pSS compared to the controls. However, there was no significant association between the expression levels of phosphorylated JAK1 or JAK2 and the degree of inflammation. In addition, immunofluorescence analysis revealed JAK2 phosphorylation in many CD3 + T cells infiltrating the LSG tissues. These results suggested the activation of JAK/STAT signaling in both the ductal epithelial cells and the infiltrating CD3 + T cells in the LSG tissues of patients with pSS. Therefore, JAK inhibitors may be effective therapeutic agents for pSS by regulating both effector T cells and target cells.

108 Background: In VOLTAGE-A, CRT (50.4 Gy with capecitabine of 1,650 mg/m2) followed by five cycles of consolidation Nivo (240 mg q2 weeks [W]) and radical surgery showed 30% of pathological complete response (pCR) in pts with MSS and 60% in MSI-H T3–4 NanyM0 LARC. Here, we report survival outcomes and functional results. Methods: All 39 MSS and 5 MSI-H pts were included in the VOLTAGE-A from Jan 2017 to Oct 2019. Survival outcomes, late adverse events, and patient-reported outcome measurements for urogenital and anal functions were analyzed. Urinary function was evaluated using the International Prostate Symptom Score (I-PSS) periodically at 1W, 1, 3, 6, and 12 months (M), postoperatively. Sexual function in sexually active male pts was evaluated using the International Index of Erectile Function (IIEF) score at 3, 6, and 12M, postoperatively. Anal function was evaluated using the Wexner score, low anterior resection syndrome (LARS) score, and fecal incontinence severity index (FISI) score at 1-year post-surgery. All functional scores were evaluated preoperatively. Results: With a median follow-up of 44.8M (range, 25.7-58.9M), the 3-year relapse-free survival (RFS) and 3-year overall survival (OS) rates were respectively 79.5% and 97.4% in MSS, and 100% each in MSI-H pts. Of the MSS pts, those with pCR, clinical CR (cCR) according to the MSKCC criteria, high PD-L1 expression (tumor proportion score [TPS] ≥1%), and CD8/eTreg ratios of ≥2.5 had a trend of better 3-year RFS and OS than those without. During the follow-up period, one patient developed CTCAE grade 3 immune-related colitis, which was diagnosed 20M after the last dose of Nivo. Postoperative functional results were acceptable in both populations; pre-surgical median I-PSS scores were 3, whereas postsurgical values were 5 (1W), 5.5 (1M), 5 (3M), 4 (6M), and 4 (12M); median IIEF score was 20 at pre-surgery and 6 (3M), 6 (6M), and 8 (12M) at post-surgery; median scores of Wexner, LARS, and FISI were 2, 23, and 7 at pre-surgery, and 9, 30, and 17 at 1-year post-surgery, respectively. Conclusions: Preoperative CRT followed by Nivo showed promising survival outcomes in both MSS and MSI-H LARC pts. The therapeutic effect of pCR, cCR, and certain biomarkers analyzed by pre-CRT samples could be used as prognostic predictors in MSS pts. Clinical trial information: NCT02948348 .[Table: see text]

416 Background: Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients (pts) with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), invading the aorta, vertebral body, or trachea. However, complete response (CR) rates are low (11–25%), with a median overall survival (OS) of 9–10 months. We previously reported atezolizumab following dCRT indicated promising 42.1% of confirmed CR (cCR) rate and 65.8% of 12-months OS (Bando H, et al., ESMO Congress 2022 ). Methods: We investigated predictive biomarkers for cCR in this multicenter phase II study. PD-L1 tumor proportion score (TPS) was examined with VENTANA PD-L1. Immunological phenotypes of tumor microenvironments were assessed with multiplex immunohistochemistry (mIHC) and multi-color flow cytometry (FCM). Cancer gene aberrations and gene expression were investigated with whole exome and whole transcriptome sequencing (WES/WTS), respectively. Results: In 35 pts with an evaluable PD-L1 TPS, the cCR rates of +CD8+PD-1+ T cells and CD3+CD8-FOXP3+ T cells prior to CRT in tumor tissue were significantly correlated with cCR and non-cCR, respectively (both are P+CD8+ T cells prior to CRT, after CRT, and after atezolizumab were significantly correlated with cCR (P+FOXP3highCD45RA-CD4+ regulatory T cells (Treg cells) after CRT were significantly correlated with non-cCR (P+CD8+ T cells prior to CRT may be a predictive biomarker for cCR of CRT followed by atezolizumab, and that several driver gene abnormalities, cancer intrinsic signatures and tumor-infiltrating Treg cells are associated with treatment resistance. These findings could enable subsequent biomarker-selected clinical trials and lead to the development of novel cancer immunotherapeutic strategies. Clinical trial information: UMIN000034373 .

The aim of this study is to investigate the association between chemotherapy-induced fever with neutropenia less than 1500/μL (FwN) and oral bacteria and/or oral immunity in patients with hematological cancer. Thirty-two patients with hematological cancer were enrolled in the study. Secretory immunoglobulin A (sIgA) in saliva and the anaerobic bacteria in tongue coating of each subject were assessed before the first chemotherapy. Eleven subjects had an onset of FwN and 21 subjects did not during the observation periods. It was revealed by the Cox-proportional hazard model analysis that the levels of sIgA were low (HR 0.98, p

Amine oxide deoxygenation is an important process for the synthesis of nitrogenous aromatic compounds and de-protection of amine compounds; however, precious metals, organic solvents and undesirabl...

Objectives The aim of this study was to investigate the effect of an oral care tablet containing kiwifruit powder on oral bacteria in tongue coating compared with tongue brushing. Material and methods Thirty-two healthy, young adults were enrolled, and a crossover clinical trial was conducted. The volatile sulfur compound (VSC) concentration, Winkel tongue-coating index (WTCI), and the number of total bacteria in addition to Fusobacterium nucleatum in tongue coating were measured. We instructed subjects to remove tongue coating by tongue brush for Intervention I, to keep the oral care tablet containing kiwifruit powder on the tongue dorsum and to let it dissolve naturally for Intervention II, and three oral care tablets 1 day before the measurement for Intervention III. Results There were significant differences in terms of the level of H2 S, VSC, and WTCI at Intervention I and all evaluation values at Intervention II. There were significant differences in terms of the level of H2 S, VSC, WTCI, the number of total bacteria, and F. nucleatum at Intervention III. The value of WTCI, the number of bacteria, and F. nucleatum decreased significantly after taking the oral care tablets than after tongue brushing. When compared with Interventions I and III, Intervention III showed the effective results; there were significant differences in the number of total bacteria and F. nucleatum between tongue brushing and taking tablets. Conclusions These results suggested that the oral care tablet containing kiwifruit powder could be effective in reducing total bacteria and F. nucleatum in tongue coating when compared with tongue brushing.

Purpose: Preoperative chemoradiotherapy (CRT) and surgical resection are the standard treatment for locally advanced rectal cancer (LARC). Combining immune checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC. Patients and Methods: In phase I, we investigated the feasibility of sequentially combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated. Results: Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathologic complete response (pCR) was centrally confirmed in 30% [11/37; 90% confidence interval (CI), 18%–44%] and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30; P = 0.004, Fisher exact test) were observed in those with programmed cell death ligand 1 (PD-L1) tumor proportion score ≥1% and Conclusions: CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.

The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis (UMIN000027887). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment., The multicenter phase 2 TRIUMPH trial shows the utility of ctDNA genotyping as a screening platform to select patients with HER2-amplified metastatic colorectal cancer who benefit from dual-HER2 blockade with trastuzumab and pertuzumab

Objective : The aim of this study was to evaluate the association between diabetes-related indicators and oral health behavior among patients with type 2 diabetes. Methods : Seventy-four outpatients were included. We administered a questionnaire and divided the patients into two groups according to oral health behavior and eating habits. We then compared diabetes-related clinical records between the groups and performed logistic regression analysis. Results : Participants who brushed their teeth before bedtime every night had lower BMIs than those who did not. Participants who reported eating slowly and chewing well every day had significantly lower HbA1c than their counterparts. Participants who reported gum bleeding had significantly higher LDL-cholesterol than their counterparts. Binominal logistic regression analysis revealed that BMI < 25 was associated with not brushing teeth before bedtime every night, HbA1c < 7.5 with not eating slowly or chewing well every day, and LDL-cholesterol < 120 with gum bleeding (odds ratio : 0.140, 95% confidence interval : 0.036-0.540 ; OR : 0.085, 95% CI : 0.010-0.736, OR : 0.275, 95% CI : 0.077-0.979, respectively). Conclusions : Our findings suggest that toothbrushing before bedtime every night is associated with reduced risk of obesity and that eating slowly and chewing well are advantageous for glycemic control in patients with type 2 diabetes.J. Med. Invest. 68 : 140-147, February, 2021.

Introduction and importance Recently cementless total hip arthroplasty (THA) has shown good long-term results with excellent stability resulted from the porous coating of the implant. A hydroxyapatite-tricalcium phosphate (HA-TCP) coating on the porous surface is expected to promote bone ingrowth and to improve initial fixation of the implant. Here we report a case of bone ingrowth observed in a cup removed during revision surgery for early dislocation, 37 days after primary THA using a porous coating cup with HA-TCP. Case presentation A 61-year-old woman who has bilateral osteoarthritis underwent same-day bilateral THA. Both sides used porous coating cups with HA-TCP. Line-to-line technique and screw fixation were utilized. Anterior dislocation of the left hip occurred on days 27 and 31, and we performed cup revision on day 37 after surgery. We noted bone-like tissue on the posterior surface of the cup and in a vacant screw hole. Bone tissue was also confirmed in pathological findings. Clinical discussion Studies in animals have confirmed early bone ingrowth about 4 weeks after surgery with HA-TCP coated implants. In humans, the earliest report of bone ingrowth in cups is for a cup without HA-TCP coating, detected 5 weeks after surgery. In the present case, we used a porous coating cup with HA-TCP, and bone ingrowth was confirmed at approximately the same time as for the previous case. Conclusion Early clinical bone ingrowth was confirmed in an HA-TCP coated cup, occurring at about the same time after surgery as in previous reports., Highlights • Cementless THA shows excellent long-term results for porous coating of implant. • HA-TCP coating promotes bone ingrowth of mesenchymal cells. • Post-THA revision showed good initial fixation with porous coating cup and HA-TCP.

Aims To identify more reliable and cost-effective methods to detect gingivitis, such as visual examinations, questionnaires, and salivary occult blood tests (SOBT). Methods Sixty-five elementary school students in Yahiko Village, Niigata, Japan were recruited. Questionnaire was used to assess subjective gingival status. Hemoglobin (Hb) and lactate dehydrogenase (LDH) levels were measured by SOBT. Bleeding on marginal probing (BOMP) method at three labial sites per tooth for all anterior teeth was used to examine clinical gingiva condition. Occurrence of at least 1 site with BOMP positive was defined as gingivitis. Visual gingival redness examination was done at the same sites examined by probing. Results Participants with gingivitis had higher numbers of sites with redness than those without [6 (0.25–12) vs 0 (0–2), p p = 0.002). The overall model had a 77.3% probability of predicting a gingivitis event by the number of sites with gingival redness ( p Conclusion(s) This study found that a predictive model using visual gingival redness examination is a viable non-invasive screening test for gingivitis.

Hydrogen (H 2 )-free and poison (lead and quinoline)-free semihydrogenation of alkynes to cis -alkenes under gentle conditions is one of the challenges to be solved. In this study, a titanium(IV) oxide photocatalyst having two functions (visible light responsiveness and semihydrogenation activity) was prepared by modification with 2,3-dihydroxynaphthalene (DHN) and a copper (Cu) co-catalyst, respectively. The photocatalyst (DHN/TiO 2 -Cu) showed high performance for diastereoselective semihydrogenation of alkynes to cis -alkenes in water-acetonitrile solution under visible light irradiation without the use of H 2 and poisons. Alkynes having reducible functional groups were converted to the corresponding alkenes with the functional groups being preserved. The addition of water to acetonitrile changed the amount of alkynes adsorbed on the photocatalyst, which was a decisive factor determining the rate of hydrogenation. A relatively large apparent activation energy, 27 kJ mol −1 , was obtained by a kinetic study, indicating that the rate-determining step of this reaction was not an electron production process but a thermal catalytic semihydrogenation process over the Cu co-catalyst. Semihydrogenation and hydrogen evolution occurred competitively on Cu metals and the former became predominant at slightly elevated temperatures, which is discussed on the basis of the kinetic parameters of two reactions.

A titanium(IV) oxide photocatalyst modified with 2,3-dihydroxynaphthalene (DHN/TiO2) responds to visible light, and electrons are photogenerated to the conduction band of TiO2 under light irradiation in the presence of a suitable hole scavenger. The reducing potential of DHN/TiO2 was applied for photocatalytic conversion of a nitro group to an amino group of aromatics having other reducible groups under hydrogen-free and noble metal-free conditions at room temperature. Various nitro aromatics having vinyl, chloro, bromo, and acetyl groups were converted to amino aromatics with high yields with the reducible groups being preserved. Some parameters affecting the catalytic performance were investigated, and the reaction rate was almost determined by the amount of the substrate adsorbed on DHN/TiO2.

Objective In this study, we investigated the effect of smoking on the oral health and the cost of dental treatment in Japanese latter-stage elderly people. Methods The number of subjects enrolled in this study were 931 (males: 347, females: 584) who was 75 years of age living in Tokushima City, Japan, and who was able to grasp the smoking period until the age of 75. Dental-health examination was conducted in 2015-2017. According to the questionnaire on smoking habit, the subjects were divided into two groups; the smoking group were current smokers and former smokers who quit smoking after the age of 55, and the control group were never smokers and former smokers who quit smoking before the age of 55. Statistical analysis regarding oral condition and the cost of dental treatment was performed according to gender. Results The number of the smoking groups and control groups were 253:94 for males, and 573:11 for females, respectively. Among males, the number of teeth in the smoking group (18.6±8.9) was significantly lower (p=0.008, t-test) than that in the control group (21.4±7.5), and the cost of dental treatment in the smoking group (65,036±53,706 Japanese Yen/ year) was significantly higher (p=0.012, t-test) than that in the control group (48,902±52,179 Japanese Yen/ year). In addition, there is a significant problem with swallowing in the smoking group when compared to that in the control group (odds ratio=1.873; 95% CI=1.067 - 3.302). On the other hand, no significant differences were found between the two groups in females. Conclusions Results from the cross-sectional survey suggested that long-term smoking affects the oral health of later-stage elderly males and also increases the cost of dental treatment.

3555 Background: HER2 amp occurs in 1-4% of mCRC pts. Two single arm phase 2 studies, HERACLES and MyPathway, showed efficacy for dual HER2-targeted therapy in pts with RAS wild type ( RAS wt) mCRC with HER2 amp detected in tumor tissue; however, efficacy for pts prospectively enrolled with HER2 amp identified in ctDNA is unknown. Furthermore, the efficacy of real-world non-HER2-targeted SOC for HER2 amplified RASwt mCRC pts is not clear. Methods: We conducted a phase 2 trial to evaluate the efficacy of pertuzumab (P) plus trastuzumab (T) in RASwt mCRC pts with HER2 amp centrally confirmed by tissue (IHC and/or FISH) and/or ctDNA (Guardant360) who had progressed on SOC including EGFR blockade. Pts received intravenous P (840 mg loading dose followed by 420 mg) and T (8 mg/kg loading dose followed by 6 mg/kg) every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) by investigator assessment, analyzed for two primary populations: pts with HER2 amp in tissue (tissue+) or in ctDNA (ctDNA+). Efficacy of real-world non-HER2-targeted SOC for HER2 amplified RASwt mCRC pts was prospectively assessed in a concurrent registry: the SCRUM-Japan registry. Results: Among 75 pts screened, concordance of HER2 amp between tissue and ctDNA was 83%. The primary endpoint was met in each cohort of TRIUMPH, with confirmed ORR of 30% (95% CI 14-50%) in 27 tissue+ pts and 28% (12-49%) in 25 ctDNA+ pts. In contrast, ORR in first salvage SOC after EGFR blockade was 0% (0.0-24.7%) in the real-world cohort. Median progression free and overall survival were 4.0 months (1.4-5.6) and 10.1 months (4.5-16.5) in the tissue+ pts and 3.1 months (1.4-5.6) and 8.8 months (4.3-12.9) in the ctDNA+ pts. One pt withdrew due to an adverse event (grade 3 decreased ejection fraction), but no treatment related deaths occurred. In exploratory analyses, pts without ctDNA mutations of RAS/ BRAFV600/ PIK3CA/ HER2 were more likely to respond to P+T than those with a ctDNA mutation in at least one of these genes (ORR 44% vs. 0% in tissue+ and 37% vs. 0% in ctDNA+). Decreased ctDNA fraction and HER2 plasma copy number at 3 weeks after treatment initiation corresponded to P+T response. At least one actionable alteration emerged after progression in 16 (62%) of 26 pts with ctDNA results at both baseline and progression. Among 5 pts who achieved response and had ctDNA results at both time points, 4 pts acquired actionable alteration at progression. Conclusions: We demonstrate promising efficacy and safety of P+T for RASwt mCRC pts with HER2 amp in either tumor tissue or ctDNA. Our results show that complete ctDNA genotyping identifies pts most likely to benefit from dual HER2 blockade and can be used to monitor response and detect actionable resistance biomarkers. Clinical trial information: UMIN000027887 and UMIN000028058.

Background ERBB2 amp occurs in approximately 4% of pts with mCRC. We conducted a phase II trial to evaluate the efficacy and safety of T and P in pts with ERBB2-amplified mCRC identified by tissue and/or ctDNA analysis. Methods We enrolled pts with central tissue and/or ctDNA (Guardant360) confirmed wild-type RAS and ERBB2-amplified mCRC, refractory or intolerant to standard chemotherapy including EGFR blockade. Pts received T and P every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) by investigator assessment, analyzed for two primary populations: tissue-positive and ctDNA-positive. The required sample size for each group was 25 (one-sided α = 2.5%, β = 10%) to test the threshold ORR of 5% against the expected ORR of 30%; 5 confirmed responses were needed to determine statistical significance. Results The first response evaluation was done on Jan 7, 2019. Of 19 pts enrolled at 7 sites, 18 were evaluable for response. ERBB2-amp was confirmed in both tissue and ctDNA for 14 pts, in tissue alone for 3, and in ctDNA alone for 1; therefore, 17 and 15 pts were assigned to the tissue-positive and the ctDNA-positive group, respectively. With median follow-up of 5.4 months, there were 6 confirmed responders in the tissue-positive group (ORR = 35%, 95% confidence interval [CI] 14-62%; 1 CR and 5 PR) and 5 in the ctDNA positive group (ORR = 33%, 95% CI 12-62%; 1 CR and 4 PR). Median progression-free survival for both groups was 4.0 months (95% CI = 1.4-5.6 months and 1.3-5.6 months, respectively). Clonal ctDNA mutations in KRAS, BRAF, PIK3CA, or ERBB2 at baseline were observed only in pts with disease progression as best response. The safety profile of T and P was consistent with prior reports. Severe adverse events were reported in 2 pts: Gr 3 decreased ejection fraction and Gr 3 infusion related reaction. Conclusions The TRIUMPH study met its primary endpoint, demonstrating that combination of T and P has promising activity, with an acceptable toxicity profile, in treatment-refractory mCRC pts with ERBB2 amp in tissue and/or ctDNA. Clonal oncogenic ctDNA driver mutations may predict for primary resistance. Clinical trial identification UMIN000027887. Legal entity responsible for the study SCRUM-Japan GI-SCREEN. Funding Japan Agency for Medical Research and Development. Disclosure Y. Nakamura: Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Ono Pharmaceutical. W. Okamoto: Research grant / Funding (self): MSD. T. Kato: Honoraria (self), Research grant / Funding (self): Chugai Pharma; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Lilly; Honoraria (self): Yakult Honsha; Honoraria (self): Sanofi. K. Kato: Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy: MSD; Advisory / Consultancy: Oncolys BioPharma; Research grant / Funding (self): Shionogi; Research grant / Funding (self): MSD Oncology. S. Iwasa: Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Ono Pharmaceutical; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Bayer. T. Esaki: Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan; Honoraria (self): Eisai; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self): Takeda; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Sanofi; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Nihonkayaku; Research grant / Funding (institution): Pfizer. Y. Komatsu: Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharma; Speaker Bureau / Expert testimony: Merck Serono; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer; Honoraria (institution), Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Speaker Bureau / Expert testimony: Bristol-Myers Squibb Japan; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: TOWA; Speaker Bureau / Expert testimony: Nipro Corporation; Research grant / Funding (self): MSD; Research grant / Funding (self): Yakult Pharmaceutical; Research grant / Funding (self): Sumitomo Dainippon Pharma; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Sysmex. T. Masuishi: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Merck Serono; Honoraria (self): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self): Takeda; Honoraria (self): Lilly; Honoraria (self): Bayer Yakuhin; Honoraria (self): Sanofi. T. Nishina: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Lilly; Research grant / Funding (institution): Lilly Japan; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Takeda; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Nihonkayaku; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Ono Pharmaceutical. J.I. Odegaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Guardant Health. S. Olsen: Full / Part-time employment: Guardant Health AMEA; Shareholder / Stockholder / Stock options: Guardant Health; Shareholder / Stockholder / Stock options: AstraZeneca. T. Yoshino: Research grant / Funding (institution): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Sanofi. K.K.; Research grant / Funding (institution): Daiichi Sankyo Company, Limited; Research grant / Funding (institution): Parexel International Inc.; Research grant / Funding (institution): Ono Pharmaceutical Co., Ltd.; Research grant / Funding (institution): MSD. K. K. All other authors have declared no conflicts of interest.

100 Background: In VOLTAGE-A, chemoradiotherapy (CRT; 50.4Gy with capecitabine, 1,650mg/m2) followed by five cycles of consolidation nivolumab (nivo) (240mg q2 weeks) showed 30% pathological complete response [pCR; AJCC tumor regression grade (TRG) 0] and 38% major pathological responses (AJCC TRG 0-1) in patients with microsatellite stable (MSS) locally advanced primary rectal cancer (LARC). In addition, 60% pCR was observed in patients with microsatellite instability-high (MSI-H) LARC. In this study, we aimed to determine the predictive biomarkers for efficacy of sequential preoperative CRT and consolidation nivo. Methods: Serial tumor biopsies were performed at four time points:pre-CRT; post-CRT; post-3 cycles of nivo; and pre-surgery. We analyzed the immune status of the patients by flow cytometry using the collected tumor-infiltrating lymphocytes (TILs) dissociated from tumor samples. Whole exome and RNA sequencing analyses were conducted using the extracted DNA and RNA from tumor, respectively. The PD-L1 status of tumor samples was also evaluated by in vitro diagnostic immunohistochemistry staining. Results: Of the 38 MSS patients whose PD-L1 tumor proportion score (TPS) was analyzable in pre-CRT samples, the pCR rates were 67% (6/9) and 17% (5/29) in positive (≥1%) and negative PD-L1 status (p = 0.009), respectively. Among the 24 MSS patients whose samples were serially collected, the pCR rates according to CD8+ T cells/effector regulatory T cells (CD8/eTreg) ratio in TILs of pre-CRT samples ≥2.5 and < 2.5 were 78% (7/9) and 13% (2/15), respectively (p = 0.003). The CD8/eTreg ratio in TILs was consistently high in patients with pCR during the study treatments. Ki-67 and PD-1 expression by CD8+ T cells in TILs was significantly high in pre-CRT samples from patients TRG 0-1. Conversely, in patients with TRG 2-3, CTLA-4 expression by both CD4+ T cells and CD8+ T cells in TILs was significantly high after five cycles of nivo, suggesting the potential resistance mechanisms of nivo monotherapy. Of the 21 MSS patients whose consensus molecular subtype (CMS) was analyzable, those with CMS1 and CMS3 tumors achieved 100% (2/2) and 60% (4/6) TRG 0-1, respectively. In contrast, patients with CMS2 and CMS4 tumors achieved 43% (3/7) and 29% (2/7) TRG 0-1, respectively. The tumor mutational burden (TMB) of pre-CRT samples in five MSI-H patients was higher than that in the 24 MSS patients (median: 13.2 vs. 0.99 mutation/Mbp, p < 0.0001). Among MSS patients, TMB was higher in patients with TRG 0-1 than in patients with TRG 2-3 (median: 1.45 vs. 0.84 mutation/Mbp, p = 0.016). Conclusions: Positive PD-L1 TPS; high CD8/eTreg ratio; Ki-67, PD-1, and CTLA-4 expression by CD8+ T cells in TILs; CMS 1 or 3; and high TMB can be good predictors of efficacy of preoperative CRT followed by nivo. Clinical trial information: NCT02948348.

The wound healing process attempts to restore the integrity and function of the injured tissue. Additionally, proinflammatory cytokines, growth factors, and oxidative stress play important roles in wound healing. The aim of this study was to determine whether hydrogen-rich water intake induces the activation of the Nrf2/antioxidant defense pathway in rat palatal tissue, thereby reducing systemic oxidative stress and proinflammatory cytokine levels and promoting healing-associated genes. A circular excisional wound was created in the oral palatal region, and the wound healing process was observed. The rats were divided into two experimental groups in which either hydrogen-rich water or distilled water was consumed. In the drinking hydrogen-rich water, the palatal wound healing process was accelerated compared to that in the control group. As molecular hydrogen upregulated the Nrf2 pathway, systemic oxidative stresses were decreased by the activation of antioxidant activity. Furthermore, hydrogen-rich water intake reduced proinflammatory cytokine levels and promoted the expression of healing-associated factors in rat palatal tissue. In conclusion, hydrogen-rich water intake exhibited multiple beneficial effects through activation of the Nrf2/antioxidant defense pathway. The results of this study support the hypothesis that oral administration of hydrogen-rich water benefits the wound healing process by decreasing oxidative stress and inflammatory responses.

Organically modified titania having a metal catalyst (OMTC), 2,3-dihydroxynaphthalene-modified titania having palladium metal, successfully worked as a hydrogen-transfer (C[double bond, length as m-dash]C hydrogenation) photocatalyst in the presence of triethanolamine as the hydrogen source under visible light irradiation and hydrogen-free conditions.

Since reduction and oxidation reactions simultaneously occur over a photocatalyst, a hole scavenger (a hydrogen source in the field of organic chemistry) is required to obtain a reduced product. The use of organic waste as the hole scavenger is environmentally favorable because the organic waste is degraded during the photocatalytic reduction. In this study, methylamine was used as the hole scavenger for photocatalytic reduction (hydrogenation) of nitrobenzenes over a titanium(IV) oxide photocatalyst. Corresponding anilines were obtained almost quantitatively at room temperature and under atmospheric pressure without the use of a precious metal and hydrogen gas. Nitrobenzenes having reducible functional groups such as chloro and acetyl groups were chemoselectively hydrogenated to corresponding anilines with the groups being preserved. Various parameters affecting the efficiency and the rate of the photocatalytic reaction are discussed on the basis of results of the physicochemical analyses.

Oral health status is known to be associated with lifestyle-related diseases such as diabetes and chronic kidney disease. In Japan, around 40% of hemodialysis cases are patients with diabetic nephropathy. The aim of this study was to clarify the association between oral health status and diabetic nephropathy-related indices in Japanese middle-aged men. Sixty-six men (age range: 55–64 years) with ≥20 remaining teeth and who received public medical checkups and oral examinations were enrolled. We examined correlations of age, body mass index, HbA1c, HDL-C, LDL-C, neutral fat, serum creatinine, and the estimated glomerular filtration rate (eGFR) with the number of remaining teeth or the community periodontal index (CPI) score (periodontal pocket<4 mm: 0, 4–6 mm: 1, ≥6 mm: 2). A positive correlation between the CPI score and serum creatinine and a negative correlation between CPI score and eGFR (Spearman’s rank correlation coefficient, r=0.459, p<0.01, and r=−0.460, p<0.01, respectively) were observed. The mean eGFR in the CPI score 0 group was significantly higher than that in the CPI score 1/2 group (82.6 vs. 70.7, Student’s t-test, p<0.01). Logistic regression analysis using eGFR as a dependent variable and age, CPI score, body mass index, HbA1c, and neutral fat as independent variables suggested that low eGFR (OR=3.169, 95% CI: 1.031–9.742, p=0.044). These results suggest a possible association between periodontal status and renal function in Japanese middle-aged men. Periodontal condition is controlled by oral prophylaxis, and periodontal disease and chronic kidney disease have some common risk factors. Thus, periodontal management can contribute to the prevention of severe chronic kidney disease.

4100 Background: Chemoradiotherapy (CRT) followed by radical surgery (S) is standard therapy for patients (pts) with locally advanced rectal cancer (LARC). Sequential use of an anti-PD-1 antibody after radiation demonstrates synergistic effects in in vivo models, and an anti-PD-1 antibody is effective in pts with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivolumab (nivo) and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: After the quality-assured CRT, 240 mg q2 weeks x 5 cycles of nivo and radical S were investigated. In cohort A-1, for pts with microsatellite stable (MSS) LARC, the primary endpoint was a centrally confirmed pathological complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. In Cohort A-2, 5 pts with MSI-H LARC were included in an exploratory manner. Results: From Jan/2017 to Oct/2019, a targeted number of pts was included and assessed. In cohort A-1, 30% (11/37; 90% CI 18-44%) of pCR (AJCC grade (gr) 0) rate and 38% (14/37) of major pathological response (MPR) (AJCC gr 0+1) rate were observed. Clinical CR was observed in one additional pt (3%) refusing S after nivo. In cohort A-2, 60% (3/5) of pCR rate and 60% (3/5) of MPR rate were observed. As of Jan/2020, only 2 pts (1 local and 1 metastatic) in cohort A-1 and none in cohort A-2 recurred. Immune-related severe adverse events were observed in 3 pts (gr 3 myasthenia, gr 3 interstitial nephritis, and gr 2 peripheral motor neuropathy); all fully recovered and received radical S. During the follow-up period, one additional pt with gr 2 colitis was observed. No treatment-related deaths were observed. Conclusions: Promising pCR rates of 30% and 60%, with mild toxicities, were shown in MSS and MSI-H LARC pts treated with nivo plus radical S after CRT, suggesting the candidate therapy for the future non-surgical approach. Clinical trial information: NCT02948348 .

4073 Background: In VOLTAGE-A1, after 5 cycles of nivolumab (240 mg q2 weeks) plus radical surgery following chemoradiotherapy (CRT; 50.4 Gy with capecitabine 1,650 mg/m2), a major pathologic response is observed in 38% (AJCC tumor regression grade 0-1) of 37 patients with microsatellite-stable locally advanced primary rectal cancer. Here, biomarkers for predicting the efficacy of this treatment were investigated. Methods: Serial tumor biopsies and blood collections were performed at 4 time points; before CRT, after CRT, after 3 cycles of nivolumab, and before surgery. Tumor-infiltrating lymphocytes (TILs) and DNA/RNA were extracted from tumor samples, and peripheral blood mononuclear cells (PBMCs) were extracted from blood samples. We analyzed the immune status of the patients by flow cytometry using the collected TILs and PBMCs. Whole exome and RNA sequencing analyses were conducted using the extracted DNA and RNA, respectively. The PD-L1 status of tumor samples was also evaluated by in vitro diagnostic immunohistochemistry staining. Results: Among the 24 patients whose samples were serially collected, 11 (46%) were AJCC grade 0-1 and 13 were 2-3. Before CRT, effector regulatory T (eTreg) cells in TILs were higher in patients with AJCC grade 2-3, and both the CD8+ T cell/eTreg cell ratio in TILs and PD-L1-positive tumor cells (≥1%) were higher in patients with AJCC grade 0-1 (p = 0.047, p = 0.083, respectively). Ki67 expression by CD8+ T cells in TILs was higher before CRT in patients with AJCC grade 0-1 (p = 0.037) and increased after CRT in all patients. Patients with consensus molecular subtype (CMS) 1 and CMS3 achieved AJCC grade 0-1 at rates of 100% (2/2) and 60% (4/6), respectively. In contrast, patients with CMS2 and CMS4 achieved AJCC grade 0-1 at rates of 43% (3/7) and 29% (2/7), respectively. The tumor mutation burden of pre-CRT samples was significantly higher in patients with AJCC grade 0-1 (median 1.45/MB) than in patients with AJCC grade 2-3 (0.84/MB) (p = 0.016). Conclusions: A higher CD8+ T cell/eTreg cell ratio, PD-L1-positive, Ki67 expression by CD8+ T cells in TILs, CMS1 or 3, and higher tumor mutation burden are good predictors of the efficacy of the sequential combination of CRT and nivolumab. Further results will be reported in the meeting. Clinical trial information: NCT02948348 .